KR20250003858A - Methods and intermediates for the synthesis of adagrasib - Google Patents

Abstract

The present invention relates to a novel synthetic route for synthesizing adagrasib. The present invention also provides intermediates used in the provided synthetic route.

Description

Methods and intermediates for the synthesis of adagrasib

The present invention relates to a novel and improved synthetic route for the synthesis of adagrasib.

Kirsten rat sarcoma 2 viral oncogene homolog (“KRas”) is a small GTPase and member of the Ras family of oncogenes. KRas functions as a molecular switch cycling between an inactive (GDP-bound) and an active (GTP-bound) state, transducing upstream cellular signals received from several tyrosine kinases to downstream effectors that regulate diverse processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

A role for activated KRas in malignancy was observed more than 30 years ago (see, e.g., Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and induce constitutive activation of KRas and downstream signaling have been reported in 25–30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928--942 doi: 10.1038/nrd428). Single nucleotide substitutions resulting in missense mutations in codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinomas, with the G12C transversion being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi: 10.1158/1078-0432.CCR- 11-3265).

The well-known role of KRas in malignancy and the frequent discovery of KRas mutations in a variety of tumor types have made KRas a very attractive target for the pharmaceutical industry for cancer therapy. Despite a massive 30-year discovery effort to develop KRas inhibitors for cancer treatment, no KRas inhibitor has demonstrated sufficient safety and/or efficacy to obtain regulatory approval (e.g., McCormick (2015) Clin Cancer Res. 21 (8): 1797-1801).

The KRas G12C inhibitor compound 2-[( 2S )-4-[7-(8-chloro-1-naphthyl)-2-[[( 2S )-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro- 5H -pyrido[3,4- d ]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849 and adagrasib) has the following structure:

Adagrasip is described, for example, in Example 478 of PCT application WO 2019/099524.

Although WO 2019/099524 describes a process for preparing adagrasib, there is a need in the art for novel and improved synthetic routes for the preparation of adagrasib.

The present invention provides, in one embodiment, a novel and improved method for preparing adagrasip.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

a) A compound having the following structure:

By reacting with a compound of the following structure in the presence of a base and a polar solvent:

A method of producing a final compound of step (a) having the following structure:

In one embodiment, step (a) is performed at a temperature of about 20° C. to about 120° C.

In one embodiment, the method comprises step (b):

b) further comprising the step of reacting the final compound of step (a) with a derivative of phosgene in the presence of an acid and a polar aprotic solvent to produce the final compound of step (b) having the following structure:

In one embodiment, step (b) is performed at a temperature of about 0° C. to about 120° C.

In one embodiment, the method comprises step (c):

c) The final compound of step (b) is prepared in the presence of a base and a polar aprotic solvent. It further comprises a step of producing a final compound of step (c) having the following structure by reacting with:

In one embodiment, step (c) is performed at a temperature of about 0° C. to about 120° C.

In one embodiment, the method comprises step (d):

d) further comprising a step of reacting the final product of step (c) with an activator in the presence of an additive, a polar aprotic solvent and a base to produce the final compound of step (d) having the following structure:

(In the above formula, LG is a leaving group).

In one embodiment, step (d) is performed at a temperature of about -20° C. to about 70° C.

In one embodiment, the method comprises step (e):

e) further comprising the step of reacting the final compound of step (d) with a base in the presence of ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and at least one polar aprotic solvent to produce the final compound of step (e) having the following structure:

In one embodiment, the method comprises step (f):

f) A further step of reacting the final compound of step (e) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

In one embodiment, step (f) is performed at a temperature of about -10° C. to about 50° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- - In the above formula, LG is a leaving group - is reacted with a base in the presence of ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and at least one polar aprotic solvent.

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;

- A step of generating - where LG is a leaving group;

- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- in the presence of bases and polar aprotic solvents. Steps for producing the following compound by reacting:

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;

- A step of generating - where LG is a leaving group;

- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- A step of reacting a derivative of phosgene in the presence of an acid and a polar solvent to produce the following compound:

- in the presence of bases and polar aprotic solvents. Steps for producing the following compound by reacting:

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;

- A step of generating - where LG is a leaving group;

- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- in the presence of base and polar solvent. Steps for producing the following compound by reacting with:

- A step of reacting a derivative of phosgene in the presence of an acid and a polar solvent to produce the following compound:

- in the presence of bases and polar aprotic solvents. Steps for producing the following compound by reacting:

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;

- A step of generating - where LG is a leaving group;

- A step of reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent to produce the following compound:

; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- In the presence of MeONa and MeOH Steps for producing the following compound by reacting:

- Step of reacting triphosgene with hydrogen chloride and 2-MeTHF to produce the following compound:

- In the presence of sodium tert -amylate and 2-MeTHF Steps for producing the following compound by reacting:

- Step of reacting bis(trifluoromethanesulfonyl)aniline in the presence of tribasic potassium phosphate K ₃ PO ₄ and dibasic potassium phosphate K ₂ HPO ₄ in MeCN to produce the following compound:

- ( S )-2-(piperazin-2-yl)acetonitrile dihydrochloride, 2-MeTHF and MeCN were reacted with tribasic potassium phosphate.

a step of generating; and

- A method comprising the step of reacting a sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

In another embodiment, the present invention provides an alternative route for synthesizing adagrasib. Accordingly, in one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

a') in the presence of base and polar solvent. and a step of reacting the same to produce a final compound of step (a') having the following structure:

In one embodiment, step (a') is performed at a temperature of about 0° C. to about 100° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (b'):

b') A step of reacting the final compound of step (a') with an alkylating agent or an arylating agent using a base in the presence of a polar solvent to produce the final compound of step (b') having the following structure:

(In the above formula, R is methyl, ethyl, isopropyl, or benzyl).

In one embodiment, step (b') is performed at a temperature of about 20° C. to about 120° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (c'):

c') The final compound of step (b') is reacted with an oxidizing agent in the presence of a polar aprotic solvent, and optionally a catalyst and a base, to produce the final compound of step (c') having the following structure:

(In the above formula, R is methyl, ethyl, isopropyl, or benzyl).

In one embodiment, step (c') is performed at a temperature of about 0° C. to about 120° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (d'):

d') The final product of step (c') is reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce the final compound of step (d') having the following structure:

In one embodiment, step (d') is performed at a temperature of about -20° C. to about 50° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (e'):

e') The step of reacting the final product of step (d') with an activator in the presence of a base, an additive and a polar aprotic solvent to produce the final compound of step (e') having the following structure:

, (in the above formula, LG is a leaving group).

