HK40101079A - Methods of preparing carbanucleosides using amides - Google Patents

Description

Method for preparing carbazoside using amide

Cross-references to related applications

This application claims the right of preference to PCT/CN2021/087731, filed on April 16, 2021, entitled METHODS OF PREPARING CARBANUCLEOSIDES USING AMIDES.

Background Technology

Compound 7-((3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine and its substituted compounds are important synthetic intermediates (see, for example, WO2016/069825). Improved methods for preparing such intermediates and other carbanucleosides are still needed.

Summary of the Invention

In one embodiment, this disclosure provides a method for preparing compounds of formula (II-a) or (II-b):

include:

(a) Preparing a first input mixture, wherein the first input mixture comprises an amine protecting agent, a first base, a metallizing agent, and a compound of formula (IV):

To provide the first output mixture; and

(b) Preparing a second input mixture comprising a first output mixture and a compound of formula (V) to provide a second output mixture comprising a compound of formula (II-a) or formula (II-b), wherein the compound of formula (V) has the following structure:

in

R ^a is

Ma ^is either Li or MgX ^a ;

X ^a is Cl, Br, or I; and

^Xb can be Cl, Br, or I.

In another embodiment, this disclosure provides a method for preparing compounds of formula (II-a) or (II-b):

include:

(a) Preparing a first input mixture in a first reactor, wherein the first input mixture comprises

Amine protecting agents, primary bases, metallizing agents, and compounds of formula (IV):

The first reactor provides the first output mixture; and

(b) Add the first output mixture and the compound of formula (V) to the second reactor to form the second...

Input a mixture in which the compound of formula (V) has the following structure:

in

R ^a is

Ma ^is either Li or MgX ^a ;

X ^a is Cl, Br, or I;

^Xb is Cl, Br, or I; and

The second reactor provides a second output mixture containing either formula (II-a) or formula (II-b).

Detailed Implementation

I. Overview

This disclosure describes a method for preparing carbazoside. The methods described herein can relate to efficient and scalable methods that can be performed at any scale. In some embodiments, the method includes preparing compounds of formula (II-a) or (II-b) from compounds of formula (V):

^Ra and ^Ma are as defined in this paper.

II. Definition

When referring to values, “about” includes the specified value plus or minus 10% of the specified value. For example, about 50% includes a range of 45% to 55%, while about 20 molar equivalents includes a range of 18 molar equivalents to 22 molar equivalents. Therefore, when referring to ranges, “about” means each of the specified values plus or minus 10% of the specified value at each end of the specified range. For example, a ratio of about 1 to about 3 (weight/weight) includes a range of 0.9 to 3.3.

As used herein, “input mixture” means a mixture of one or more reagents and/or solvents that enter the reactor.

As used herein, “output mixture” refers to a mixture of one or more reagents and/or solvents leaving the reactor.

A "reactor" is a container into which a mixture of chemicals and reagents is added as input, and is configured to allow the transformation of chemicals, reagents, and other dependent variables to take place within the reactor. Each reactor can be individually a round-bottom flask, batch reactor, continuous flow reactor, plug flow reactor, continuous tubular reactor, continuous stirred tank reactor, mixed flow reactor, semi-batch reactor, or a combination thereof. One or more reactors may be used in the methods disclosed herein. When multiple reactors are present, these reactors may be the same or different types of reactors.

A catalyst is a chemical reactant that increases the reaction rate without being consumed itself.

A Lewis acid is a chemical group that can accept an electron pair from a second chemical group capable of donating an electron pair. Lewis acids can be inorganic compounds, including but not limited to boron salts such as boron trifluoride, or aluminum salts such as aluminum trichloride; organic compound salts such as trimethylsilyl trifluoromethanesulfonate (TMSOTf); or metal complexes containing organic and/or inorganic ligands, such as indium(III) chloride or titanium(IV) dichlorodiisopropoxy. Exemplary Lewis acids include, but are not limited to, diethyl ether of boron trifluoride ( _BF3 · _Et2O ), _{trimethylsilyl} trifluoromethanesulfonate (TMSOTf), TiCl4, _SnCl4 , and _FeCl3 .

"Brønsted acid" or "Brønsted-Lorrelic acid" refers to an acid that can donate a proton and form a conjugate base. Examples of Brønsted acids include, but are not limited to: inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen tetrafluoroborate, and sulfuric acid; and organic acids such as carboxylic acids such as acetic acid and trifluoroacetic acid (TFA), or sulfonic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid. Exemplary Brønsted acids include, but are not limited to, formic acid, acetic acid, dichloroacetic acid, and trifluoroacetic acid.

"Inorganic acid" or "mineral acid" is an acid derived from one or more inorganic compounds. When dissolved in water, inorganic acids form hydrogen ions and a conjugate base. Exemplary inorganic acids include, but are not limited to, hydrochloric acid and phosphoric acid.

"Organic acid" is an organic compound containing a carbon-hydrogen bond and having an acidic moiety. Organic acids include, but are not limited to, alkyl carboxylic acids whose acidity is related to their carboxyl group –COOH and aryl sulfonic acids containing the group _–SO₂OH . Exemplary organic acids include, but are not limited to, acetic acid and p-toluenesulfonic acid.

A "protecting group" is a part of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of protecting groups varies considerably. One function of protecting groups is as an intermediate in the synthesis of the desired compound. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See also *Protective Groups in Organic Chemistry*, Peter G.M. Wuts and Theodora W. Greene, 4th ed., 2006. Protecting groups are often used to mask the reactivity of certain functional groups to contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. An "amine protecting group" is a protecting group that can be used to protect an amine with at least one uncharged hydrogen atom.

A "protecting agent" is a chemical reactant that enables the attachment of protecting groups. An "amine protecting agent" is a reactant that enables the attachment of an amine protecting group to an amine.

"Metalizing agents" are chemical reactants that enable the transfer of organic ligands from compounds, wherein the ligands have carbon atoms that are bonded to metal atoms on the compound.

