HK40066086A - Synthesis of polycyclic-carbamoylpyridone compounds - Google Patents

Description

Synthesis of polycyclic carbamoylpyridinone compounds

This application is a divisional application of patent application No. 201580033052.1, filed on June 16, 2015, entitled "Synthesis of Polycyclic Carbamoylpyridinone Compounds"—which was filed on June 16, 2015, with application number 201910271534.0, also entitled "Synthesis of Polycyclic Carbamoylpyridinone Compounds".

Background Technology

Technical Field

This paper discloses a novel method for synthesizing polycyclic carbamoylpyridinone compounds. Intermediates in the synthetic pathway of polycyclic carbamoylpyridinone compounds are also disclosed.

Description of related technologies

Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown efficacy, especially when used in combination, toxicity and the development of resistant strains limit their effectiveness (Palel la et al., N. Engl. J Med. (1998) 338:853-860; Richman, D.D. Nature (2001) 410:995-1001). Therefore, there is a need for new agents that can inhibit HIV replication and minimize PXR activation when co-administered with other drugs.

Several polycyclic carbamoylpyridinone compounds have been found to possess antiviral activity, as disclosed in PCT/US2013/076367. Therefore, a synthetic route for such compounds is needed.

Summary of the Invention

This invention relates to a novel synthetic method for preparing polycyclic carbamoylpyridinone compounds of formula I, using the synthetic steps described herein. The invention also relates to specific individual steps in this method, and specific individual intermediates used in the method. One embodiment of the invention provides a method for preparing compounds of formula I:

Another aspect of the present invention provides a method for preparing compound I according to the following general route I:

The method includes the following steps:

C-1 is reacted with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 is reacted with at least one acid and N-1 or its salt or eutectic in the presence of a base to produce G-1;

G-1 is reacted under conditions suitable for the synthesis of compound I;

in

Halogens can be the same or different.

n is 1, 2, or 3.

L is -C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ - or -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ -,

Each ^Rc is independently hydrogen, halogen, hydroxyl, or _C1 - _C4 alkyl.

Each ^Ra , ^R1 and ^R2 is independently ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl.

In some implementations, each ^Rb is independently ( _C1 - _C4 ) alkyl.

In some embodiments, each ^Ra , ^R1 and ^R2 is independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl.

Another implementation provides a method for preparing compound I according to the following general route II:

The method includes the following steps:

A-1 reacts with H-1 in the presence of a catalyst, a base, and an acylation reagent to generate B-1;

B-1 and J-1 react in the presence of acid to produce C-1;

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 is reacted with at least one acid and N-1 in the presence of a base to produce G-1;

G-1 is reacted under conditions suitable for the formation of compound I;

in

Hal is a halogen.

n is 1, 2, or 3.

L is -C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ - or -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ -,

Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl.

^Ra , ^Rb , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl.

In some implementations, Hal is a halogen, which can be the same or different.

In some embodiments, ^Ra , ^Rb , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl.

In some implementations, J-1 is in the form of a salt or a eutectic.

In some implementations, N-1 is in the form of a salt or a eutectic.

Another embodiment provides a method for preparing compound of formula I.

This method is carried out according to the following general route III:

The method includes the following steps:

B-1 reacts with Q-1 to generate BB-1;

BB-1 reacts with J-1 to produce C-1;

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 is reacted with at least one acid and N-1 or its salt or eutectic in the presence of a base to produce G-1;

G-1 is reacted under conditions suitable for the formation of compound I;

in

Hal is a halogen.

n is 1, 2, or 3.

L is -C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ - or -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ -,

Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl.

^Ra , ^Rb , ^Rd , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl.

In some implementations, Hal is a halogen, which can be the same or different.

In some embodiments, ^Ra , ^Rb , ^Rd , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl.

In some implementations, J-1 is in the form of a salt or a eutectic.

Another embodiment provides a method for preparing compound I:

This method is based on the following general route IV:

The method includes the following steps:

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with M-1 to generate EE-1;

EE-1 reacts with K-1 to produce F-1;

F-1 is reacted with at least one acid and N-1 in the presence of a base to produce G-1;

G-1 is reacted under conditions suitable for the formation of compound I;

in

Hal is a halogen.

n is 1, 2, or 3.

L is -C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ - or -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ -,

Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl.

^Ra , ^Rb , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl.

In some implementations, Hal is a halogen, which can be the same or different.

In some embodiments, ^Ra , ^Rb , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl.

In some implementations, N-1 is in the form of a salt or a eutectic.

Another embodiment provides a method for preparing compound II:

This method is based on the following general route V:

The method includes the following steps:

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 reacts with a base to produce compound of formula II;

in

Hal is a halogen.

n is 1, 2, or 3.

^Ra , ^Rb , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl.

In some implementations, Hal is a halogen, which can be the same or different.

In some embodiments, ^Ra , ^Rb , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl.

Another embodiment provides a method for preparing compound I:

This method is based on the following general route VI:

The method includes the following steps:

B-1·J-1 is reacted under conditions suitable for the formation of C-1;

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 reacts with at least one acid to produce FF-1;

FF-1 is reacted with N-1 or its salt or eutectic in the presence of an additive to generate G-1;

G-1 is reacted under conditions suitable for the formation of compound I;

in

Halogens are elements that can be the same or different.

n is 1, 2, or 3.

L is -C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ - or -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ -,

Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl.

^Rb are each independently ( _C1 - _C4 ) alkyl groups.

^Ra , ^R1 , and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl.

Other embodiments and features will be set forth in the following detailed description of the embodiments, and some will be readily understood from the description or learned through practice of the claimed invention. The foregoing description should be understood as a brief and general summary of some embodiments disclosed herein, provided for the reader's convenience only, and is not intended to limit the scope of protection or equivalents of the invention in any way, as the appended claims legally confer those scopes.

Detailed Implementation

The following description sets forth specific details to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. The following description of several embodiments should be understood as examples of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. Headings used in this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

definition

Unless the context otherwise requires, throughout this specification and claims, the word “comprising” and its variations, such as “including” and “comprise”, shall be interpreted in an open, inclusive sense, meaning “including but not limited to”.

Prefixes such as " _Cuv " or ( _Cu - _Cv ) indicate that the following group has u to v carbon atoms. For example, "( _C1 - _C6 )alkyl" indicates that the alkyl group has 1 to 6 carbon atoms, and ( _C6 - _C10 )aryl( _C1 - _C6 )alkyl indicates that the aryl portion of the group has 6 to 10 carbon atoms, and the alkyl portion of the group has 1 to 6 carbon atoms.

Throughout this specification, references to "one embodiment" or "implementation" mean that a particular feature, structure, or characteristic described for that embodiment is included in at least one embodiment of the invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in different places in this specification do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

"Amino" refers to the -NH ₂ group.

"Cyano" refers to the -CN group.

"Hydroxy group" refers to the -OH group.

"Imine" refers to the =NH substituent.

"Nitro" refers to the _-NO2 group.

"Oxyto" refers to the =O substituent.

"Thio" refers to the =S substituent.

"BzOH" refers to benzoic acid or

"Alkyl" refers to a straight-chain or branched saturated hydrocarbon chain group consisting only of carbon and hydrogen atoms, having 1-12 carbon atoms ( _C1 - _C12 alkyl), 1-8 carbon atoms ( _C1 - _C8 alkyl), one to six carbon atoms ( _C1 - _C6 alkyl), or 1-4 carbon atoms ( _C1 - _C4 alkyl), and connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, vinyl, propenyl, butenyl, pentenyl, pent-1,4-dienyl, ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. Unless otherwise expressly stated in the specification, alkyl groups may optionally be substituted.

In some embodiments, "alkyl" refers to a straight-chain or branched saturated hydrocarbon chain group consisting only of carbon and hydrogen atoms, having 1-12 carbon atoms ( _C1 - _C12 alkyl), 1-8 carbon atoms ( _C1 - _C8 alkyl), one to six carbon atoms ( _C1 - _C6 alkyl), or 1-4 carbon atoms ( _C1 - _C4 alkyl), and connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless otherwise expressly stated in the specification, alkyl groups may optionally be substituted.

"Alkenyl" refers to any group derived from a straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, vinyl, allyl, 1-butenyl, 1,3-butadienyl, etc. Unless otherwise stated, alkenyl groups have 2 to about 10 carbon atoms, for example, 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms, for example, 2 to 4 carbon atoms.

"Alynyl" means any group derived from a straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond, including those groups having one triple bond and one double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl ( _-CH₂C≡CH ), (E)-pent-3-en-1-alkynyl, etc. Unless otherwise stated, alkynyl groups have 2 to about 10 carbon atoms, for example, 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms, for example, 2 to 4 carbon atoms.

"Alkoxy" refers to a group of the formula -OR ^A , wherein ^RA is an alkyl group containing one to twelve carbon atoms, one to eight carbon atoms, one to six carbon atoms, or one to four carbon atoms as defined above. Unless otherwise specified in the specification, the alkoxy group may optionally be substituted.

"alkylamino" refers to a group of the formula -NHR ^A or -NR ^ARA , wherein each ^RA is independently an alkyl ^group containing one to twelve carbon atoms, one to eight carbon atoms, one to six carbon atoms, or one to four carbon atoms as defined above. Unless otherwise expressly stated in the specification, alkylamino groups may optionally be substituted.

"Thioalkyl" refers to a group of the formula -SR ^A , wherein ^RA is an alkyl group as defined above containing one to twelve carbon atoms, one to eight carbon atoms, one to six carbon atoms, or one to four carbon atoms. Unless otherwise specifically stated in the specification, thioalkyl groups may optionally be substituted.

"Aryl" means a monocyclic hydrocarbon ring system group comprising hydrogen and 6 to 18 carbon atoms, or 6 to 10 carbon atoms, or 6 to 8 carbon atoms. Aryl groups include, but are not limited to, aryl groups derived from benzene. Unless otherwise expressly stated in the specification, the term "aryl" or the prefix "aromatic-" (e.g., in "aralkyl") is intended to include optionally substituted aryl groups.

"Arylalkyl" (also called "aryl group") refers to a group of the ^{formula -RBRC} , where ^RB is an alkyl group as defined above, and ^RC is one or more aryl groups as defined above, such as benzyl. Arylalkyl groups include, but are not limited to, those derived from benzyl, tolyl, dimethylphenyl, 2-phenylethyl-1-yl, 2-naphthylmethyl, phenylmethylbenzyl, 1,2,3,4-tetrahydronaphthyl, etc. Arylalkyl groups contain 6 to about 30 carbon atoms; for example, alkyl groups may contain 1 to about 10 carbon atoms, and aryl groups may contain 5 to about 20 carbon atoms. Unless otherwise specifically stated in the specification, arylalkyl groups may optionally be substituted.

In some embodiments, "arylalkyl" (also referred to as "aralkyl group") refers to a group of the ^{formula -RBRC} , where ^RB is an alkyl group as defined above, and ^RC is one or more aryl groups as defined above, such as benzyl. Aralkyl groups include, but are not limited to, those derived from benzyl, tolyl, dimethylphenyl, 2-phenylethyl-1-yl, 2-naphthylmethyl, phenylmethylbenzyl, 1,2,3,4-tetrahydronaphthyl, etc. Aralkyl groups contain 6 to about 30 carbon atoms; for example, an alkyl group may contain 1 to about 10 carbon atoms, and an aryl group may contain 6 to about 20 carbon atoms. Unless otherwise specifically stated in the specification, aralkyl groups may optionally be substituted.

"Cycloalkyl" refers to a cyclic alkyl group. A cycloalkyl group may have one or more rings and includes fused and bridged groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc. Unless otherwise specified in the specification, the carbocyclic group may optionally be substituted.

A "carbocyclic ring" or "carbocycle" refers to a stable, non-aromatic monocyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and which is either saturated or unsaturated and connected to the rest of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specified in the specification, the carbocyclic group may optionally be substituted.

"Cycloalkylalkyl" refers to a group of ^the formula ^-RBRD , where ^RB is an alkyl group as defined above, and ^RD is a carbocyclic group as defined above. Unless otherwise specified in the specification, cycloalkylalkyl groups may optionally be substituted.

In some embodiments, "cycloalkylalkyl" refers to a group of ^the formula ^-RBRD , where ^RB is an alkyl group as defined above and ^RD is a carbocyclic group as defined above. Unless otherwise specified in the specification, cycloalkylalkyl groups may optionally be substituted.

"Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine.

"Halogenated alkyl" refers to an alkyl group as defined above that has been substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise expressly stated in the specification, halogenated alkyl groups may be optionally substituted.

A "heterocyclic group" or "heterocycle" refers to a stable 3- to 18-membered non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic group is a 3- to 12-membered non-aromatic ring, a 3- to 8-membered non-aromatic ring, or a 3- to 6-membered non-aromatic ring. In some embodiments, the heterocyclic group contains one to four heteroatoms, one to three heteroatoms, one to two heteroatoms, or one heteroatom. In the embodiments disclosed herein, the heterocyclic group is a monocyclic ring system; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolane, thiophene, [1,3]dithiaalkyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, oxazolyl, piperidinyl, piperazine, 4-piperidinone, pyrrolyl, pyrazolyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specifically stated in the specification, the heterocyclic group may optionally be substituted.

In some embodiments, "heterocyclic group" or "heterocycle" refers to a stable 4- to 18-membered nonaromatic ring group consisting of 3 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic group is a 4- to 12-membered nonaromatic ring, a 4- to 8-membered nonaromatic ring, or a 4- to 6-membered nonaromatic ring. In some embodiments, the heterocyclic group contains one to four heteroatoms, one to three heteroatoms, one to two heteroatoms, or one heteroatom. Unless otherwise specifically stated in the specification, the heterocyclic group may optionally be substituted.

"N-Heterocyclic group" refers to a heterocyclic group as defined above containing at least one nitrogen atom, wherein the connection point between the heterocyclic group and the rest of the molecule is through a nitrogen atom in the heterocyclic group. Unless otherwise expressly stated in the specification, the N-heterocyclic group may optionally be substituted.

"Heterocyclic alkyl ^" refers to a group of the formula ^-RBRE , where ^RB is an alkyl group as defined above, ^RE is a heterocyclic group as defined above, and if the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group may be attached to the nitrogen atom of the alkyl group. Unless otherwise specifically stated in the specification, heterocyclic alkyl groups may optionally be substituted.

"Heteroaryl" refers to an aryl group in which one or more carbon atoms (and any attached hydrogen atoms) are each independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, a heteroaryl group has 5 to about 20 carbon atoms, for example 5 to 18 carbon atoms, for example 5 to 14 carbon atoms, for example 5 to 10 carbon atoms. A heteroaryl group has 1 to 6 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. Unless specifically stated in the specification, a heteroaryl group may optionally be substituted.

In some embodiments, "heteroaryl" refers to an aryl group in which one or more carbon atoms (and any attached hydrogen atoms) are each independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl groups include, but are not limited to, those derived from furans, imidazoles, isothiazoles, isoxazoles, oxadiazoles, oxazoles, pyrazines, pyrazoles, pyridazines, pyridines, pyrimidines, pyrroles, tetrazolium, thiadiazoles, thiazolium, thiophene, triazoles, etc. Unless otherwise stated, a heteroaryl group has 5 to about 20 carbon atoms, for example, 5 to 18 carbon atoms, for example, 5 to 14 carbon atoms, for example, 5 to 10 carbon atoms. A heteroaryl group has 1 to 6 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. Unless specifically stated in the specification, a heteroaryl group may optionally be substituted.

"N-Heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the connection between the heteroaryl group and the rest of the molecule is through the nitrogen atom in the heteroaryl group. Unless otherwise expressly stated in the specification, the N-heteroaryl group may optionally be substituted.

"Heteroarylalkyl" refers to a group of ^the formula ^-RBRF , where ^RB is an alkyl group as defined above and ^RF is a heteroaryl group as defined above. Unless otherwise specified in the specification, heteroarylalkyl groups may optionally be substituted.

As used herein, the term "substituted" refers to any of the aforementioned groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) in which at least one hydrogen atom is replaced by a bond attached to a non-hydrogen atom, such as, but not limited to: halogen atoms such as F, Cl, Br and I; oxygen atoms, such as oxygen atoms in groups such as hydroxyl, alkoxy and ester groups; sulfur atoms, such as sulfur atoms in groups such as thiol, thioalkyl, sulfonyl, sulfonyl and sulfoxide groups; nitrogen atoms, such as nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide and enamine groups; silicon atoms, such as silicon atoms in trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl groups; and heteroatoms in a variety of other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a heteroatom in a higher-order bond (e.g., a double or triple bond), such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile groups.

For example, "substituted" includes any of the above-mentioned groups in which one or more hydrogen atoms are replaced with -NR _{GR H} , -NR _GR C(=O) GR _H , -NR _GR C(=O) NR _{GR H} , -NR _GR C(=O) OR _H , -NR _GR C(=NR _g ) NR _{GR H} , -NR _GR SO _{2 GR H} , -OC(=O) NR GR _H , -OR _G , -SR _G , -SOR _G , -SO _{2 RG} , -OSO _{2 RG} , -SO ₂ OR _G , =NSO _{2 RG} , and -SO ₂ NR _{GR H.} "Substituted" also refers to any of the above-mentioned groups in which one or more hydrogen atoms are replaced with -C(=O) _RG , -C(=O) OR _G , -C(=O) NR _{GR H} , -CH ₂ SO _{2 RG} , and -CH ₂ SO ₂ NR _{GR H.} The aforementioned R _G and _RH are identical or different and independently represent hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and/or heteroarylalkyl. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a bond with amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and/or heteroarylalkyl. Furthermore, each of the aforementioned substituents may optionally be substituted by one or more of the aforementioned substituents.

As used in this article, the term "alkylated formamide acetal" refers to compounds with the following formula:

Each ^Rb is independently ( _C1 - _C4 ) alkyl, and ^Rv1 and ^Rv2 are independently ( _C1 - _C6 ) alkyl, or ^Rv1 and ^Rv2 together with the atoms they are attached to form 5 to 10-membered heterocyclic groups.

"Alkylated formamide acetal" includes, but is not limited to, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal, and N,N-dimethyl acetal.

As used herein, the term "acyl donor" refers to a reactive compound that transfers a group -CO- ^Rx to another molecule, wherein ^Rx is ( _C1 - _C6 )alkyl- _Ry , and _Ry is selected from H, CN, –NR ^z1 R ^z2 , C(O)R ^z1 , –C(O)OR ^z1 , -C(O)NR ^z1 R ^z2 , –OC(O)NR ^z1 R ^z2 , –NR ^z1 C(O)R ^z2 , –NR ^z1 C(O)NR ^z2 , –NR ^z1 C(O)OR ^z2 , -SR ^z1 , –S(O) _1-2 R ^z1 , –S(O) ₂ NR ^z1 R ^z2 , –NR ^z1 S(O) ₂ R ^z2 , NR ^z1 S(O) ₂ R ^z2 , and OR ^z1 . R ^z1 and R ^z2 are independently selected from H, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 heteroalkyl, _C3-10 cycloalkyl, 3-12-membered heterocyclic, _C6-10 aryl, and 5-10-membered heteroaryl. In some embodiments, R _y is H. In some embodiments, R ^z1 and R ^z2 are independently selected from H and _C1-6 alkyl. Acyl donors include, but are not limited to, acid anhydrides, esters, and acyl chlorides, such as succinic anhydride, glutaric anhydride, acetic anhydride, vinyl acetate, isopropyl acetate, 4-chlorophenyl acetate, ethyl methoxyacetate, acetyl chloride, and benzoyl chloride.

Those skilled in the art will understand that, in this application, and more specifically in routes I, II, III, V, and VI, compound E-1 may be present in either the E or Z configuration, or as a mixture of the E and Z configurations. Therefore, in some embodiments, compound E-1 is in the E or Z configuration, or a mixture thereof. In some embodiments, compound E-1 is in the E configuration. In some embodiments, compound E-1 is in the Z configuration. In some embodiments, compound E-1 is a mixture of the Z and E configurations.

Those skilled in the art will understand that compound B-1·J-1 is a salt in this application:

As used herein, the term "protecting group" refers to an unstable chemical moiety known in the art, used to protect reactive groups (including, but not limited to, hydroxyl and amino groups) from unwanted reactions during synthesis. Hydroxyl groups and amino groups protected by protecting groups are referred to herein as "protected hydroxyl" and "protected amino," respectively. Protecting groups are typically used selectively and/or orthogonally to protect sites during reactions at other reaction sites, and can then be removed to retain unprotected groups or for use in further reactions. Protecting groups known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999).

Typically, the protecting group is protected or exists as a precursor, and is inert to the reaction of altering other regions of the parent molecule to convert it into its final group at the appropriate time. Other representative protecting groups or precursor groups are discussed in Agrawal et al., Protocols for Oligonucleotide Conjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72. Examples of “hydroxyl protecting groups” include, but are not limited to, tert-butyl, tert-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl (TBDPS), triphenylsilyl, benzoyl carbamate, acetate, chloroacetate, neopentanoate, benzoate, p-phenylbenzoate, 9-fluorenylmethyl carbonate, methanesulfonate, and toluenesulfonate. Examples of “amino protecting groups” include, but are not limited to, urethane protecting groups such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimide and dithiosuccinyl.

The invention disclosed herein is also intended to include all pharmaceutically acceptable compounds of Formula I and Formula II by means of isotopic labelling of one or more atoms having atoms with different atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ^2H , ^3H , ^11C , ^13C , ^14C , 13N, ^15N , 15O, ^17O , ^18O , ^31P , ^32P , ^35S , ^18F , ^36Cl , ^123I , and ^125I . These radiolabeled compounds can be used to help determine or measure ^the effectiveness of compounds, ^for example by characterizing the site or pattern of action or binding affinity to sites of significant pharmacological importance. Certain isotopic-labeled compounds of Formula I and Formula II, such as those incorporating radioisotopes, can be used for drug and/or substrate tissue distribution studies. Radioactive isotopes tritium, i.e. ^3H , and carbon-14, i.e. ^14C , are particularly suitable for this purpose due to their ease of incorporation and readily available detection methods.

Replacing with a heavier isotope, such as deuterium (i.e., ^2H ), can provide certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life can be increased or the dosage requirement can be reduced. Therefore, in some cases, a heavier isotope may be preferred.

Substitution with positron-emitting isotopes (e.g., ^11C , ^18F , ^15O , and ^13N ) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of Formula I and Formula II can generally be replaced with previously used unlabeled reagents using appropriate isotopically labeled reagents, either by conventional techniques known to those skilled in the art or by methods similar to those described in the examples below.

The present invention disclosed herein is also intended to include in vivo metabolites of the disclosed compounds. Such products can be generated by, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Therefore, the present invention includes compounds produced by methods comprising administering the compounds of the present invention to mammals for a period sufficient to produce their metabolites. Such products are typically identified by administering the radiolabeled compounds described in the embodiments herein at a detectable dose to animals such as rats, mice, guinea pigs, monkeys, or humans, allowing sufficient time for metabolism, and separating their metabolites from urine, blood, or other biological samples.

"Stable compound" and "stable structure" mean a compound that is stable enough to withstand separation from the reaction mixture to a useful purity and to be formulated into an effective therapeutic agent.

A Lewis acid is a group that can accept non-bonded electron pairs, i.e., an electron pair acceptor. Lewis acids can react with Lewis bases by sharing electron pairs provided by Lewis bases to form Lewis adducts.

"Mammals" include humans and livestock, such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), as well as non-livestock animals, such as wild animals.

"Optional" or "optionally" means that the event described below may or may not occur, and the description includes both the scenario in which the event or situation occurs and the scenario in which it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups.

"Pharmaceutically acceptable carriers, diluents, or excipients" include, but are not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye/coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration (USFDA) as acceptable to humans or domestic animals.

A “pharmaceutically acceptable salt” is a salt of a compound that is pharmaceutically acceptable and has (or can be converted into) the desired pharmacological activity of the parent compound. Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein include those derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX ₄₊ (where X is a C ₁ - ^C ₄ alkyl group). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, organic carboxylic acids such as acetic acid, benzoic acid, camphorsulfonic acid, citric acid, glucoheponic acid, gluconic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, mandelic acid, hydroxyethanesulfonic acid, lactobionic acid, succinic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, and trimethylacetic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and aminosulfonic acid. Pharmaceutically acceptable salts of hydroxyl compounds include anions of the compound with suitable cations such as Na ⁺ and N× ₄ ⁺ (where X is independently selected from H or _C1 - _C4 alkyl). Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated with an organic base such as diethanolamine, triethanolamine, N-methylglucosamine, etc. Ammonium and substituted or quaternized ammonium salts are also included in this definition. A non-limiting list of representative pharmaceutically acceptable salts can be found in SMBerge et al., J. PharmaSci., 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Tables 38-5, both of which are incorporated herein by reference.

For therapeutic purposes, the salts of the active ingredients of the compounds disclosed herein are generally pharmaceutically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not pharmaceutically acceptable may also be used for the preparation or purification of, for example, compounds of Formula I, compounds of Formula II, or another compound described herein. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of this invention.

Metal salts are salts in which the cation is a metal. For example, they are formed when the acidic protons in a compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions, or aluminum ions; or when metal ions coordinate with organic bases such as diethanolamine, triethanolamine, or N-methylglucosamine.

The metal can be an alkali metal, an alkaline earth metal, a transition metal, or a main group metal. Non-limiting examples of suitable metals include lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, and zinc.

Non-limiting examples of suitable metal salts include lithium salts, sodium salts, potassium salts, cesium salts, cerium salts, magnesium salts, manganese salts, iron salts, calcium salts, strontium salts, cobalt salts, titanium salts, aluminum salts, copper salts, cadmium salts, and zinc salts.

In addition, salts can be formed by adding certain organic and inorganic acids ₍ such as HCl, HBr, _H₂SO₄ , _H₃PO₄ , or organic sulfonic _acids ) to a basic center (usually an amine).

Finally, it should be understood that the compositions herein comprise unionized compounds disclosed herein, as well as compounds disclosed herein in zwitterionic form, and compounds disclosed herein in combination with stoichiometric amounts of water, such as hydrates.

Typical crystallization produces solvates of the compounds described in the embodiments disclosed herein. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compound described herein and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds described herein may be true solvates, while in other cases, the compounds described herein may contain only external water, or a mixture of water and some indeterminate solvents.

"Pharmaceutical composition" means the compounds described herein and formulations generally accepted in the art for the delivery of biologically active compounds to mammals, such as humans. Such media include all pharmaceutically acceptable carriers, diluents, or excipients.