In one embodiment, step (e') is performed at a temperature of about -20° C. to about 70° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (f'):

f') The final product of step (e') is reacted with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and a polar aprotic solvent to produce the final compound of step (f') having the following structure:

In one embodiment, step (f') is performed at a temperature of about 20° C. to about 120° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (g'):

g') A step of reacting the final compound of step (f') with 2-fluoroacrylic acid (or the corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

In one embodiment, step (g') is performed at a temperature of about -10° C. to about 50° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising: A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- - In the above formula, LG is a leaving group - A step of reacting with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- - A step of reacting ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent, wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl, to produce the following compound:

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- - A step of reacting R in the above formula, wherein R is methyl, ethyl, isopropyl, or benzyl, with an oxidizing agent in the presence of a polar aprotic solvent and optionally a catalyst and a base to produce the following compound:

- Step of reacting ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce the following compound:

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- By reacting with an alkylating agent or an arylating agent and a base in the presence of a polar solvent

- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;

- reacting with an oxidizing agent in the presence of a polar aprotic solvent and optionally a catalyst and a base;

- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;

- Step of reacting ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce the following compound:

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- in the presence of base and polar solvent. Step (a') of producing the final compound having the following structure by reacting with:

- By reacting with an alkylating agent or an arylating agent and a base in the presence of a polar solvent

- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;

- reacting with an oxidizing agent in the presence of a polar aprotic solvent and optionally a catalyst and a base;

- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;

- Step of reacting ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce the following compound:

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- In the presence of MeONa and MeOH Steps for producing the following compound by reacting with:

- Step of reacting 2-iodopropane and sodium hydroxide in the presence of methanol to produce the following compound:

- was reacted with sodium methoxide, sodium tungstate and hydrogen peroxide in the presence of 2-propanol.

Steps to generate;

- was reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of potassium tert -butoxide and THF.

Steps to generate;

- was reacted with bis(trifluoromethanesulfonyl)aniline in the presence of tribasic potassium phosphate K ₃ PO ₄ and dibasic potassium phosphate K ₂ HPO ₄ in MeCN.

Steps to generate;

- Reacted with tribasic potassium phosphate, ( S )-2-(piperazin-2-yl)acetonitrile dihydrochloride and MeCN.

Steps to generate;

- A method comprising the step of reacting a sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

In another embodiment, the present invention provides novel intermediate compounds such as the following compounds:

;

; and

The present invention relates to an improved synthetic route for synthesizing adagrasib as well as novel intermediates used in the provided route.

Although methods for synthesizing adagrasib are known (see WO 2019/099524), the synthesis provided by the present invention is significantly improved in that it has fewer steps overall, provides higher isolation yields and higher or similar purities.

A novel and improved synthesis strategy for MRTX849 - Adagrasib - introduces expensive building blocks at a late stage of the process and features five high-yield steps.

Previous adagrasip synthesis methods involved sequential introduction of two expensive chiral fragments in the first and second steps. The new approach introduces these two fragments at the end of the synthesis, significantly improving the cost-effectiveness of the production.

The new route also avoids the use of protection steps, eliminating both Boc and Cbz protectors, saving time and resources for their introduction and removal, and making the route more environmentally friendly.

The new route bypasses the major cost contributor, palladium catalyst. Palladium, which is increasingly expensive, was used in two of the six steps of the previous synthesis, dramatically increasing the cost. The new procedure described is completely transition metal-free.

definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications referenced herein are incorporated by reference.

As used herein, "KRas G12C" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of cysteine for glycine at amino acid position 12. Assignments of amino acid codons and residue positions for human KRas are based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gly12Cys.

As used herein, “KRas G12C associated disease or disorder” refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. A non-limiting example of a KRas G12C associated disease or disorder is a KRas G12C associated cancer.

As used herein, the term "adagrasib" refers to a compound having the name 2-[( 2S )-4-[7-(8-chloro-1-naphthyl)-2-[[( 2S )-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro- 5H -pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849) and having the following structure:

Adagrasip is described, for example, in Example 478 of PCT application WO 2019/099524.

The term "adagrasib" includes all chiral (enantiomers and diastereoisomers) and racemic forms of this compound.

In one embodiment, the term "adagrasib" refers to salts of the compound, for example, salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and salts formed from quaternary ammonium compounds of the formula --NR+Z- (wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl), toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, benzyloate, and diphenyl acetate).

Whenever this application refers to a chemical compound, unless specifically stated otherwise, the compound includes all chiral (enantiomers and diastereoisomers) and racemic forms of the compound.

"LG" refers to a leaving group, and has the meaning commonly associated with the term "leaving group" in synthetic organic chemistry, i.e., an atom or group which is replaceable under alkylation or nucleophilic aromatic substitution conditions. The term "leaving group" includes, but is not limited to, halogens, such as chlorine and bromide; alkanesulphonyloxy, such as methanesulfonyloxy and ethanesulfonyloxy; arenesulfonyloxy, such as benzylsulfonyloxy and tosyloxy; thienyloxy; dihalophosphinoyloxy; tetrahalophosphaoxy; perfluoroalkanesulfonyloxy, such as trifluoromethanesulfonyloxy, and the like. The leaving group should be chosen to be chemically less reactive than the reactive group, bromine, to ensure proper reaction (except, of course, when the leaving group is bromine, in which case it will be equally reactive).

Unless otherwise specified in this application, "R" refers to a group such as alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, carbocycle, cycloalkyl, heteroalkyl, heterocycle, aryl, aralkyl or arylalkyl.

The term "alkyl" is intended to mean a straight-chain or branched aliphatic group having from 1 to 12 carbon atoms, alternatively from 1 to 8 carbon atoms, and alternatively from 1 to 6 carbon atoms. Other examples of alkyl groups have from 2 to 12 carbon atoms, alternatively from 2 to 8 carbon atoms, and alternatively from 2 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. A "C0" alkyl (as in "C0-C3 alkyl") is a covalent bond.

The term "alkenyl" is intended to mean an unsaturated straight-chain or branched aliphatic group having from 2 to 12 carbon atoms, alternatively from 2 to 8 carbon atoms, alternatively from 2 to 6 carbon atoms and having at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl and hexenyl.

The term "alkynyl" is intended to mean an unsaturated straight-chain or branched aliphatic group having from 2 to 12 carbon atoms, alternatively from 2 to 8 carbon atoms, alternatively from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

As used herein, the terms "alkylene", "alkenylene", or "alkynylene" are intended to mean an alkyl, alkenyl, or alkynyl group, as defined above, which is positioned between two other chemical groups to serve as a linkage therebetween, respectively. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

As used herein, the term "carbocycle" is intended to mean a cycloalkyl or aryl moiety.

The term "cycloalkyl" is intended to mean a saturated or unsaturated mono-, bi-, tri-, or poly-cyclic hydrocarbon group having about 3 to 15 carbons, alternatively 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, and alternatively 5 or 6 carbons. In certain embodiments, the cycloalkyl group is fused to an aryl, heteroaryl, or heterocyclic group. Examples of cycloalkyl groups include, but are not limited to, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and the like.

The term "heteroalkyl" is intended to mean a saturated or unsaturated straight-chain or branched aliphatic group wherein one or more carbon atoms in the group are independently replaced by a heteroatom selected from the group consisting of O, S, and N.

The term "aryl" is intended to mean a mono-, bi-, tri- or polycyclic aromatic moiety, for example, a C6-C14 aromatic moiety, for example, comprising 1 to 3 aromatic rings. Alternatively, the aryl group is a C6-C10 aryl group, alternatively a C6 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl.