III. Preparation Method

This document provides methods for preparing compounds of formula (II-a) or (II-b) on various scales (such as grams or kilograms). In some embodiments, this disclosure provides a method for preparing compounds of formula (II-a) or (II-b):

include:

(a) Preparing a first input mixture, wherein the first input mixture comprises an amine protecting agent, a first base, a metallizing agent, and a compound of formula (IV):

To provide the first output mixture; and

(b) Preparing a second input mixture comprising a first output mixture and a compound of formula (V) to provide a second output mixture comprising a compound of formula (II-a) or formula (II-b), wherein the compound of formula (V) has the following structure:

in

R ^a is

Ma ^is either Li or MgX ^a ;

X ^a is Cl, Br, or I; and

^Xb can be Cl, Br, or I.

In some embodiments, this disclosure provides a method for preparing compounds of formula (II-a) or (II-b):

include:

(a) A first input mixture is prepared in a first reactor, wherein the first input mixture comprises an amine protecting agent, a first base, a metallizing agent, and a compound of formula (IV):

The first reactor provides the first output mixture; and

(b) The first output mixture and the compound of formula (V) are added to the second reactor to form the second input mixture, wherein the compound of formula (V) has the following structure:

in

R ^a is

Ma ^is either Li or MgX ^a ;

X ^a is Cl, Br, or I;

^Xb is Cl, Br, or I; and

The second reactor provides a second output mixture containing either formula (II-a) or formula (II-b).

In some embodiments, this disclosure provides a method for preparing compounds of formula (II-a) or (II-b):

include:

(a) reacting the first input mixture to provide a first output mixture; and

(b) React the first output mixture with a compound of formula (V) to provide a compound of formula (II-a) or formula (II-b);

The first input mixture contains an amine protecting agent, a first base, a metallizing agent, and a compound of formula (IV):

and

The compound of formula (V) is:

in

R ^a is

Ma ^is either Li or MgX ^a ;

X ^a is Cl, Br, or I; and

^Xb can be Cl, Br, or I.

In some embodiments, methods for preparing compounds of formula (II-a) or (II-b) include:

include:

(a) A first input mixture is prepared in a first reactor, wherein the first input mixture comprises an amine protecting agent, a first base, a metallizing agent, and a compound of formula (IV):

The first reactor provides the first output mixture; and

(b) The first output mixture and the compound of formula (V) are added to the second reactor to form the second input mixture, wherein the compound of formula (V) has the following structure:

in

R ^a is

Ma ^is either Li or MgX ^a ;

X ^a is Cl, Br, or I;

^Xb is Cl, Br, or I;

^The first base is ^R1MgX1 or ^R1Li ;

^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl;

^X1 is Cl, Br, or I; and

The second reactor provides a second output mixture containing compounds of formula (II-a) or (II-b).

The condition is that when ^Ra is ^MgCl and ^R1 is a methyl group, then ^X1 is Cl or I.

In some embodiments, methods for preparing compounds of formula (II-a) or (II-b) include:

include:

(a) A first input mixture is prepared in a first reactor, wherein the first input mixture comprises an amine protecting agent, a first base, a metallizing agent, and a compound of formula (IV):

The first reactor provides the first output mixture; and

(b) The first output mixture and the compound of formula (V) are added to the second reactor to form the second input mixture, wherein the compound of formula (V) has the following structure:

in

R ^a is

Ma ^is either Li or MgX ^a ;

X ^a is Cl, Br, or I;

^Xb is Cl, Br, or I;

^The metallizing agent is ^R₂MgX₂ or ^R₂Li ;

^R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl;

X ² is Cl, Br, or I; and

The second reactor provides a second output mixture containing either formula (II-a) or formula (II-b).

In some embodiments, methods for preparing compounds of formula (II-a) or (II-b) include:

include:

(a) Preparing a first input mixture in a first reactor, wherein the first input mixture comprises

Amine protecting agents, primary bases, metallizing agents, and compounds of formula (IV):

The first reactor provides the first output mixture; and

(b) Add the first output mixture and the compound of formula (V) to the second reactor to form the second...

Input a mixture in which the compound of formula (V) has the following structure:

in

R ^a is

Ma ^is either Li or MgX ^a ;

X ^a is Cl, Br, or I;

^Xb is Cl, Br, or I;

^The first base is ^R1MgX1 or ^R1Li ;

^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl;

X ¹ is Cl, Br, or I;

^The metallizing agent is ^R₂MgX₂ or ^R₂Li ;

^R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl;

X ² is Cl, Br, or I; and

The second reactor provides a second output mixture containing compounds of formula (II-a) or (II-b).

The condition is that when ^Ra is ^MgCl and ^R1 is a methyl group, then ^X1 is Cl or I.

In some embodiments, ^Xa is Cl, Br, or I. In some embodiments, ^Xa is Br or I. In some embodiments, ^Xa is Cl. In some embodiments, ^Xa is Br. In some embodiments, ^Xa is I.

In some embodiments, ^Ma is Li or MgX ^a . In some embodiments, Ma is Li. In some embodiments, ^Ma is MgX ^a . In some embodiments, ^Ma is MgCl. In some embodiments, ^Ma is MgBr. In some ^embodiments , ^Ma is MgI.

In some embodiments, ^Xb is Cl, Br, or I. In some embodiments, ^Xb is Br or I. In some embodiments, ^Xb is Cl. In some embodiments, ^Xb is Br. In some embodiments, ^Xb is I.