"Effective amount" or "therapeutic effective amount" means an amount of such an invention compound, when administered to a patient in need, that is sufficient to treat the disease state, symptom, or condition to which those compounds are of benefit. Such an amount would be sufficient to elicit a biological or medical response in the tissue system or patient sought by the investigator or clinician. The amount of the compound according to the invention constituting a therapeutic effective amount will vary depending on factors such as: the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of compound excretion, the duration of treatment, the type and severity of the disease state or symptom being treated, the drugs used in combination with or concurrently with the compounds described herein, and the patient's age, weight, general health condition, sex, and diet. Such a therapeutic effective amount can be conventionally determined by those skilled in the art in consideration of their own knowledge, the level of the prior art, and the content of this disclosure.

As used herein, the term "treatment" means the administration of the compounds or compositions of the present invention to alleviate or eliminate symptoms of HIV infection and/or reduce viral load in a patient. The term "treatment" also includes administering the compounds or compositions of the present invention after an individual's exposure to the virus but before the onset of disease symptoms, and/or before the virus is detected in the blood, to prevent the onset of disease symptoms and/or to prevent the virus from reaching detectable levels in the blood, and by administering the compounds or compositions of the present invention to the mother before childbirth and to the child within the first day of life to prevent perinatal transmission of HIV from mother to infant.

As used herein, the term "antiviral agent" means an agent (compound or biological agent) that effectively inhibits the formation and/or replication of viruses in humans, including but not limited to agents that interfere with the viral mechanisms necessary for the formation and/or replication of the host or virus in the human body.

The term “HIV replication inhibitor” as used in this article refers to an agent that can reduce or eliminate the ability of HIV to replicate in host cells, whether in vitro, ex vivo, or in vivo.

The compounds described herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers, which, according to absolute stereochemistry, may be defined as (R) or (S) or (D) or (L) of amino acids. This invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing/separating individual enantiomers include chiral synthesis or resolution of racemates (or racemates of salts or derivatives) from suitable optically pure precursors using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, the compound includes E and Z geometric isomers unless otherwise stated. Similarly, all tautomeric forms are also intended to be included.

"Stereoisomers" are compounds composed of the same atoms, bonded by the same bonds, but with different three-dimensional structures and are not interchangeable. This invention covers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

"Tautomerism" refers to the movement of a proton from one atom of a molecule to another atom of the same molecule. This invention includes tautomers of any of the compounds described.

"Enantiomer-enriched" compounds are those containing more than 50% of one of a pair of enantiomers. "Enantiomer-enriched" compounds may have an enantiomer excess (%ee) of more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 99%, or more than 99.9%.

References to “about” a value or parameter herein include (and describe) embodiments of that value or parameter itself. For example, a description relating to “about X” includes a description of “X”. Furthermore, the singular forms “a” and “the” include plural references unless the context clearly indicates otherwise. Thus, for example, references to “the compound” include a plurality of such compounds, and references to “the assay” include one or more assays and their equivalents known to those skilled in the art.

General Route

Some implementations involve the following general multi-step synthesis method, namely general schemes I-VI. All substitutions in the steps described below are as defined below:

Hal is a halogen.

n is 1, 2, or 3.

L is -C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ -, -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ - or -C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ C(R ^c ) ₂ -,

Each ^Rc is independently hydrogen, halogen, hydroxyl, or _C1 - _C4 alkyl.

^Ra , ^Rb , ^R1 , and ^R2 are each independently alkyl, aryl, or aralkyl.

In some implementations, Hal is a halogen, which can be the same or different.

In some embodiments, ^Ra , ^Rb , ^Rd , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl.

In some embodiments, ^Ra , ^Rb , ^R1 and ^R2 are each independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl.

In some embodiments, each ^Rb is independently hydrogen, -F, -Cl, hydroxyl, or methyl. In some embodiments, each ^Rc is independently hydrogen, -F, or -Cl. In some embodiments, each ^Rc is hydrogen.

In some embodiments, ^Ra , ^Rb , ^Rd , ^R1 , and ^R2 are each independently methyl, ethyl, phenyl, or benzyl. In some embodiments, each of ^Ra , ^Rb , ^R1 , and ^R2 is methyl. In a particular embodiment, ^Rd is ethyl.

In some embodiments, each ^R1 is a _C1 - _C4 alkyl group, and each ^R1 forms a heterocycle together with the atoms to which they are bonded. In some embodiments, each ^R1 is methyl or ethyl, and each ^R1 forms a heterocycle together with the atoms to which they are bonded. In some embodiments, each ^R1 is methyl, and each ^R1 forms a heterocycle together with the atoms to which they are bonded.

General Route I:

Some implementation schemes provide a method based on general route I:

The method includes the following steps:

C-1 is reacted with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 is reacted with at least one acid and N-1 or its salt or eutectic in the presence of a base to produce G-1;

G-1 is reacted under conditions suitable for the synthesis of compound I.

In some implementations, N-1 is in the form of a salt or a eutectic.

General Route II:

Some implementation schemes provide a method based on General Route II:

The method includes the following steps:

A-1 reacts with H-1 in the presence of a catalyst, a base, and an acylation reagent to generate B-1;

B-1 and J-1 react in the presence of acid to produce C-1;

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 is reacted with at least one acid and N-1 in the presence of a base to produce G-1;

G-1 is reacted under conditions suitable for the formation of compound I.

In some implementations, J-1 is in the form of a salt or a eutectic.

In some implementations, N-1 is in the form of a salt or a eutectic.

General Route III:

Some implementation schemes provide a method based on General Route III:

The method includes the following steps:

B-1 reacts with Q-1 to generate BB-1;

BB-1 reacts with J-1 to produce C-1;

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 is reacted with at least one acid and N-1 or its salt or eutectic in the presence of a base to produce G-1;

G-1 is reacted under conditions suitable for the formation of compound I.

In some implementations, J-1 is in the form of a salt or a eutectic.

General Route IV:

Some implementation schemes provide a method based on the general route IV:

The method includes the following steps:

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with M-1 to generate EE-1;

EE-1 reacts with K-1 to produce F-1;

F-1 is reacted with at least one acid and N-1 in the presence of a base to produce G-1;

G-1 is reacted under conditions suitable for the formation of compound I.

In some implementations, N-1 is in the form of a salt or a eutectic.

General Route V

Some implementation schemes provide a method based on the total route V:

The method includes the following steps:

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 reacts with a base to produce compound II.

General Route VI

Some implementation schemes provide a method based on the general route VI:

The method includes the following steps:

B-1·J-1 is reacted under conditions suitable for the formation of C-1;

C-1 reacts with alkylated formamide acetal to generate D-1;

D-1 reacts with K-1 to produce E-1;

E-1 and M-1 react in the presence of a base to produce F-1;

F-1 reacts with at least one acid to produce FF-1;

FF-1 is reacted with N-1 or its salt or eutectic in the presence of an additive to generate G-1;

G-1 is reacted under conditions suitable for the formation of compound I.

In some embodiments, F-1 is reacted with at least one acid to produce the following aldehyde:

It hydrates to form FF-1.

General Route VII

Some implementation schemes involve a multi-step synthesis approach as described below, namely, general route VII:

The method includes the following steps:

Hydrogenation of (-)-Vince lactam and protection of the reduction product to generate a-1;

a-1 reacts with ^R3 -M to generate b-1;

b-1 is oxidized and the oxidation product is hydrolyzed to generate c-1.

In General Route VII:

PG is a protective group; and

^R3M is a n-alkyl Grignard reagent or an organoalkyl lithium reagent.

In some embodiments, the protecting group (PG) is selected from Boc, phthalimide, benzyl, FMoc, acetyl, triphenylmethyl, trifluoroacetyl, benzylene, p-toluenesulfonamide, p-methoxybenzylcarbonyl, benzoyl, p-methoxybenzyl, carbamate, 3,4-dimethoxybenzyl, p-methoxyphenyl, sulfonamide, and benzyloxycarbonyl. In a specific embodiment, the protecting group is Boc.

In some embodiments, ^R3M is an ethyl magnesium halide, n-propyl magnesium halide, n-butyl magnesium halide, methyl lithium, n-butyl lithium, or n-hexyl lithium. In a specific embodiment, ^R3M is methyl magnesium bromide.

Route VIII

Some implementation schemes involve a multi-step synthesis approach as described below, i.e., route VIII:

The method includes the following steps:

Under effective conditions, g-1x reacts to produce h-1x; and

Under effective conditions, h-1x is reacted to generate N-1x.

In some implementations, the method further includes the following steps:

f-1x is reacted to generate g-1x under effective conditions.

In some implementations, g-1x reacts in the presence of a catalyst and a hydrogen source to generate h-1x.

In some embodiments, the catalyst is selected from palladium (Pd)-based catalysts, _PtO₂ , RhCl( _PPh₃ ) _₃ , Nyori catalysts, and Crabtree catalysts. Exemplary palladium catalysts include Pd/C. In some embodiments, the catalyst is selected from Pd/C, _PtO₂ , RhCl( _PPh₃ ) _₃ , Nyori catalysts, and Crabtree catalysts. In some embodiments, the catalyst is _PtO₂ .

In some embodiments, the hydrogen source is formic acid, hydrazine, dihydronaphthalene, dihydroanthracene, _H2 gas, or Hantzch ester and isopropanol. In a particular embodiment, the hydrogen source is _H2 gas. In a particular embodiment, the hydrogen source is _H2 gas in a hydrogen atmosphere.

In some embodiments, h-1x reacts with an acid to generate N-1x. In some embodiments, the acid is a sulfonic acid, including but not limited to methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid; an inorganic acid, including but not limited to phosphoric acid, hydrochloric acid, and sulfuric acid; or a carboxylic acid, including but not limited to trifluoroacetic acid, oxalic acid, and benzoic acid. In some embodiments, the acid is an inorganic acid. In a specific embodiment, the acid is hydrochloric acid. In a specific embodiment, the acid is anhydrous hydrochloric acid.

In some implementations, g-1x is N-1x.

In some implementations, f-1x is

Route IX

Some implementation schemes involve a multi-step synthesis method as described below, i.e., Route IX:

The method includes the following steps:

Racemic c-1a (which is a mixture of cc-1b and cc-1a) is reacted with an acyl donor and an enzyme to give cc-1b and e-1;

Separate e-1 from cc-1b; and

Hydrolyzing e-1 produces enantiomer-enriched cc-1a.

In some embodiments, ^Rx is ( _C1 - _C6 )alkyl- ^Ry , and ^Ry is selected from H, CN, –NR ^z1 R ^z2 , C(O)R ^z1 , –C(O)OR ^z1 , –C(O)NR ^z1 R ^z2 , –OC(O)NR ^z1 R ^z2 , –NR ^z1 C(O)R ^z2 , –NR ^z1 C(O)NR ^z2 , –NR ^z1 C(O)OR ^z2 , –SR ^z1 , –S(O) _1-2 R ^z1 , –S(O) ₂ NR ^z1 R ^z2 , –NR ^z1 S(O) ₂ R ^z2 , NR ^z1 S(O) ₂ R ^z2 , and OR ^z1 .

In some embodiments, R ^z1 and R ^z2 are independently selected from H, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 heteroalkyl, _C3-10 cycloalkyl, 3-12 heterocyclic, _C6-10 aryl, and 5-10 heteroaryl.

In some embodiments, ^Rx is ( _C1 - _C6 )alkyl- ^Ry , and ^Ry is selected from H, –C(O) ^ORz1 , and ^Rz1 is selected from H, _C1-6 alkyl, _C3-10 cycloalkyl and 3-12 heterocyclic groups.

In some embodiments, ^Rx is ( _C1 - _C6 )alkyl- ^Ry , and ^Ry is selected from H,–C(O) ^ORz1 , and ^Rz1 is selected from H and _C1-6 alkyl.

In some embodiments, ^Rx is ( _C1 - _C4 )alkyl- ^Ry , and ^Ry is selected from H and _CO2H .

In some embodiments, ^Rx is methyl or _{( CH2 ) 3} ^- _{CO2H .}

In some embodiments, the acyl donor is an acid anhydride or ester. In some embodiments, the acid anhydride includes, but is not limited to, glutaric anhydride and acetic anhydride. In some embodiments, the ester includes, but is not limited to, vinyl acetate, isopropylene acetate, 4-chlorophenyl acetate, and ethyl methoxyacetate. In a specific embodiment, the acyl donor is glutaric anhydride.

In some embodiments, the enzyme is a lipase. In some embodiments, the lipase includes, but is not limited to, Novozyme 435, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL, and MML. In some embodiments, the enzyme is CAL-B. In some embodiments, the enzyme is Novozyme 435.

Novozyme 435 is a CAL-B lipase immobilized on a hydrophobic carrier (acrylic resin).

CAL-B is a lipase from Candida antartica B.

CAL-A is a lipase from Candida antartica A.

PPL is porcine pancreatic lipase.

PSL is a lipase from Pseudomonas cepacia.

PSL-C is an immobilized lipase from Pseudomonas cepacia.

CRL is a lipase from Candida rugosa.

MML is a lipase from Mucor miehei.

Route X

Some implementation schemes involve a multi-step synthesis method as described below, i.e., the overall route X:

The method includes the following steps:

Racemic c-1a (which is a mixture of cc-1b and cc-1a) is reacted with an acyl donor to give racemic ee-1;

Racemic ee-1 (a mixture of e-1 and e-2) is reacted with an enzyme to yield e-2 and cc-1a; and

Separate enantiomers enriched in cc-1a.

In some embodiments, ^Rx is ( _C1 - _C6 )alkyl- ^Ry , and ^Ry is selected from H, CN, –NR ^z1 R ^z2 , C(O)R ^z1 , –C(O)OR ^z1 , –C(O)NR ^z1 R ^z2 , –OC(O)NR ^z1 R ^z2 , –NR ^z1 C(O)R ^z2 , –NR ^z1 C(O)NR ^z2 , –NR ^z1 C(O)OR ^z2 , –SR ^z1 , –S(O) _1-2 R ^z1 , –S(O) ₂ NR ^z1 R ^z2 , –NR ^z1 S(O) ₂ R ^z2 , NR ^z1 S(O) ₂ R ^z2 , and OR ^z1 .

In some embodiments, each R ^z1 and R ^z2 is independently selected from H, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C3-10 cycloalkyl, 3-12 heterocyclic, _C6-10 aryl, and 5 to 10 heteroaryl.

In some embodiments, ^Rx is ( _C1 - _C6 )alkyl- ^Ry , and ^Ry is selected from H, –C(O) ^ORz1 , and ^Rz1 is selected from H, _C1-6 alkyl, _C3-10 cycloalkyl and 3-12 heterocyclic groups.

In some embodiments, ^Rx is ( _C1 - _C6 )alkyl- ^Ry , and ^Ry is selected from H, –C(O) ^ORz1 , and ^Rz1 is selected from H and _C1-6 alkyl.

In some embodiments, ^Rx is ( _C1 - _C4 )alkyl- ^Ry , and ^Ry is selected from H and _CO2H .

In some embodiments, ^Rx is methyl or _{( CH2 ) 3} ^- _{CO2H .}

In some embodiments, the acyl donor includes, but is not limited to, acid anhydrides or acyl chlorides. In some embodiments, the acid anhydrides include, but are not limited to, succinic anhydride and acetic anhydride. In some embodiments, the acyl chlorides include, but are not limited to, acetyl chloride and benzoyl chloride. In a specific embodiment, the acyl donor is glutaric anhydride.

In some embodiments, the enzyme is a lipase, such as, but not limited to, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL, and MML. In a specific embodiment, the enzyme is CAL-B.

Route XI

Some implementation schemes involve a multi-step synthesis method as described below, namely route XI:

The method includes the following steps:

Reaction of racemic c-1a (which is a mixture of c-1b and c-1a) with a chiral acid yields dd-1 and dd-2; and

Separate enantiomer-enriched dd-1.

In some implementations, the chiral acid is selected from:

Single enantiomers of α-carboxylic acids, including but not limited to: naproxen, phenylsuccinic acid, malic acid, 2-phenylpropionic acid, α-methoxyphenylacetic acid, aniline tartrate, 3-phenyllactic acid, α-hydroxyisovaleric acid, 2'-methoxyaniline tartrate, (α-methylbenzyl)-o-carbamoylbenzoic acid, 2'-chloro-aniline tartrate, and pyroglutamic acid;

- Single enantiomers of mandelic acid derivatives, including but not limited to: mandelic acid, 2-chloromandelic acid, 4-bromomandelic acid, O-acetylmandelic acid, and 4-methylmandelic acid;

-Enantiomers of sulfonic acids, including but not limited to: camphor sulfonic acid;

- Single enantiomers of tartaric acid derivatives, including but not limited to: tartaric acid, dibenzoyl tartaric acid hydrate, di-p-methoxybenzoyl tartaric acid, dibenzoyl tartaric acid, and dibenzoyl tartaric acid hydrate.

-Single enantiomers of phosphoric acid derivatives, including but not limited to: 4-phenyl-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxophosphacyclohexane hydrate, 4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxophosphacyclohexane, 4-(2-methoxyphenyl)-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxophosphacyclohexane, and BINAP phosphate; and

- Single enantiomers of amino acids, including but not limited to: N-acetyl-phenylalanine, N-acetyl-leucine, N-acetyl-proline, boc-phenylalanine, and boc-homophenylalanine.

In some implementations, the chiral acid is a single enantiomer of a carboxylic acid.

In a specific embodiment, the acid is (R)-naproxen. In a specific embodiment, the acid is R-(+)-mandelic acid.

In a specific embodiment, the acid is (S)-naproxen. In a specific embodiment, the acid is S-(+)-mandelic acid.

In some embodiments, the reaction with the chiral acid takes place in a mixture selected from water, acetonitrile, ethanol, isopropanol, methyl ethyl ketone, isopropyl acetate, dioxane, water, and water-miscible organic solvents (such as ethanol and isopropanol), halogenated solvents such as dichloromethane and chloroform. In specific embodiments, the solvent is water or isopropanol or a mixture thereof. In specific embodiments, the solvent is water. In specific embodiments, the solvent is isopropanol.

In some embodiments, the reaction with the chiral acid is stirred at 0 to 120°C, 20 to 120°C, 50 to 120°C, 80 to 120°C, or about 100°C. In some embodiments, the reaction is stirred at about 20°C.

In some embodiments, separating dd-1 includes selective recrystallization of dd-1. In some embodiments, recrystallization occurs in water, acetonitrile, ethanol, isopropanol, methyl ethyl ketone, isopropyl acetate, dioxane, water, and a mixture of water and a water-miscible organic solvent (such as ethanol and isopropanol), or a halogenated solvent such as dichloromethane or chloroform. In some embodiments, recrystallization occurs in a mixture of methyl ethyl ketone and water.

In some implementations, dd-1 is precipitated from the solution and filtered.

Route VII-XI discloses the steps and intermediates that can be used in the methods for preparing N-1 and/or Formula I compounds of the present invention.

Overall route – single step

Other embodiments involve the individual steps of the above-described multi-step general synthetic method, namely, general routes I-V and VI to XI. These individual steps and intermediates of the invention are described in detail below. All substituents in the following steps are as defined in the above-described multi-step method.

Acylation and amidation of Meldrum's acids to provide C-1:

Transformation from A-1 to B-1

In a specific embodiment, 1 equivalent of Meldram acid (A-1) and a suitable catalyst are suspended in a suitable solvent, and the resulting solution is treated with about 1.2 equivalents of H-1. About 2 equivalents of a suitable base are slowly added to the resulting solution, followed by about 1.1 equivalents of a suitable acylation reagent. The reaction is carried out at about 20 to 80°C and is allowed to continue until the Meldram acid is completely consumed, as monitored by any suitable method known in the art.

In some embodiments, the catalyst is a nucleophilic amine compound, such as, but not limited to, 4-dimethylaminopyridine, imidazole, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or pyridine. In other embodiments, the catalyst is a nucleophilic phosphine compound, such as, but not limited to, triphenylphosphine. In one specific embodiment, the catalyst is 4-dimethylaminopyridine.

In some embodiments, the solvent used for the above reaction is a polar aprotic solvent or an aromatic solvent. In some embodiments, the solvent used for the above reaction is a polar aprotic solvent. In some embodiments, the solvent used for the above reaction is an aromatic solvent. Exemplary polar aprotic solvents include, but are not limited to, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone. Exemplary aromatic solvents used for the above reaction include, but are not limited to, pyridine, toluene, xylene, benzene, or chlorobenzene. In other embodiments, the solvent is a mixture comprising at least one of the aforementioned solvents. For example, in some embodiments, the solvent is a mixture of up to three or up to two polar aprotic solvents selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidone. In other embodiments, the solvent is a mixture of up to three or up to two aromatic solvents selected from pyridine, toluene, xylene, benzene, and chlorobenzene. In one embodiment, the solvent is selected from at most three or at most two of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidone, pyridine, toluene, xylene, benzene, and chlorobenzene. In another embodiment, the solvent is acetonitrile.

In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Ra is ( _C1 - _C4 )alkyl. In some embodiments, ^Ra is _–CH3 , i.e., H-1 is methoxyacetic acid.

In some embodiments, the base is an amine base, an aromatic base, an inorganic carbonate, a metal hydride, an alkoxide, or a mixture thereof. In some embodiments, the base is an amine base. In some embodiments, the base is an aromatic base. In some embodiments, the base is an inorganic carbonate. In some embodiments, the base is a metal hydride. In some embodiments, the base is an alkoxide. Exemplary amine bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, quinine ring, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, tripropylamine, and tributylamine. Exemplary aromatic amine bases include, but are not limited to, pyridine. Exemplary inorganic carbonates include, but are not limited to, lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate. Exemplary metal hydrides include, but are not limited to, sodium hydride or potassium hydride. Exemplary alkoxides include, but are not limited to, sodium methoxide, sodium tert-butoxide, or lithium tert-butoxide. In another embodiment, the base is a mixture comprising at least one of the aforementioned bases. For example, in some embodiments, the base is a mixture of up to three or up to two amine bases. In some embodiments, the base is a mixture of up to three or up to two aromatic bases. In some embodiments, the base is a mixture of up to three or up to two inorganic carbonates. In some embodiments, the base is a mixture of up to three or up to two metal hydrides. In some embodiments, the base is a mixture of up to three or up to two alkoxides. In some embodiments, the base is up to three or up to two selected from triethylamine, N,N-diisopropylethylamine, quinine ring, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo-diazabicyclo[5.4.0]undec-7-ene, tripropylamine, tributylamine, pyridine, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium methoxide, sodium tert-butoxide, and lithium tert-butoxide. In one specific embodiment, the base is triethylamine.

In some embodiments, the acylation agent is a carboxylic acid activator, a carbodiimide derivative, or a mixture thereof. In some embodiments, the acylation agent is a carboxylic acid activator. In some embodiments, the acylation agent is a carbodiimide derivative. In some embodiments, the acylation agent is a mixture of a carboxylic acid activator and a carbodiimide derivative. Exemplary carboxylic acid activators include, but are not limited to, pentanoyl chloride, carbonyl diimidazole, thionyl chloride, and oxalyl chloride. Exemplary carbodiimide derivatives include, but are not limited to, carbonyl diimidazole and N,N'-dicyclohexylcarbodiimide. In some embodiments, the acylation agent is pentanoyl chloride, carbonyl diimidazole, thionyl chloride, oxalyl chloride, or N,N'-dicyclohexylcarbodiimide. In some embodiments, the acylation agent is pentanoyl chloride. In some embodiments, the reaction occurs at approximately 20 to 70°C, approximately 20 to 60°C, approximately 20 to 50°C, approximately 20 to 40°C, approximately 20 to 30°C, approximately 30 to 80°C, approximately 30 to 70°C, approximately 30 to 60°C, approximately 30 to 50°C, approximately 30 to 40°C, approximately 40 to 80°C, approximately 40 to 70°C, approximately 40 to 60°C, approximately 40 to 50°C, approximately 50 to 80°C, approximately 50 to 70°C, approximately 50 to 60°C, approximately 60 to 80°C, approximately 60 to 70°C, approximately 70 to 80°C, or any subrange thereof. In specific embodiments, the reaction occurs at approximately 35 to 40°C, approximately 40 to 45°C, approximately 45 to 50°C, or any subrange thereof.

In a specific implementation, the catalyst is 4-dimethylaminopyridine, the solvent is acetonitrile, ^Ra is _–CH3 , the base is triethylamine, the acylation reagent is neopentanoyl chloride, and the reaction is carried out at about 45 to 50°C.

Transformation from B-1 to C-1

In a separate container, approximately 1.2 equivalents of J-1 are suspended in a suitable solvent. The resulting solution is treated with approximately 1.5 equivalents of a suitable acid, and this acidic solution is then added to the ongoing acylation reaction described above. The reaction is continued at approximately 20 to 80°C for approximately 12 to approximately 24 hours, after which the solvent is removed, and C-1 is recovered and purified from the residue using any suitable technique known in the art, such as, but not limited to, solvent extraction, silica gel chromatography, and crystallization.

In some embodiments, J-1 is suspended in a polar aprotic solvent or an aromatic solvent. In some embodiments, J-1 is suspended in a polar aprotic solvent. In some embodiments, J-1 is suspended in an aromatic solvent. Exemplary polar aprotic solvents include, but are not limited to, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidone. Exemplary aromatic solvents include, but are not limited to, pyridine, toluene, xylene, benzene, and chlorobenzene. In other embodiments, J-1 is suspended in a solvent mixture comprising one or more polar aprotic solvents and/or one or more aromatic solvents. In some embodiments, J-1 is suspended in a solvent mixture comprising up to three or up to two polar aprotic solvents. In some embodiments, J-1 is suspended in a solvent mixture comprising up to three or up to two aromatic solvents. In some embodiments, J-1 is suspended in a mixture containing up to three or two of a mixture selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidone, pyridine, toluene, xylene, benzene, and chlorobenzene. In another embodiment, J-1 is suspended in acetonitrile.

In specific embodiments, the acid is an inorganic acid, an organic acid, or a halogenated organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is an organic acid. Exemplary inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, and hydroiodic acid. Exemplary organic acids include, but are not limited to, formic acid and acetic acid. In other embodiments, the organic acid is a halogenated organic acid. Exemplary halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In further embodiments, the acid is a mixture comprising one or more organic acids and one or more inorganic acids. In some embodiments, the acid is a mixture comprising up to three or up to two organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two halogenated organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two inorganic acids. In one embodiment, the acid is a mixture of up to three or up to two acids selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In one specific embodiment, the acid is trifluoroacetic acid.

In specific implementations, each Hal is independently either -F or -Cl. In one specific implementation, Hal is -F. In some implementations, n = 1-3. In some implementations, n = 2. In some implementations, n = 3. In a further implementation, J-1 is...

In another embodiment, J-1 is in the form of a salt or eutectic, such as, but not limited to, a salt or eutectic of hydrochloric acid or trifluoroacetic acid. In some embodiments, J-1 is a salt or eutectic of methanesulfonic acid.