The term "aralkyl" or "arylalkyl" is intended to mean a group comprising an aryl group covalently linked to an alkyl group. When an aralkyl group is described as "optionally substituted", it is intended that either or both of the aryl and alkyl moieties may independently be optionally substituted or unsubstituted. Alternatively, the aralkyl group is (C1-C6)alk(C6-C10)aryl, including but not limited to benzyl, phenethyl, and naphthylmethyl. For simplicity, when this term and related terms are referred to as "aralkyl", the order of the groups in the compound is intended to be "aryl-alkyl". Similarly, "alkyl-aryl" is intended to indicate the same order of the groups in the compound as "alkyl-aryl".

The term "pharmaceutically acceptable salt" as used herein refers to a salt which retains the desired biological activity of the identified compound and exhibits minimal or no undesirable toxic effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, specifically including quaternary ammonium salts of the formula --NR+Z-, wherein R is hydrogen, alkyl, or benzyl and Z is a counterion including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

As used herein, the term "mineral acid" (or "inorganic acid") refers to any acid derived from an inorganic compound that dissociates to produce hydrogen ions (H+) in water. Non-limiting examples of mineral acids include hydrogen halides of the general formula HX (wherein X is F, Cl, Br or I), nitric acid, phosphoric acid, sulfuric acid, boric acid and perchloric acid.

As used herein, the term "organic acid" refers to any organic compound having acidic properties. Non-limiting examples of organic acids include sulfonic acids having the general formula RSO3H, wherein R is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl as defined above, carboxylic acids having one or more carboxylic acid moieties having the general formula RCO2H, wherein R is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl as defined above. Non-limiting examples of organic acids are lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.

Synthetic reaction formula

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

a) A compound having the following structure:

By reacting with a compound of the following structure in the presence of a base and a polar solvent:

A method of producing a final compound of step (a) having the following structure:

In one embodiment, step (a) is performed at a temperature of about 20° C. to about 120° C.

In one embodiment, the method further comprises step (b):

b) A further step of reacting the final compound of step (a) with a derivative of phosgene in the presence of an acid and a polar aprotic solvent to produce the final compound of step (b) having the following structure:

In one embodiment, step (b) is performed at a temperature of about 0° C. to about 120° C.

In one embodiment, the method further comprises step (c):

c) The final compound of step (b) is prepared in the presence of a base and a polar aprotic solvent. Step (c) of producing the final compound having the following structure by reacting with:

In one embodiment, step (c) is performed at a temperature of about 0° C. to about 120° C.

In one embodiment, the method further comprises step (d):

d) A step of reacting the final product of step (c) with an activator in the presence of an additive, a polar aprotic solvent and a base to produce the final compound of step (d) having the following structure:

(In the above formula, LG is a leaving group).

In one embodiment, step (d) is performed at a temperature of about -20° C. to about 70° C.

In one embodiment, the method further comprises step (e):

e) The final compound of step (d) is ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a step of reacting with a base in the presence of at least one polar aprotic solvent to produce the final compound of step (e) having the following structure:

In one embodiment, the method further comprises step (f):

f) A step of reacting the final compound of step (e) with 2-fluoroacrylic acid (or the corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

In one embodiment, step (f) is performed at a temperature of about -10° C. to about 50° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- - In the above formula, LG is a leaving group - is reacted with a base in the presence of ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and at least one polar aprotic solvent.

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;

- A step of generating - where LG is a leaving group;

- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- in the presence of bases and polar aprotic solvents. And react with

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;

- A step of generating - where LG is a leaving group;

- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- reacted with a derivative of phosgene in the presence of acid and polar solvent.

Steps to generate;

- in the presence of bases and polar aprotic solvents. And react with

Steps to generate;

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;

- A step of generating - where LG is a leaving group;

- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- in the presence of base and polar solvent. And react with

Steps to generate;

- reacted with a derivative of phosgene in the presence of acid and polar solvent.

Steps to generate;

- in the presence of bases and polar aprotic solvents. Steps for producing the following compound by reacting:

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;

- A step of generating - where LG is a leaving group;

- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;

a step of generating; and

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- In the presence of MeONa and MeOH And react with

Steps to generate;

- Step of reacting hydrogen chloride and 2-MeTHF in the presence of hydrogen chloride and 2-MeTHF triphosgene to produce the following compound:

- In the presence of sodium tert -amylate and 2-MeTHF And react with

Steps to generate;

- was reacted with bis(trifluoromethanesulfonyl)aniline in the presence of tribasic potassium phosphate K ₃ PO ₄ and dibasic potassium phosphate K ₂ HPO ₄ in MeCN.

Steps to generate;

- ( S )-2-(piperazin-2-yl)acetonitrile dihydrochloride, 2-MeTHF and MeCN were reacted with tribasic potassium phosphate.

a step of generating; and

- A method comprising the step of reacting a sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

In another embodiment, the present invention provides an alternative route for synthesizing adagrasib. Accordingly, in one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

a') in the presence of base and polar solvent. and a step of reacting the same to produce a final compound of step (a') having the following structure:

In one embodiment, step (a') is performed at a temperature of about 0° C. to about 100° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (b'):

b') Further comprising the step of reacting the final compound of step (a') with an alkylating agent or an arylating agent using a base in the presence of a polar solvent to produce the final compound of step (b') having the following structural formula:

(In the above formula, R is methyl, ethyl, isopropyl, or benzyl).

In one embodiment, step (b') is performed at a temperature of about 20° C. to about 120° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (c'):

c') The final compound of step (b') is reacted with an oxidizing agent in the presence of a polar aprotic solvent, and optionally, a catalyst and a base, to produce the final compound of step (c') having the following structure:

(In the above formula, R is methyl, ethyl, isopropyl, or benzyl).

In one embodiment, step (c') is performed at a temperature of about 0° C. to about 120° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (d'):

d') The final product of step (c') is reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce the final compound of step (d') having the following structure:

In one embodiment, step (d') is performed at a temperature of about -20° C. to about 50° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (e'):

e') The step of reacting the final product of step (d') with an activator in the presence of a base, an additive and a polar aprotic solvent to produce the final compound of step (e') having the following structure:

(In the above formula, LG is a leaving group).

In one embodiment, step (e') is performed at a temperature of about -20° C. to about 70° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (f'):

f') The final product of step (e') is reacted with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and a polar aprotic solvent to produce the final compound of step (f') having the following structure:

In one embodiment, step (f') is performed at a temperature of about 20° C. to about 120° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib further comprising step (g'):

g') A step of reacting the final compound of step (f') with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

In one embodiment, step (g') is performed at a temperature of about -10° C. to about 50° C.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

을 용매 및 선택적으로 염기의 존재 하에서 2-플루오로아크릴산(또는 상응하는 알칼리 또는 금속 염) 및 커플링제와 반응시켜 아다그라십을 생성하는 단계를 포함한다.

A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- - In the above formula, LG is a leaving group - is reacted with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and a polar aprotic solvent.

Steps to generate;

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasip, the method comprising:

- - In the above formula, R is methyl, ethyl, isopropyl, or benzyl - reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent.