In some embodiments, the compound of formula (IV) has the following structure:

In some embodiments, the compound of formula (IV) has the following structure:

In some embodiments, the compound of formula (IV) has the following structure:

In some implementations, ^Ra is

In some implementations, ^Ra is

In some implementations, ^Ra is

In some implementations, ^Ra is

In some embodiments, the compound of formula (V) has the following structure:

In some embodiments, the compound of formula (V) has the following structure:

In some embodiments, the compound of formula (V) has the following structure:

In some embodiments, the compound of formula (V) has the following structure:

In preparing compounds of formula (II-a) or (II-b), any suitable amine protecting agent known in the art may be used. In some embodiments, the amine protecting agent is an anhydride, a silyl halide, or a silyl trifluoromethanesulfonate. Suitable anhydrides include, but are not limited to, trifluoroacetic anhydride and di-tert-butyl dicarbonate. Silyyl halides include, but are not limited to, trimethylsilyl halide (TMS- ^X4 ), triethylsilyl halide (TES- ^X4 ), triisopropylsilyl halide (TIPS- ^X4 ), tert-butyldimethylsilyl halide (TBDMS- ^X4 ), tert-butyldiphenylsilyl halide (TBDPS- ^X4 ), triphenylsilyl halide (TPS- ^X4 ), and ^1,2 -bis _{( halodimethylsilyl} )ethane ( _X4Me2SiCH2 - _CH2SiMe2X4 ⁾ , wherein ^X4 is Cl, Br, or I. Trifluoromethane sulfonate silyl esters include, but are not limited to, trimethyl silyl trifluoromethane sulfonate (TMSOTf), triethyl silyl trifluoromethane sulfonate (TESOTf), triisopropyl silyl trifluoromethane sulfonate, tert-butyl dimethyl silyl trifluoromethane sulfonate (TBDMSOTf), tert-butyl diphenyl silyl trifluoromethane sulfonate (TBDPSOTf), and triphenyl silyl trifluoromethane sulfonate. In some embodiments, the amine protecting agent is trifluoroacetic anhydride, di(tert-butyl) dicarbonate, trimethyl silyl chloride (TMSCl), triethyl silyl chloride (TESCl), triisopropyl silyl chloride, tert-butyl dimethyl silyl chloride (TBDMSCl), tert-butyl diphenyl silyl chloride (TBDPSCl), triphenyl silyl chloride, or 1,2-bis(chlorodimethyl silyl)ethane. In some implementations, the amine protecting agent is trimethylsilyl chloride (TMSCl).

In preparing compounds of formula (II-a) or (II-b), any suitable first base capable of deprotonating a compound of formula (IV) may be used. In some embodiments, the first base is a Grignard reagent, such as an alkyl magnesium halide optionally complexed with lithium halide, for example iPrMgCl or iPrMgCl-LiCl; an alkyl lithium reagent; an aryl lithium reagent; or an inorganic hydride, such as sodium hydride or potassium hydride. In some embodiments, the first base ^{is R1MgX1} or ^R1Li ; ^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X1 is Cl, Br, or I.

In some embodiments, the first base is ^R1MgX1 or ^R1Li ; ^R1 is methyl, ethyl, n ^- propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X1 is Cl, Br, or I, provided ^that when ^R1 is methyl, ^X1 is Cl or I. In some embodiments, the first base is ^R1MgX1 or ^R1Li ; ^R1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X1 is Cl, Br, or I. In some embodiments, the first base is ^R1MgX1 or ^R1Li ; ^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X1 is Cl or I. In some embodiments, the first base is ^R1MgX1 or ^R1Li ; ^R1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, ^or phenyl; and ^{X1 is} Cl or I.

In some embodiments, the first base is ^{R1MgX1 ; R1} is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X1 is Cl, Br, or I, provided that when ^R1 is methyl, ^X1 is Cl or I. In some embodiments, the first base is ^R1MgX1 ; ^R1 is ethyl, n- ^propyl , isopropyl, n-butyl, tert-butyl, or phenyl; and ^X1 is Cl, Br, or I. In some embodiments, the first base is ^R1MgX1 ; ^R1 is methyl, ethyl, n ^- propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X1 is Cl or I. In some embodiments, the first base is ^R1MgX1 ; ^R1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^{X1 is} Cl or I.

In some embodiments, the first base is ^{R1MgX1 .} In some embodiments, ^R1 is isopropyl or phenyl. In some embodiments, ^R1 is isopropyl. In some embodiments, ^R1 is phenyl. In some embodiments, ^X1 is Cl. In some embodiments, the first base is iPrMgCl or PhMgCl. In some embodiments, the first base is iPrMgCl. In some embodiments, the first base is PhMgCl.

In preparing compounds of formula (II-a) or (II-b), any suitable metallizing agent capable of achieving metal transfer of compounds of formula (IV) can be used. For example, the metallizing agent is a Grignard reagent, such as an alkyl magnesium halide optionally complexed with lithium halides, e.g., iPrMgCl or iPrMgCl- ^LiCl ; an alkyl lithium reagent; or an aryl lithium reagent. In some embodiments, the metallizing agent is ^R₂MgX₂ or ^R₂Li ; ^R₂ is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X₂ is ^Cl , Br, or I. In some embodiments, the metallizing agent is ^R₂MgX₂ . In some embodiments, ^R₂ is isopropyl or phenyl. In some embodiments, ^R₂ is isopropyl. In some embodiments, ^R₂ is phenyl. In some embodiments, ^X₂ is Cl. In some embodiments, the metallizing agent is iPrMgCl or PhMgCl. In some embodiments, the metallizing agent is iPrMgCl. In some implementations, the metallizing agent is PhMgCl.

In some embodiments, the first base and the metallizing agent are each alkyllithium reagents. In some embodiments, one of the first base and the metallizing agent is an alkyllithium reagent, and the other is a Grignard reagent. In some embodiments, both the first base and the metallizing agent are Grignard reagents. In some embodiments, the first base is PhMgCl; and the metallizing agent is iPrMgCl. In some embodiments, the first base is PhMgCl; and the metallizing agent is iPrMgCl-LiCl. In some embodiments, the first base is iPrMgCl; and the metallizing agent is PhMgCl. In some embodiments, the first base is iPrMgCl; and the metallizing agent is iPrMgCl. In some embodiments, the first base is iPrMgCl-LiCl; and the metallizing agent is iPrMgCl-LiCl.