For example, in some implementations, J-1 is:

In one specific implementation plan, J-1 is

In one specific implementation plan, J-1 is

For example, in some implementations, J-1 is:

In one specific implementation plan, J-1 is

In one specific implementation plan, J-1 is

In some embodiments, the reaction occurs within the ranges of approximately 20 to 70°C, approximately 20 to 60°C, approximately 20 to 50°C, approximately 20 to 40°C, approximately 20 to 30°C, approximately 30 to 80°C, approximately 30 to 70°C, approximately 30 to 60°C, approximately 30 to 50°C, approximately 30 to 40°C, approximately 40 to 80°C, approximately 40 to 70°C, approximately 40 to 60°C, approximately 40 to 50°C, approximately 50 to 80°C, approximately 50 to 70°C, approximately 50 to 60°C, approximately 60 to 80°C, approximately 60 to 70°C, approximately 70 to 80°C, or any subrange thereof. In specific embodiments, the reaction occurs within the ranges of approximately 35 to 40°C, approximately 40 to 45°C, approximately 45 to 50°C, or any subrange thereof.

In some embodiments, the solvent is removed under reduced pressure. In a specific embodiment, C-1 is extracted from the crude residue by solvent extraction. In a specific embodiment, the crude residue is dissolved in an organic solvent such as ethyl acetate, and the organic layer is washed with water. The combined aqueous layers are extracted with an organic solvent such as ethyl acetate. The combined organic layers are washed with a saturated sodium bicarbonate solution, and the combined bicarbonate washes are back-extracted with an organic solvent such as ethyl acetate. The total combined organic layers are dried with a drying agent such as magnesium sulfate, filtered, and concentrated under reduced pressure. The crude substance obtained is purified using any suitable technique, such as silica gel chromatography, to obtain C-1.

In a specific implementation, J-1 is suspended in acetone, the acid is trifluoroacetic acid, J-1 is [missing information], and the reaction occurs at approximately 45 to 50°C.

C-1 is formed via B-1·J-1 salt

Alternatively, in some embodiments, C-1 is formed via B-1·J-1 salt according to the following procedure.

B-1·J-1 salt is formed through addition from J-1 to B-1.

The free acid of B-1 (about 1 equivalent) is dissolved in a solvent, and then J-1 (about 1 to about 5 equivalents) is added. In some embodiments, the salt is aged for up to 12 hours, up to 10 hours, up to 8 hours, up to 6 hours, up to 4 hours, or up to 3 hours. The salt is obtained by any suitable method known in the art, including but not limited to solvent filtration, extraction, crystallization, and silica gel chromatography.

In some embodiments, the solvent used for the above reaction is a polar aprotic solvent or an aromatic solvent. In some embodiments, the solvent used for the above reaction is a polar aprotic solvent. In some embodiments, the solvent used for the above reaction is an aromatic solvent. Exemplary polar aprotic solvents include, but are not limited to, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone. Exemplary aromatic solvents used for the above reaction include, but are not limited to, pyridine, toluene, xylene, benzene, or chlorobenzene. In other embodiments, the solvent is a mixture comprising at least one of the aforementioned solvents. For example, in some embodiments, the solvent is a mixture of up to three or up to two polar aprotic solvents selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidone. In other embodiments, the solvent is a mixture of up to three or up to two aromatic solvents selected from pyridine, toluene, xylene, benzene, and chlorobenzene. In one embodiment, the solvent is selected from at most three or at most two of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidone, pyridine, toluene, xylene, benzene, and chlorobenzene. In another embodiment, the solvent is acetonitrile.

In some implementations, B-1·J-1 is

In some embodiments, the reactants are stirred to about 15 to 30°C, about 20 to 70°C, about 20 to 60°C, about 20 to 50°C, about 20 to 40°C, about 20 to 30°C, about 30 to 80°C, about 30 to 70°C, about 30 to 60°C, about 30 to 50°C, about 30 to 40°C, about 40 to 80°C, about 40 to 70°C, about 40 to 60°C, about 40 to 50°C, about 50 to 80°C, about 50 to 70°C, about 50 to 60°C, about 60 to 80°C, about 60 to 70°C, about 70 to 80°C, or any subrange thereof. In other embodiments, the reaction is carried out at about 15 to about 25°C.

In some embodiments, the solvent is acetonitrile, and the reaction is carried out at about 18 to about 25°C.

C-1 is formed from B-1·J-1

Salt B-1·J-1 (about 1 equivalent) is suspended in a suitable solvent. The resulting solution is treated with about 0.1 to 1 equivalent of a suitable acid. The reaction is continued at about 20 to 80 °C for about 12 to about 24 hours, after which the solvent is removed, and C-1 is recovered and purified from the residue using any suitable technique known in the art, such as, but not limited to, solvent extraction, silica gel chromatography, crystallization, and filtration.

In some embodiments, the solvent used for the above reaction is a polar aprotic solvent or an aromatic solvent. In some embodiments, the solvent used for the above reaction is a polar aprotic solvent. In some embodiments, the solvent used for the above reaction is an aromatic solvent. Exemplary polar aprotic solvents include, but are not limited to, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone. Exemplary aromatic solvents used for the above reaction include, but are not limited to, pyridine, toluene, xylene, benzene, or chlorobenzene. In other embodiments, the solvent is a mixture comprising at least one of the aforementioned solvents. For example, in some embodiments, the solvent is a mixture of up to three or up to two polar aprotic solvents selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone. In other embodiments, the solvent is a mixture of up to three or up to two aromatic solvents selected from pyridine, toluene, xylene, benzene, and chlorobenzene. In one embodiment, the solvent is a mixture of up to three or up to two selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane or N-methyl-2-pyrrolidone, pyridine, toluene, xylene, benzene and chlorobenzene. In another embodiment, the solvent is acetonitrile.

In specific embodiments, the acid is an inorganic acid, an organic acid, or a halogenated organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is an organic acid. Exemplary inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, and hydroiodic acid. Exemplary organic acids include, but are not limited to, formic acid and acetic acid. In still other embodiments, the organic acid is a halogenated organic acid. Exemplary halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In some embodiments, the acid is trifluoroacetic acid. In further embodiments, the acid is a mixture comprising one or more organic acids and one or more inorganic acids. In some embodiments, the acid is a mixture comprising up to three or up to two organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two halogenated organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two inorganic acids. In one embodiment, the acid is a mixture of up to three or up to two acids selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In one specific implementation, the acid is trifluoroacetic acid.

In some embodiments, after the addition is complete, the reaction is heated to approximately 20 to 70°C, approximately 20 to 60°C, approximately 20 to 50°C, approximately 20 to 40°C, approximately 20 to 30°C, approximately 30 to 80°C, approximately 30 to 70°C, approximately 30 to 60°C, approximately 30 to 50°C, approximately 30 to 40°C, approximately 40 to 80°C, approximately 40 to 70°C, approximately 40 to 60°C, approximately 40 to 50°C, approximately 50 to 80°C, approximately 50 to 70°C, approximately 50 to 60°C, approximately 60 to 80°C, approximately 60 to 70°C, approximately 70 to 80°C, or any subrange thereof. In other embodiments, the reaction is carried out at approximately 60°C.

In the specific implementation plan, the solvent is acetonitrile, the acid is trifluoroacetic acid, and the reaction is carried out at about 60°C.

Alkylation of C-1 to form E-1:

A solution of about 1 equivalent of C-1 in a suitable solvent is treated with about 1 to 1.5 equivalents of alkylated formamide acetal and stirred at about 0 to 60°C for about 10 to about 18 hours. The reaction is then treated with about 1 equivalent of K-1 and allowed to continue for about 1 to about 4 hours, followed by quenching the reaction by the addition of acid. E-1 is then extracted and purified by any suitable method known in the art, including but not limited to solvent extraction, crystallization, and silica gel chromatography.

In one specific embodiment, the solvent is an aprotic polar organic solvent, such as, but not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidone, or mixtures thereof. In another embodiment, the solvent is 2-methyltetrahydrofuran.

In some embodiments, the alkylated formamide acetal is selected from N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In one specific embodiment, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

In a specific implementation scheme, 1 equivalent of C-1 is treated with approximately 1.1 equivalents of alkylated formamide acetal.

In some embodiments, ^R1 is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R1 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R1 is ( _C1 - _C4 )alkyl. In a further embodiment, ^R1 is _-CH3 , i.e., K-1 is aminoacetaldehyde dimethyl acetal.

In some embodiments, the reaction is quenched with an inorganic acid, an organic acid, or a halogenated organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is an organic acid. In some embodiments, the acid is a halogenated organic acid. Exemplary inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, and hydroiodic acid. Exemplary organic acids include, but are not limited to, formic acid and acetic acid. Exemplary halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In other embodiments, the acid is a mixture comprising one or more organic acids, one or more inorganic acids, and/or one or more halogenated organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two halogenated organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two inorganic acids. In one embodiment, the acid is a mixture of up to three or up to two selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In one specific embodiment, the acid is trifluoroacetic acid. In another specific embodiment, the reaction is quenched with hydrochloric acid. In a particular embodiment, the reaction is quenched with 2N HCl. In some embodiments, the reaction is not quenched.

In some embodiments, the reaction is carried out at a temperature of about 10 to 60°C, about 10 to 50°C, about 10 to 40°C, about 10 to 30°C, about 10 to 20°C, 20 to 60°C, about 20 to 50°C, about 20 to 40°C, about 20 to 30°C, about 30 to 60°C, about 30 to 40°C, about 40 to 60°C, about 40 to 50°C, about 50 to 60°C, or any subrange thereof. In a specific embodiment, the reaction is carried out at room temperature. In another embodiment, the reaction is carried out at a temperature of about 15 to about 25°C.

In a specific implementation, the solvent is 2-methyltetrahydrofuran, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, ^R1 is _-CH3 , and the reaction is carried out at about 18 to about 23°C.

The cyclization of E-1 forms F-1:

In a particular embodiment, solutions of about 1 equivalent of E-1 and about 1 to 5 equivalents of M-1 in a first suitable solvent are combined and cooled to about 0 to 5°C. In some embodiments, the base is slowly introduced into the reaction mixture while the internal temperature of the reaction is kept cool throughout the addition process (e.g., below room temperature, or below about 25°C, or below about 20°C, or below about 15°C). After the addition is complete, the reaction is heated to about 20 to 80°C for at least about 14 hours.

After this time has elapsed, the reaction can be diluted with an acidic aqueous solution and another suitable organic solvent, and the product can be extracted and purified by any suitable method known in the art, including but not limited to solvent extraction, crystallization, and silica gel chromatography. In some embodiments, the acidic aqueous solution is hydrochloric acid and acetic acid. For example, in some embodiments, the acidic aqueous solution is glacial acetic acid.

In specific embodiments, the first solvent is one or more alcohols, one or more polar organic solvents, or a mixture of one or more alcohols and one or more polar organic solvents. In some embodiments, the first solvent is up to three alcohols, up to three polar organic solvents, or a mixture thereof (i.e., a mixture of up to three or two alcohols and up to three or two polar organic solvents). In some embodiments, the first solvent is one or two alcohols, one or two polar organic solvents, or a mixture thereof (i.e., a mixture of one or two alcohols and one or two polar organic solvents). In some embodiments, the first solvent is an alcohol. In some embodiments, the first solvent is a polar organic solvent. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, and tert-butanol. Exemplary polar organic solvents include, but are not limited to, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidone. In some embodiments, the first solvent is methanol, ethanol, n-propanol, 2-propanol, butanol, tert-butanol, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone. In one embodiment, the first solvent is methanol.

In specific embodiments, the base is a metal hydride, an alkoxide, or a bis(trialkylsilyl)amide. In some embodiments, the base is a metal hydride. In some embodiments, the base is an alkoxide. In some embodiments, the base is a bis(trialkylsilyl)amide. Exemplary metal hydrides include, but are not limited to, lithium hydride, sodium hydride, and potassium hydride. Exemplary alkoxides include, but are not limited to, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, and lithium tert-butoxide. Exemplary bis(trialkylsilyl)amine bases include, but are not limited to, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, and potassium bis(trimethylsilyl)amino. In other embodiments, the base is a mixture of at least one of the aforementioned bases. In some embodiments, the base is a mixture of up to three or up to two metal hydrides. In some embodiments, the base is a mixture of up to three or up to two alkoxides. In some embodiments, the base is a mixture of up to three or up to two metal bis(trialkylsilyl)amides. In some embodiments, the base is a mixture of up to three or up to two of the following bases: lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, lithium tert-butoxide, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, or potassium bis(trimethylsilyl)amino. In a specific embodiment, the base is sodium methoxide.

In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is _C1 - _C4 alkyl. In some embodiments, ^R2 is _–CH3 .

In some embodiments, after the addition is complete, the reaction is heated to about 20 to 70°C, about 20 to 60°C, about 20 to 50°C, about 20 to 40°C, about 20 to 30°C, about 30 to 80°C, about 30 to 70°C, about 30 to 60°C, about 30 to 50°C, about 30 to 40°C, about 40 to 80°C, about 40 to 70°C, about 40 to 60°C, about 40 to 50°C, about 50 to 80°C, about 50 to 70°C, about 50 to 60°C, about 60 to 80°C, about 60 to 70°C, about 70 to 80°C, or any subrange thereof.

In a specific embodiment, the first solvent is an alcohol, the base is an alkoxide, the reaction is heated to about 40 to about 50°C after the addition is complete, and ^R2 is a ( _C1 - _C4 ) alkyl group.

In a specific implementation, the first solvent is methanol, the base is sodium methoxide, and after the addition is complete, the reaction is heated to about 40 to about 50°C, and ^R2 is _–CH3 .

Alkylation and cyclization of C-1 to form F-1:

1. Alkylated formamide acetal

In some embodiments, about 1 equivalent of C-1 and about 1 to about 5 equivalents of alkylformamide acetal are combined in a reaction vessel, and the reaction mixture is stirred for about 30 minutes. In some embodiments, about 1 equivalent of C-1 and about 1 to about 3 equivalents of alkylformamide acetal are mixed in a reaction vessel. A first suitable solvent and about 1 equivalent of K-1 are added to the mixture, the reaction is allowed to proceed for several hours, and then the first solvent is removed by any suitable method known in the art.

Dissolve the resulting material in a second suitable solvent and add about 1 to about 5 equivalents of M-1. Cool the reaction mixture to about 0°C to about 5°C, and then slowly add about 1.5 to 2 equivalents of base to the reaction mixture. Keep the internal temperature of the reaction cold throughout the addition process (e.g., below room temperature, or below about 25°C, or below about 20°C, or below about 15°C). After the addition is complete, heat the reaction to about 20 to 80°C for about 8 to about 16 hours.

After this time has elapsed, the reaction is cooled to room temperature, quenched by adding acid, and diluted by adding an organic solvent. Product F-1 can then be extracted and purified by any suitable method known in the art, including but not limited to solvent extraction, crystallization, and silica gel chromatography.

In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl(C1- _C4 )alkyl. In some embodiments, ^Ra is ( _{C1 - C4} )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Ra is _C1 - _C4 alkyl. In some embodiments, ^Ra is _–CH3 .

In a specific embodiment, the first solvent is an aprotic polar organic solvent, such as, but not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidone, or mixtures thereof. In another embodiment, the first solvent is 2-methyltetrahydrofuran.

In some embodiments, the alkylated formamide acetal is selected from N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In one specific embodiment, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

In some embodiments, ^R1 is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R1 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R1 is _C1 - _C4 alkyl. In other embodiments, ^R1 is _–CH3 , i.e., K-1 is aminoacetaldehyde dimethyl acetal.

In specific embodiments, the base is a metal hydride, a bis(trialkylsilyl)amine base, or an alkoxide. In some embodiments, the base is a metal hydride. In specific embodiments, the base is a bis(trialkylsilyl)amine base. In specific embodiments, the base is an alkoxide. Exemplary metal hydrides include, but are not limited to, lithium hydride, sodium hydride, and potassium hydride. Exemplary bis(trialkylsilyl)amine bases include, but are not limited to, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, and potassium bis(trimethylsilyl)amino. Exemplary alkoxides include, but are not limited to, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-pentoxide, and lithium tert-butoxide. In other embodiments, the base is a mixture of at least one of the aforementioned bases. In some embodiments, the base is a mixture of up to three or up to two metal hydrides. In some embodiments, the base is a mixture of up to three or up to two bis(trialkylsilyl)amine bases. In some embodiments, the base is a mixture of up to three or up to two alkoxides. In some embodiments, the base is selected from at most three or at most two of lithium hydride, sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, and lithium tert-butoxide. In a specific embodiment, the base is sodium methoxide. In a specific embodiment, a solution of the base in an alcohol is added to the reaction. Suitable alcohols include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, or tert-butanol. In one embodiment, the base is sodium methoxide. In one embodiment, the base is added as a 30% sodium methoxide methanol solution.

In specific embodiments, the second solvent is an alcohol or a polar solvent. In some embodiments, the second solvent is an alcohol. In some embodiments, the second solvent is a polar solvent. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, and tert-butanol. Exemplary polar organic solvents include, but are not limited to, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone. In one embodiment, the second solvent is methanol.

In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is _C1 - _C4 alkyl. In some embodiments, ^R2 is _–CH3 .

In some embodiments, after the addition is complete, the reaction is heated to about 20 to 70°C, about 20 to 60°C, about 20 to 50°C, about 20 to 40°C, about 20 to 30°C, about 30 to 80°C, about 30 to 70°C, about 30 to 60°C, about 30 to 50°C, about 30 to 40°C, about 40 to 80°C, about 40 to 70°C, about 40 to 60°C, about 40 to 50°C, about 50 to 80°C, about 50 to 70°C, about 50 to 60°C, about 60 to 70°C, about 70 to 80°C, or any subrange thereof.

In a specific embodiment, ^Ra is ( _C1 - _C4 ) alkyl, the first solvent is 2-methyltetrahydrofuran, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, ^R1 is ( _C1 - _C4 ) alkyl, the base is an alkoxide, the second solvent is an alcohol, the reactants are heated to about 40 to about 50°C after addition, and ^R2 is ( _C1 - _C4 ) alkyl.

In the specific implementation scheme, ^Ra is _–CH3 , the first solvent is 2-methyltetrahydrofuran, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, ^R1 is _–CH3 , the base is sodium methoxide, the second solvent is methanol, the reaction is heated to about 40 to about 50°C after the addition, and ^R2 is _–CH3 .

EE-1 prepared from D-1

D-1 reacts with M-1 to give EE-1. For example, D-1 is dissolved in a suitable solvent, and about 1 to about 5 equivalents of M-1 are added. The reaction mixture is cooled to about 0°C to about 5°C, and then about 1.5 to 2 equivalents of base are slowly added to the reaction mixture. The internal temperature of the reaction is kept cool throughout the addition process (e.g., below room temperature, or below about 25°C, or below about 20°C, or below about 15°C). After the addition is complete, the reaction is heated to about 20 to 80°C for about 8 to about 16 hours.

After this time has elapsed, the reaction is cooled to room temperature, quenched by adding acid, and diluted by adding an organic solvent. The product EE-1 can then be extracted and purified by any suitable method known in the art, including but not limited to solvent extraction, crystallization, and silica gel chromatography.

In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl(C1- _C4 )alkyl. In some embodiments, ^Ra is ( _{C1 - C4} )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Ra is _C1 - _C4 alkyl. In a specific embodiment, ^Ra is _–CH3 .

In some embodiments, ^Rb is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, each ^Rb is independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Rb is _C1 - _C4 alkyl. In other embodiments, ^Rb is _–CH3 . In some embodiments, each ^Rb is _–CH3 .

In specific embodiments, the base is an inorganic carbonate, a metal hydride, or an alkoxide, or a mixture thereof. In specific embodiments, the base is an inorganic carbonate. In specific embodiments, the base is a metal hydride. In specific embodiments, the base is an alkoxide. Exemplary inorganic carbonates include, but are not limited to, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Exemplary metal hydrides include, but are not limited to, sodium hydride and potassium hydride. Exemplary alkoxides include, but are not limited to, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, and lithium tert-butoxide. In some embodiments, the base is a mixture of up to three, or in other embodiments, up to two inorganic carbonates. In some embodiments, the base is a mixture of up to three, or in other embodiments, up to two metal hydrides. In some embodiments, the base is a mixture of up to three, or in other embodiments, up to two alkoxides. In some embodiments, the base is up to three, or in other embodiments, up to two are selected from a mixture of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, and lithium tert-butoxide. In a specific embodiment, the base is sodium methoxide.

In specific embodiments, the solvent is an alcohol or a polar solvent. In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is a polar solvent. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, and tert-butanol. Exemplary polar organic solvents include, but are not limited to, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone. In some embodiments, the solvent is N-methyl-2-pyrrolidone.

In some embodiments, the reaction is quenched with an inorganic acid, an organic acid, or a haloorganic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is an organic acid. In some embodiments, the acid is a haloorganic acid. Exemplary inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, and hydroiodic acid. Exemplary organic acids include, but are not limited to, formic acid and acetic acid. Exemplary haloorganic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In other embodiments, the acid is a mixture comprising one or more organic acids, one or more inorganic acids, and/or one or more halogenated organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two organic acids. In some embodiments, the acid is a mixture comprising up to three or up to two haloorganic acids. In some embodiments, the acid is a mixture comprising up to three or up to two inorganic acids. In one embodiment, the acid is a mixture of up to three or up to two selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In one specific embodiment, the acid is trifluoroacetic acid. In another specific embodiment, the reaction is quenched with hydrochloric acid. In yet another specific embodiment, the reaction is quenched with 2N HCl. In some embodiments, the reaction is not quenched.

In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C2 - _C10 )aryl, or ( _C2 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is _C1 - _C4 alkyl. In some embodiments, ^R2 is _–CH3 .

In some embodiments, after the addition is complete, the reaction is heated to about 20 to 80°C, about 20 to 80°C, about 20 to 60°C, about 20 to 50°C, about 20 to 40°C, about 20 to 30°C, about 30 to 80°C, about 30 to 70°C, about 30 to 60°C, about 30 to 50°C, about 30 to 40°C, about 40 to 80°C, about 40 to 70°C, about 40 to 60°C, about 40 to 50°C, about 50 to 80°C, about 50 to 70°C, about 50 to 60°C, about 60 to 80°C, about 60 to 70°C, about 70 to 80°C, or any subrange thereof.

In a specific embodiment, ^R2 is a ( _C1 - _C4 ) alkyl group, each ^Rb is a ( _C1 - _C4 ) alkyl group, which may be the same or different, ^Ra is a ( _C1 - _C4 ) alkyl group, the base is an alkoxide, and the solvent is an organic solvent.

In the specific implementation scheme, ^R2 is _–CH3 , each ^Rb is _–CH3 , ^Ra is _–CH3 , the base is sodium methoxide, and the solvent is N-methyl-2-pyrrolidone.

F-1 and N-1 condense to form G-1:

Combine 1 equivalent of F-1 and a suitable solvent in a reaction vessel, and add about 5 to 8 equivalents of the first acid and about 0.2 to about 0.5 equivalents of the second acid. The reaction can be carried out between about 20 and about 100°C.

Allow the reaction to proceed for approximately 2 to 5 hours, then slowly add approximately 1.5 equivalents of N⁻¹ and approximately 2 to 3 equivalents of base to the reaction vessel. After the addition is complete, allow the reaction to proceed for at least approximately 1 hour.

Water and other solvents are added to the reaction vessel, and G-1 is extracted and purified by any suitable method known in the art, including but not limited to solvent extraction, silica gel chromatography, and crystallization.

In specific embodiments, the solvent is a proton-polar organic solvent, such as, but not limited to, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone, or mixtures thereof. In some embodiments, the solvent is one, a mixture of two, or three, or in some embodiments, a mixture of one or two of the following solvents: tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, or N-methyl-2-pyrrolidone. In other embodiments, the solvent is acetonitrile.

In some embodiments, the first acid is an organic acid, an organic carboxylic acid, or an inorganic acid. In some embodiments, the first acid is an organic acid. In some embodiments, the first acid is an organic carboxylic acid. In some embodiments, the first acid is an inorganic acid. Exemplary organic acids include, but are not limited to, methanesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid. Exemplary organic carboxylic acids include, but are not limited to, acetic acid, formic acid, butyric acid, propionic acid, and benzoic acid. Exemplary inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, or sulfuric acid. In another embodiment, the first acid is acetic acid.

In some embodiments, the second acid is an organic acid, an organic carboxylic acid, or an inorganic acid. In some embodiments, the second acid is an organic acid. In some embodiments, the second acid is an organic carboxylic acid. In some embodiments, the first acid is an inorganic acid. Exemplary organic acids include, but are not limited to, methanesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid. Exemplary inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, and sulfuric acid. Exemplary organic carboxylic acids include, but are not limited to, acetic acid, formic acid, butyric acid, propionic acid, or benzoic acid. In a specific embodiment, the second acid is methanesulfonic acid or formic acid.

In some implementations, the first acid is acetic acid and the second acid is methanesulfonic acid.

In some embodiments, the first acid and the second acid are the same acid. In other embodiments, the first acid and the second acid are formic acid or acetic acid.

In some embodiments, N-1 is in solution when added to the reaction mixture.

In other embodiments, L is –CH ₂ -CH ₂ -, that is, N-1 is (1R,3S)-3-aminocyclopentan-1-ol: in some embodiments, N-1 is (3-aminocyclopentanol).

In a specific embodiment, N-1 is a salt or cocrystal. Suitable salts or cocrystals of N-1 include, but are not limited to, oxalic acid, hydrochloric acid, mandelic acid, R-mandelic acid, and S-mandelic acid. Suitable salts or cocrystals of N-1 include, but are not limited to, benzoic acid, naproxen, S-naproxen, and R-naproxen.

In a further implementation, N-1 is

In another implementation, N-1 is

In some embodiments, after the addition of acid, the reaction is maintained at approximately 20 to approximately 90°C, approximately 20 to approximately 80°C, approximately 20 to approximately 70°C, approximately 20 to approximately 60°C, approximately 20 to approximately 50°C, approximately 20 to approximately 40°C, approximately 20 to approximately 30°C, approximately 30 to approximately 100°C, approximately 30 to approximately 90°C, approximately 30 to approximately 80°C, approximately 30 to approximately 70°C, approximately 30 to approximately 60°C, approximately 30 to approximately 50°C, approximately 30 to approximately 40°C, approximately 40°C. The temperature ranges from approximately 100°C to approximately 90°C, from approximately 40°C to approximately 80°C, from approximately 40°C to approximately 70°C, from approximately 40°C to approximately 60°C, from approximately 40°C to approximately 50°C, from approximately 50°C to approximately 100°C, from approximately 50°C to approximately 90°C, from approximately 50°C to approximately 80°C, from approximately 50°C to approximately 70°C, from approximately 50°C to approximately 60°C, from approximately 60°C to approximately 100°C, from approximately 60°C to approximately 90°C, from approximately 60°C to approximately 80°C, from approximately 60°C to approximately 70°C, from approximately 70°C to approximately 80°C, or any subrange thereof. In another embodiment, after the addition of acid, the reaction is maintained at approximately 65°C to approximately 70°C, from approximately 70°C to approximately 75°C, from approximately 75°C to approximately 80°C, or any subrange thereof.