Steps to generate;

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- reacting with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent

Steps to generate;

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasip, the method comprising:

- - A step of reacting R in the above formula, wherein R is methyl, ethyl, isopropyl, or benzyl, with an oxidizing agent in the presence of a polar aprotic solvent to produce the following compound:

- Step of reacting ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce the following compound:

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasip, the method comprising:

- By reacting with an alkylating agent or an arylating agent using a base in the presence of a polar solvent.

- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;

- reacting with an oxidizing agent in the presence of a polar aprotic solvent and optionally a catalyst and a base;

- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;

- Step of reacting ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce the following compound:

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating, where LG is a leaving group in the above formula;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasip, the method comprising:

in the presence of base and polar solvent. Step (a') of producing the final compound having the following structure by reacting with:

- By reacting with an alkylating agent or an arylating agent using a base in the presence of a polar solvent.

- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;

- reacting with an oxidizing agent in the presence of a polar aprotic solvent and optionally a catalyst and a base;

- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;

- was reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent.

Steps to generate;

- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.

- A step of generating - where LG is a leaving group;

- A step of reacting a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce the following compound:

- A method of producing adagrasib comprises the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base.

In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising:

- In the presence of MeONa and MeOH Steps for producing the following compound by reacting with:

- Step of reacting 2-iodopropane and sodium hydroxide in the presence of methanol to produce the following compound:

- A step of reacting sodium methoxide, sodium tungstate and hydrogen peroxide in the presence of 2-propanol to produce the following compound:

- was reacted with ( S )-(1-methylpyrrolidin-yl)methanol in the presence of potassium tert -butoxide and THF.

Steps to generate;

- was reacted with bis(trifluoromethanesulfonyl)aniline in the presence of tribasic potassium phosphate K ₃ PO ₄ and dibasic potassium phosphate K ₂ HPO ₄ in MeCN.

Steps to generate;

- Reacted with tribasic potassium phosphate, ( S )-2-(piperazin-2-yl)acetonitrile dihydrochloride and MeCN.

Steps to generate;

- A method comprising the step of reacting a sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

In one embodiment, in step (a), the polar solvent is selected from the group consisting of dimethyl acetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), N- methylpyrrolidone (NMP), and an alcohol having the formula R-OH, wherein R is alkyl, allyl or aryl.

In one embodiment, in step (a), the polar solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-Me THF, MeCN, DMSO, NMP and an alcohol having the formula R-OH, wherein R can be, but is not limited to, alkyl, allyl or aryl.

In one embodiment, in step (a), the polar solvent is methanol (MeOH).

In one embodiment, in step (a), the base is selected from the group consisting of methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (a), the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (a), the base is sodium methoxide.

In one embodiment, in step (b), the phosgene derivative is selected from the group consisting of phosgene, diphosgene, triphosgene, thiophosgene and 1,1'-carbonyldiimidazole.

In one embodiment, in step (b), the phosgene derivative comprises, but is not limited to, one or more of the following: phosgene, diphosgene, triphosgene, thiophosgene, and 1,1'-carbonyldiimidazole.

In one embodiment, in step (b), the phosgene derivative is triphosgene.

In one embodiment, in step (f), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in step (b), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in step (b), the polar aprotic solvent is 2-MeTHF.

In one embodiment, in step (b), the mineral acid is selected from the group consisting of hydrochloric acid, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

In one embodiment, in step (b), the mineral acid comprises, but is not limited to, one or more of the following: hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

In one embodiment, in step (b), the mineral acid is hydrogen chloride.

In one embodiment, in step (c), the base is a butyl alkoxide selected from the group consisting of iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (c), the base is a butyl alkoxide, which includes but is not limited to one or more of the following: iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (c), the base is sodium tert -amylate,

In one embodiment, in step (c), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in step (c), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in step (c), the polar aprotic solvent is 2-MeTHF.

In one embodiment, in steps (d) and (e), the activator is selected from the group consisting of sulfonyl halides R-SO ₂ X (wherein R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, or Br), anhydrides (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride), and organic triflate reagents R ^l -N-Tf2 (wherein R ₁ is phenyl, 5-chloro-2-pyridine, 2-pyridine).

In one embodiment, in steps (d) and (e), the activator comprises one or more of the following: a sulfonyl halide R-SO ₂ X (wherein R can be but is not limited to tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X can be but is not limited to F, Cl or Br), an anhydride (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride), and an organic triflate reagent R ¹ -N-Tf ₂ (wherein R ¹ is phenyl, 5-chloro-2-pyridine, 2-pyridine).

In one embodiment, in step (d), the activator is bis(trifluoromethanesulfonyl)aniline.

In one embodiment, in steps (d) and (e), the base is an inorganic base.

In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

In one embodiment, the inorganic base comprises, but is not limited to, one or more of the following: carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

In one embodiment, the inorganic base is used as an alkali salt selected from the group consisting of lithium, sodium and potassium.

In one embodiment, the inorganic base is used as an alkali salt including, but not limited to, one or more of lithium, sodium and potassium.

In one embodiment, in step (d), the base is tribasic and dibasic potassium phosphate.

In one embodiment, in steps (d) and (e), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in steps (d) and (e), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in step (d), the polar aprotic solvent is MeCN.

In one embodiment, in step (e), the polar aprotic solvent is MeCN.

In one embodiment, in step (f), 2-fluoroacrylic acid can be used in neutral form, the free acid or in ionic form (as a metal or alkali salt).

In one embodiment, in step (f), the coupling agent is selected from the group consisting of propylphosphonic anhydride (T3P®), carbonyldiimidazole (CDI), a carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-( N',N' -dimethylamino)propylcarbodiimide hydrochloride (EDC.HCl)), a phosphonium ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)) and a uronium ( O- (benzotriazol-1-yl)- N,N,N',N' -tetramethyluronium hexafluorophosphate (HBTU), O -(7-azabenzotriazol-1-yl)- N,N,N',N' -tetramethyluronium hexafluorophosphate (HATU) is selected from the group consisting of.

In one embodiment, in step (f), the base is an organic base.

In one embodiment, the organic base is selected from the group consisting of DIPEA, Et ₃ N, DABCO, and DBU.

In one embodiment, in step (f), the base is an inorganic base.

In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

In one embodiment, in step (f), the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

In one embodiment, in step (f), the solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

In one embodiment, the polar solvent in steps (a') and (b') is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol having the formula R-OH, wherein R is alkyl, allyl or aryl.

In one embodiment, in steps (a') and (b'), the polar solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP and an alcohol having the formula R-OH, wherein R can be, but is not limited to, alkyl, allyl or aryl.

In one embodiment, in step (a'), the polar solvent is MeOH.

In one embodiment, in step (a'), the base is selected from the group consisting of methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (a'), the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (a'), the base is sodium methoxide.

In one embodiment, in step (b'), the alkylating agent or arylating agent is selected from the group consisting of aryl halide or alkyl halide R-X (wherein R is methyl, ethyl, isopropyl, or benzyl, and X is Cl, Br, I, alkyl sulfonate, aryl sulfonate, triflate, or nonaflate), di-alkyl sulfates, and carbonates.