In some embodiments, the first base is PhMgCl; the metallizing agent is iPrMgCl; and ^Ma is MgCl. In some embodiments, the first base is PhMgCl; the metallizing agent is iPrMgCl-LiCl; and ^Ma is MgCl. In some embodiments, the first base is iPrMgCl; the metallizing agent is PhMgCl; and ^Ma is MgCl. In some embodiments, the first base is iPrMgCl; the metallizing agent is iPrMgCl-LiCl; and ^Ma is MgCl. In some embodiments, the first base is iPrMgCl-LiCl; the metallizing agent is iPrMgCl-LiCl; and ^Ma is MgCl.

In some embodiments, the amine protecting agent is trimethylsilyl chloride (TMSCl); the first base is PhMgCl; the metallizing agent is iPrMgCl; and ^Ma is MgCl. In some embodiments, the amine protecting agent is triethylsilyl chloride (TESCl); the first base is PhMgCl; the metallizing agent is iPrMgCl; and ^Ma is MgCl. In some embodiments, the amine protecting agent is triisopropylsilyl chloride, tert-butyldimethylsilyl chloride (TBDMSCl), tert-butyldiphenylsilyl chloride (TBDPSCl), triphenylsilyl chloride, or 1,2-bis(chlorodimethylsilyl)ethane; the first base is PhMgCl; the metallizing agent is iPrMgCl; and ^Ma is MgCl.

In some embodiments, the first input mixture further comprises a first solvent. In some embodiments, the first output mixture further comprises a first solvent. In some embodiments, the first solvent is added to a first reactor. In some embodiments, the first solvent is added to a second reactor. Any suitable solvent can be used as the first solvent in the preparation of compounds of formula (II-a) or (II-b). Suitable solvents include, but are not limited to: ether solvents, such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and cyclopentylmethyl ether; hydrocarbon solvents, such as toluene and n-heptane; and halogenated solvents, such as 1,2-dichloroethane, chloroform, and chlorobenzene. In some embodiments, the first input mixture further comprises a first solvent, which is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or combinations thereof. In some embodiments, the first solvent is tetrahydrofuran (THF).

Compounds of formula (II-a) or (II-b) can be prepared using any suitable reactor or combination of reactors known in the art. Exemplary reactors that can be used to prepare compounds of formula (II-a) or (II-b) include, but are not limited to, batch reactors, continuous flow reactors, plug flow reactors, continuous tubular reactors, continuous stirred tank reactors, mixed flow reactors, semi-batch reactors, or combinations thereof. In some embodiments, one reactor is used. In some embodiments, two reactors are used. In some embodiments, three reactors are used.

In some embodiments, the first reactor and the second reactor are different reactors. In some embodiments, the first reactor and the second reactor are reactors of the same type. In some embodiments, the first reactor and the second reactor are reactors of different types. In some embodiments, the first reactor and the second reactor are a single reactor. In some embodiments, the single reactor is a continuous flow reactor, a plug flow reactor, a continuous tubular reactor, or a mixed flow reactor. In some embodiments, the first reactor is the first reaction zone within a single reactor, and the second reactor is the second reaction zone within a single reactor.

In some embodiments, a reactor having a first reaction zone and a second reaction zone is used to prepare a compound of formula (II-a) or (II-b). A first input mixture can be prepared in the first reaction zone of the reactor for a first time amount under a first set of reaction conditions, including a first temperature and a first pressure. As the mixture moves from the first reaction zone to the second reaction zone, the first input mixture can react to provide a first output mixture. A compound of formula (V) can be added to the second reaction zone of the reactor for a second time amount under a second set of reaction conditions, including a second temperature and a second pressure. In some embodiments, the reactor having the first reaction zone and the second reaction zone is a plug flow reactor. In some embodiments, the reactor having the first reaction zone and the second reaction zone is a continuous tubular reactor. In some embodiments, the reactor having the first reaction zone and the second reaction zone includes a recirculation loop. In some embodiments, the first input mixture and the compound of formula (V) are added separately. In some embodiments, the first input mixture is added to the first reaction zone and the compound of formula (V) is added to the second reaction zone. In some implementations, the first input mixture and the compound of formula (V) are simultaneously added to the first reaction zone.

In some embodiments, a reactor having a reaction zone is used to prepare the compound of formula (II-a) or (II-b). A first input mixture and the compound of formula (V) may be added to a reaction zone for a first time amount under first set of reaction conditions, including a first temperature and a first pressure. The reaction zone of the reactor may then be switched to a second set of reaction conditions for a second time amount, including a second temperature and a second pressure. In some embodiments, the reactor having a reaction zone is a batch reactor. In some embodiments, a first input mixture is added to a reaction zone under first set of reaction conditions, then the compound of formula (V) is added to the reaction zone, and the reactor is switched to a second set of reaction conditions. In some embodiments, the reactor having a reaction zone is a semi-batch reactor. In some embodiments, a first input mixture and the compound of formula (V) are added to a reaction zone for a time amount of about 1 hour to about 24 hours at a temperature of about -20°C to about 20°C and a pressure of about 0.1 bar to about 10 bar to produce the compound of formula (II-a) or (II-b).

In some embodiments, a compound of formula (II-a) or (II-b) is prepared using two reactors, including a first reactor and a second reactor. The first reactor can be operated under a first set of reaction conditions including a first temperature and a first pressure. The second reactor can be operated under a second set of reaction conditions including a second temperature and a second pressure. In some embodiments, the first reactor and the second reactor are reactors of the same type. In some embodiments, the first reactor and/or the second reactor are batch reactors. In some embodiments, the first reactor and/or the second reactor are reactors of different types. In some embodiments, the first reactor and/or the second reactor are semi-batch reactors. In some embodiments, the first reactor and the second reactor are continuous stirred tank reactors.

Any suitable temperature can be used in the first reactor used to prepare the compound of formula (II-a) or (II-b). The first reactor is maintained at a suitable first temperature to provide a first output mixture in a suitable time and yield. In some embodiments, the first reactor is maintained at a first temperature of about -78°C to about 20°C. In some embodiments, the first reactor is cooled to a first temperature of about -20°C to about 0°C. In some embodiments, the first reactor is cooled to a first temperature of about -20°C to about -5°C. In some embodiments, the first reactor is cooled to a first temperature of about -20°C to about -10°C. In some embodiments, the first reactor is cooled to a first temperature of about -20°C.