In a specific implementation, the solvent is acetonitrile, the first acid is an organic carboxylic acid, the second acid is an organic carboxylic acid, and after the acid is added, the reaction is maintained at about 70 to about 75°C.

In the specific implementation scheme, the solvent is acetonitrile, the primary acid is acetic acid, the secondary acid is methanesulfonic acid, and after adding the acids, the reaction is maintained at approximately 70 to approximately 75°C, and N-1 is...

G-1 is deprotected to form compound I:

Add about 1 equivalent of G-1 and a suitable solvent to the reaction vessel. Add about 2 to 3 equivalents of a metal salt, Lewis acid, or other reagent to the solution. Stir the resulting suspension at about 40 to about 100°C for about 10 minutes to about 3 hours. Quench the reaction by adding acid, and then extract and purify the compound of formula I by any suitable technique known in the art, such as, but not limited to, solvent extraction, preparative HPLC, and crystallization.

In one specific embodiment, the solvent is an aprotic polar organic solvent, such as, but not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidone, or mixtures thereof. In another embodiment, the solvent is acetonitrile.

In some embodiments, G-1 reacts with at least one reagent selected from metal salts, Lewis acids, sodium ethanethiol, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof.

In other embodiments, the metal salt is selected from magnesium bromide, lithium chloride, lithium bromide, and lithium iodide. In yet another embodiment, the metal salt is lithium chloride.

In specific embodiments, the Lewis acid is selected from boron trifluoride methyl ether, boron trifluoride diethyl ether, boron trifluoride dibutyl ether, aluminum chloride, aluminum bromide, boron trichloride, boron tribromide, trichloromethylsilane, triiodomethylsilane, palladium, and boron trifluoride diethyl ether. In some embodiments, the Lewis acid is selected from trichloromethylsilane, triiodomethylsilane, sodium ethanethiol, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl ether, and trifluoroacetic acid.

In specific implementation schemes, other suitable reagents for promoting conversion are sodium ethanethiol, sodium hexamethyldisiloxane, and trifluoroacetic acid.

In a specific embodiment, the deprotection of G-1 is carried out in the presence of about 2 to about 3 equivalents of a reagent selected from the following: magnesium bromide, lithium chloride, lithium bromide, lithium iodide, boron trifluoride methyl ether, boron trifluoride diethyl ether, boron trifluoride dibutyl ether, aluminum chloride, aluminum bromide, boron trichloride, boron tribromide, trimethylchlorosilane, trimethyliodosilane, palladium, boron trifluoride diethyl ether, trimethylchlorosilane, iodotrimethylsilane, sodium ethanethiol, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl ether, and trifluoroacetic acid.

In some embodiments, the reaction is carried out at about 40 to about 50°C, about 40 to about 60°C, about 40 to about 70°C, about 50 to about 60°C, about 50 to about 70°C, about 50 to about 80°C, about 60 to about 70°C, about 60 to about 80°C, or any subrange therebetween. In a particular embodiment, the reaction is carried out at about 50°C.

In the specific implementation plan, the solvent is acetonitrile, the metal salt is magnesium bromide, and the reaction is carried out at about 50°C.

The hydrolysis of F-1 forms compound II:

Approximately 1 equivalent of F-1, a preparative solution consisting of approximately 10 to 15 parts of a first organic solvent and approximately 3 to 8 parts of water, is added to the reaction vessel. Approximately 2 equivalents of base are added to the solution. The resulting suspension is stirred at approximately 0 to approximately 50°C for approximately 14 to approximately 17 hours. The conversion can be monitored by any suitable method known in the art, such as, but not limited to, HPLC.

Water and a second organic solvent are added to the suspension, and the pH is adjusted to approximately pH 3 by adding an appropriate acid dropwise. The product, i.e., the compound of formula II, can then be extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, silica gel chromatography, and crystallization.

In some embodiments, the first organic solvent is an alcohol solvent or a polar organic solvent. In some embodiments, the first organic solvent is an alcohol solvent. In some embodiments, the first organic solvent is a polar organic solvent. Exemplary alcohol solvents include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol, and tert-butanol. Exemplary polar organic solvents include, but are not limited to, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidone. In a specific embodiment, the first organic solvent is methanol.

In other embodiments, the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. In yet another embodiment, the base is lithium hydroxide monohydrate.

In some embodiments, the reaction is carried out at about 10 to about 50°C, about 10 to about 40°C, about 10 to about 30°C, about 10 to about 20°C, about 20 to about 50°C, about 20 to about 40°C, about 20 to about 30°C, about 30 to about 50°C, about 30 to about 40°C, about 40 to about 50°C, or any subrange thereof. In a specific embodiment, the reaction is carried out at room temperature. In other embodiments, the reaction is carried out at about 18 to about 23°C.

In a specific implementation scheme, the base is lithium hydroxide monohydrate, the reaction is carried out at about 10 to about 50°C, and the first organic solvent is methanol.

In a specific implementation, the base is lithium hydroxide monohydrate, the reaction is carried out at about 18 to about 23°C, and the first organic solvent is methanol.

BB-1 was prepared from B-1 and Q-1:

Approximately 1 equivalent of B-1 and 8 to 12 equivalents of Q-1 were added to a reaction vessel and dissolved in a suitable organic solvent. The solution was then heated to approximately 85 to approximately 115°C and allowed to proceed for approximately 2–6 hours, after which the reaction was cooled to room temperature. BB-1 was then purified using techniques known in the art, such as, but not limited to, silica gel chromatography.

In some embodiments, the solvent is a nonpolar aromatic solvent or a polar aprotic solvent. In some embodiments, the solvent is a nonpolar aromatic solvent. In some embodiments, the solvent is a polar aprotic solvent. Exemplary nonpolar aromatic compounds include, but are not limited to, toluene, xylene, chlorobenzene, and dichlorobenzene. Exemplary polar aprotic solvents include, but are not limited to, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methylpyrrolidone. In other embodiments, the reaction can be carried out without an additional solvent. In a specific embodiment, the solvent is toluene.

In some embodiments, the reaction is carried out at about 85 to about 105°C, about 85 to about 95°C, about 95 to about 105°C, about 95 to about 115°C, about 105 to about 115°C, about 100 to about 105°C, about 105 to about 110°C, about 110 to about 115°C, or any subrange thereof.

In a specific implementation, the reaction is carried out at approximately 95 to approximately 115°C, using toluene as the solvent.

In a specific implementation, the reaction is carried out at about 110 to about 115°C, and the solvent is toluene.

Preparation of C-1 from BB-1:

About 1 equivalent of BB-1 and about 1 to about 3 equivalents of J-1 are combined in a reaction vessel. The compound is dissolved in a polar aprotic solvent or an aromatic solvent. In some embodiments, the compound is dissolved in a polar aprotic solvent. In some embodiments, the compound is dissolved in an aromatic solvent. Exemplary polar aprotic solvents include, but are not limited to, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidone. Exemplary aromatic solvents include, but are not limited to, pyridine, toluene, xylene, benzene, and chlorobenzene. In another embodiment, the compound is dissolved in a solvent mixture comprising one or more polar aprotic solvents and/or one or more aromatic solvents. In some embodiments, the compound is dissolved in a solvent mixture comprising up to three or up to two polar aprotic solvents. In some embodiments, the compound is dissolved in a solvent mixture comprising up to three or up to two aromatic solvents. In some embodiments, the compound is dissolved in a solvent mixture comprising up to three or two solvents selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidone, pyridine, toluene, xylene, benzene, and chlorobenzene. In another embodiment, the compound is dissolved in toluene.

In specific implementations, each Hal is independently -F or -Cl. In certain implementations, Hal is -F. In some implementations, n = 1-3. In some implementations, n = 2. In some implementations, n = 3. In other implementations, J-1 is...

In another embodiment, J-1 is in the form of a salt or eutectic, such as, but not limited to, a salt or eutectic of hydrochloric acid or trifluoroacetic acid. In some embodiments, J-1 is a salt or eutectic of methanesulfonic acid.

In some embodiments, the reaction is carried out at about 65 to about 115°C, about 75 to about 115°C, about 85 to about 115°C, about 95 to about 115°C, about 105 to about 115°C, about 65 to about 70°C, about 70 to about 80°C, about 80 to about 90°C, about 90 to about 100°C, about 100 to about 110°C, about 110 to about 115°C, or any subrange thereof.

In some embodiments, the solvent is removed under reduced pressure. In a specific embodiment, C-1 is extracted from the crude residue by solvent extraction. The crude material is then purified using any suitable technique, such as silica gel chromatography or crystallization, to obtain C-1.

In a specific embodiment, the compound is dissolved in an aromatic solvent, J-1 being [missing information], and the reaction is carried out at approximately 65 to approximately 115°C.

In a specific embodiment, the compound is dissolved in toluene, J-1 is [missing information], and the reaction is carried out at about 100 to about 110°C.

C-1 prepared from B-1.J-1

B-1, J-1, solvent, and acid are combined in the reactor under conditions that effectively generate C-1.

In some embodiments, the acid is absent. In some embodiments, the acid is a protic acid or a Lewis acid. In some embodiments, the protic acid includes, but is not limited to, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, acetic acid, formic acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, and methanesulfonic acid. In some embodiments, the Lewis acid includes, but is not limited to, zinc chloride, magnesium bromide, magnesium trifluoromethanesulfonate, copper trifluoromethanesulfonate, and scandium trifluoromethanesulfonate. In a specific embodiment, the acid is trifluoroacetic acid.

In some embodiments, about 10 equivalents, about 5 equivalents, about 1 equivalent, or about 0.1 equivalents of acid are used in the reaction of B-1.J-1 forming C-1.

In some embodiments, the solvent is toluene, heptane, water, 2-methyltetrahydrofuran, isopropyl acetate, N,N-dimethylformamide, N-methyl-2-pyrrolidone, methyl tert-butyl ether, dimethyl sulfoxide, n-butanol, acetonitrile, acetone, or mixtures thereof. In one specific embodiment, the solvent is acetonitrile.

In some embodiments, the concentration of B-1.J-1 ranges from about 2 to 40 mL/g, about 2 to 20 mL/g, and about 5 to 15 mL/g. In one specific embodiment, the concentration of B-1.J-1 is about 10 mL/g.

In some embodiments, the reaction mixture is heated to about 20 to 110°C, about 30 to 90°C, about 40 to 80°C, about 50 to 70°C, about 55 to 65°C, or about 58 and 61°C. In one specific embodiment, the reaction mixture is heated to about 60°C.

In some embodiments, other additives are added to the reaction. In some embodiments, the additives include, but are not limited to, lithium chloride, sodium chloride, and potassium chloride.

In some embodiments, B-1.J-1 is added to the reactor all at once at about 20°C, followed by heating. In other embodiments, B-1.J-1 is added to the reactor in batches over one hour during heating.

In some embodiments, the reaction is heated for about 1 to 24 hours, about 2 to 12 hours, or about 3 to 6 hours. In one specific embodiment, the reaction is heated for about 2.5 hours.

In some embodiments, the formed product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some implementations, the reaction is cooled and the reactor contents are partially distilled.

In some embodiments, the organic phase is washed at least once with an aqueous solution. In some embodiments, the aqueous solution contains about 23% NaCl, about 1.5% _{H₂SO₄ ,} and about 76% water. In some embodiments, the aqueous solution contains about 20% NaCl.

In some embodiments, the solution of the product is inoculated with pre-separated C-1 seeds. In some embodiments, solid C-1 is separated by filtration.

In specific implementations, each Hal is independently -F or -Cl. In specific implementations, each Hal is -F. In some implementations, n = 1-3. In some implementations, n = 2. In some implementations, n = 3. In other implementations, J-1 is...

In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _{C1-C4)alkyl. In some embodiments, Ra is (C1 -} ^C4 _{) alkyl} . In some embodiments, ^Ra is methyl.

In a specific embodiment, Ra is ^a ( _C1 - _C4 ) alkyl group, the solvent is acetonitrile, the reaction mixture is heated to approximately 60°C, and J-1 is...

In a specific embodiment, ^Ra is methyl, the solvent is acetonitrile, the reaction mixture is heated to approximately 60°C, and J-1 is...

Enamines are formed from C-1 to provide D-1.

To a solution of C-1 and acid in a solvent, add about 0.5 to about 1.5 equivalents of alkylated formamide acetal under conditions that effectively generate D-1.

In a specific implementation, 1 equivalent of C-1 is combined with approximately 1.1 equivalents of alkylated formamide acetal.

In some embodiments, the alkylated formamide acetal is selected from N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylmethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal, and N,N-diisopropylformamide dimethyl acetal. In one specific embodiment, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal.

In some embodiments, the solvent is dichloromethane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, isopropyl acetate, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, or N-methyl-2-pyrrolidone. In one specific embodiment, the solvent is 2-methyltetrahydrofuran.

In some embodiments, the acid is an organic acid. In some embodiments, the organic acid includes, but is not limited to, trifluoroacetic acid, formic acid, acetic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, and perfluoropropionic acid. In some embodiments, the acid is a mixture containing up to three or up to two organic acids. In one specific embodiment, the acid is trifluoroacetic acid.

In some embodiments, the reaction mixture is heated to an internal temperature of approximately 40°C before the addition of the alkylated formamide acetal.

In some embodiments, the reaction is carried out at about 0 to 75°C, about 10 to 60°C, about 20 to 50°C, about 40 to 50°C, or about 30 to 40°C. In a specific embodiment, the reaction is carried out at room temperature. In other embodiments, the reaction is carried out at about 40°C.

In some embodiments, the reaction takes place for about 0.1 hours to about 12 hours, about 0.1 hours to about 6 hours, about 0.1 hours to about 3 hours, about 0.1 hours to about 1 hour, or about 0.2 hours to about 0.5 hours.

In some embodiments, D-1 is extracted and purified by any suitable method known in the art, including but not limited to solvent extraction, crystallization, and chromatography.

In some embodiments, seed crystals of D-1 are added and the mixture is stirred. In some embodiments, the mixture is stirred at about 40°C for at least 1 hour.

In some embodiments, about 0.2 to 0.6 equivalents of alkylformamide acetal are added, and the reaction mixture is stirred for at least about 25 minutes. The reaction mixture is then cooled to room temperature and stirred for about 12 hours.

In some embodiments, the contents of the reactor are filtered, and the filter cake is washed with a solvent and dried to obtain D-1. In some embodiments, the solvent is a combination of 2-methyltetrahydrofuran and heptane.

In some implementations, each Hal is independently -F or -Cl. In some implementations, each Hal is -F. In some implementations, n = 1-3. In some implementations, n = 2. In some implementations, n = 3.

In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Ra is ( _C1 - _C4 )alkyl. In some embodiments, ^Ra is methyl.

In some embodiments, each ^Rb is independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, each ^Rb is independently ( _C1 - _C4 )alkyl. In some embodiments, ^Rb is methyl.

In the specific implementation, ^Rb is ( _C1 - _C4 )alkyl, ^Ra is ( _C1 - _C4 )alkyl, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, the solvent is 2-methyltetrahydrofuran, the reaction is carried out at about 10 to about 60°C, the acid is trifluoroacetic acid, each Hal is –F, and n=3.

In the specific implementation scheme, ^Rb is methyl, ^Ra is methyl, the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal, the solvent is 2-methyltetrahydrofuran, the reaction is carried out at about 40°C, the acid is trifluoroacetic acid, Hal is –F, and n=3.

F-1 is formed from D-1 via E-1.

Approximately 1.1 equivalents of K-1 are added to a solution of D-1 in a solvent, under conditions that effectively generate E-1.

In some embodiments, the solvent is an alcohol solvent, such as, but not limited to, ethanol, n-propanol, 2-propanol, butanol, methanol, and tert-butanol, or an aprotic polar organic solvent, such as, but not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, and N-methyl-2-pyrrolidone. In a specific embodiment, the solvent is methanol.

In some embodiments, K-1 is an aminoacetaldehyde acetal, such as, but not limited to, aminoacetaldehyde diethyl acetal, aminoacetaldehyde dipropyl acetal, aminoacetaldehyde dimethyl acetal, and aminoacetaldehyde dibutyl acetal. In some embodiments, K-1 is aminoacetaldehyde dimethyl acetal.

In some embodiments, the reaction is carried out at a temperature of about 10 to 60°C, about 10 to 50°C, about 10 to 40°C, about 10 to 30°C, about 10 to 20°C, 20 to 60°C, about 20 to 50°C, about 20 to 40°C, about 20 to 30°C, about 30 to 60°C, about 30 to 40°C, about 40 to 60°C, about 40 to 50°C, about 50 to 60°C, or any subrange thereof. In a specific embodiment, the reaction is carried out at room temperature. In other embodiments, the reaction is carried out at a temperature of about 16°C to about 23°C.

In some embodiments, the reaction is stirred for about 0.1 to about 12 hours, about 0.5 to about 4 hours, or about 1 to about 2 hours.

Once the reaction has proceeded sufficiently to produce E-1, M-1 is added to the reaction mixture.

In some embodiments, about 1 to about 10 or about 1 to about 5 equivalents of M-1 are added. In one specific embodiment, about 5 equivalents of M-1 are added.

In some embodiments, M-1 is dimethyl oxalate, diethyl oxalate, dipropyl oxalate, or dibutyl oxalate. In one specific embodiment, M-1 is dimethyl oxalate.

The reaction mixture is stirred at a temperature sufficient to dissolve M-1. In some embodiments, the reaction mixture is stirred at about 20-80°C, about 20-70°C, about 20-60°C, about 30-60°C, about 40-50°C, or about 45°C.

In some embodiments, a base is added to the reaction mixture after M-1 is added.

In some embodiments, the base is a metal hydride, an alkoxide, an inorganic carbonate, or a bis(trialkylsilyl)amide. In some embodiments, the base is a metal hydride. In some embodiments, the base is an alkoxide. In some embodiments, the base is an inorganic carbonate. In some embodiments, the base is a bis(trialkylsilyl)amide. Exemplary metal hydrides include, but are not limited to, lithium hydride, sodium hydride, and potassium hydride. Exemplary alkoxides include, but are not limited to, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, and lithium tert-butoxide. Exemplary bis(trialkylsilyl)amine bases include, but are not limited to, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, and potassium bis(trimethylsilyl)amino. Exemplary carbonates include, but are not limited to, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.

In another embodiment, the base is a mixture of at least one of the aforementioned bases. In some embodiments, the base is a mixture of up to three or up to two metal hydrides. In some embodiments, the base is a mixture of up to three or up to two alkoxides. In some embodiments, the base is a mixture of up to three or up to two metal bis(trialkylsilyl)amides. In some embodiments, the base is a mixture of up to three or up to two of the following bases: lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, lithium tert-butoxide, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, and potassium bis(trimethylsilyl)amino.

In a specific implementation, the alkali is sodium methoxide. In a specific implementation, the alkali is a methanol solution of sodium methoxide.

In some embodiments, after the addition of the base, the reaction is heated to about 20 to 80°C, 20 to 70°C, about 20 to 60°C, about 20 to 50°C, about 20 to 40°C, about 20 to 30°C, about 30 to 80°C, about 30 to 70°C, about 30 to 60°C, about 30 to 50°C, about 30 to 40°C, about 40 to 80°C, about 40 to 70°C, about 40 to 60°C, about 40 to 50°C, about 50 to 80°C, about 50 to 70°C, about 50 to 60°C, about 60 to 80°C, about 60 to 70°C, about 70 to 80°C, or any subrange thereof. In one specific embodiment, the reaction is heated to about 42 to 48°C. In one specific embodiment, the reaction is heated to about 45°C.

In some embodiments, the reaction is stirred for about 1 to about 24 hours, about 6 to about 24 hours, about 12 to about 20 hours, or about 14 to about 18 hours.

In some embodiments, the reactants are diluted with an aqueous solution and F-1 is extracted and purified by any suitable method known in the art, including but not limited to solvent extraction, crystallization and silica gel chromatography.

In some embodiments, the temperature is lowered to about 34-37°C over about 1 hour, F-1 seed crystals are optionally added, and the mixture is aged for about 1-2 hours. At this point, water is added, and the temperature is lowered to about 18-22°C over 1 hour. The resulting slurry is then filtered.

In some embodiments, the liquid is recycled to displace the solids remaining in the reactor. The solids collected on the filter are then washed with a 1:1 mixture of water and methanol, followed by washing with water. The collected wet filter cake is dried in a vacuum oven at approximately 36-42°C for approximately 16 hours to obtain F-1.

In some embodiments, ^R1 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R1 is _C1 - _C4 alkyl. In other embodiments, ^R1 is _–CH3 , that is, K-1 is aminoacetaldehyde dimethyl acetal.

In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is _C1 - _C4 alkyl. In some embodiments, ^R2 is _–CH3 .

In specific implementations, each Hal is independently either –F or -Cl. In one specific implementation, Hal is -F. In some implementations, n = 1-3. In some implementations, n = 2. In some implementations, n = 3.

In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Ra is ( _C1 - _C4 )alkyl. In some embodiments, ^Ra is methyl.

In some embodiments, each ^Rb is independently ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, each ^Rb is independently ( _C1 - _C4 )alkyl. In some embodiments, ^Rb is methyl.

In the specific implementation scheme, ^Rb is methyl, ^Ra is ( _C1 - _C4 )alkyl, each Hal is –F, n=3, ^R2 is ( _C1 - _C4 )alkyl, ^R1 is ( _C1 - _C4 )alkyl, the solvent is an alcohol solvent, K-1 is aminoacetaldehyde dimethyl acetal, the first reaction is carried out at about 2 to about 40°C, the second reaction is heated to about 20 to about 80°C, the base is an alkoxide, and M-1 is dimethyl oxalate.

In the specific implementation scheme, ^Rb is methyl, ^Ra is methyl, Hal is –F, n=3, ^R2 is _–CH3 , ^R1 is _–CH3 , the solvent is methanol, K-1 is aminoacetaldehyde dimethyl acetal, the first reaction is carried out at about 16 to about 23°C, the second reaction is heated to about 45°C, the base is sodium methoxide, and M-1 is dimethyl oxalate.

F-1 undergoes acetal hydrolysis to form FF-1.

Under conditions that effectively generate FF-1, about 0.1 to 1 equivalent of a first acid and about 2 to 20 equivalents of a second acid are added to a solution of F-1 in a solvent.

In some embodiments, about 0.1 to 0.5 equivalents of the first acid are added. In a specific embodiment, about 0.1 equivalents of the first acid are added.

In some embodiments, the solvent is a polar organic solvent or a weak protic acid. In some embodiments, the polar organic solvent includes, but is not limited to, propionitrile, tetrahydrofuran, 1,4-dioxane, acetonitrile, and ethyl acetate. In some embodiments, the weak protic acid includes, but is not limited to, formic acid, propionic acid, and butyric acid. In one specific embodiment, the solvent is acetonitrile.

In some implementations, the first acid is a strong protic acid, including but not limited to methanesulfonic acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and camphorsulfonic acid.

In one specific implementation, the first acid is p-toluenesulfonic acid. In another specific implementation, the first acid is p-toluenesulfonic acid monohydrate.

In some embodiments, the second acid is a weak protic acid, including but not limited to acetic acid, formic acid, propionic acid, and butyric acid. In one specific embodiment, the second acid is acetic acid.

The reaction is then heated to approximately 20 to 120°C, approximately 40 to 100°C, approximately 60 to 80°C, or approximately 70 to 80°C. In one specific embodiment, the reaction is heated to approximately 75°C.

In some embodiments, the reaction is stirred for about 1 to about 24 hours, about 4 to about 14 hours, or about 8 to about 10 hours.

In some implementations, water is added to the reaction mixture.

In some embodiments, the product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some embodiments, the mixture is concentrated under reduced pressure to remove the solvent. The resulting slurry is then aged at room temperature for about 2 hours, filtered, and washed with water. The filter cake is dried in a vacuum oven at 50°C for at least 10 hours to obtain FF-1.

In some embodiments, ^R1 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R1 is _C1 - _C4 alkyl. In other embodiments, ^R1 is _–CH3 .

In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is _C1 - _C4 alkyl. In some embodiments, ^R2 is _–CH3 .

In specific implementations, each Hal is independently –F or -Cl. In specific implementations, Hal is -F. In some implementations, n = 1-3. In some implementations, n = 2. In some implementations, n = 3.

In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Ra is ( _C1 - _C4 )alkyl. In some embodiments, ^Ra is methyl.

In a specific embodiment, Ra is ^a ( _C1 - _C4 ) alkyl, each Hal is –F, n=3, ^R2 is a ( _C1 - _C4 ) alkyl, ^R1 is a ( _C1 - _C4 ) alkyl, the reaction is heated to about 20 to about 120°C, the first acid is p-toluenesulfonic acid, the second acid is acetic acid, and the solvent is acetonitrile.

In the specific implementation scheme, ^Ra is methyl, Hal is –F, n=3, ^R2 is _–CH3 , ^R1 is _–CH3 , the reaction is heated to about 75°C, the first acid is p-toluenesulfonic acid, the second acid is acetic acid, and the solvent is acetonitrile.

Cyclic formation of FF-1 and N-1 to form G-1

The starting materials FF-1, N-1 or their salts or eutectics and additives are mixed with a solvent under conditions that effectively generate G-1.

In some embodiments, the additive is a carboxylate, such as, but not limited to, sodium acetate, potassium acetate, lithium acetate, sodium propionate, and potassium propionate. In some embodiments, the additive is a carbonate, such as, but not limited to, sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate. In some embodiments, the additive is a water scavenger, such as, but not limited to, molecular sieves, trimethyl orthoacetate, and trimethyl orthoformate. In a specific embodiment, the additive is potassium acetate.

In some embodiments, about 1 to about 2 or about 1 to about 1.5 equivalents of N-1 or its salt or eutectic are used.

In some embodiments, about 1 to about 5 equivalents of additive are used. In a specific embodiment, about 2.5 equivalents of additive are added.

In some embodiments, the solvent is acetonitrile, ethyl acetate, toluene, 2-methyltetrahydrofuran, isopropyl acetate, dichloromethane, or a mixture thereof. In a specific embodiment, the solvent is dichloromethane.

In some embodiments, the reaction is stirred at about 0 to about 40°C, about 10 to about 30°C, about 15 to about 25°C, and about 20°C.

In some embodiments, G-1 is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In one embodiment, the reaction mixture is washed with an aqueous solution and evaporated to dryness. In another embodiment, the residue is dissolved in dimethylformamide, and the resulting solution is added to water over approximately 2 hours with stirring. The product slurry is aged at approximately 20°C for approximately 12 hours and filtered. The product filter cake is washed with water and dried to obtain G-1.

In some embodiments, N-1 is in solution when added to the reaction mixture.

In other implementations, L is _–CH2 - _CH2- .