In one embodiment, in step (b'), the alkylating agent or arylating agent comprises but is not limited to one or more of the following: aryl halides, alkyl halides R-X (wherein R can be but is not limited to methyl, ethyl, isopropyl, or benzyl, and X can be but is not limited to CI, Br, I, alkyl sulfonate, aryl sulfonate, triflate, or nonaflate), di-alkyl sulfates, and carbonates.

In one embodiment, the alkylating agent is 2-iodopropane.

In one embodiment, in step (b'), the base is an inorganic base.

In one embodiment, the inorganic base is selected from the group consisting of hydroxides, carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

In one embodiment, the inorganic base comprises, but is not limited to, one or more of the following: hydroxides, carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

In one embodiment, the inorganic base is used as an alkali salt selected from the group consisting of lithium, sodium and potassium.

In one embodiment, in step (b'), the base is sodium hydroxide.

In one embodiment, in step (c'), the oxidizing agent is selected from the group consisting of peroxide, oxone, bleach, hydrogen peroxide and urea hydrogen peroxide.

In one embodiment, in step (c'), the oxidizing agent comprises, but is not limited to, one or more of the following: a peracid (e.g., meta-chloroperbenzoic acid or peracetic acid), oxone, bleach, hydrogen peroxide and urea hydrogen peroxide.

In one embodiment, in step (c'), the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogensulfate.

In one embodiment, in step (c'), the catalyst comprises, but is not limited to, one or more of the following: sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogensulfate.

In one embodiment, in step (c'), the catalyst is sodium tungstate.

In one embodiment, in step (c'), the base is selected from the group consisting of methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (c'), the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (c'), the ammonium salt or alkali salt is selected from the group consisting of lithium, sodium and potassium.

In one embodiment, in step (c'), the ammonium salt or alkali salt comprises, but is not limited to, one or more of the following: lithium, sodium and potassium.

In one embodiment, in step (c'), the base is sodium methoxide.

In one embodiment, in step (c'), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol and NMP.

In one embodiment, in step (c'), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol and NMP.

In one embodiment, in step (d'), the base is a butyl alkoxide selected from the group consisting of iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (d'), the base is a butyl alkoxide, which includes but is not limited to one or more of the following: iso -propoxide, tert -butoxide and tert -amylate.

In one embodiment, in step (d'), the base is potassium tert -butoxide.

In one embodiment, in step (d'), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in step (d'), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in step (d'), the polar aprotic solvent is THF.

In one embodiment, in steps (e') and (f'), the activator is selected from the group consisting of sulfonyl halides R-SO ₂ X (wherein R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, or Br), anhydrides (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride) and organic triflate reagents R ^l -N-Tf2 (wherein R ₁ is phenyl, 5-chloro-2-pyridine, 2-pyridine).

In one embodiment, in steps (e') and (f'), the activator comprises but is not limited to one or more of the following: a sulfonyl halide R-SO ₂ X (wherein R can be but is not limited to tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X can be but is not limited to F, Cl or Br), an anhydride (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride), and an organic triflate reagent R ¹ -N-Tf ₂ (wherein R ¹ is phenyl, 5-chloro-2-pyridine or 2-pyridine).

In one embodiment, the activator in step (e') and/or (f') is bis(trifluoromethanesulfonyl)aniline.

In one embodiment, in steps (e') and (f'), the base is an inorganic base.

In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

In one embodiment, the inorganic base comprises, but is not limited to, one or more of the following: carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

In one embodiment, the inorganic base is used as an alkali salt selected from the group consisting of lithium, sodium and potassium.

In one embodiment, the inorganic base is used as an alkali salt including, but not limited to, one or more of lithium, sodium and potassium.

In one embodiment, in step (e'), the inorganic base is tribasic and dibasic potassium phosphate.

In one embodiment, in steps (e') and (f'), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in steps (e') and (f'), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

In one embodiment, in steps (e') and (f'), the polar aprotic solvent is MeCN.

In one embodiment, in step (g'), 2-fluoroacrylic acid can be used in neutral form, the free acid, or in ionic form (as a metal or alkali salt).

In one embodiment, in step (g'), the coupling agent is selected from the group consisting of T3P®, CDI, carbodiimide (e.g., DCC, DIG, EDC.HC1), BOP, PyBOP, HBTU, HATU.

In one embodiment, in step (g'), the base is an organic base.

In one embodiment, the organic base is selected from the group consisting of DIPEA, Et ₃ N, DABCO, and DBU.

In one embodiment, in step (g'), the base is an inorganic base.

In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

In one embodiment, in step (g'), the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IP Ac, and NMP.

In one embodiment, in step (g'), the solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

The following examples are intended to illustrate further specific embodiments of the present invention and are not intended to limit the scope of the present invention.

Example 1

Step (a)

Methyl 1-(8-chloronaphthalen-1-yl)-5-hydroxy-1,2,3,6-tetrahydropyridine-4-carboxylate (75 g, 236 mmol, 1.0 equiv) was placed in a 2 L glass-lined reactor, followed by thiourea (54 g, 708 mmol, 3 equiv). Methanol (750 mL) was then added. The reaction was stirred at 20 °C. Sodium methoxide (34 g, 590 mmol, 2.5 equiv) was added to the reaction in one portion at 20 °C. The reaction was then reacted at 60 °C until the starting material area was less than 1.0 area % (approximately 4 h). The mixture was then cooled to 20 °C, and purified water (750 mL) was added. The mixture was filtered through a pad of Celite and transferred to a clean reactor. 2 N hydrochloric acid solution was slowly added to the reaction mixture at 15-25°C until pH = 4-5. Violent precipitation was observed after the addition of hydrochloric acid solution. The solid was then filtered, reslurried with purified water (375 mL) and filtered a second time. The solid was dried at T below 45°C under nitrogen flow and low vacuum until constant mass. 7-(8-Chloronaphthalen-1-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4( 1H )-one was obtained as a pale yellow solid (77 g, 225 mmol, 95% yield).

Mp: 237.5 - 237.6℃ (dec.).

¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 2.35 (br d, J = 16.4 Hz, 1H), 2.51 - 2.59 (m, 1H), 3.05 - 3.16 (m, 1H), 3.36 - 3.45 (m , 1H), 3.57 (br d, J = 17.0 Hz, 1H), 3.94 (d, J = 17.5 Hz, 1H), 7.27 - 7.36 (m, 1H), 7.39 - 7.48 (m, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.59 (dd, J = 7.4, 1.4 ㎐, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.85 - 7.96 (m, 1H), 11.68 - 12.50 (br s, 1H).

¹³ C NMR (126 ㎒, DMSO- d ₆ ) δ ppm 21.6, 49.7, 53.5, 109.8, 119.7, 125.5, 126.5, 127.3, 129.1, 129.3, 130.1, 137.5, 148.3, 150.1, 161.9, 172.9, 174.9.

HRMS (ESI) Calculated for C ₁₇ H ₁₅ CIN ₃ OS: 344.0624 [M+H] ⁺ , Found: 344.0779.