The method for preparing compounds of formula (II-a) or (II-b) can be performed at any suitable pressure. For example, the first reactor can have a first pressure. A suitable first pressure can be less than atmospheric pressure, atmospheric pressure, or greater than atmospheric pressure. Other suitable first pressures can be, but are not limited to, 0.1 bar to 10 bar, 0.2 bar to 9 bar, 0.3 bar to 8 bar, 0.4 bar to 7 bar, 0.5 bar to 6 bar, 0.6 bar to 5 bar, 0.7 bar to 4 bar, 0.8 bar to 3 bar, 0.9 bar to 2 bar, or about 1 bar. In some embodiments, the first pressure can be atmospheric pressure. In some embodiments, the first pressure can be about 1 bar.

The method for preparing the compound of formula (II-a) or (II-b) can be performed for any suitable period of time. For example, the first period of time for preparing the compound of formula (II-a) or (II-b) can be, but is not limited to, 1 to 600 minutes, 30 to 600 minutes, 60 to 600 minutes, 60 to 300 minutes, 60 to 240 minutes, 60 to 180 minutes, 90 to 150 minutes, or about 120 minutes. In some embodiments, the first period of time for preparing the compound of formula (II-a) or (II-b) can be about 120 minutes. In some embodiments, the first period of time for preparing the compound of formula (II-a) or (II-b) can be about 90 minutes.

In some embodiments, the second input mixture further comprises a second solvent. In some embodiments, the second output mixture further comprises a second solvent. In some embodiments, the second solvent is added to a second reactor. In some embodiments, the second solvent is the same as the first solvent. In some embodiments, the second solvent is different from the first solvent. Any suitable solvent can be used as the second solvent in the preparation of compounds of formula (II-a) or (II-b). Suitable solvents include, but are not limited to: ether solvents, such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and cyclopentylmethyl ether; hydrocarbon solvents, such as toluene and n-heptane; and halogenated solvents, such as 1,2-dichloroethane, chloroform, and chlorobenzene. In some embodiments, the second input mixture further comprises a second solvent, which is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or combinations thereof. In some embodiments, the second solvent is tetrahydrofuran (THF).

Any suitable temperature can be used in the second reactor for preparing the compound of formula (II-a) or (II-b). The second reactor is maintained at a suitable temperature to provide a second output mixture containing the compound of formula (II-a) or (II-b) in a suitable time and yield. In some embodiments, the second reactor is maintained at a temperature of about -20°C to about 40°C. In some embodiments, the second reactor is maintained at a temperature of about 10°C to about 30°C. In some embodiments, the second reactor is maintained at a temperature of about 20°C.

The method for preparing compounds of formula (II-a) or (II-b) can be performed at any suitable pressure. For example, a second reactor can have a second pressure. A suitable second pressure can be less than atmospheric pressure, atmospheric pressure, or greater than atmospheric pressure. Other suitable first pressures can be, but are not limited to, 0.1 bar to 10 bar, 0.2 bar to 9 bar, 0.3 bar to 8 bar, 0.4 bar to 7 bar, 0.5 bar to 6 bar, 0.6 bar to 5 bar, 0.7 bar to 4 bar, 0.8 bar to 3 bar, 0.9 bar to 2 bar, or about 1 bar. In some embodiments, the first pressure can be atmospheric pressure. In some embodiments, the first pressure can be about 1 bar.

The method for preparing the compound of formula (II-a) or (II-b) can be performed for any suitable period of time. For example, the second period of time for preparing the compound of formula (II-a) or (II-b) can be, but is not limited to, 1 hour to 50 hours, 1 hour to 48 hours, 1 hour to 40 hours, 1 hour to 30 hours, 1 hour to 24 hours, 2 hours to 12 hours, 4 hours to 12 hours, 6 hours to 10 hours, 6 hours to 24 hours, 10 hours to 20 hours, or 12 hours to 18 hours. In some embodiments, the second period of time for preparing the compound of formula (II-a) or (II-b) can be about 8 hours. In some embodiments, the second period of time for preparing the compound of formula (II-a) or (II-b) can be 12 hours to 18 hours.

Compounds of formula (II-a) or (II-b) can be separated by any suitable method known in the art, including concentration, extraction, grinding, crystallization and/or chromatography.

In some embodiments, the method further includes combining a second output mixture with an acid. In some embodiments, the acid includes Brønsted acid. In some embodiments, the acid includes organic or mineral acids or combinations thereof. In some embodiments, the acid includes formic acid, acetic acid, citric acid, propionic acid, butyric acid, benzoic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, sulfuric acid, or combinations thereof. In some embodiments, the acid includes organic acids. In some embodiments, the acid includes formic acid, acetic acid, citric acid, propionic acid, butyric acid, or benzoic acid. In some embodiments, the acid includes acetic acid.

In some embodiments, the method for preparing a compound of formula (II-a) or (II-b) further includes preparing a compound of formula (V), the method comprising: (a1) forming a third reaction mixture comprising a compound of formula (III):

An amine of the formula HR ^a ; and a third base, which is ^R3MgX3 or ^R3Li ; wherein ^R3 is methyl, ethyl, n ^- propyl, isopropyl, n-butyl, tert-butyl or phenyl; and ^X3 is Cl, Br or I;

This provides a compound of formula (V).

In some implementations, the amine has the following formula:

In some implementations, the amine has the following formula:

In some implementations, the amine has the following formula:

In some implementations, the amine has the following formula:

In some embodiments, ^X3 is Cl, Br, or I. In some embodiments, ^X3 is Br or I. In some embodiments, ^X3 is Cl. In some embodiments, ^X3 is Br. In some embodiments, ^X3 is I.

In some embodiments, the third base is ^R3MgX3 ; wherein ^R3 is methyl, ethyl, n ^- propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X3 is Cl, Br, or I. In some embodiments, the third base is ^R3MgX3 , wherein ^R3 is methyl, isopropyl, n ^- butyl, tert-butyl, or phenyl; and ^X3 is Cl or Br. In some embodiments, the third base is ^R3MgCl , wherein ^R3 is methyl, isopropyl, tert-butyl, or phenyl. In some embodiments, the third base is MeMgCl, iPrMgCl, or t-BuMgCl. In some embodiments, the third base is iPrMgCl.