In the specific implementation scheme, N-1 is (1R,3S)-3-aminocyclopentan-1-ol:

In the specific implementation plan, N-1 is a free base or a synthetic base, which is used directly without separation.

In a specific implementation, N-1 is a salt or cocrystal. Suitable salts or cocrystals of N-1 include, but are not limited to, benzoic acid, acetic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, hydrochloric acid, naproxen, S-naproxen, R-naproxen, mandelic acid, R-mandelic acid, and S-mandelic acid.

In a further implementation, N-1 is

In a specific implementation, N-1 is a salt or co-crystal of benzoic acid.

In the specific implementation plan, N-1 is...

In specific implementations, each Hal is independently –F or -Cl. In specific implementations, each Hal is -F. In some implementations, n = 1-3. In some implementations, n = 2. In some implementations, n = 3.

In some embodiments, ^R2 is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^R2 is _C1 - _C4 alkyl. In some embodiments, ^R2 is _–CH3 .

In some embodiments, ^Ra is ( _C1 - _C4 )alkyl, ( _C6 - _C10 )aryl, or ( _C6 - _C10 )aryl( _C1 - _C4 )alkyl. In some embodiments, ^Ra is ( _C1 - _C4 )alkyl. In some embodiments, ^Ra is methyl.

In the specific implementation scheme, Ra is ^a ( _C1 - _C4 ) alkyl group, each Hal is –F, n=3, ^R2 is _–CH3 , N-1 is dichloromethane as the solvent, the reaction is stirred at about 0 to about 40°C, and the additive is potassium acetate.

In the specific implementation scheme, ^Ra is methyl, Hal is –F, n=3, ^R2 is _–CH3 , N-1 is dichloromethane as the solvent, the reaction is stirred at about 20°C, and the additive is potassium acetate.

(-)-Vince lactam is converted to β-1 via α-1.

The catalyst, solvent, and (-)-Vince lactam are stirred in the reactor and purged with an inert gas. A hydrogen source is then added.

In some embodiments, the hydrogen source is formic acid, hydrazine, dihydronaphthalene, dihydroanthracene, hydrogen, or Hantzch ester and isopropanol. In a specific embodiment, the hydrogen source is hydrogen.

In some embodiments, the catalyst is a platinum catalyst such as _PtO₂ , a nickel catalyst such as Ramane nickel, a rhodium catalyst such as RhCl( _PPh₃ ) _₃ , a palladium catalyst, a ruthenium catalyst such as Nyori catalyst, or an iridium catalyst such as Crabtree catalyst. In some embodiments, the catalyst is selected from Pd/C, _PtO₂ , Ramane nickel, RhCl( _PPh₃ ) _₃ , Nyori catalyst, and Crabtree catalyst. In a specific embodiment, the catalyst is Pd/C.

In some embodiments, the solvent is a polar aprotic solvent such as THF, 2-MeTHF, dioxane, diethyl ether, diisopropyl ether, DME, MTBE, CPME, EtOAc, and DCM. In some embodiments, the solvent is a polar protic solvent, such as methanol, ethanol, n-butanol, and isopropanol. In a specific embodiment, the solvent is 2-methyltetrahydrofuran.

In some embodiments, the reaction is stirred at about 0 to 65°C, about 10 to 55°C, about 15 to 45°C, about 20 to 40°C, and about 25 to 35°C.

In some embodiments, the reactor is maintained at about 0.30 to about 0.35 MPa.

In some implementations, the reaction takes about 1 to about 24 hours, about 1 to about 12 hours, about 3 to about 9 hours, or about 6.5 hours.

In some embodiments, the product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some embodiments, the hydrogenated product is obtained by filtration of the reaction with diatomaceous earth and washing with 2-MeTHF.

In some embodiments, a second catalyst and an activation source for the protecting group are added to the solution of the hydrogenation product.

In some embodiments, the second catalyst is a compound containing a nucleophilic amine, such as imidazole, a derivative of 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, and pyridine, or a compound containing a nucleophilic phosphine, such as triphenylphosphine. In a specific embodiment, the second catalyst is 4-dimethylaminopyridine (DMAP).

In some embodiments, the activation source of the protecting group is _Boc₂O . In a specific embodiment, _Boc₂O is prepared in a solution of 2-MeTHF.

In some implementations, the protecting group is Boc.

In some embodiments, the reaction is carried out in a polar aprotic solvent such as THF, EtOAc, DCM, acetonitrile, or 2-MeTHF. In a specific embodiment, the reaction occurs in 2-MeTHF.

In some implementations, the reaction occurs in a temperature range of about 20 to about 80°C, about 25 to 70°C, about 35 to 60°C, and about 45 to 50°C.

In some implementations, the reaction takes about 0.5 to about 12 hours, about 1 to about 6 hours, about 1 to about 3 hours, or about 2 hours.

In some embodiments, the product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some implementations, the solution is concentrated and a second solvent is added.

In some embodiments, the second solvent is a polar aprotic solvent such as THF, dioxane, DME, diisopropyl ether, diethyl ether, MTBE, CPME, 2-MeTHF, and toluene. In a specific embodiment, the second solvent is 2-MeTHF.

In some implementations, the solution is maintained at approximately -50 to 30°C, approximately -50 to 30°C, approximately -30 to 20°C, approximately -20 to 10°C, or approximately -10 to 0°C.

After hydrogenation and the addition of the protecting group PG, the nucleophile ^R3M is added to the reaction mixture.

In some embodiments, the nucleophile ^R3M is a n-alkyl Grignard reagent such as ethyl magnesium halide, n-propyl magnesium halide, and n-butyl magnesium halide, or an organolithium reagent such as methyllithium, n-butyllithium, and n-hexyllithium. In a specific embodiment, the nucleophile is methyl magnesium bromide.

In some embodiments, the nucleophile ^R3M is added while the reaction is maintained within the desired temperature range for about 1 to about 12 hours, about 3 to about 9 hours, about 5 to about 7 hours, and about 6 hours. After the addition is complete, the mixture is stirred again for about 0.5 to about 12 hours, about 0.5 to about 6 hours, about 0.5 to about 4 hours, and about 1 to about 2 hours.

In some embodiments, the product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some embodiments, after adding the nucleophile ^R3M , a 15% aqueous solution of AcOH is added while maintaining the temperature at about 0 to 5°C to adjust the pH to about 7. The layers are separated, with the organic layer being rinsed twice with water. The organic layer is concentrated to 4 to 5 volumes under reduced pressure at about ≤45°C. This solution is azeotropically reacted with 2-MeTHF. The final solution is concentrated to about 2.5 to 3 volumes under reduced pressure, and n-heptane is slowly added while maintaining the temperature at 30 to 35°C. In some embodiments, b-1 seed crystals are added, and the mixture is stirred at about 30 to 35°C for about 5 to 10 hours.

In some embodiments, additional n-heptane is added while maintaining the temperature at 30 to 35°C for about 5 hours. The contents are cooled to -5 to 0°C and maintained for about 1 to 2 hours. The product is collected by filtration, washed with n-heptane at -5 to 0°C, and dried under reduced pressure at 40 to 45°C to give b-1.

In a specific implementation, the hydrogen source is hydrogen gas, the catalyst is a palladium catalyst, the solvent for the hydrogenation reaction is 2-methyltetrahydrofuran, the hydrogenation reaction is stirred at about 0 to about 65°C, the second catalyst is a nucleophilic amine compound, the activation source for the protecting group is _Boc₂O , the protecting reaction is carried out in 2-MeTHF at about 25 to 70°C, the second solvent is 2-MeTHF, and the nucleophile is methylmagnesium bromide.

In a specific implementation, the hydrogen source is hydrogen gas, the catalyst is Pd/C, the solvent for the hydrogenation reaction is 2-methyltetrahydrofuran, the hydrogenation reaction is stirred at about 25 to 35°C, the second catalyst is 4-dimethylaminopyridine, the activation source for the protecting group is _Boc₂O , the protecting reaction occurs in 2-MeTHF at about 45 to 50°C, the second solvent is 2-MeTHF, and the nucleophile is methylmagnesium bromide.

b-1 is converted into c-1

An oxidizing agent was added to a solution of b-1 in a solvent and the mixture was stirred to react.

In some embodiments, PG is a protecting group. In some embodiments, the protecting group PG is Boc.

In some embodiments, the solvent is a polar aprotic solvent such as DCM, 1,2-dichloroethane, toluene, chlorobenzene, dichlorobenzene, chloroform, carbon tetrachloride, and DMF, or a polar protic solvent such as water, acetic acid, methanol, and ethanol. In a specific embodiment, the solvent is toluene.

In some embodiments, the oxidant is hydrogen peroxide, potassium persulfate, tert-butyl hydroperoxide, trifluoroperacetic acid (TFPAA), nitroperbenzoic acid, monopermaleic acid (MPMA), monoperphthalic acid, magnesium monoperphthalate, persulfate, performic acid, peracetic acid, perbenzoic acid, silylated peracid, phenylperoxyselenic acid, sodium perborate, m-chloroperoxybenzoic acid, or resin-bonded peracid. In a specific embodiment, the oxidant is m-chloroperoxybenzoic acid (mCPBA).

In some implementations, mCPBA is added in several parts every 4 to 6 hours.

In some implementations, the reaction occurs in a temperature range of -10 to 50°C, 0 to 40°C, 10 to 45°C, 15 to 40°C, 20 to 35°C, and 25 to 30°C.

In some implementations, the reaction is stirred for 1-48 hours, 6-36 hours, or 10-20 hours.

In some embodiments, the product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In a specific implementation, 20% _NaHSO₃ is added, followed by 10% NaOH. The organic layer is washed with water and concentrated to obtain the oxidation product in solution.

Add water, solvent, and base or acid to the solution of the oxidation product.

In some embodiments, the solvent is a polar protic solvent such as methanol, ethanol, isopropanol, or water, or a combination of at least one polar protic solvent and a polar aprotic solvent such as THF, dioxane, DME, dipropyl ether, diethyl ether, MTBE, CPME, or toluene. In a specific embodiment, the solvent is a combination of toluene, methanol, and water.

In some embodiments, the base is a hydroxide base such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, or a silanol base such as sodium trimethylsilanol and potassium trimethylsilanol. In a specific embodiment, the base is lithium hydroxide.

In some implementations, the acid is a concentrated strong acid, such as sulfuric acid and hydrochloric acid.

In some embodiments, the reaction is stirred at about 0 to 80°C, about 5 to 70°C, about 10 to 60°C, about 15 to 50°C, about 20 to 40°C, and about 25 to 30°C.

In some embodiments, the product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In a specific embodiment, toluene and 25% NaCl are added, and the layers are separated. The organic layer is washed with a 20% NaCl solution—adjusted to approximately pH 7 to approximately pH 8 with 1N HCl. The organic layer is filtered and concentrated. Toluene is added and distillation continues. Toluene and activated carbon are added. The mixture is heated to approximately 30 to approximately 40°C and stirred for approximately 2 to 6 hours. The contents are cooled, filtered through diatomaceous earth, and washed with toluene. The filtrate is concentrated. n-Heptane is added over approximately 1 to 2 hours, and optionally, c-1 seed crystals are added to the mixture and stirred for approximately 2 to 3 hours. n-Heptane is added and the mixture is stirred for approximately 2 to 3 hours. The mixture is cooled to approximately 10 to 15°C and stirred for approximately 3 to 5 hours. The product is collected by filtration and washed with n-Heptane at approximately 10 to 15°C. The product is dried to give c-1.

In the specific implementation scheme, the protecting group PG is Boc, the solvent is a polar aprotic solvent, the oxidant is mCPBA, the reaction is stirred at 10 to 45°C, the hydrolysis is carried out in a combination of toluene, methanol and water at about 10 to 60°C, and the base is a hydroxide base.

In the specific implementation scheme, the protecting group PG is Boc, the solvent is toluene, the oxidant is mCPBA, the reaction is stirred at 25 to 30°C, the hydrolysis is carried out at about 25 to 30°C in a combination of toluene, methanol and water, and the base is lithium hydroxide.

C-1a Resolution – Selective Acylation

c-1a(+/-): a racemic mixture of cc-1b and cc-1a

In some implementations, enantiomer-enriched cc-1a is obtained by enzyme-catalyzed selective acylation.

In this method, the racemic raw material c-1a is a mixture of cc-1b and cc-1a (i.e., c-1a(+/-)) and is dissolved in a solvent.

In some embodiments, the solvent is a polar aprotic solvent, a nonpolar solvent, a polar protic solvent, a mixture of an organic solvent and an aqueous buffer, or a mixture thereof. Exemplary polar aprotic solvents include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane, and chloroform. Exemplary nonpolar solvents include, but are not limited to, toluene, hexane, and heptane. Exemplary polar protic solvents include, but are not limited to, tert-butanol. In a specific embodiment, the solvent used is toluene.

Once the racemic starting material c-1a is dissolved in the solvent, approximately one equivalent of an acyl donor is added. In some embodiments, the acyl donor is an acid anhydride or an ester. In some embodiments, the acid anhydride includes, but is not limited to, glutaric anhydride and acetic anhydride. In some embodiments, the ester includes, but is not limited to, vinyl acetate, isopropylene acetate, 4-chlorophenyl acetate, and ethyl methoxyacetate. In a specific embodiment, the acyl donor is glutaric anhydride.

In some embodiments, ^Rx is ( _C1 - _C6 )alkyl- ^Ry , and ^Ry is selected from H, CN, –NR ^z1 R ^z2 , C(O)R ^z1 , –C(O)OR ^z1 , –C(O)NR ^z1 R ^z2 , –OC(O)NR ^z1 R ^z2 , –NR ^z1 C(O)R ^z2 , –NR ^z1 C(O)NR ^z2 , –NR ^z1 C(O)OR ^z2 , –SR ^z1 , –S(O) _1-2 R ^z1 , –S(O) ₂ NR ^z1 R ^z2 , –NR ^z1 S(O) ₂ R ^z2 , NR ^z1 S(O) ₂ R ^z2 , and OR ^z1 .

In some embodiments, R ^z1 and R ^z2 are independently selected from H, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 heteroalkyl, _C3-10 cycloalkyl, 3-12 heterocyclic, _C6-10 aryl and 5 to 10 heteroaryl.

In some embodiments, ^Rx is ( _C1 - _C4 )alkyl- ^Ry , and ^Ry is selected from H and _CO2H .

In some embodiments, ^Rx is methyl or _{( CH2 ) 3} ^- _{CO2H .}

Approximately 15% by weight of an enzyme is added. In some embodiments, the enzyme is a lipase. In some embodiments, the lipase includes, but is not limited to, Novozyme 435, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL, and MML. In a specific embodiment, the enzyme used is Novozyme 435.

In some embodiments, the reactants are stirred for about 1 to 48 hours, about 6 to 48 hours, about 12 to 30 hours, about 20 to 26 hours, or about 23 hours.

In some embodiments, the reaction is stirred at about 0 to 60°C, about 5 to 30°C, or about 10 to 15°C.

In some embodiments, an additional enzyme is added and the reaction is carried out at about 0 to 60°C for about 1 to 48 hours. In some embodiments, about 5% by weight of an additional enzyme is added and the reaction is carried out at about 5 to 30°C for about 6 to 24 hours. In a specific embodiment, an additional enzyme is added and the reaction is carried out at about 10 to 15°C for about 12 hours.

In some embodiments, the formed ester e-1 is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some embodiments, the precipitated enzyme solid is removed by filtration and washed with a solvent. The desired e-1 is extracted into an alkaline aqueous layer, such as an aqueous solution _{of Na₂CO₃} . The aqueous solution is washed with an organic solvent (e.g., MTBE) to remove unwanted substances. A solvent (e.g., THF) is then added to the aqueous layer containing e-1, followed by the addition of a hydroxide.

In some embodiments, the solvent is a polar aprotic solvent. Exemplary polar aprotic solvents include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane, and chloroform. In a specific embodiment, the solvent is THF.

Exemplary hydroxide sources include, but are not limited to, sodium hydroxide, potassium hydroxide, and lithium hydroxide. In a specific embodiment, the hydroxide source is sodium hydroxide.

In some embodiments, the mixture is stirred at about 0 to 60°C for about 1 to 24 hours. In some embodiments, the mixture is stirred at about 5 to 30°C for about 1 to 12 hours. In a specific embodiment, the mixture is stirred at about 15 to 20°C for about 4 hours.

In some embodiments, the extractant cc-1a is optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In a specific implementation, the layers are separated, and the organic layer is concentrated.

In some embodiments, the organic phase is concentrated and cc-1a is recrystallized in a solvent containing cc-1a seed crystals. In some embodiments, the solvent is a mixture of THF, dichloromethane, and water, and recrystallization is carried out at about 40 to 50°C.

In some embodiments, the enantiomeric excess (%ee) of the product is about 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 to 99, about 99 to 100, about 99.5 to 100, or about 99.9 to 100.

In a specific implementation, c-1a is dissolved in a nonpolar solvent, the acyl donor is glutaric anhydride, ^Rx is ( _CH2 ) ₃ - _CO2H , the enzyme used is lipase, the reaction is stirred at about 10 to 15°C, cc-1b is removed by filtration, hydrolysis is carried out in THF at about 5 to 30°C, and the hydroxide source is sodium hydroxide.

In the specific implementation scheme, c-1a is dissolved in toluene, the acyl donor is glutaric anhydride, ^Rx is ( _CH2 ) ₃ - _CO2H , the enzyme used is Novozyme 435, the reaction is stirred at about 10 to 15°C, cc-1b is removed by filtration, hydrolysis is carried out in THF at about 15 to 20°C, and the hydroxide source is sodium hydroxide.

C-1a splitting – selective hydrolysis

In some implementations, enantiomer-enriched cc-1a is obtained via an enzyme-catalyzed selective hydrolysis reaction.

A mixture of raw material c-1a, acyl donor, base and catalyst in a solvent is stirred.

In some embodiments, the acyl donor includes, but is not limited to, acid anhydrides or acyl chlorides. In some embodiments, the acid anhydrides include, but are not limited to, succinic anhydride and acetic anhydride. In some embodiments, the acyl chlorides include, but are not limited to, acetyl chloride and benzoyl chloride. In a specific embodiment, the acyl donor is glutaric anhydride.

In some embodiments, ^Rx is ( _C1 - _C6 )alkyl- ^Ry , and ^Ry is selected from H, CN, –NR ^z1 R ^z2 , C(O)R ^z1 , –C(O)OR ^z1 , –C(O)NR ^z1 R ^z2 , –OC(O)NR ^z1 R ^z2 , –NR ^z1 C(O)R ^z2 , –NR ^z1 C(O)NR ^z2 , –NR ^z1 C(O)OR ^z2 , –SR ^z1 , –S(O) _1-2 R ^z1 , –S(O) ₂ NR ^z1 R ^z2 , –NR ^z1 S(O) ₂ R ^z2 , NR ^z1 S(O) ₂ R ^z2 , and OR ^z1 .

In some embodiments, R ^z1 and R ^z2 are independently selected from H, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 heteroalkyl, _C3-10 cycloalkyl, 3-12 heterocyclic, _C6-10 aryl and 5 to 10 heteroaryl.

In some embodiments, ^Rx is ( _C1 - _C4 )alkyl- ^Ry , and ^Ry is selected from H and _CO2H .

In some embodiments, ^Rx is methyl or _{( CH2 ) 3} ^- _{CO2H .}

In some embodiments, the catalyst includes, but is not limited to, nucleophilic amine compounds and nucleophilic phosphine compounds. In some embodiments, the nucleophilic amine compounds include, but are not limited to, imidazoles, derivatives of 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, and pyridine. In some embodiments, the nucleophilic phosphine compounds include, but are not limited to, triphenylphosphine. In a specific embodiment, the catalyst is 4-dimethylaminopyridine.

In some embodiments, the base includes, but is not limited to, amine bases, aromatic amine bases, inorganic carbonates, metal hydrides, and alkoxides. In some embodiments, the amine base includes, but is not limited to, N,N-diisopropylethylamine, quinine ring, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, tripropylamine, and tributylamine. In some embodiments, the aromatic amine base includes, but is not limited to, pyridine. In some embodiments, the inorganic carbonate base includes, but is not limited to, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. In some embodiments, the metal hydride base includes, but is not limited to, sodium hydride and potassium hydride. In some embodiments, the alkoxide base includes, but is not limited to, sodium methoxide, sodium tert-butoxide, and lithium tert-butoxide. In a specific embodiment, the base is pyridine.

In some embodiments, the solvent is an aromatic solvent or a polar aprotic solvent. In some embodiments, the aromatic solvent includes, but is not limited to, pyridine, toluene, xylene, benzene, and chlorobenzene. In some embodiments, the polar aprotic solvent includes, but is not limited to, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidone, and dichloromethane. In a specific embodiment, the solvent is pyridine.

In some embodiments, the reaction mixture is stirred for about 1 to 48 hours, about 6 to 24 hours, or about 12 hours.

In some embodiments, the reaction mixture is stirred at about 0°C to 120°C, about 20°C to 100°C, about 40°C to 80°C, or about 60°C.

In some embodiments, the product ee-1 is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In a specific embodiment, the reaction mixture was evaporated to dryness, dissolved in DCM, and washed with 0.2M HCl aqueous solution. The organic layer was evaporated to dryness. The residue was stirred with water, and the pH was adjusted to approximately 7.8 with 2M NaOH solution. The aqueous layer was washed with DCM. The aqueous layer was then acidified to pH 4 with 3N HCl aqueous solution and extracted with DCM. The combined organic layers were dried with _Na₂SO₄ , filtered, and evaporated. _The mixture was ground with pentane, filtered, and dried under vacuum to give ee-1.

ee-1 is suspended in a solvent, and then the enzyme is added.

In some embodiments, the solvent is a polar aprotic solvent, a nonpolar solvent, or a mixture of an organic solvent and an aqueous buffer. In some embodiments, the polar aprotic solvent includes, but is not limited to, diisopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane, and chloroform. In some embodiments, the nonpolar solvent includes, but is not limited to, hexane and heptane. In a specific embodiment, the solvent is a 1:2 diisopropyl ether:phosphate buffer.

In some embodiments, the enzyme is a lipase, such as, but not limited to, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL, and MML. In a specific embodiment, the enzyme is CAL-B.

In some implementations, the reaction is stirred at 0 to 60°C, 10 to 50°C, 20 to 40°C, and about 30°C.

In some embodiments, the reactants are stirred for 24–200 h, 50–150 h, or about 100 h.

In some embodiments, the product cc-1a is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some embodiments, e-2 is removed by extraction in an aqueous layer. In some embodiments, product e-2 is removed by extraction in an alkaline aqueous layer.

In a specific embodiment, the reaction mixture is filtered and the filtrate layer is separated. The solids are washed with DCM, and the filtrate is used to extract the aqueous layer. The combined organic layers are washed with 5% _Na₂CO₃ and _brine and dried. The mixture is filtered and the evaporation is evaporated under reduced pressure to give cc-1a.

In a specific embodiment, the acyl donor is an acid anhydride, ^Rx is ( _C1 - _C4 )alkyl- ^Ry , ^Ry is selected from H and _CO2H , the catalyst is 4-dimethylaminopyridine, the base in the first step is pyridine, the solvent in the first step is an aromatic solvent, the reaction mixture in the first step is stirred at about 0 to about 60°C, the solvent for hydrolysis is a 1:2 diisopropyl ether:phosphate buffer, the enzyme is CAL-B, and the hydrolysis reaction is stirred at about 0 to about 30°C.

In a specific implementation, the acyl donor is glutaric anhydride, ^Rx is ( _CH2 ) ₃ - _CO2H , the catalyst is 4-dimethylaminopyridine, the base in the first step is pyridine, the solvent in the first step is pyridine, the reaction mixture in the first step is stirred at about 60°C, the hydrolysis solvent is 1:2 diisopropyl ether: phosphate buffer, the enzyme is CAL-B, the hydrolysis reaction is stirred at about 30°C, and e-2 is removed by extraction in an alkaline aqueous layer.

In some embodiments, the enantiomeric excess (%ee) of the product is about 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 to 99, about 99 to 100, about 99.5 to 100, or about 99.9 to 100.

classic split of c-1a

In some implementations, c-1a is resolved using a classical resolution method. In this method, c-1a, the acid, and the solvent are combined.

In some embodiments, the acid is selected from:

Single enantiomers of α-carboxylic acids, including but not limited to: naproxen, phenylsuccinic acid, malic acid, 2-phenylpropionic acid, α-methoxy-phenylacetic acid, aniline tartranilic acid, 3-phenyllactic acid, α-hydroxyisovaleric acid, 2'-methoxy-aniline tartranilic acid, (α-methylbenzyl)-o-carbamoylbenzoic acid, 2'-chloro-aniline tartranilic acid, and pyroglutamic acid;

- Single enantiomers of mandelic acid derivatives, including but not limited to: mandelic acid, 2-chloromandelic acid, 4-bromomandelic acid, O-acetylmandelic acid, and 4-methylmandelic acid;

-Single enantiomers of sulfonic acids, including but not limited to: camphor sulfonic acid;

- Single enantiomers of tartaric acid derivatives, including but not limited to: tartaric acid, dibenzoyl tartaric acid hydrate, di-p-methoxybenzoyl tartaric acid, dibenzoyl tartaric acid, and dibenzoyl tartaric acid hydrate.

-Single enantiomers of phosphoric acid derivatives, including but not limited to: 4-phenyl-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxophosphacyclohexane hydrate, 4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxophosphacyclohexane, 4-(2-methoxyphenyl)-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxophosphacyclohexane, and BINAP phosphate; and

- Single enantiomers of amino acids, including but not limited to: N-acetyl-phenylalanine, N-acetyl-leucine, N-acetyl-proline, boc-phenylalanine, and boc-homophenylalanine.

In some embodiments, the acid is (S)-naproxen or S-(+)-mandelic acid. In a specific embodiment, the acid is (S)-naproxen. In a specific embodiment, the acid is S-(+)-mandelic acid.

In some embodiments, the solvent is water, acetonitrile, ethanol, isopropanol, methyl ethyl ketone, isopropyl acetate, dioxane, water, and mixtures of water-miscible organic solvents such as ethanol and isopropanol, or halogenated solvents such as dichloromethane and chloroform. In specific embodiments, the solvent is water or isopropanol or a mixture thereof. In specific embodiments, the solvent is water. In specific embodiments, the solvent is isopropanol.

In some embodiments, the reaction is stirred at 0 to 120°C, 2 to 120°C, 50 to 120°C, 80 to 120°C, and about 100°C. In some embodiments, the reaction is stirred at about 20°C.

In some embodiments, the product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some implementations, dd-1 is precipitated from the solution and filtered. The solid can then be further recrystallized in a solvent such as isopropanol.

In a specific implementation, the solvent is removed by evaporation to obtain a mixture of dd-1 and dd-2. The mixture is then suspended in a solvent.