Example 2

Step (b)

7-(8-Chloronaphthalen-1-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4( 1H )-one (10 g, 29 mmol, 1.0 equiv) was placed in a 400 mL EasyMax reactor, followed by 2-MeTHF (200 mL), and the reaction was stirred at 25 °C. 4 N hydrogen chloride in dioxane (7.3 mL, 29 mmol, 1.0 equiv) was then added. Triphosgene (8.6 g, 29 mmol, 1.0 equiv) was added to the reaction at 25 °C. The reaction was then reacted at 25 °C until the starting material area was less than 0.5 area % (approximately 24 h). The mixture was then cooled to 15 °C, and purified water (50 mL) was added. While stirring, 1 N sodium hydroxide solution was slowly added to the reaction mixture at 15-25 °C until the pH = 5-6. The mixture was then stirred for 10 min at 15 °C, the layers were allowed to settle and separated. The aqueous phase was discarded, and the organic phase was concentrated until the solution volume was about 30 mL. Heptane (50 mL) was then added, and the volatiles were removed from the slurry. The solid was dried at T below 45 °C under a nitrogen flow and low vacuum until constant mass. 2-Chloro-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one was obtained as a yellow solid (8.5 g, 25 mmol, 85% yield).

Mp: 200.7 - 200.8℃ (dec.).

¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 2.54 (br s, 1H), 2.71 - 2.85 (m, 1H), 3.11 (br s, 1H), 3.44 - 3.52 (m, 1H), 3.82 ( m, 1H), 3.99 (m, 1H), 7.33 - 7.37 (m, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.57 (dd, J = 7.4, 1.4 Hz, 1H), 7.74 (d, J = 7.7 ㎐, 1H), 7.91 (dd, J = 8.2, 1.1 Hz, 1H), 13.39 (m, 1H).

¹³ C NMR (126 ㎒, DMSO- d ₆ ) δ ppm 164.5, 151.3, 148.3, 147.4, 137.5, 130.1, 129.3, 129.1, 127.3, 126.4, 125.5, 125.4, 119.5, 104.4, 57.1,49.8, 22.3.

HRMS (ESI) Calculated for C ₁₇ H ₁₄ Cl ₂ N ₃ O: 346.0514 [M+H] ⁺ found 346.0668.

Example 3

Step (c)

2-Chloro-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin- 4(3H)-one (100 mg, 0.29 mmol, 1 equiv) was placed in an 8 mL vial, followed by addition of 2-MeTHF (1.0 mL). The reaction was stirred at 20 °C. Then ( S )-(1-methylpyrrolidin-2-yl)methanol (41 μL, 0.35 mmol, 1.2 equiv) was added. Then sodium tert -amylate (160 mg, 0.87 mmol, 5.0 equiv) was added to the reaction mixture. The reaction was then reacted at 60 °C until the starting material area was less than 0.5 area % (approximately 16 h). The mixture was cooled to 20 °C and 1.0 mL of 10% w/w citric acid in water was added to the reaction mixture. The organic phase was discarded and the aqueous phase was further washed with 0.5 mL of 2-MeTHF. The organic phase was discarded, 1.0 mL of fresh 2-MeTHF was added and the pH of the aqueous solution was made neutral (6.5 < pH < 7.5). The organic phase was set aside and the neutral aqueous phase was extracted again with 0.5 mL of fresh 2-MeTHF. The combined organic phases were concentrated to half and 1.0 mL of heptane was added. After removal of volatiles, the solid was dried under nitrogen flow and low vacuum at T below 45 °C to constant mass . (S )-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one was obtained as a light beige solid (107 mg, 0.25 mmol, 87% yield).

MP: 140.9 - 141.0℃,

¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.51 - 1.61 (m, 1H), 1.66 (br d, J = 8.2 Hz, 2H), 1.84 - 1.94 (m, 1H), 2.14 - 2.25 (m , 1H), 2.33 (s, 3H), 2.42 (m, 1H), 2.52 - 2.60 (m, 1H), 2.62 - 2.72 (m, 1H), 2.90 - 2.98 (m, 1H), 3.01 - 3.09 (m, 1H), 3.42 - 3.48 ( m, 1H), 3.63 - 3.70 (m, 1H), 3.88 (d, J = 17.0 Hz, 1H), 4.16 - 4.27 (m, 2H), 7.34 (d, J = 7.1 Hz, 1H), 7.40 - 7.46 (m, 1H), 7.51 (t, J = 7.9 Hz) , 1H), 7.57 (dd, J = 7.4, 1.4 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.90 (dd, J = 8.2, 1.1 Hz, 1H), 12.2 (br s, 1H).

¹³ C NMR (126 ㎒, DMSO- d ₆ ) δ ppm 163.6, 157.8, 156.0, 148.6, 137.6, 130.0, 129.4, 129.0, 127.3, 126.4, 125.5, 125.1, 119.2, 112.4, 69.6, 63.7, 57.5, 57.3, 50.4, 41.6, 28.4, 23.1, 22.2.

Calculated for C ₂₃ H ₂₆ CIN ₄ O ₂ : 425.1744 [M+H] ¹ , found: 425.1902.

Example 4

Steps (d) and (e)

( S )-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (3.0 g, 7.06 mmol, 1 equiv), tribasic potassium phosphate (3.0 g, 14.12 mmol, 2 equiv), and dibasic potassium phosphate (1.2 g, 7.06 mmol, 1 equiv) were placed in a 100 mL reactor, and MeCN (30.0 mL) was added. The reaction was stirred at 0 °C, and bis(trifluoromethanesulfonyl)aniline (4.5 g, 12.71 mmol, 1.8 equiv) was slowly added to the reaction mixture. The reaction was then reacted at 0°C until the starting material area was less than 5 area% (approximately 24 h). Then, tribasic potassium phosphate (1.5 g, 7.06 mmol, 1 eq) was added to the same mixture, followed by ( S )-2-(piperazin-2-yl)acetonitrile dihydrochloride (g, 8.47 mmol, 1.2 eq). The reaction was then reacted at 20°C until the triflate intermediate area was less than 0.5 area% (approximately 16 h). To the mixture was added 30.0 mL of water. The phases were separated, and the organic phase was concentrated to dryness, and then diluted with 9.0 mL of DMAc. Then 3.0 mL of water was added, and the mixture was seeded with the final crystalline product (1% w/w). The mixture was stirred for 10 h, after which 9.0 mL of water was slowly added over 3 h. The slurry was stirred at rt until the black color of the forming liquid was less than 1 area %. The crystalline solid was then filtered, washed with 6.0 mL of water and then dried under nitrogen flow and low vacuum at T below 45 °C until constant mass and KF NMT 10%. 2-( (S) -4-(7-(8-chloronaphthalen-1-yl)-2-(( (S) -1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile was obtained as an off-white solid (2.6 g, 4.94 mmol, 70% yield).