In some implementations, the amine has the following formula:

and

The third base is iPrMgCl.

In some implementations, the amine has the following formula:

and

The third base is iPrMgCl.

In the methods described herein, any suitable solvent can be used in the preparation of the compound of formula (V). In some embodiments, the third reaction mixture further comprises a third solvent, which is an ether solvent or a chlorinating solvent. In some embodiments, the third reaction mixture further comprises a third solvent, which is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or combinations thereof. In some embodiments, the third reaction mixture further comprises a third solvent, which is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, or combinations thereof. In some embodiments, the third solvent is tetrahydrofuran (THF).

Any suitable temperature can be used in the compound of formula (V). In some embodiments, the third reaction mixture is maintained at a temperature of about -78°C to about 40°C. In some embodiments, the third reaction mixture is maintained at a temperature of about -20°C to about 25°C. In some embodiments, the third reaction mixture is maintained at a temperature of about 0°C to about 25°C. In some embodiments, the third reaction mixture is maintained at a temperature of about 10°C to about 25°C. In some embodiments, the third reaction mixture is maintained at a temperature of about 15°C to about 25°C. In some embodiments, the third reaction mixture is maintained at a temperature of about 20°C.

In some embodiments, the method includes: (a1) forming a third reaction mixture comprising a compound having the structure of formula (III):

Amines having the following formula:

and

iPrMgCl, thereby forming a compound of formula (V) with the following structure:

(a) A first input mixture is prepared in a first reactor, wherein the first input mixture comprises TMS-Cl, PhMgCl, iPrMgCl and a compound having the following structure (IV):

The first reactor provides the first output mixture; and

(b) The first output mixture and the compound of formula (V) are added to the second reactor to form a compound of formula (II-a) or formula (II-b) having the following structure:

Compounds having the following structure (II-a):

Also known as (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol.

Compounds of formula (II-a) having the following structure, as commonly understood in the art:

It exists in equilibrium with compounds of formula (II-b) having the following structure:

Therefore, as used herein, when listed individually, a compound having the above structure (II-a) should be understood to mean a compound of formula (II-a) and/or a compound of formula (II-b) or any combination of the two.

The method disclosed herein is applicable to the synthesis of compounds of formula (II-a) or (II-b) in grams to kilograms from compounds of formula (III). In some embodiments, the third reaction mixture comprises at least 50 g, 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 20 kg, 30 kg, 40 kg, 50 kg, 100 kg, 200 kg, 500 kg, or at least 1000 kg or more of a compound of formula (III). In some embodiments, the third reaction mixture comprises at least 1 kg of a compound of formula (III). In some embodiments, the third reaction mixture comprises about 50 g to about 100 kg, for example, about 50 g to about 20 kg, or about 30 g to about 20 kg of a compound of formula (III). In some embodiments, the third reaction mixture comprises about 5 kg to about 15 kg of a compound of formula (III). For example, in some embodiments, the third reaction mixture contains about 10 kg of the compound of formula (III).

Compounds having the following structure (III):

It is also known as (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one.

Compounds having the following structure (IV):

Also known as 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-amine.

The method of this disclosure can provide compounds of formula (II-a) or (II-b) in any suitable yield from compounds of formula (III) or (V). For example, compounds of formula (II-a) or (II-b) can be prepared in yields of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or at least 99%. In some embodiments, the yield of formula (II-a) or (II-b) is from about 60% to about 100%. In some embodiments, the yield of formula (II-a) or (II-b) is from about 70% to about 80% or from about 75% to about 85%. In some embodiments, the yield of formula (II-a) or formula (II-b) is about 60%, about 70%, about 72%, about 74%, about 75%, about 76%, about 78%, about 80%, about 82%, about 84%, about 85%, about 86%, about 88%, about 90%, about 95%, about 97%, about 98%, or about 99%. In some embodiments, the yield of formula (II-a) or formula (II-b) is about 79%. In some embodiments, the yield of formula (II-a) or formula (II-b) is about 60% to about 90%. In some embodiments, the yield of formula (II-a) or formula (II-b) is about 70% to about 90%. In some embodiments, the yield of formula (II-a) or formula (II-b) is about 70% to about 80%. In some embodiments, the yield of formula (II-a) or formula (II-b) is about 75% to about 85%.

The method of this disclosure can provide compounds of formula (II-a) or (II-b) with any suitable purity from compounds of formula (III) or (V). For example, compounds of formula (II-a) or (II-b) can be prepared with a purity of about 90% to about 100%, such as about 95% to about 100% or about 98% to about 100%. In some embodiments, the purity of the compounds of formula (II-a) or (II-b) is about 98% to about 100%. In some embodiments, compounds of formula (II-a) or (II-b) are prepared with a purity of about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.9%, about 99.99%, about 99.999%, about 99.9999%, or about 99.99999%. In some embodiments, the compound of formula (II-a) or formula (II-b) is prepared with a purity of about 99.92%. In some embodiments, the compound of formula (II-a) or formula (II-b) is prepared with a purity of about 95% to about 99.999%, about 98% to about 99.999%, about 98% to about 99.99%, or about 99% to about 99.99%. In some embodiments, the purity of the compound of formula (II-a) or formula (II-b) is about 90% to about 100%.