In some implementations, dd-1 is selectively recrystallized.

In some embodiments, the solvent is water, acetonitrile, ethanol, isopropanol, methyl ethyl ketone, isopropyl acetate, dioxane; water and a mixture of water-miscible organic solvents such as ethanol and isopropanol; or a halogenated solvent such as dichloromethane or chloroform. In a specific embodiment, the solvent is a mixture of methyl ethyl ketone and water.

In some embodiments, the mixture is stirred at about 0 to 100°C, about 20 to 80°C, or about 40 to 60°C.

In some embodiments, the mixture is cooled to room temperature, and the solid is separated by filtration, dried, and recrystallized with 10% water in methyl ethyl ketone to obtain enantiomer-enriched dd-1. In specific embodiments, the acid is S-(+)-mandelic acid or (S)-naproxen, the solvent is water or isopropanol, the reaction is stirred at about 0 to about 20°C, and the product dd-1 is separated by solvent extraction, chromatography, crystallization, or a combination thereof.

In the specific implementation scheme, the acid is S-(+)-mandelic acid, the solvent is isopropanol, the reaction is stirred at about 20°C, and dd-1 precipitates out of the solution.

In a specific implementation, the acid is (S)-naproxen, the solvent is water, the reaction is stirred at about 20°C, and dd-1 is selectively recrystallized in a mixture of methyl ethyl ketone and water.

In some embodiments, the enantiomeric excess (%ee) of the product is about 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 to 99, about 99 to 100, about 99.5 to 100, or about 99.9 to 100.

Allyl amination

In some embodiments, an allyl amination method for obtaining g-1x is provided. In this method, a ligand and a catalyst are mixed in a degassed solvent, followed by the addition of f-1x, a base, and a nucleophile.

In some embodiments, the ligand is absent, or is tricyclohexylphosphine, 1,3-bis(diphenylphosphine)propane; 1,2-bis(diphenylphosphine)ethane, triphenylphosphine, or 1,1'-bis(diphenylphosphine)ferrocene. In a specific embodiment, the ligand is triphenylphosphine.

In some embodiments, the catalyst is a palladium catalyst such as Pd(OAc) _₂ , _PdCl₂ ( _PPh₃ ), _Pd ( _tBu₂Ph ) _₂Cl₂ , tris(dibenzylacetone)dipalladium( _O ), and Pd(amphos) _₂Cl₂ . In a specific embodiment, the catalyst is tris(dibenzylacetone)dipalladium(O).

In some embodiments, the solvent is an ether such as dimethoxyethane, THF or MeTHF, or an aromatic solvent such as toluene and benzene. In a specific embodiment, the solvent is THF.

In some embodiments, the base is potassium isopropoxide, cesium hydroxide, Hunig base, or a carbonate base, such as cesium carbonate, potassium carbonate, and sodium carbonate. In a specific embodiment, the base is cesium carbonate.

In some embodiments, the nucleophile is a phthalamide such as potassium phthalimide, an azide such as sodium azide or TMS-azide, an amine such as benzylamine or dibenzylamine, or a carboxylic acid ester such as di-tert-butyl imine dicarboxylate. In a specific embodiment, the nucleophile is di-tert-butyl imine dicarboxylate.

In some implementations, approximately 1 equivalent of a nucleophile is added.

In some implementations, the reaction is stirred at about 20 to 80°C, about 30 to 70°C, about 40 to 60°C, or about 50°C.

In some embodiments, the mixture is heated to about 50°C for about 18 hours.

In some embodiments, the formed product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some embodiments, the mixture is cooled, and water and ethyl acetate are added. The layers are separated, and the organic phase is washed with ethyl acetate. The combined organic matter is concentrated to dryness. The residue is purified by silica gel column chromatography (0 to 40% ethyl acetate in hexane). The separated substance is dissolved in MeTHF, washed with 5% KOH aqueous solution, concentrated, and purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give g-1x.

In the specific implementation scheme, the ligand is triphenylphosphine, the catalyst is a palladium catalyst, the solvent is an ether, the base is a carbonate base, the nucleophile is di-tert-butyl imine dicarboxylate, and the reaction is carried out at approximately 20°C to approximately 80°C.

In the specific implementation scheme, the ligand is triphenylphosphine, the catalyst is tris(dibenzylacetone)dipalladium(0), the solvent is THF, the base is cesium carbonate, the nucleophile is di-tert-butyl imine dicarboxylate, and the reaction mixture is stirred at about 50°C.

hydrogenation

In some embodiments, a hydrogenation method for obtaining h-1x is provided. In this method, g-1x and a catalyst are mixed in a solvent, and then a hydrogen source is added.

In some embodiments, the catalyst is a platinum catalyst such as _PtO₂ , a palladium catalyst, a nickel catalyst such as Ramane nickel, a rhodium catalyst such as RhCl( _PPh₃ ) _₃ , a ruthenium catalyst such as Nyori catalyst, or an iridium catalyst such as Crabtree catalyst. In some embodiments, the catalyst is selected from Pd/C, _PtO₂ , Ramane nickel, RhCl( _PPh₃ ) _₃ , Nyori catalyst, and Crabtree catalyst. In a specific embodiment, the catalyst is _PtO₂ .

In some embodiments, the solvent is a polar aprotic solvent such as THF, 2-MeTHF, dioxane, diethyl ether, diisopropyl ether, DME, MTBE, CPME, EtOAc, and DCM, or a polar protic solvent such as methanol, isopropanol, ethanol, and n-butanol. In a specific embodiment, the solvent is isopropanol.

In some embodiments, the reaction is carried out at about 0 to 65°C, about 5 to 55°C, about 10 to 45°C, about 10 to 35°C, or about 15 to 25°C.

In some embodiments, the hydrogen source is formic acid, hydrazine, dihydronaphthalene, dihydroanthracene, _H₂ gas, or Hantzch ester and isopropanol. In a specific embodiment, the hydrogen source is _H₂ gas. In a specific embodiment, the hydrogen source is a hydrogen atmosphere.

In some implementations, the reaction is stirred for 1 to 48 hours, 6 to 24 hours, 10 to 20 hours, 16 to 20 hours, or about 18 hours.

In some embodiments, h-1x is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In some implementations, the mixture is filtered through diatomaceous earth and used without further purification in the subsequent deprotection process.

In the specific implementation plan, the catalyst is a platinum catalyst, the solvent is a polar protic solvent, the reaction is stirred at about 5 to 55°C, and the hydrogen source is _H2 gas.

In the specific implementation scheme, the catalyst is _PtO2 , the solvent is isopropanol, the reaction is stirred at about 15 to 25°C, and the hydrogen source is _H2 gas.

Deprotection

In some embodiments, a method for deprotecting N-1x is provided. In this method, h-1x is added to an acid in a solvent.

In some embodiments, the acid is a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid; an inorganic acid such as phosphoric acid, hydrochloric acid, and sulfuric acid; or a carboxylic acid such as trifluoroacetic acid, oxalic acid, and benzoic acid. In a specific embodiment, the acid is anhydrous hydrochloric acid.

In some embodiments, the solvent is an alcohol solvent such as methanol, isopropanol, and ethanol, or a polar aprotic solvent such as dioxane, acetonitrile, and dichloromethane, or water. In some embodiments, the solvent is an alcohol solvent. In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is water. In some embodiments, the solvent is methanol, isopropanol, ethanol, dioxane, acetonitrile, dichloromethane, or water. In a specific embodiment, the solvent is isopropanol.

In some embodiments, the reaction is stirred at about 0 to 80°C, about 0 to 60°C, about 5 to 45°C, about 10 to 35°C, or about 15 to 25°C.

In some implementations, about 1 to 10 equivalents, about 5 to 10 equivalents, or about 7 equivalents of acid are used.

In some implementations, the reaction is stirred for about 1 to 48 hours, about 6 to 24 hours, about 12 to 24 hours, or about 18 hours.

In some embodiments, the formed product N-1x is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization, or a combination thereof.

In a specific implementation, the reaction is cooled to approximately 0°C, and the product N-1x is collected by filtration.

In the specific implementation plan, the acid is an inorganic acid, the solvent is an alcohol solvent, and the reaction is stirred at 5 to 45°C.

In the specific implementation plan, the acid is anhydrous hydrochloric acid, the solvent is isopropanol, and the reaction is stirred at 15–25°C.

Example

To provide a more complete understanding of the invention, the following embodiments are presented. These embodiments are for illustrative purposes and should not be construed as limiting the scope of this disclosure in any way. The reactants used in the following embodiments may be obtained as described herein, or, if not described herein, may be commercially available or prepared from commercially available materials by methods known in the art.

In one embodiment, a multi-step synthetic method for preparing compound I is provided, as described below. In some embodiments, the individual steps of the route set forth below are provided. Examples and any combination of consecutive steps from two or more of the examples described below are provided.

A. Acylation and amidation of Meldrum's acid to provide C-1a:

In a reaction vessel, meldram acid (101 g, 1.0 equivalent) and 4-dimethylaminopyridine (1.8 g, 0.2 equivalent) were combined with acetonitrile (300 mL). The resulting solution was treated with methoxyacetic acid (6.2 mL, 1.2 equivalent). Triethylamine (19.4 mL, 2.0 equivalent) was slowly added to the resulting solution, followed by neopentanoyl chloride (9.4 mL, 1.1 equivalent). The reaction was then heated to approximately 45 to approximately 50 °C and aged until the consumption of meldram acid was considered complete.

Acetonitrile (50 mL) and J-1a (13.4 g, 1.2 equivalents) were added to a separate reaction vessel. The resulting solution was treated with trifluoroacetic acid (8.0 mL, 1.5 equivalents), and then the acidic solution was added to the ongoing acylation reaction at about 45°C to about 50°C.

The reaction mixture was aged at approximately 45 to approximately 50 °C for at least 18 hours, after which the solvent was removed under reduced pressure. The crude residue was dissolved in ethyl acetate (150 mL), and the organic layer was washed with water. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate solution, and the combined bicarbonate wash was back-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude substance was purified twice by silica gel chromatography to give C-1a.

¹ H NMR (400MHz, CDCl ₃ ): δ7.12 (br, 1H), 6.66 (app t, J = 8.1Hz, 2H), 4.50 (app d, J = 5.7Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ):δ203.96,164.90,162.37(ddd,J＝250.0,15.7,15.7Hz),161.71(ddd,J＝250.3,14.9,10.9Hz),110.05(ddd,J＝19.7,19.7,4.7Hz),100.42(m),77.58,59.41,45.71,31.17(t,J＝3.5Hz).LCMS,Calculated value: 275.23,Measured value: 275.97(M).

Alkylation of C-1a to form E-1a:

A solution of C-1a (248 mg, 1.0 equivalent) and 2-methyltetrahydrofuran (1.3 mL) was treated with N,N-dimethylformamide dimethyl acetal (0.1 mL, 1.1 equivalent) and stirred overnight (~14 h) at room temperature. The reactants were treated with aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalent) and aged for about 2 h, then quenched by adding 2N HCl (1.5 mL).

The phases were separated by diluting the reaction with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give E-1a.

¹ H NMR (400MHz, CDCl ₃ ): δ10.85(s,1H),9.86(s,1H),8.02(d,J＝13.1Hz,1H),6.65(dd,J＝8.7,7.7Hz,2H),4.53(d ,J＝3.9Hz,2H),4.40(t,J＝5.1Hz,1H),4.18(s,2H),3.42(s,6H),3.39(m,2H),3.37(s,3H). ¹³ C NMR (100MHz, CDCl ₃ ):δ193.30,169.15,162.10(ddd,J＝248.9,15.5,15.5Hz),161.7(ddd,J＝250.0,14.9,11.1Hz),161.66,111.08(ddd,J＝19.9,19.9,4.7Hz)103.12,100.29(ddd,J＝28.1,17.7,2.3Hz),76.30,58.83,54.98,53.53,51.57,29.89(t,J＝3.3Hz).LCMS,Calculated value: 390.36, Measured value: 390.92 (M).

The cyclization of E-1a forms F-1a:

E-1a (0.2 g, 1.0 equivalent), dimethyl oxalate (0.1 g, 2.5 equivalent), and methanol (1.5 mL) were combined and cooled to approximately 0 to approximately 5 °C. Sodium methoxide (0.2 mL, 30% methanol solution, 1.75 equivalent) was slowly introduced into the reaction while maintaining the internal temperature of the reaction below approximately 10 °C throughout the addition. After the addition was complete, the reaction was heated to approximately 40 to approximately 50 °C for at least 18 hours.

After this time had elapsed, the reaction mixture was diluted with 1.5 mL of 2N HCl and 2 mL of ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting crude oil was purified by silica gel chromatography to give F-1a.

¹ H NMR (400MHz, CDCl ₃ ): δ10.28(t,J＝5.5Hz,1H),8.38(s,1H),6.66–6.53(m,2H),4.58(d,J＝5.6Hz,2H),4 .43(t,J＝4.7Hz,1H),4.00(d,J＝4.7Hz,2H),3.92(s,3H),3.88(s,3H),3.32(s,6H). ¹³ C NMR (100MHz, CDCl ₃ ):δ173.08,163.81,162.17,162.14(ddd,J＝249.2,15.6,15.6Hz),161.72(ddd,J＝250.5,15.0,10.9Hz),149.37,144.64,134.98,119.21,110.53(ddd,J＝19.8,4.7,4.7Hz),102.70,100.22(m),60.68,56.75,55.61,53.35,30.64.LCMS,Calculated value: 458.39,Measured value: 459.15(M+H).

Alkylation and cyclization of C-1a to form F-1a:

C-1a (245 mg, 1.0 equivalent) and N,N-dimethylformamide dimethyl acetal (0.5 mL, 4.3 equivalent) were added to the reaction vessel. The reaction mixture was stirred for about 30 minutes. The reaction was then treated with 2-methyltetrahydrofuran (2.0 mL) and aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalent). The reaction mixture was aged for several hours, and then the solvent was removed under reduced pressure.

The resulting substance was dissolved in methanol, and dimethyl oxalate (0.3 g, 2.5 equivalents) was added. The reaction mixture was cooled to approximately 0 to approximately 5 °C, and then sodium methoxide (0.4 mL, 30% solution in methanol, 1.75 equivalents) was slowly introduced into the reaction. After the addition was complete, the reaction was heated to approximately 40 to approximately 50 °C.

After this time had elapsed, the reaction was cooled to room temperature and quenched by adding 1.5 mL of 2N HCl. The reaction was then diluted with ethyl acetate, and the resulting phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give F-1a.

¹ H NMR (400MHz, CDCl ₃ ): δ10.28(t,J＝5.5Hz,1H),8.38(s,1H),6.66–6.53(m,2H),4.58(d,J＝5.6Hz,2H),4 .43(t,J＝4.7Hz,1H),4.00(d,J＝4.7Hz,2H),3.92(s,3H),3.88(s,3H),3.32(s,6H). ¹³ C NMR (100MHz, CDCl ₃ ):δ173.08,163.81,162.17,162.14(ddd,J＝249.2,15.6,15.6Hz),161.72(ddd,J＝250.5,15.0,10.9Hz),149.37,144.64,134.98,119.21,110.53(ddd,J＝19.8,4.7,4.7Hz),102.70,100.22(m),60.68,56.75,55.61,53.35,30.64.LCMS,Calculated value: 458.39,Measured value: 459.15(M+H).

G-1a is formed by the condensation of F-1a and N-1a:

Add F-1a (202 mg, 1.0 equivalent) and acetonitrile (1.4 mL) to the reaction vessel. Treat the resulting solution with glacial acetic acid (0.2 mL, 6.0 equivalent) and methanesulfonic acid (0.01 mL, 0.3 equivalent). Then heat the reaction to approximately 70 to approximately 75 °C.

Three hours later, a solid mixture of N-1a (0.128 g, 1.5 equivalents) and potassium carbonate (0.2 g, 2.7 equivalents) was introduced into the reaction at approximately 70 to approximately 75°C. After the addition was complete, the reaction was allowed to proceed for at least approximately 1 hour.

After this time had elapsed, water (1.4 mL) and dichloromethane (1.4 mL) were introduced into the reaction. The phases were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, then filtered and concentrated under reduced pressure. The resulting crude substance was purified by silica gel chromatography to give G-1a.

¹ H NMR (400MHz, CDCl ₃ ): δ10.23(t,J＝5.5Hz,1H),8.39(s,1H),6.60(t,J＝8.1Hz,2H),5.29(dd,J＝9.5,3.7Hz,2H),4.57(d,J＝5.4Hz,3H),4.33(d d,J＝12.8,3.8Hz,1H),4.02–3.87(m,1H),3.94(s,3H),2.06–1.88(m,4H),1.78(dd,J＝17.2,7.5Hz,1H),1.55–1.46(m,1H). ¹³ C NMR (100MHz, CDCl ₃ ):δ174.53,163.75,162.33(dd,J＝249.4,15.7,15.7Hz),161.86(ddd,J＝250.4,14.9,10.9Hz),154.18,154.15,142.44,129.75,118.88,110.58(ddd,J＝19.8,4.7,4.7Hz),100.42(m),77.64,74.40,61.23,54.79,51.13,38.31,30.73,29.55,28.04.LCMS,Calculated value: 463.14,Measured value: 464.15(M+H).

G-1a is deprotected to form a compound of formula Ia:

G-1a (14 g) was suspended in acetonitrile (150 mL) and dichloromethane (150 mL). _MgBr₂ (12 g) was added. The reaction was heated to 40-50 °C for about 10 minutes, then cooled to room temperature. The reaction mixture was poured into 0.5 M HCl (140 mL), and the layers were separated. The organic layer was washed with water (70 mL) and then concentrated. The crude product was purified by silica gel chromatography (100% dichloromethane up to 6% ethanol/dichloromethane) to give Ia.

F-1a hydrolyzes to form II-a:

Add F-1a (480 mg, 1.0 equivalent), methanol (5.8 mL), and water (2.4 mL) to the reaction vessel. Add lithium hydroxide monohydrate (88 mg, 2.0 equivalent) to the resulting homogeneous solution. Stir the resulting suspension at room temperature for approximately 17 hours.

Add water (15 mL) and ethyl acetate, then add 1 N HCl dropwise until the pH is approximately 3. Mix and separate the layers; extract the aqueous layer with ethyl acetate (15 mL) and dry _the combined organic layer with _Na₂SO₄ . Remove the organic layer by evaporation. Adjust the pH of the aqueous layer to <2 and extract twice with ethyl acetate (2 × 15 mL). Dry the combined organic layer with _Na₂SO₄ and mix with the residue from the previous extraction; remove the solvent by evaporation. Dissolve the residue in MTBE (2.4 mL) to form a slurry, filter it _, and wash with MTBE to give 1002.

¹ H NMR (400MHz, CDCl ₃ ): δ10.43(t,J＝5.2Hz,1H),9.65(bs,1H),8.52(s,1H),6.67(t,J＝8.0Hz,2H),4.67(d, J＝6.0Hz,2H),4.58(t,J＝4.8Hz,1H),4.16(d,J＝4.8Hz,1H),3.91(s,3H),3.37(s,6H). ¹³ C NMR (100MHz, CDCl ₃ ): δ173.04,164.15,162.10,148.63,145.28,137.25,118.66,102.46,100.35(t,J＝30.7Hz),87.42,61.30,57.09,55.55,30.94.

Preparation of BB-1a from B-1a:

0.2 g (1.0 equivalent) of BB-1a and 1.0 mL (10.0 equivalent) of 3-pentanone were added to a reaction vessel. These compounds were then dissolved in toluene (1.0 mL) and heated to approximately 110-115 °C. The reaction was maintained at this temperature for approximately 4 hours, after which the reaction was cooled to room temperature and the solvent was removed. The resulting crude product was purified on silica gel to give BB-1a.

^¹H NMR (400MHz, _CDCl₃ ): 5.46 (t, J = 1.1Hz, 1H), 3.97 (d, J = 1.0Hz, 2H), 3.42 (s, 3H), 1.99 (m, 4H), 0.98 (t, J = 7.5Hz, 6H). ^¹³C NMR (100MHz, _CDCl₃ ): 167.63, 160.94, 111.05, 93.04, 70.07, 59.27, 28.08, 7.40. LCMS, calculated value: 200.10, measured value: 200.79 ( ^M⁺ ).

Preparation of C-1a from BB-1a:

BB-1a (0.08 g, 1.0 equivalent) and N-1a (0.08 g, 1.1 equivalent) were added to the reaction vessel. These compounds were then dissolved in toluene (1.5 mL) and heated to approximately 115 °C. After about 1 hour, the reaction was cooled and the solvent was removed. The resulting crude substance was purified by silica gel chromatography to give C-1a.

All spectral data collected for C-1a are matched with those provided above.

Formation of B-1a·J-1a salts:

The free acid of B-1a (4.4 g) was dissolved in 50 mL of acetonitrile, and J-1a (3.3 g, 1.0 equivalent) was added to 30 mL of acetonitrile. The desired salt was obtained and aged at room temperature for about 1 hour. The solid was filtered, and the filter cake was washed with 2 × 10 mL of acetonitrile to obtain the product.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ7.40 (bs, 3H), 6.11 (t, J = 7.7Hz, 2H), 3.12 (s, 2H), 2.92 (s, 2H), 2.08 (s, 3H), 0.35 (s, 6H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ191.98,164.66,163.06(dt,J＝248.6,16.2Hz),161.82(ddd,J＝250.4,15.8,10.4Hz ),107.39(td,J＝20.0,4.7Hz),101.16(m),100.01,87.01,77.71,58.39,30.45,26.37.

Formation of B-1a·J-1a salts:

Meldram acid (10.1 g, 1.1 equivalents) and DMAP (0.6 g, 0.08 equivalents) were dissolved in 300 mL of acetonitrile. Methoxyacetic acid (5.8 g, 1 equivalent) and 17.6 g (2.1 equivalents) of Hunig base were added. The solution was warmed to approximately 45°C, and over approximately 1 hour, 8.4 g (1.1 equivalents) of neopentanoyl chloride was added to 30 mL of acetonitrile.

After approximately 2.5 hours at about 45°C, the solution was cooled to room temperature and concentrated under vacuum. The resulting oil was dissolved in 110 mL of dichloromethane, cooled on an ice bath, and extracted with 50 mL of 1N HCl. The layers were separated, and the aqueous layer was extracted with 40 mL of dichloromethane. The combined organic layers were concentrated and diluted in acetonitrile, then evaporated again. The substance was dissolved in 220 mL of acetonitrile.

After cooling in an ice bath, the mixture of trifluorobenzylamine (11.4 g, 1.1 equivalents) and approximately 9°C was heated to room temperature and stirred as the slurry thickened. After approximately 2 hours, 220 mL of MTBE was slowly added, and the slurry was aged overnight. The slurry was cooled in an ice bath for approximately 3 hours, filtered, washed with 50 mL of cold 1:1 acetonitrile/MTBE, and dried overnight in a vacuum oven to obtain the product.

Using B-1a·J-1a hydromidation to form C-1a

Salt B-1a·J-1a (3.7 g, 1.0 equivalent) was suspended in 50 mL of acetonitrile and then treated with trifluoroacetic acid (0.1 mL, 0.1 equivalent). The reaction mixture was heated to approximately 40 to approximately 50 °C for approximately 18 hours, and then cooled to room temperature. The solvent was removed under reduced pressure, and the resulting residue was suspended in 5 volumes of 2-methyltetrahydrofuran, with 5 volumes of hexane added dropwise over 1 hour. The resulting mixture was stirred for at least 24 hours, and then the resulting slurry was filtered to give the product.

Amide formation of C-1a from B-1a and J-1a:

In a reactor, B-1a.J-1a (75.077 g, 198.97 mmol, 1.0 equivalent), acetonitrile (750 mL), and trifluoroacetic acid (1.5 mL, 20 mmol, 0.1 equivalent) were combined. The reactor was heated to an internal temperature of approximately 58 °C, and the reactor contents were aged at approximately 58–61 °C for approximately 3.5 hours. The jacket temperature was then adjusted to approximately 45 °C and a vacuum was applied. The reactor contents were distilled until approximately 150 mL remained. Isopropyl acetate (300 mL) was then added to the reactor, and distillation continued until the volume reached approximately 150 mL. Isopropyl acetate (150 mL) was then added to the reactor, the jacket temperature was adjusted to approximately 20 °C, and the internal temperature of the contents was brought to <25 °C. A washing solution (22.8% NaCl, 1.5% _H₂SO₄ , 75.7% water, 300 _mL ) was added to the reactor, and the contents were stirred for approximately 30 minutes. Separate the bottom phase and add a second washing solution (22.8% NaCl, 1.5% _H₂SO₄ , 75.7% water, 300 _mL ) to the reactor. After stirring for about 15 minutes, separate the bottom phase and add a 20% NaCl aqueous solution (300 mL) to the reactor and stir for about 15 minutes. Separate the bottom phase again. Add heptane (150 mL) to the reactor, followed by seed crystals (51 mg, 0.1% by weight). Age the mixture for about 30 minutes, during which time a slurry is formed. Then add another 450 mL of heptane over a period of not less than 30 minutes. Then adjust the jacket temperature to about 29°C and distill the solvent under vacuum until the reactor contents reach a volume of about 450 mL. Then cool the slurry to an internal temperature of about 5°C over a period of not less than 1 hour. Drain the reactor contents and collect the solids by filtration. Recirculate the mother liquor twice to displace the solids from the reactor, each time allowing the internal temperature to reach about <6°C before discharge. A solution of heptane/isopropyl acetate (75% v/v, 225 mL) was then added to the reactor, and the slurry was flushed forward through the filter cake when the internal temperature reached <6 °C. The wet filter cake was then vacuum dried at approximately 40 °C for about 18 hours to obtain C-1a.

¹ H NMR (400MHz, CDCl ₃ ): δ7.12 (br, 1H), 6.66 (app t, J = 8.1Hz, 2H), 4.50 (app d, J = 5.7Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ):δ203.96,164.90,162.37(ddd,J＝250.0,15.7,15.7Hz),161.71(ddd,J＝250.3,14.9,10.9Hz),110.05(ddd,J＝19.7,19.7,4.7Hz),100.42(m),77.58,59.41,45.71,31.17(t,J＝3.5Hz).LCMS,Calculated value: 275.23,Measured value: 275.97(M).

The formation of enamine D-1a from C-1a

C-1a (8.4 g, 1.0 equivalent) was loaded into the reactor, followed by the addition of 2-methyltetrahydrofuran (166.7 mL, 20 volumes, 0.18 M) and trifluoroacetic acid (231.9 μL, 0.1 equivalent). The reaction mixture was heated to an internal temperature of approximately 40 °C, and DMF-DMA (3.0 mL, 0.75 equivalent) was rapidly added. The reaction mixture was stirred for a few minutes, and then D-1a seed crystals (20 mg, 0.002 equivalent) were added at approximately 40 °C. The heterogeneous mixture was aged at 40 °C for approximately 1 hour. A further portion of DMF-DMA (1.5 mL, 0.37 equivalent) was added, and the reaction mixture was stirred for approximately 25 minutes. The final portion of DMF-DMA (1.5 mL, 0.37 equivalent) was added, and the reaction mixture was cooled from approximately 40 °C to room temperature and stirred overnight.