Mp: 60.3 - 60.4℃.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.52 - 1.73 (m, 3H), 1.84 - 1.96 (m, 1H), 2.13 (q, J = 8.7 Hz, 1H), 2.32 (d, J = 1.8 Hz, 3H), 2.44 - 2.49 (m, 1H), 2.61 - 2.83 (m, 5H), 2.85 - 2.98 (m, 3H), 3.07 (br s, 3H), 3.37 (br s, 2H), 3.42 - 3.51 (m, 1H), 3.72 (s, 1H), 3.85 (br d, J = 12.4 Hz, 1H) 4.01 (ddd, J = 10.5, 6.7, 3.3 ㎐, 1H), 4.17 (br d, J = 17.4 Hz, 1H), 4.24 (dd, J = 10.7, 4.9 ㎐, 1H) 7.31 (ddd, J = 7.6, 3.4, 0.9 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.57 (dd, J = 7.6 , 1.3 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.87 - 7.95 (m, 1H).

¹³ C NMR (101 ㎒, DMSO- d ₆ ) δ ppm 21.2, 22.5, 25.6, 28.5, 41.2, 44.6, 47.6, 50.0, 51.0, 51.6, 56.9, 58.6, 63.4, 68.7, 108.2, 118.7, 118.8, 124.6, 124.9, 125.9, 126.8, 128.5, 128.8, 129.5, 137.0, 148.0, 162.1, 163.8, 165.6.

HRMS (ESI) Calculated for C ₂₉ H ₃₅ CIN ₇ O: 532.2592 [M+H] ⁺ , Found: 532.2706.

Example 5

Step (f)

Acetonitrile (1093.0 kg) was added to a 3000 L glass lined reactor. Next, MR84916 (81.6 kg, mass corrected to HPLC assay wt % 68.1 kg, 128.0 mol, 1.0 eq) was added to the reactor. The mixture was concentrated under reduced pressure (P ≤ -0.06 MPa) at a temperature below 45 °C until 3 to 4 vol (204 to 272 L) remained. Acetonitrile (268.0 kg) was then added to the mixture at a temperature below 45 °C. The mixture was concentrated under reduced pressure (P ≤ -0.06 MPa) at a temperature below 45 °C until 3 to 4 vol (204 to 272 L) remained. The mixture was sampled to determine that the moisture content was less than 0.3% (actual 0.1%) as determined by Karl-Fischer analysis. The mixture was cooled to a temperature of 10 to 25°C (actual 16.5°C). Acetonitrile (163.9 kg) was added to a separate 3000 L Hastelloy reactor. The mixture was sampled to determine that the moisture content was less than 0.3% (actual 0.02%). Sodium 2-fluoroacrylate (25.0 kg, 218 mol, 1.7 eq) was added to the Hastelloy reactor under nitrogen protection at a temperature of 10 to 20°C. It was determined that the sodium 2-fluoroacrylate was finely powdered prior to addition. The reactor walls were rinsed with acetonitrile (13.7 kg). A 50 w/w% solution of propylphosphonic anhydride in ethyl acetate (124.7 kg, 192 mol, 1.5 eq) was added to the sodium 2-fluoroacrylate solution in a Hastelloy reactor at 10 to 20°C under nitrogen protection. The mixture was stirred at 10 to 20°C for more than 2 hours. The mixture containing MR84916 in a 3000 L glass lined reactor was slowly added to the mixture containing 2-fluoroacrylate in a 3000 L Hastelloy reactor at 10 to 20°C. The 3000 L glass lined reactor containing MR84916 was rinsed with acetonitrile (18.2 kg) and transferred to the Hastelloy reactor with the acrylate. The reaction was allowed to proceed at 10 to 20 °C (14.5 to 18.0 °C) and after 1 h, the mixture was sampled every 1 to 3 h for HPLC purity analysis until the area % of MR84916/(MR84916 + MRTX849) was less than 0.4% (0.3% observed at 5 h 1 min). The mixture was adjusted to pH 8 to 9 using potassium carbonate solution (348.3 kg) prepared from potassium carbonate (41.6 kg) and purified water (307.2 kg) at a temperature of 10 to 30 °C. The mixture was continued to be stirred for an additional 0.5 h and then the pH was retested for confirmation (actual pH 8). The mixture was adjusted to a temperature of 25 to 35 °C, stirring was stopped and the layers were allowed to settle before separation. The aqueous phase was transferred and retained. The mixture was washed with potassium phosphate tribasic solution prepared from potassium phosphate tribasic (50.1 kg) and purified water (204.4 kg) at a temperature of 25 to 35°C. The mixture was stirred for an additional 0.5 to 3 h at a temperature of 25 to 35°C and allowed to stand before separation. The aqueous phase was transferred and retained. The aqueous layers were combined and extracted with 2-MeTHF (175.9 kg). The mixture was stirred for an additional 20 to 30 min at a temperature of 25 to 35°C and the layers were allowed to stand before separation. The organic fractions were combined and the combined mixture was then concentrated under reduced pressure (P ≤ -0.06 MPa) at a temperature of up to 45°C until 2 to 3 vol (136 to 204 L) remained. Isopropanol (429.2 kg) was added to the mixture at a temperature of up to 45°C. (136 to 204 L) The mixture was concentrated at a temperature below 45°C under reduced pressure (P ≤ -0.06 MPa) until 2 to 3 vol remained. Isopropanol (320.1 kg) was added to the mixture at a temperature below 45°C. The mixture was circulated through a CUNO filtration system. The CUNO filter was then rinsed with isopropanol (106.9 kg) and added to the reactor. The mixture was concentrated at a temperature below 45°C under reduced pressure (P ≤ 0.06 MPa) until 4.5 to 5.5 vol (306 to 374 L) remained. The mixture was sampled to ensure that the acetonitrile residue remaining was less than 1.5% (actual 0.05%). The mixture was adjusted to a temperature of 33 to 38°C (actual 35.3°C). Purified water (170.0 kg) was added to the mixture at 33 to 38°C. Form 2 seed crystals (0.2 kg) were added to the mixture at a temperature of 33 to 38°C. The mixture was maintained at this temperature and stirred for 2 to 3 hours. The mixture was slowly cooled to 15 to 20°C. The mixture was maintained at this temperature and stirred for 6 to 10 hours. Purified water (170.0 kg) was added to the reactor at a temperature of 15 to 20°C. The mixture was slowly cooled to -3 to 7°C (actual 4.8°C). The mass was stirred at -3 to 7°C for crystallization and after 8 hours the mixture was sampled every 3 to 5 hours until the mother liquor assay wt% of MRTX849 was less than 0.7% or the difference between two consecutive samples was less than 0.1 wt% (observed 0.7 wt%). The mixture was filtered using a stainless steel centrifuge. Purified water (102.6 kg) and isopropanol (16.4 kg) were added to a 3000 L Hastelloy-lined reactor and then transferred to a stainless steel centrifuge to rinse the filter cake. The wet filter cake was swept with nitrogen for 6 to 8 hours and dried in a rotary cone dryer at T below 40 °C until the moisture content was below 1% as determined by Karl-Fischer analysis. After drying was complete, the solid was cooled to 20 to 30 °C. Isopropanol (368.4 kg) was added to a 1000 L glass-lined reactor and stirring was then started. The solid from the filter cake was added to the 1000 L reactor and the mixture was heated to a temperature of 55 to 60 °C (actual 57.2 °C). The mixture was maintained at this temperature and stirred until the solid was completely dissolved as confirmed by visual inspection. The mixture was then filtered through a filtration system heated to 55-60°C into a 1000 L Hastelloy reactor (T-jacket = preheated to 55-60°C). The mixture was maintained at 55-60°C. n-Heptane (80.5 kg) was added to the reactor passing through the filter first for rinsing. The mixture was stirred in the reactor for 0.5 h. After the solids were completely dissolved, the mixture was cooled to a temperature of 43-47°C. Isopropanol (5.5 kg) and n-heptane (1.3 kg) were added through a capsule filter to a 20 L 4-necked flask, and Form 2 seed crystals (MRTX849 Form 2, 0.8 kg) maintained at a temperature of 20-25°C were added to prepare a seed slurry. The mixture was stirred until uniformly mixed, and then it was recycled through a wet mill. Prior to adding the slurry feed to the reactor, the reactor was checked to ensure that the MRTX849 was completely dissolved and no precipitation occurred. The Form 2 seed slurry was then added to a 1000 L Hastelloy reactor at a temperature of 43 to 47 °C. The mixture was stirred at 43 to 47 °C for 3 to 4 hours. The mixture was then cooled to a temperature of 28 to 32 °C and stirred at that temperature (actual 30.6 °C) for 4 to 5 hours. After that time, the mixture was cooled to 18 to 22 °C and stirred for 4 to 5 hours (actual 20.9 °C). The mixture was then cooled to -3 to 7 °C (actual 3.5 °C) while stirring. After 12 hours, the supernatant of the mixture was sampled every 3 to 5 hours to check the assay wt % of MRTX849 in the mother liquor and ensure that the level was less than or equal to 1.2% or, alternatively, that the difference between samples was less than or equal to 0.2%. During crystallization, nitrogen was intermittently bubbled through the bottom port of the reactor. Upon checking the mother liquor, the assay wt % of MRTX849 was found to be 1.0%. The mixture was recirculated through the wet mill at -3 to 10°C, and the batch temperature can be expected to rise by 2 to 3°C during this process. The solids were sampled for particle size until the D(90) was less than 100 μm (actually 22 μm). The mixture was maintained at -3 to 7°C for 0.5 to 1 hour. The mixture was then filtered through a stainless steel Nutsche filter. The reactor walls were rinsed with a mixed solvent system of n-heptane (15.9 kg) and isopropanol (74.1 kg) through a liquid material filter. The wet mill was then rinsed with this rinsing liquid, transferred to the reactor, and then discharged through a filter to rinse the filter cake. The above operation was repeated once more using a mixed solvent of n-heptane (15.9 kg) and isopropanol (74.2 kg). Due to the small particle size from the wet milling, the filtration appeared to be very slow. The solid inside the filter was swept with nitrogen at T- _jacket =20 to 30°C for 8 to 10 hours and then dried at T-jacket =35 to 45°C until the isopropanol residue was less than 6300 ppm (actual 3488 ppm) and the n -heptane residue was less than 3500 ppm (not detected, LOD 432 ppm) as measured by GC. After drying was complete, the solid was cooled to a temperature of 20 to 30°C. The solid was sieved until the appearance of the product was uniform and free of blocking. The working area RH% should be less than 50%. The product (MRTX849) was obtained as an off-white solid (51.1 kg, mass corrected for assay wt% 50.0 kg, 100.4 assay wt%, 64.7% yield).