IV. Examples

Example 1. Synthesis of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol

Under nitrogen and atmospheric pressure, a compound of formula (IV) (1.2 equivalents) and tetrahydrofuran (5.6 volumes) were added to a reactor. The contents were cooled to about -5°C, and trimethylsilyl chloride (2.4 equivalents) was added. After stirring for about 30 minutes, the contents were cooled to about -10°C, and phenyl magnesium chloride (2.4 equivalents) was added. The contents were then stirred at about -10°C for about 30 minutes, and then adjusted to about -20°C. Isopropyl magnesium chloride (1.2 equivalents) was added. The contents were adjusted to about -20°C and stirred for about 1 hour. A compound of formula (III) (1.0 equivalent, scaling factor), N,O-dimethylhydroxylamine·HCl (1.1 equivalents), and tetrahydrofuran (5.6 volumes) were added to a second reactor. The contents were cooled to about -20°C, and isopropyl magnesium chloride (2.25 equivalents) was added. The contents were adjusted to about 20°C and stirred for about 30 minutes. The contents from the two reactors were combined and then forward washed with tetrahydrofuran (1.7 v/v). The mixture was stirred at about 20 °C for about 8 hours. A solution of acetic acid (0.95 v/v) in water (6 v/v) was added, followed by toluene (3.8 v/v), and the mixture was stirred at about 20 °C for about 30 minutes. The layers were separated (discarding the aqueous solution), and the organic layer was washed with a 10 wt% potassium bicarbonate solution (5 v/v), followed by three washes with a 10 wt% sodium chloride solution (5 v/v). The organic layer was concentrated under vacuum to about 5 v/v. Toluene (10 v/v) was added and the concentration was repeated. The contents were then finely filtered, forward washed with toluene (1.5 v/v), and concentrated under vacuum to 3 v/v. Methyl tert-butyl ether (7.4 v/v) was added, followed by seed crystals (0.001X) of the compound of formula (II-a), and the mixture was stirred at about 22 °C for about 1 hour. Then, n-heptane (4.4 volumes) was added over about 1 hour, and the contents were adjusted to about 0°C over about 3 hours. The mixture was then stirred at about 0°C for about 12 hours. The slurry was filtered and the filter cake was washed with n-heptane (0.4 volumes) and methyl tert-butyl ether (1.5 volumes), and then dried under vacuum to give the compound of formula (II-a).

While the foregoing disclosure has been described in considerable detail by way of illustration and example for clarity and purpose, those skilled in the art will understand that certain variations and modifications may be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated in its entirety as if it were incorporated individually. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims (46)