The contents of the reactor were filtered and the filter cake was washed with a solvent mixture of 2-methyltetrahydrofuran and heptane (67.1 mL, 8 volumes) to obtain D-1a.

^¹H NMR (400MHz, _CDCl₃ ): δ 8.34 (br, ¹H), 7.83 (s, ¹H), 6.63 (m, 2H), 4.53 (s, 2H), 4.12 (s, 2H), 3.34 (s, 3H), 3.10 (s, 6H). ^¹³C NMR (100MHz, _CDCl₃ ): δ 192.33, 165.85, 163.03, 160.54, 158.00, 110.89, 103.50, 100.05, 76.11, 58.77, 44.74, 30.61. LCMS, calculated value: 330.12, measured value: 330.91 (M).

F-1a is formed from D-1a via E-1a through condensation and cyclization.

D-1a (70.0 g, 212 mmol, 1.0 equivalent) was charged into an inert 1 L reactor. Then, methanol (420 mL, 6 volumes) and aminoacetaldehyde dimethyl acetal (1, 28.8 mL, 233 mmol, 1.1 equivalent) were added to the reactor. The reactor jacket temperature was maintained between approximately 16 and 23 °C.

After aging the reaction for approximately 1-2 hours, dimethyl oxalate (2,125 g, 1.06 mol, 5.0 equivalents) is added to the reactor, and the reactor jacket temperature is raised to approximately 42-48°C. When the dimethyl oxalate is completely dissolved, a methanol solution of sodium methoxide (84.7 g, 25 wt%, 197 mmol, 1.85 equivalents) is added to the reactor. The reactor jacket temperature is maintained at approximately 42-48°C for approximately 14-18 hours.

During approximately 1 hour, the reactor jacket temperature is lowered to approximately 34-37°C. Once a stable temperature within this range is reached, F-1a seed crystals (0.350 g, approximately 0.5% by weight) are added to the reactor and allowed to age for approximately 1-2 hours. At this point, water (420 mL, 6 volumes) is added to the reactor over approximately 2-3 hours. The reactor jacket temperature is then lowered to approximately 18-22°C over approximately 1 hour.

The resulting slurry was discharged from the reactor, and the solids were collected by filtration. The liquid was circulated to displace the remaining solids in the reactor. The solids collected on the filter were then washed with a 1:1 mixture of water and methanol (420 mL, 6 V), followed by washing with water (420 mL, 6 V). The collected wet filter cake was dried in a vacuum oven at approximately 36–42 °C for approximately 16 hours to obtain F-1a.

¹ H NMR (400MHz, CDCl ₃ ): δ10.28(t,J＝5.5Hz,1H),8.38(s,1H),6.66–6.53(m,2H),4.58(d,J＝5.6Hz,2H),4 .43(t,J＝4.7Hz,1H),4.00(d,J＝4.7Hz,2H),3.92(s,3H),3.88(s,3H),3.32(s,6H). ¹³ C NMR (100MHz, CDCl ₃ ):δ173.08,163.81,162.17,162.14(ddd,J＝249.2,15.6,15.6Hz),161.72(ddd,J＝250.5,15.0,10.9Hz),149.37,144.64,134.98,119.21,110.53(ddd,J＝19.8,4.7,4.7Hz),102.70,100.22(m),60.68,56.75,55.61,53.35,30.64.LCMS,Calculated value: 458.39,Measured value: 459.15(M+H).

F-1a acetal hydrolyzes to form FF-1a:

To a solution of F-1a (10.0 g, 1.0 equivalent) and acetonitrile (50 mL), p-toluenesulfonic acid monohydrate (0.414 g, 0.10 equivalent) and acetic acid (16.3 mL, 12 equivalent) were added. The reaction was then heated to approximately 75 °C and aged for approximately 8–10 hours. Once the reaction was confirmed to be complete by HPLC, it was cooled to room temperature, and water (60 mL) was added. The mixture was then concentrated under reduced pressure to remove acetonitrile. The resulting slurry was then aged at room temperature for approximately 2 hours, filtered, and washed with water (2 × 30 mL). The filter cake was dried in a vacuum oven at approximately 50 °C for approximately 10 hours to obtain FF-1a.

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.34(t,J＝8.0Hz,1H),8.45(s,1H),7.19(m,2H),6.37(m,2H),4.96(m,1H),4.55(d,J＝4.0Hz,2H),3.95(m,2H),3.93(s,3H).3.79(s,3H). ¹³ CNMR(100MHz,DMSO-d ₆ ):δ172.32,163.47,162.10,161.93(dt,J＝246,15.0Hz),161.41(ddd,J＝247,15.0,11.0Hz),148.01,145.57,135.84,118.32,111.48(td,J＝20.0,5.0Hz),101.17(m),87.99,60.55,60.50,53.98,30.37.LCMS,Calculated value: 431.1061,Measured value: 431.1062(M+H).

Cyclicating FF-1a and N-1a.BzOH to form G-1a

FF-1a (90.0 g, 1.0 equivalent), N-1a.BzOH (60.7 g, 1.3 equivalent), and potassium acetate (51.3 g, 2.5 equivalent) were added to the reactor. Dichloromethane (DCM, 1.1 L) was added, and the mixture was stirred at approximately 20 °C until the reaction was complete. A 5% _NaHCO3 aqueous solution (540 mL) was added to the reactor, and the mixture was stirred until the solids were completely dissolved. The phases were separated, and the bottom organic phase was backfilled into the reactor. Water (450 mL) was added to the reactor, and the mixture was stirred for approximately 15 minutes. The phases were separated, and the organic phase was distilled to dryness.

Crude G-1a was dissolved in dimethylformamide (DMF, 180 mL), and the resulting solution was added to a reactor containing water (1.1 L) over approximately 2 hours while the water was stirred. The product slurry was aged at approximately 20°C for approximately 12 hours, and then filtered. The filter cake was washed with water (360 mL) and dried to obtain G-1a.

¹ H NMR (400MHz, CDCl ₃ ): δ10.23(t,J＝5.5Hz,1H),8.39(s,1H),6.60(t,J＝8.1Hz,2H),5.29(dd,J＝9.5,3.7Hz,2H),4.57(d,J＝5.4Hz,3H),4.33(d d,J＝12.8,3.8Hz,1H),4.02–3.87(m,1H),3.94(s,3H),2.06–1.88(m,4H),1.78(dd,J＝17.2,7.5Hz,1H),1.55–1.46(m,1H). ¹³ C NMR (100MHz, CDCl ₃ ):δ174.53,163.75,162.33(dd,J＝249.4,15.7,15.7Hz),161.86(ddd,J＝250.4,14.9,10.9Hz),154.18,154.15,142.44,129.75,118.88,110.58(ddd,J＝19.8,4.7,4.7Hz),100.42(m),77.64,74.40,61.23,54.79,51.13,38.31,30.73,29.55,28.04.LCMS,Calculated value: 463.14,Measured value: 464.15(M+H).

Convert (-)-Vince lactam to β-1a

Wet Pd/C (0.138 kg) was loaded into the reactor, followed by the addition of 2-MeTHF (421 kg) and (-)-Vince lactam (55 kg). The container was purged with nitrogen, then with hydrogen. The contents were adjusted to approximately 25 to 35 °C, and the hydrogen pressure was maintained at approximately 0.30 to 0.35 MPa. After approximately 6.5 hours, the reaction was confirmed to be complete by HPLC. The contents were filtered through diatomaceous earth (11 kg) and washed with 2-MeTHF (102 kg). The product was obtained in solution.

A solution of _Boc₂O in 2-MeTHF was prepared as follows: 123 kg of _Boc₂O was added to a reactor, followed by 60 kg of 2-MeTHF. After obtaining the solution, it was drained into a container and flushed forward with 44.6 kg of 2-MeTHF and held until further use.

The solution of the hydrogenation product was loaded into a reactor and concentrated under reduced pressure at ≤45°C to approximately 5 to 6 V. DMAP (0.34 kg) was added, and the mixture was heated to approximately 45 to 50°C. A solution of _Boc₂O was added over approximately 2 hours, and the mixture was stirred at the target temperature for another 2 hours. The reaction was then confirmed to be complete by HPLC. 2-MeTHF (480 kg) was added, and the solution was concentrated under reduced pressure at approximately ≤45°C to approximately 4 to 5 V. This process was repeated twice to remove t-BuOH. 2-MeTHF (278.8 kg) was added to obtain α-1a in the solution.

The solution of a-1a was diluted with 405.8 kg of 2-MeTHF and cooled to -10 to 0 °C. MeMgBr (35%, in 2-MeTHF, 201.3 kg) was added over approximately 6 hours while maintaining the temperature at approximately -10 to 0 °C. After the addition was complete, the mixture was stirred for approximately 1 to 2 hours, at which point the reaction was confirmed to be complete by HPLC. Maintaining the temperature at approximately 0 to 5 °C, 350 kg of 15% AcOH aqueous solution was added to adjust the pH to approximately 7. The layers were separated, and the organic layer was washed twice with water (726 kg of water used in total). The organic layer was concentrated under reduced pressure at approximately ≤45 °C to approximately 4 to 5 °C. The solution was azeotropically treated three times with 2-MeTHF, each time at approximately 4 to 5 °C (using 2810 kg of 2-MeTHF). The final solution was concentrated under reduced pressure to approximately 2.5 to 3 °C. 126 kg of n-heptane was slowly added while maintaining the temperature at 30 to 35 °C. Add seed b-1a (0.7 kg) and stir the mixture at about 30 to 35°C for 5 to 10 hours. Maintaining the temperature at about 30 to 35°C, add the remaining n-heptane (200.4 kg) over about 5 hours. Distill the contents under reduced pressure at about ≤45°C to about 6 to 7V. Maintaining the temperature at about 30 to 35°C, add the remaining n-heptane (243.2 kg) over about 1 to 2 hours. Distill the contents under reduced pressure at about ≤45°C to about 6 to 7V. Maintaining the temperature at about 30 to 35°C, add the remaining n-heptane (241.4 kg) over about 1 to 2 hours. Distill the contents under reduced pressure at about ≤45°C to about 6 to 7V. Maintaining the temperature at about 30 to 35°C, add the remaining n-heptane (253.6 kg) over about 1 to 2 hours. Cool the contents to about -5 to 0°C and maintain this temperature for about 1 to 2 hours. The product was collected by filtration, washed with n-heptane (187 kg) at about -5 to 0 °C, and dried under reduced pressure at about 40 to 45 °C to obtain a single enantiomer b-1a.

b-1a is converted into cc-1a

90.9 kg of b-1a and 822 kg of toluene were charged into a reactor and stirred at 25–30 °C to obtain a solution. 174 kg of m-CPBA was added to the reactor in five portions (4–6 hours between additions). The reaction was stirred at approximately 25–30 °C until completion was confirmed by HPLC (approximately 10–20 hours). 428 kg of 20% _NaHSO₃ was added, and the temperature was maintained at approximately below 30 °C. The mixture was stirred until negative using starch-potassium iodide paper. 698 kg of 10% NaOH was added, and the temperature was maintained at approximately below 30 °C. The mixture was stirred for approximately 30–60 minutes. The organic layer was washed with water (500 kg) and concentrated under reduced pressure to 5–6 V at approximately ≤45 °C. The temperature was adjusted to 15–25 °C to obtain the oxidation product in solution.

Water (90 kg), methanol (70 kg), and LiOH· _H₂O (29.5 kg) were added to the solution of the oxidation product. The mixture was stirred at 25–30 °C for 3–6 hours, at which point the reaction was confirmed to be complete by HPLC. Toluene (390 kg) and 25% NaCl (278 kg) were added to the mixture and stirred for approximately 30–60 minutes. The layers were separated, and 20% NaCl (259 kg) was added to the organic layer. The pH of the solution was adjusted to approximately 7–8 with 1N HCl (7.6 kg), and the layers were separated. The organic layer was washed with 20% NaCl (259.4 kg). The organic layer was filtered and concentrated under reduced pressure at approximately ≤45 °C to approximately 4.5–5.5 V. Toluene (385.6 kg) was added, and the distillation/toluene addition was repeated until KF ≤0.05%. Toluene (385.3 kg) was added, followed by activated carbon (6.5 kg). The mixture was heated to approximately 30 to 40 °C and stirred for approximately 2 to 6 hours. The contents were cooled, filtered through diatomaceous earth (6.3 kg), and washed with toluene (146 kg). The filtrate was concentrated under reduced pressure at approximately ≤45 °C to approximately 1.5 to 1.6 V. The mixture was stirred at approximately 30 to 35 °C for approximately 30 to 60 minutes. Over approximately 1 to 2 hours, n-heptane (87 kg) was added, and the mixture was inoculated with cc-1a (0.516 kg), and stirred for an additional 2 to 3 hours. N-heptane (286.4 kg) was slowly added and stirred for approximately 2 to 3 hours. The mixture was cooled to approximately 10 to 15 °C and stirred for approximately 3 to 5 hours. The product was collected by filtration and washed with n-heptane (40 kg) at approximately 10 to 15 °C. The product was dried under reduced pressure at approximately 35 to 45 °C to give the single enantiomer cc-1a.

Classic Analysis of c-1a

c-1a(+/-): a racemic mixture of cc-1b and cc-1a

Add c-1a (10.0 g, 1 equivalent), (S)-Nepsen (11.5 g, 1.03 mmol), and water (200 mL) to a container. Reflux the mixture overnight, after which the mixture darkens in color. Remove the solvent by rotary evaporation to obtain the desired salt as a brown solid. Suspend a mixture of dd-2a and dd-1a (3.0 g) in MEK (50 mL) and heat the mixture to reflux. Add water (4 mL). Cool the mixture to room temperature. Separate the solid by filtration, dry, and recrystallize from 10% water in MEK (30 mL) to obtain dd-1a with an optical purity >90% ee.

Classic Analysis of c-1a

c-1a(+/-): a racemic mixture of cc-1b and cc-1a

A solution of S-(+)-mandelic acid (134.9 mg, 1.0 equivalent) in IPA (0.9 mL) was rapidly added to a solution of c-1a (89.7 mg, 1.0 equivalent) in IPA (0.9 mL). The mixture was stirred at approximately room temperature, and a solid precipitate was observed after approximately 20 minutes. The slurry was stirred for another 15 minutes, filtered, and the solid was collected. The solid obtained from the initial salt formation was recrystallized in IPA and slowly cooled from approximately 80 °C to approximately 0 °C to provide the enantiomer-enriched product dd-1b.

Enzymatic resolution of c-1a – selective acylation

Toluene (500 mL) was added to the reaction vessel, followed by c-1a (50 g, 1 equivalent). Glutaric anhydride (28.4 g, 1 equivalent) was added, followed by Novozyme 435 (7.5 g, 15 wt%). The reaction mixture was stirred at about 10 to 15 °C for about 23 hours. Additional Novozyme (2.5 g, 5 wt%) was added, and the reaction was allowed to proceed at about 10 to 15 °C for about 12 hours. The solids were removed by filtration and washed with _toluene (100 mL). The organic phase was washed with 10% _Na₂CO₃ (250 mL), followed by 5% _Na₂CO₃ (250 _mL ). The combined aqueous phases were washed with MTBE (2 × 500 mL). THF (150 mL) was added to the resulting aqueous phase, followed by sodium hydroxide (14.9 g, 3 equivalents). The mixture was stirred at about 15 to 20 °C for about 4 hours. Separate the layers and concentrate the THF layer. Extract the aqueous layer with dichloromethane (2 × 250 mL). Dissolve the residue from the THF layer in the combined dichloromethane and wash the mixture with water (250 mL). Concentrate the organic phase to about 100 mL and add water (300 mL). Further concentrate the mixture to about 250 mL at about 55 to 60 °C. Cool the mixture to about 47 °C over about 1 hour, add seed crystals of the product (200 mg), and age the mixture at about 45 to 47 °C for about 1 hour. Cool the mixture to about 25 °C over about 2 hours and age for about 0.5 hours. Collect the solid by filtration and wash with water (50 mL). Dry the product under vacuum at about 35 to 40 °C to give the desired product cc-1a (>95% ee).

Enzymatic resolution of c-1a – selective hydrolysis

A mixture of compound c-1a (50 g, 1 equivalent), glutaric anhydride (42.5 g, 1.5 equivalent), and DMAP (50 mg, 0.001 equivalent) in 300 mL of pyridine was stirred overnight at approximately 60 °C. The reaction mixture was evaporated to dryness. The residue was then dissolved in DCM (250 mL) and washed with 3 × 250 mL of 0.2 M HCl (aqueous solution). The organic layer was evaporated to dryness. The residue was stirred with 300 mL of water and the pH was adjusted to 7.8 with approximately 300 mL of 2 M NaOH solution. The aqueous layer was washed with DCM (3 × 70 mL). The aqueous layer was then acidified to pH 4 with 3 N HCl (aqueous solution) and extracted with DCM (4 × 150 mL and 2 × 100 mL). The combined organic layers were dried _{over Na₂SO₄} , filtered, and evaporated to give a colorless oil that crystallized upon standing. The mixture was ground with pentane (~100 mL), then filtered and dried under vacuum to obtain racemic ee-1a.

Racemic ee-1a (1.008 g) was suspended in diisopropyl ether (10 mL). 200 mM sodium phosphate buffer (pH 7) (20 mL) and Cal-B (0.2 g) were added to the suspension. The reaction mixture was shaken at 250 rpm and 30 °C for approximately 100 h (>80% ee was observed after 91.5 h). The reaction mixture was filtered, and the filtrate layer was separated. The solid was washed with DCM (2 × 10 mL). The aqueous layer was extracted with the filtrate. The aqueous layer was extracted a second time with DCM (10 mL). The combined _organic layers were washed with 5% _Na₂CO₃ (2 × 20 mL) and brine (10 _mL ), and dried over _Na₂SO₄ . The mixture was filtered, and the evaporation was evaporated under reduced pressure to give the desired product cc-1a.

Allyl amination of f-1a to form g-1a

Triphenylphosphine (0.37 g, 0.02 equivalents) and _Pd₂ (dba) _₃ (0.32 g, 0.005 equivalents) were mixed in degassed THF (200 mL) for about 20 minutes at approximately room temperature. f-1a (10 g, 1 equivalent, monoenantiomer), _Cs₂CO₃ (46 g, 2 equivalents) _, and di-tert-butyl iminodiacarboxylate (16.05 g, 1.05 equivalents) were added, and the mixture was heated to 50 °C for about 18 hours. The mixture was cooled, and water (100 mL) and ethyl acetate (50 mL) were added. The layers were separated, and the organic phase was washed with 2× ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography (0 to 40% ethyl acetate in hexane). The separated substance was dissolved in MeTHF, washed with 5% KOH aqueous solution, concentrated, and purified by silica gel column chromatography (0 to 10% methanol in dichloromethane solution) to obtain the desired product g-1a.

Hydrogenation of g-1a to form h-1a

1.0 g of g-1a and 0.008 _g of PtO2 were combined in 10 mL of isopropanol. The container was rinsed with _H2 gas and stirred at approximately room temperature for about 18 hours under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth and used for subsequent deprotection without further purification.

h-1a deprotection to form N-1a

Acetyl chloride (1.7 mL, 7 eq) was combined with isopropanol (5 mL) and stirred at approximately room temperature for about 15 minutes to generate HCl in the isopropanol. Crude feedstock h-1a was added to isopropanol (2.5 mL) and the mixture was forward washed with isopropanol (2.5 mL). After approximately 18 hours, the slurry was cooled to approximately 0 °C, and N-1a was collected by filtration. ¹H NMR ( _CD₃OD ) confirmed the separation of the desired product.

Every reference cited in this application, including all patents, patent applications, and publications, is incorporated herein by reference in its entirety as if each of them were individually incorporated. Furthermore, it should be understood that, given the foregoing teachings of this invention, those skilled in the art may make changes or modifications to the invention, and such equivalents remain within the scope of this disclosure as defined by the appended claims.

Claims (242)

1. A method for preparing compound of formula I: This method is based on the following general route I: The method includes the following steps: C-1 is reacted with alkylated formamide acetal to generate D-1; D-1 reacts with K-1 to produce E-1; E-1 and M-1 react in the presence of a base to produce F-1; F-1 is reacted with at least one acid and N-1 or its salt or eutectic in the presence of a base to produce G-1; G-1 is reacted under conditions suitable for the synthesis of compound I; in Hal is a halogen. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Each Rc is independently hydrogen, halogen, hydroxyl, or C1 - C4 alkyl. Each Ra , R1 and R2 is independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl or ( C6 - C10 )aryl( C1 - C4 )alkyl. 2. The method according to claim 1, wherein the alkylated formamide acetal is selected from N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal and N,N-diisopropylformamide dimethyl acetal. 3. The method of claim 1, wherein the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal. 4. The method according to any one of claims 1 to 3, wherein Ra , R1 and R2 are each independently C1 - C4 alkyl. 5. The method according to any one of claims 1 to 4, wherein R1 is -CH3 . 6. The method according to any one of claims 1 to 5, wherein E-1 and M-1 react in the presence of a base selected from metal hydrides, alkoxides, bis(trialkylsilyl)amine bases and mixtures thereof. 7. The method according to claim 6, wherein the base is selected from sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, lithium tert-butoxide, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and mixtures thereof. 8. The method according to claim 7, wherein the base is sodium methoxide. 9. The method according to any one of claims 1-8, wherein R2 is -CH3 . 10. The method according to any one of claims 1-9, wherein F-1 reacts with at least one acid selected from organic acids, inorganic acids, organic carboxylic acids and mixtures thereof. 11. The method of claim 10, wherein at least one acid is selected from methanesulfonic acid, acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, butyric acid, propionic acid, benzoic acid, and mixtures thereof. 12. The method of claim 11, wherein the at least one acid is methanesulfonic acid or acetic acid. 13. The method according to any one of claims 1-12, wherein G-1 reacts with at least one reagent selected from metal salts, Lewis acids, sodium ethanethiol, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof. 14. The method according to claim 13, wherein the at least one reagent is selected from magnesium bromide, lithium chloride, lithium bromide, lithium iodide, aluminum trichloride, aluminum tribromide, trimethylchlorosilane, trimethyliodosilane, boron trichloride, boron tribromide, sodium ethanethiol, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl ether, and trifluoroacetic acid. 15. The method according to any one of claims 1-14, wherein L is –CH2 - CH2- . 16. The method according to any one of claims 1-15, wherein N-1 is 17. The method according to any one of claims 1-15, wherein N-1 is in the form of a salt or a eutectic. 18. The method of claim 17, wherein N-1 is 19. The method of claim 17, wherein N-1 is 20. The method according to any one of claims 1-19, wherein N-1 is in solution. 21. The method according to any one of claims 1-20, wherein the reaction of F-1 and N-1 occurs in the presence of a base selected from inorganic carbonates, metal hydrides, alkoxides, and mixtures thereof. 22. The method according to claim 21, wherein the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, and lithium tert-butoxide. 23. The method of claim 22, wherein the base is potassium carbonate. 24. The method according to any one of claims 1-23, wherein each Hal is independently -F or -Cl. 25. The method according to any one of claims 1-24, wherein n is 3. 26. A method for preparing compound I: It proceeds according to the following general route II: The method includes the following steps: A-1 reacts with H-1 in the presence of a catalyst, a base, and an acylation reagent to generate B-1; B-1 and J-1 react in the presence of acid to produce C-1; C-1 reacts with alkylated formamide acetal to generate D-1; D-1 reacts with K-1 to produce E-1; E-1 and M-1 react in the presence of a base to produce F-1; F-1 is reacted with at least one acid and N-1 in the presence of a base to produce G-1; G-1 is reacted under conditions suitable for the formation of compound I; in Hal is a halogen. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl. Ra , Rb , R1 and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 27. The method of claim 26, wherein the catalyst is a nucleophilic amine catalyst or a nucleophilic phosphine catalyst. 28. The method according to claim 27, wherein the catalyst is imidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undecyl-7-ene, pyridine, triphenylphosphine, or a mixture thereof. 29. The method of claim 28, wherein the catalyst is 4-dimethylaminopyridine. 30. The method according to any one of claims 26-29, wherein A-1 reacts with methoxyacetic acid in the presence of a base, said base being selected from amine bases, aromatic amine bases, inorganic carbonates, metal hydrides, alkoxides, and mixtures thereof. 31. The method according to claim 30, wherein the base is triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, quinine ring, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undecyl-7-ene, pyridine, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, or a mixture thereof. 32. The method according to any one of claims 26-31, wherein the acylation reagent is selected from carboxylic acid activating reagents, carbodiimide derivatives, and mixtures thereof. 33. The method according to any one of claims 32, wherein the acylation agent is selected from pentanoyl chloride, carbonyl diimidazole, thioyl chloride, oxalyl chloride, N,N'-dicyclohexylcarbodiimide, and mixtures thereof. 34. The method of claim 33, wherein the acylation agent is pivaloyl chloride. 35. The method according to any one of claims 26-34, wherein B-1 reacts with J-1 in the presence of an acid selected from inorganic acids, organic acids, haloorganic acids and mixtures thereof. 36. The method according to claim 35, wherein the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, perfluoropropionic acid, and mixtures thereof. 37. The method of claim 36, wherein the acid is trifluoroacetic acid. 38. The method according to any one of claims 26-37, wherein J-1 is in the form of a salt or a eutectic. 39. The method according to any one of claims 26-38, wherein Hal is F. 40. The method according to any one of claims 26-39, wherein J-1 is 41. The method according to any one of claims 26-39, wherein J-1 is 42. The method according to any one of claims 26-39, wherein J-1 is 43. The method according to any one of claims 26-42, wherein G-1 reacts with at least one reagent selected from metal salts, Lewis acids, sodium ethanethiol, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof. 44. The method of claim 43, wherein the at least one reagent is selected from magnesium bromide, lithium chloride, lithium bromide, lithium iodide, aluminum trichloride, aluminum tribromide, trimethylchlorosilane, trimethyliodosilane, boron trichloride, boron tribromide, sodium ethanethiol, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl ether, and trifluoroacetic acid. 45. A method for preparing compound of formula I: This method is carried out according to the following general route III: The method includes the following steps: B-1 reacts with Q-1 to generate BB-1; BB-1 reacts with J-1 to produce C-1; C-1 reacts with alkylated formamide acetal to generate D-1; D-1 reacts with K-1 to produce E-1; E-1 and M-1 react in the presence of a base to produce F-1; F-1 is reacted with at least one acid and N-1 or its salt or eutectic in the presence of a base to produce G-1; G-1 is reacted under conditions suitable for the formation of compound I; in Hal is a halogen. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl. Ra , Rb , Rd , R1 and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 46. The method of claim 45, wherein Rd is -CH2CH3 . 47. The method according to claim 45 or 46, wherein J-1 is in the form of a salt or a eutectic. 48. The method according to any one of claims 45-47, wherein Hal is F. 49. The method according to any one of claims 45-48, wherein J-1 is 50. The method according to any one of claims 45-48, wherein J-1 is 51. The method according to any one of claims 45-48, wherein J-1 is 52. The method according to any one of claims 45-51, wherein G-1 reacts with at least one reagent selected from metal salts, Lewis acids, sodium ethanethiol, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof. 53. The method of claim 52, wherein the at least one reagent is selected from magnesium bromide, lithium chloride, lithium bromide, lithium iodide, aluminum trichloride, aluminum tribromide, trimethylchlorosilane, trimethyliodosilane, boron trichloride, boron tribromide, sodium ethanethiol, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl ether, and trifluoroacetic acid. 54. A method for preparing compound of formula I: This method is based on the following general route IV: The method includes the following steps: C-1 reacts with alkylated formamide acetal to generate D-1; D-1 reacts with M-1 to generate EE-1; EE-1 reacts with K-1 to produce F-1; F-1 is reacted with at least one acid and N-1 in the presence of a base to produce G-1; G-1 is reacted under conditions suitable for the formation of compound I; in Hal is a halogen. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl. Ra , Rb , R1 and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 55. The method of claim 54, wherein G-1 reacts with at least one reagent selected from metal salts, Lewis acids, sodium ethanethiol, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof. 56. The method of claim 55, wherein the at least one reagent is selected from magnesium bromide, lithium chloride, lithium bromide, lithium iodide, aluminum trichloride, aluminum tribromide, trimethylchlorosilane, trimethyliodosilane, boron trichloride, boron tribromide, sodium ethanethiol, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl ether, and trifluoroacetic acid. 57. A method for preparing compounds of formula II: This method is based on the following general route V: The method includes the following steps: C-1 reacts with alkylated formamide acetal to generate D-1; D-1 reacts with K-1 to produce E-1; E-1 and M-1 react in the presence of a base to produce F-1; F-1 reacts with a base to produce compound II; in Hal is a halogen. n is 1, 2, or 3. Ra , Rb , R1 and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 58. The method of claim 57, wherein the alkylated formamide acetal is selected from N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal and N,N-diisopropylformamide dimethyl acetal. 59. The method of claim 58, wherein the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal. 60. The method according to any one of claims 57-59, wherein R1 is a C1 - C4 alkyl group. 61. The method of claim 60, wherein R1 is -CH3 . 62. The method according to any one of claims 57-61, wherein E-1 reacts with M-1 in the presence of a base selected from inorganic carbonates, metal hydrides, alkoxides, and mixtures thereof. 63. The method of claim 62, wherein the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, lithium tert-butoxide, and mixtures thereof. 64. The method of claim 63, wherein the base is sodium methoxide. 65. The method according to any one of claims 57-64, wherein R2 is a C1 - C4 alkyl group. 66. The method of claim 65, wherein R2 is -CH3 . 67. The method according to any one of claims 57-66, wherein F-1 reacts with a base to produce a compound of formula II, wherein the base is selected from hydroxide bases, carbonate bases, and mixtures thereof. 68. The method of claim 67, wherein the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, or a mixture thereof. 69. The method of claim 68, wherein the base is lithium hydroxide. 70. A method for preparing a compound of formula D-1, which follows the route below: The method includes reacting C-1 with alkylated formamide acetal to generate D-1; and in Hal is a halogen. n is 1, 2, or 3. Ra and Rb are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 71. The method of claim 70, wherein the alkylated formamide acetal is selected from N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal and N,N-diisopropylformamide dimethyl acetal. 72. The method of claim 71, wherein the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal. 73. The method according to any one of claims 70-72, wherein Ra and Rb are each independently C1 - C4 alkyl. 74. The method according to any one of claims 70-73, wherein each Hal is independently -F or -Cl. 75. The method according to any one of claims 70-74, wherein n is 3. 76. A method for preparing a compound of formula E-1, the method being carried out according to the following route: The method includes the step of reacting D-1 with K-1 to generate E-1, and in Hal is a halogen. n is 1, 2, or 3. Ra , Rb and R1 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 77. The method of claim 76, wherein Ra , Rb and R1 are each independently C1 - C4 alkyl. 78. The method of claim 76 or 77, wherein R1 is -CH3 . 79. The method according to any one of claims 76-78, wherein each Hal is independently -F or -Cl. 80. The method according to any one of claims 76-79, wherein n is 3. 81. A method for preparing compound F-1, which is carried out according to the following route: The method includes reacting E-1 and M-1 in the presence of a base to generate F-1; and in Hal is a halogen. n is 1, 2, or 3. Ra , Rb , R1 and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 82. The method of claim 81, wherein Ra , Rb , R1 and R2 are each independently C1 - C4 alkyl. 83. The method according to claim 81 or 82, wherein R1 is -CH3 . 84. The method according to any one of claims 81-83, wherein E-1 and M-1 react in the presence of a base selected from metal hydrides, alkoxides, bis(trialkylsilyl)amine bases, and mixtures thereof. 85. The method according to claim 84, wherein the base is selected from sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, lithium tert-butoxide, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and mixtures thereof. 86. The method of claim 85, wherein the base is sodium methoxide. 87. The method according to any one of claims 81-86, wherein R2 is -CH3 . 88. The method according to any one of claims 81-87, wherein each Hal is independently -F or -Cl. 89. The method according to any one of claims 81-88, wherein n is 3. 90. A method for preparing a compound of formula G-1, which is carried out according to the following route: The method includes reacting F-1 with at least one acid and N-1 or its salt or eutectic in the presence of a base to generate G-1; in Hal is a halogen. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Each Rc is independently hydrogen, halogen, hydroxyl, or C1 - C4 alkyl. Ra , R1 , and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 91. The method of claim 90, wherein Ra , R1 and R2 are each independently C1 - C4 alkyl. 92. The method according to claim 90 or 91, wherein R1 is -CH3 . 93. The method according to any one of claims 90-92, wherein R2 is -CH3 . 94. The method according to any one of claims 90-93, wherein F-1 reacts with at least one acid selected from organic acids, inorganic acids, organic carboxylic acids and mixtures thereof. 95. The method of claim 94, wherein at least one acid is selected from methanesulfonic acid, acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, butyric acid, propionic acid, benzoic acid, and mixtures thereof. 96. The method of claim 95, wherein the at least one acid is methanesulfonic acid and acetic acid. 97. The method according to any one of claims 90-96, wherein L is -CH2 - CH2- . 98. The method according to any one of claims 90-97, wherein N-1 is 99. The method according to any one of claims 90-97, wherein N-1 is in the form of a salt or a eutectic. 100. The method of claim 99, wherein N-1 is 101. The method of claim 99, wherein N-1 is 102. The method according to any one of claims 90-99, wherein N-1 is in solution. 103. The method according to any one of claims 90-102, wherein the reaction of F-1 and N-1 occurs in the presence of a base selected from inorganic carbonates, metal hydrides, alkoxides, and mixtures thereof. 104. The method of claim 103, wherein the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, and lithium tert-butoxide. 105. The method of claim 104, wherein the base is potassium carbonate. 106. The method according to any one of claims 90-105, wherein each Hal is independently -F or -Cl. 107. The method according to any one of claims 90-106, wherein n is 3. 108. A method for preparing a compound of formula I, which is carried out according to the following route: This method involves reacting G-1 under conditions suitable for producing compound I: in Hal is a halogen. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Each Rc is independently hydrogen, halogen, hydroxyl, or C1 - C4 alkyl. Ra is ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 109. The method of claim 108, wherein Ra is a C1 - C4 alkyl group. 110. The method according to claim 108 or 109, wherein G-1 reacts with at least one reagent selected from metal salts, Lewis acids, sodium ethanethiol, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof. 111. The method of claim 110, wherein the at least one reagent is selected from magnesium bromide, lithium chloride, lithium bromide, lithium iodide, aluminum trichloride, aluminum tribromide, trimethylchlorosilane, trimethyliodosilane, boron trichloride, boron tribromide, sodium ethanethiol, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl ether, and trifluoroacetic acid. 112. The method according to any one of claims 108 to 111, wherein L is -CH2 - CH2- . 113. The method according to any one of claims 108-112, wherein each Hal is independently -F or -Cl. 114. The method according to any one of claims 108-113, wherein n is 3. 115. A method for preparing compound B-1, which proceeds according to the following route: The method comprises reacting A-1 with H-1 in the presence of a catalyst, a base, and an acylation agent to generate B-1, wherein Ra is ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 116. The method of claim 115, wherein the catalyst is a nucleophilic amine catalyst or a nucleophilic phosphine catalyst. 117. The method of claim 116, wherein the catalyst is imidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undecyl-7-ene, pyridine, triphenylphosphine, or a mixture thereof. 118. The method of claim 117, wherein the catalyst is 4-dimethylaminopyridine. 119. The method according to any one of claims 115-118, wherein A-1 reacts with methoxyacetic acid in the presence of a base selected from amine bases, aromatic amine bases, inorganic carbonates, metal hydrides, alkoxides, and mixtures thereof. 120. The method of claim 119, wherein the base is triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, quinine ring, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undecyl-7-ene, pyridine, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, or a mixture thereof. 121. The method according to any one of claims 115-120, wherein the acylation agent is selected from carboxylic acid activating agents, carbodiimide derivatives, and mixtures thereof. 122. The method of claim 121, wherein the acylation agent is selected from pentanoyl chloride, carbonyl diimidazole, thioyl chloride, oxalyl chloride, N,N'-dicyclohexylcarbodiimide, and mixtures thereof. 123. The method of claim 122, wherein the acylation agent is pivaloyl chloride. 124. A method for preparing a C-1 compound, which is carried out according to the following route: The method described herein includes reacting the free acid of B-1 with one to five equivalents of J-1; and in Hal is a halogen. n is 1, 2, or 3. Ra is ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 125. The method of claim 124, wherein B-1 and J-1 react in the presence of an acid selected from inorganic acids, organic acids, haloorganic acids and mixtures thereof. 126. The method of claim 125, wherein the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, perfluoropropionic acid, and mixtures thereof. 127. The method of claim 126, wherein the acid is trifluoroacetic acid. 128. The method according to any one of claims 124-127, wherein J-1 is in the form of a salt or a eutectic. 129. The method according to any one of claims 124-128, wherein Hal is F. 130. The method according to any one of claims 124-129, wherein J-1 is 131. The method according to any one of claims 124-129, wherein J-1 is 132. The method according to any one of claims 124-129, wherein J-1 is 133. A method for preparing a compound of formula BB-1, which is carried out according to the following route: The method includes reacting B-1 with Q-1 to generate BB-1, and Ra and Rb are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 134. The method of claim 133, wherein Rd is CH2CH3 . 135. A method for preparing a C-1 compound, which is carried out according to the following route: The method includes reacting BB-1 with J-1 to generate C-1, and in Hal is a halogen. n is 1, 2, or 3. Ra and Rd are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 136. The method of claim 135, wherein Hal is F. 137. The method according to claim 135 or 136, wherein J-1 is 138. The method according to claim 135 or 136, wherein J-1 is 139. The method according to claim 135 or 136, wherein J-1 is 140. A method for preparing a compound of formula EE-1, The method includes reacting D-1 with M-1 to generate EE-1; in Hal is a halogen. n is 1, 2, or 3. Ra , Rb , and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 141. A method for preparing compound F-1, The method includes reacting EE-1 with K-1 to generate F-1; in Hal is a halogen. n is 1, 2, or 3. Ra , R1 , and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 142. A method for preparing a compound of formula II, The method described herein includes reacting F-1 with a base to generate a compound of formula II. in Hal is a halogen. n is 1, 2, or 3. Ra , R1 , and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 143. The method of claim 142, wherein F-1 is reacted with a base to produce a compound of formula II, said base being selected from hydroxy bases, carbonate bases, and mixtures thereof. 144. The method of claim 143, wherein the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, or a mixture thereof. 145. The method of claim 144, wherein the base is lithium hydroxide. 146. A method for preparing a salt of formula B-1·J-1: The method described herein includes dissolving the free acid of B-1 and adding an equivalent amount of J-1. in Hal is a halogen. n is 1, 2, or 3. Ra is ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 147. A method for preparing a C-1 compound, The method described herein involves reacting a salt of formula B-1·J-1 with about 0.1 to 1 equivalent of a suitable acid, and in Hal is a halogen. n is 1, 2, or 3. Ra is ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 148. Compounds having the following structure: Its salt or its eutectic, in Hal is a halogen. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl. Ra , Rb , Rd , R1 and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 149. The compound according to claim 148, having the following structure: 150. The compound according to claim 148, having the following structure: 151. The compound according to claim 148, having the following structure: 152. Compounds having the following structure: Or its salt or eutectic. 153. Compounds having the following structure: 154. A method for preparing compound of formula I: This method is based on the following general route VI: The method includes the following steps: B-1·J-1 is reacted under conditions suitable for the formation of C-1; C-1 reacts with alkylated formamide acetal to generate D-1; D-1 reacts with K-1 to produce E-1; E-1 and M-1 react in the presence of a base to produce F-1; F-1 reacts with at least one acid to produce FF-1; FF-1 is reacted with N-1 or its salt or eutectic in the presence of an additive to generate G-1; G-1 is reacted under conditions suitable for the formation of compound I; in Halogens are elements that can be the same or different. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Rc can be independently hydrogen, halogen, hydroxyl, or C <sub>1 -C 4  alkyl. Ra , R1 , and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. Each Rb is an independent ( C1 - C4 ) alkyl group. 155. The method of claim 154, wherein B-1·J-1 reacts in the presence of an acid. 156. The method of claim 155, wherein the acid is selected from inorganic acids, organic acids, haloorganic acids, Lewis acids, and mixtures thereof. 157. The method according to any one of claims 155-156, wherein the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, perfluoropropionic acid, dichloroacetic acid, chloroacetic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, zinc chloride, magnesium bromide, magnesium trifluoromethanesulfonate, copper trifluoromethanesulfonate, scandium trifluoromethanesulfonate, and mixtures thereof. 158. The method according to any one of claims 155-157, wherein the acid is trifluoroacetic acid. 159. The method of claim 154, wherein the alkylated formamide acetal is selected from N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, N,N-diethylformamide dimethyl acetal and N,N-diisopropylformamide dimethyl acetal. 160. The method according to any one of claims 154-159, wherein the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal. 161. The method according to any one of claims 154-160, wherein C-1 reacts with alkylformamide acetal in the presence of an acid. 162. The method of claim 161, wherein the acid is selected from trifluoroacetic acid, formic acid, acetic acid, trifluoroacetic acid sulfate, trichloroacetic acid, and perfluoropropionic acid. 163. The method according to any one of claims 161-162, wherein the acid is trifluoroacetic acid. 164. The method according to any one of claims 154-163, wherein K-1 is selected from aminoacetaldehyde diacetal, aminoacetaldehyde dipropional, aminoacetaldehyde dimethylal, and aminoacetaldehyde dibutylal. 165. The method according to any one of claims 154-164, wherein K-1 is aminoacetaldehyde dimethyl acetal. 166. The method according to any one of claims 154-165, wherein M-1 is selected from dimethyl oxalate, diethyl oxalate, dipropyl oxalate, and dibutyl oxalate. 167. The method according to any one of claims 154-166, wherein M-1 is dimethyl oxalate. 168. The method according to any one of claims 154-167, wherein E-1 reacts with M-1 in the presence of a base selected from metal hydrides, alkoxides, inorganic carbonates, bis(trialkylsilyl)amine bases, and mixtures thereof. 169. The method of claim 168, wherein the base is selected from sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyloxide, lithium tert-butoxide, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. 170. The method according to any one of claims 168 to 169, wherein the base is sodium methoxide. 171. The method according to any one of claims 154 to 170, wherein F-1 reacts with at least one acid selected from organic acids, inorganic acids, organic carboxylic acids and mixtures thereof. 172. The method of claim 171, wherein at least one acid is selected from methanesulfonic acid, acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, butyric acid, propionic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, and mixtures thereof. 173. The method according to any one of claims 171 to 172, wherein the at least one acid is p-toluenesulfonic acid. 174. The method according to any one of claims 154 to 173, wherein L is -CH2 - CH2- . 175. The method according to any one of claims 154 to 174, wherein N-1 is 176. The method according to any one of claims 154 to 175, wherein N-1 is in the form of a salt or a eutectic. 177. The method of claim 176, wherein N-1 is 178. The method according to any one of claims 154 to 177, wherein N-1 is in solution. 179. The method according to any one of claims 154 to 178, wherein the additive is selected from carboxylates, inorganic carbonates, metal hydrides, alkoxides, water scavengers, and mixtures thereof. 180. The method according to any one of claims 154 to 179, wherein the additive is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyl alcohol, lithium tert-butoxide, sodium propionate, potassium propionate, molecular sieve, trimethyl orthoacetate, potassium acetate, sodium acetate, lithium acetate, and trimethyl orthoformate. 181. The method according to any one of claims 154 to 180, wherein the additive is potassium acetate. 182. The method according to any one of claims 154 to 181, wherein G-1 reacts with at least one reagent selected from metal salts, Lewis acids, sodium ethanethiol, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof. 183. The method of claim 182, wherein at least one reagent is selected from magnesium bromide, lithium chloride, lithium bromide, lithium iodide, aluminum trichloride, aluminum tribromide, trimethylchlorosilane, trimethyliodosilane, boron trichloride, boron tribromide, sodium ethanethiol, sodium hexamethyldisiloxane, palladium, boron trifluoride diethyl ether, and trifluoroacetic acid. 184. The method according to any one of claims 182 to 183, wherein the at least one reagent is magnesium bromide. 185. The method according to any one of claims 154 to 184, wherein Ra , Rb , R1 and R2 are each independently C1 - C4 alkyl. 186. The method according to any one of claims 154 to 185, wherein R2 is -CH3 . 187. The method according to any one of claims 154 to 186, wherein R1 is -CH3 . 188. The method according to any one of claims 154 to 187, wherein Ra is -CH3 . 189. The method according to any one of claims 154 to 188, wherein Rb is -CH3 . 190. The method according to any one of claims 154 to 189, wherein Hal is independently -F or -Cl. 191. The method according to any one of claims 154 to 190, wherein Hal is F. 192. The method according to any one of claims 154 to 191, wherein n is 3. 193. The method according to any one of claims 154 to 192, wherein J-1 is 194. A method for preparing a C-1 compound, The method involves reacting a compound of formula B-1·J-1 with about 0.1 to 1 equivalent of a suitable acid, and in Halogens can be the same or different. n is 1, 2, or 3. Ra is ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 195. The method of claim 194, wherein the acid is selected from inorganic acids, organic acids, haloorganic acids, Lewis acids, and mixtures thereof. 196. The method of any one of claims 194 to 195, wherein the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, perfluoropropionic acid, dichloroacetic acid, chloroacetic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, zinc chloride, magnesium bromide, magnesium trifluoromethanesulfonate, copper trifluoromethanesulfonate, scandium trifluoromethanesulfonate, and mixtures thereof. 197. The method according to any one of claims 194 to 196, wherein the acid is trifluoroacetic acid. 198. A method for preparing a compound of formula FF-1, which is carried out according to the following route: The method includes reacting F-1 with at least one acid to generate FF-1; in Halogens can be the same or different. n is 1, 2, or 3. Ra , R1 , and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 199. The method of claim 198, wherein F-1 reacts with at least one acid selected from organic acids, inorganic acids, organic carboxylic acids and mixtures thereof. 200. The method according to any one of claims 198 to 199, wherein the at least one acid is selected from methanesulfonic acid, acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, butyric acid, propionic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, and mixtures thereof. 201. The method according to any one of claims 198 to 200, wherein the at least one acid is p-toluenesulfonic acid. 202. The method according to any one of claims 198 to 201, wherein Ra , R1 and R2 are each independently C1 - C4 alkyl. 203. The method according to any one of claims 198 to 202, wherein R1 is -CH3 . 204. The method according to any one of claims 198 to 203, wherein R2 is -CH3 . 205. The method according to any one of claims 198 to 204, wherein Hal is independently -F or -Cl. 206. The method according to any one of claims 198 to 205, wherein n is 3. 207. A method for preparing a compound of formula G-1, which is carried out according to the following route: The method includes reacting FF-1 with at least one additive and N-1 or its salt or eutectic to generate G-1; in Halogens can be the same or different. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Each Rc is independently hydrogen, halogen, hydroxyl, or C1 - C4 alkyl. Ra , R1 , and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl, or ( C6 - C10 )aryl( C1 - C4 )alkyl. 208. The method of claim 207, wherein L is -CH2 - CH2- . 209. The method according to claim 207 or 208, wherein N-1 is 210. The method according to any one of claims 207 to 209, wherein N-1 is a salt or a eutectic. 211. The method according to any one of claims 207, 208, and 210, wherein N-1 is 212. The method according to any one of claims 207 to 211, wherein N-1 is in solution. 213. The method according to any one of claims 207 to 212, wherein the additive is selected from carboxylates, inorganic carbonates, metal hydrides, alkoxides, water scavengers, and mixtures thereof. 214. The method according to any one of claims 207 to 213, wherein the additive is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert-amyl alcohol, lithium tert-butoxide, sodium propionate, potassium propionate, molecular sieve, trimethyl orthoacetate, potassium acetate, sodium acetate, lithium acetate, and trimethyl orthoformate. 215. The method according to any one of claims 207 to 214, wherein the additive is potassium acetate. 216. The method according to any one of claims 207 to 215, wherein Ra , R1 and R2 are each independently C1 - C4 alkyl. 217. The method according to any one of claims 207 to 216, wherein R1 is -CH3 . 218. The method according to any one of claims 207 to 217, wherein R2 is -CH3 . 219. The method according to any one of claims 207 to 218, wherein Hal is independently -F or -Cl. 220. The method according to any one of claims 207 to 219, wherein n is 3. 221. A method for preparing a compound of formula N-1x, which is carried out according to the following route: The method includes the following steps: To cause g-1x to react and generate h-1x; and h-1x reacts to produce N-1x. 222. The method of claim 221, wherein the method further comprises the following steps: f-1x reacts to produce g-1x. 223. The method according to any one of claims 221 to 222, wherein g-1x is hydrogenated in the presence of a catalyst and a hydrogen source to produce h-1x. 224. The method of claim 223, wherein the catalyst is selected from Pd/C, PtO2 , RhCl( PPh3 ) 3 , Nyori catalyst and Crabtree catalyst. 225. The method according to any one of claims 223 to 224, wherein the catalyst is PtO2 . 226. The method according to any one of claims 223 to 225, wherein the hydrogen source is hydrogen gas. 227. The method of any one of claims 221 to 226, wherein h-1x reacts with an acid to produce N-1x. 228. The method of claim 227, wherein the acid is hydrochloric acid. 229. A method for preparing enantiomer-enriched cc-1a from racemic c-1a, which is carried out according to the following route: The method includes the following steps: Racemic c-1a is reacted with an acyl donor and an enzyme to yield c-1b and e-1; Separate e-1 from cc-1b; and Hydrolysis of e-1 generates cc-1a; Wherein, Rx is ( C1 - C6 ) alkyl- Ry , and Ry is selected from H , CN, -NRz1Rz2 , C(O) Rz1 , –C(O) ORz1 , –C(O) NRz1Rz2 , –OC(O) NRz1Rz2 , –NRz1C (O) Rz2 , –NRz1C (O) NRz2 , –NRz1C (O) ORz2 , –SRz1 , –S( O ) 1-2Rz1 , –S (O) 2NRz1Rz2 , –NRz1S (O) 2Rz2 , NRz1S (O) 2Rz2 , and ORz1 ; and R z1 and R z2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 heteroalkyl, C3-10 cycloalkyl, 3- to 12-membered heterocyclic, C6- to 10- membered aryl and 5- to 10-membered heteroaryl. 230. The method of claim 229, wherein the acyl donor is selected from glutaric anhydride, acetic anhydride, vinyl acetate, isopropylene acetate, 4-chlorophenyl acetate, and ethyl methoxyacetate. 231. The method of any one of claim 229 or 230, wherein the acyl donor is glutaric anhydride. 232. The method of any one of claims 229 to 231, wherein the enzyme is a lipase selected from CAL-B, CAL-A, PPL, PSL-C, PSL, CRL and MML. 233. The method of any one of claims 229 to 232, wherein the enzyme is CAL-B lipase. 234. A method for preparing enantiomer-enriched cc-1a from racemic c-1a, which is carried out according to the following route: The method includes the following steps: The racemic c-1a reacts with an acyl donor to generate a racemic ee-1; The racemic ee-1 reacts with the enzyme to produce e-2 and cc-1a; and Separate cc-1a; Wherein, Rx is ( C1 - C6 ) alkyl- Ry , and Ry is selected from H , CN, -NRz1Rz2 , C(O) Rz1 , –C(O) ORz1 , –C(O) NRz1Rz2 , –OC(O) NRz1Rz2 , –NRz1C (O) Rz2 , –NRz1C (O) NRz2 , –NRz1C (O) ORz2 , –SRz1 , –S( O ) 1-2Rz1 , –S (O) 2NRz1Rz2 , –NRz1S (O) 2Rz2 , NRz1S (O) 2Rz2 , and ORz1 ; and R z1 and R z2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 heteroalkyl, C3-10 cycloalkyl, 3- to 12-membered heterocyclic, C6- to 10- membered aryl and 5- to 10-membered heteroaryl. 235. The method of claim 234, wherein the acyl donor is glutaric anhydride. 236. The method of any one of claims 234 to 235, wherein the enzyme is CAL-B lipase. 237. A method for preparing enantiomer-enriched dd-1 from racemic c-1a, which proceeds according to the following route: The method includes the following steps: Reaction of racemic c-1a with a chiral acid yields dd-1 and dd-2; and Separate the enantiomer dd-1. 238. The method of claim 237, wherein the chiral acid is selected from (S)-naproxen and (+)-mandelic acid. 239. The method of any one of claims 237 to 238, wherein separating dd-1 comprises selective recrystallizing dd-1 from racemic dd-1. 240. The method of claim 239, wherein the recrystallization occurs in a mixture of methyl ethyl ketone and water. 241. A compound having the following structure: Or its salt or eutectic, in Halogens can be the same or different. n is 1, 2, or 3. L is -C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 -, -C(R c ) 2 C(R c ) 2 C(R c ) 2 - or -C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 -, Each Rc is independently hydrogen, halogen, hydroxyl, or C1 - C4 alkyl. Ra , Rb , Rd , R1 and R2 are each independently ( C1 - C4 )alkyl, ( C6 - C10 )aryl or ( C6 - C10 )aryl( C1 - C4 )alkyl. 242. A compound having the following structure: Or its salt or eutectic.