1. A method for preparing a compound of formula (II-a) or (II-b): include: (a) Preparing a first input mixture, wherein the first input mixture comprises an amine protecting agent, a first base, a metallizing agent, and a compound of formula (IV): To provide the first output mixture; and (b) Preparing a second input mixture comprising the first output mixture and a compound of formula (V) to provide a second output mixture comprising a compound of formula (II-a) or formula (II-b), wherein the compound of formula (V) has the following structure: in R ^a is Ma ^is either Li or MgX ^a ; X ^a is Cl, Br, or I; and ^Xb can be Cl, Br, or I. 2. The method according to claim 1, for preparing compounds of formula (II-a) or (II-b): include: (a) The first input mixture is prepared in a first reactor, wherein the first input mixture comprises an amine protecting agent, the first base, the metallizing agent, and a compound of formula (IV): The first reactor provides the first output mixture; and (b) The first output mixture and the compound of formula (V) are added to the second reactor to form the second input mixture, wherein the compound of formula (V) has the following structure: in R ^a is Ma ^is either Li or MgX ^a ; X ^a is Cl, Br, or I; ^Xb is Cl, Br, or I; and The second reactor provides the second output mixture containing a compound of formula (II-a) or formula (II-b). 3. The method according to claim 2, used for preparing compounds of formula (II-a) or (II-b): include: (a) The first input mixture is prepared in a first reactor, wherein the first input mixture comprises an amine protecting agent, the first base, the metallizing agent, and a compound of formula (IV): The first reactor provides the first output mixture; and (b) The first output mixture and the compound of formula (V) are added to the second reactor to form the second input mixture, wherein the compound of formula (V) has the following structure: in R ^a is Ma ^is either Li or MgX ^a ; X ^a is Cl, Br, or I; ^Xb is Cl, Br, or I; ^The first base is ^R1MgX1 or ^R1Li ; ^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; ^X1 is Cl, Br, or I; and The second reactor provides a second output mixture comprising a compound of formula (II-a) or formula (II-b). The condition is that when ^Ra is ^MgCl and ^R1 is a methyl group, then ^X1 is Cl or I. 4. The method according to claim 2, for preparing compounds of formula (II-a) or (II-b): include: (a) The first input mixture is prepared in the first reactor, wherein the first input mixture comprises an amine protecting agent, the first base, the metallizing agent, and a compound of formula (IV): The first reactor provides the first output mixture; and (b) The first output mixture and the compound of formula (V) are added to the second reactor to form the second input mixture, wherein the compound of formula (V) has the following structure: in R ^a is Ma ^is either Li or MgX ^a ; X ^a is Cl, Br, or I; ^Xb is Cl, Br, or I; The metallizing agent is ^R₂MgX₂ or ^{R₂Li ; R2} is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; X ² is Cl, Br, or I; and The second reactor provides the second output mixture containing a compound of formula (II-a) or formula (II-b). 5. The method according to claim 2, for preparing compounds of formula (II-a) or (II-b): include: (a) The first input mixture is prepared in the first reactor, wherein the first input mixture comprises an amine protecting agent, the first base, the metallizing agent, and a compound of formula (IV): The first reactor provides the first output mixture; and (b) The first output mixture and the compound of formula (V) are added to the second reactor to form the second input mixture, wherein the compound of formula (V) has the following structure: in R ^a is Ma ^is either Li or MgX ^a ; X ^a is Cl, Br, or I; ^Xb is Cl, Br, or I; ^The first base is ^R1MgX1 or ^R1Li ; ^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; X ¹ is Cl, Br, or I; The metallizing agent is ^R₂MgX₂ or ^{R₂Li ; R2} is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; X ² is Cl, Br, or I; and The second reactor provides a second output mixture comprising a compound of formula (II-a) or formula (II-b). The condition is that when ^Ra is ^MgCl and ^R1 is a methyl group, then ^X1 is Cl or I. 6. The method according to any one of claims 1 to 5, wherein the amine protecting agent is trifluoroacetic anhydride, di(tert-butyl) dicarbonate, trimethylsilyl chloride (TMSCl), triethylsilyl chloride (TESCl), triisopropylsilyl chloride, tert-butyldimethylsilyl chloride (TBDMSCl), tert-butyldiphenylsilyl chloride (TBDPSCl), triphenylsilyl chloride, or 1,2-bis(chlorodimethylsilyl)ethane. 7. The method according to any one of claims 1 to 6, wherein ^The first base is ^R1MgX1 or ^R1Li ; ^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and X ¹ is Cl, Br or I. 8. The method according to any one of claims 1 to 6, wherein ^The first base is ^R1MgX1 or ^R1Li ; ^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and ^X1 is Cl, Br, or I. The condition is that when ^R1 is a methyl group, then ^X1 is either Cl or I. 9. The method according to any one of claims 1 to 6, wherein ^The first base is ^R1MgX1 or ^R1Li ; ^R1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and X ¹ is Cl, Br or I. 10. The method according to any one of claims 1 to 6, wherein ^The first base is ^R1MgX1 or ^R1Li ; ^R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and X ¹ is either Cl or I. 11. The method according to any one of claims 1 to 6, wherein ^The first base is ^R1MgX1 or ^R1Li ; ^R1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and X ¹ is either Cl or I. 12. The method according to any one of claims 1 to 11, wherein the first base is PhMgCl. 13. The method according to any one of claims 1 to 12, wherein The metallizing agent is ^R₂MgX₂ or ^{R₂Li ; R2} is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and X ² is Cl, Br or I. 14. The method according to any one of claims 1 to 13, wherein the metallizing agent is iPrMgCl. 15. The method of claim 1, wherein The amine protecting agent is trimethylsilyl chloride (TMSCl); The first base is PhMgCl; The metallizing agent is iPrMgCl; and ^Ma represents MgCl. 16. The method according to any one of claims 1 to 15, wherein the first input mixture further comprises a first solvent, the first solvent being tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof. 17. The method of claim 16, wherein the first solvent is tetrahydrofuran (THF). 18. The method according to any one of claims 2 to 17, wherein the first reactor is maintained at a temperature of about -78°C to about 20°C. 19. The method according to any one of claims 2 to 18, wherein the first reactor is cooled to a temperature of about -20°C to about 0°C. 20. The method according to any one of claims 1 to 19, wherein the second input mixture further comprises a second solvent, the second solvent being tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or combinations thereof. 21. The method of claim 20, wherein the second solvent is tetrahydrofuran (THF). 22. The method according to any one of claims 2 to 21, wherein the second reactor is maintained at a temperature of about -20°C to about 40°C. 23. The method according to any one of claims 2 to 22, wherein the second reactor is maintained at a temperature of about 10°C to about 30°C. 24. The method according to any one of claims 2 to 23, wherein the second reactor is maintained at a temperature of about 20°C. 25. The method according to any one of claims 1 to 24, further comprising combining the second output mixture with the acid. 26. The method of claim 25, wherein the acid comprises an organic acid or a mineral acid or a combination thereof. 27. The method according to claim 25 or 26, wherein the acid comprises formic acid, acetic acid, citric acid, propionic acid, butyric acid, benzoic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, sulfuric acid, or combinations thereof. 28. The method according to any one of claims 25 to 27, wherein the acid comprises an organic acid. 29. The method according to any one of claims 25 to 28, wherein the acid comprises formic acid, acetic acid, citric acid, propionic acid, butyric acid, or benzoic acid. 30. The method according to any one of claims 25 to 29, wherein the acid comprises acetic acid. 31. The method according to any one of claims 1 to 30, further comprising a compound of formula (V), the method comprising: (a1) Forming a third reaction mixture comprising a compound of formula (III): Amines of formula HR ^a ; and ^The third base is ^R3MgX3 or ^R3Li ; in ^R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and X ³ is Cl, Br or I; This provides a compound of formula (V). 32. The method of claim 31, wherein the amine has the following formula: 33. The method according to claim 31 or 32, wherein The amine has the following formula: and The third alkali is iPrMgCl. 34. The method according to any one of claims 31 to 33, wherein the third reaction mixture further comprises a third solvent, said third solvent being tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or combinations thereof. 35. The method of claim 34, wherein the third solvent is tetrahydrofuran (THF). 36. The method according to any one of claims 31 to 35, wherein the third reaction mixture is maintained at a temperature of about -78°C to about 40°C. 37. The method according to any one of claims 31 to 36, wherein the third reaction mixture is maintained at a temperature of about -20°C to about 25°C. 38. The method according to any one of claims 2 to 37, wherein the method comprises: (a1) Forming the third reaction mixture, the third reaction mixture comprising a compound having the following structure (III): Amines having the following formula: and iPrMgCl, thereby forming a compound of formula (V) with the following structure: (a) The first input mixture is added to the first reactor, wherein the first input mixture comprises TMS-Cl, PhMgCl, iPrMgCl and a compound having the following structure (IV): The first reactor provides the first output mixture; and (b) The first output mixture and the compound of formula (V) are added to the second reactor to form a compound of formula (II-a) or formula (II-b) having the following structure: 39. The method according to any one of claims 1 to 38, wherein the yield of the compound of formula (II-a) or (II-b) is from about 60% to about 90%. 40. The method according to any one of claims 1 to 39, wherein the purity of the compound of formula (II-a) or formula (II-b) is from about 90% to about 100%. 41. The method according to any one of claims 2 to 40, wherein the first reactor and the second reactor are different reactors. 42. The method according to any one of claims 2 to 41, wherein the first reactor and the second reactor are reactors of the same type. 43. The method according to any one of claims 2 to 42, wherein the first reactor and the second reactor are reactors of different types. 44. The method according to any one of claims 2 to 40, wherein the first reactor and the second reactor are single reactors. 45. The method of claim 44, wherein the single reactor is a continuous flow reactor, a plug flow reactor, a continuous tubular reactor, or a mixed flow reactor. 46. The method according to claim 44 or 45, wherein the first reactor is a first reaction zone in the single reactor, and the second reactor is a second reaction zone in the single reactor.