Mp: 128.3 - 128.4℃.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.56 - 1.77 (m, 3H), 1.96 (br dd, J = 11.9, 7.6 Hz, 1H), 2.20 (dd, J = 8.2, 2.4 Hz, 1H ), 2 37 (d, J = 3.5 Hz, 3H), 2.72 (br d, J = 1.8 Hz, 1H), 2.91 - 3.03 (m, 2H), 3.04 - 3.23 (m, 4H), 3.28 (br del, J = 13.8, 3.7 Hz, 1H ), 3.33 - 3.63 (m, 4H), 3.73-3.86 (m, 1H), 3.89 - 3.98 (m, 1H), 3.99 - 4.15 (m, 3H), 4.17 - 4.36 (m, 2H), 5.22 - 5.41 (m, 1H), 5.42 - 5.50 (m) , 1H), 7.34 - 7.44 (m, 1H), 7.46 - 7.53 (m, 1H), 7.58 (q, J = 7.6 Hz, 1H), 7.63 (dt, J = 7.5, 1.1 Hz, 1H), 7.75 - 7.83 (m, 1H), 7.93 - 8.00 (m, 1H).

¹³ C NMR (101 ㎒, DMSO- d ₆ ) δ ppm 22.5, 25.0, 25.3, 25.5, 26.8, 28.5, 41.2, 47.5, 50.0, 57.0, 58.4, 58.7, 63.4, 68.9, 99.5, 108.6, 118.1, 118.8, 124.7, 124.9, 125.9, 126.9, 128.5, 128.9, 129.5, 137.0, 148.0, 155.5 (d, J = 266.39 Hz), 161.0 (d, J - 11.71 ㎐), 162.0, 164.3, 165.9.

¹⁹ F NMR (376 ㎒, DMSO-d ₆ ) δ ppm -106.4,

Calculated for C ₃₂ H ₃₆ CIFN ₇ O ₂ : 604.2603 [M+H] ⁺ , Found : 604.2690,

Example 6

Selective isolation of MRTX849 as a tartrate salt:

3.5 L of ethanol was added to the reactor containing MRTX849 (875 g) and stirred until completely dissolved. In a separate reactor IM, 1.59 L of THF and 0.24 kg of L-tartaric acid were added to prepare L-tartaric acid in THF and heated to 35-40°C. The tartaric acid solution prepared above was added to the ethanol reaction mixture of MRTX849 at 45-50°C.

MRTX849 free base seed (60 mg) was added at 45 to 50°C, and gradual formation of a precipitate was observed. The slurry was stirred at 45 to 50°C for at least 1 hour, filtered, washed with cold ethanol, and dried under vacuum at 40°C for 24 hours.

Example 7

Step (a')

Methyl 1-(8-chloronaphthalen-1-yl)-5-hydroxy-1,2,3,6-tetrahydropyridine-4-carboxylate (75 g, 236 mmol, 1.0 equiv) was placed in a 2 L glass-lined reactor, followed by thiourea (54 g, 708 mmol, 3 equiv). Methanol (750 mL) was then added. The reaction was stirred at 20 °C. Sodium methoxide (34 g, 590 mmol, 2.5 equiv) was added to the reaction in one portion at 20 °C. The reaction was then reacted at 60 °C until the starting material area was less than 1.0 area % (approximately 4 h). The mixture was then cooled to 20 °C, and purified water (750 mL) was added. The mixture was filtered through a pad of Celite and transferred to a clean reactor. 2 N hydrochloric acid solution was slowly added to the reaction mixture at 15-25°C until pH = 4-5. Violent precipitation was observed after the addition of hydrochloric acid solution. The solid was then filtered, reslurried with purified water (375 mL) and filtered a second time. The solid was dried at T below 45°C under nitrogen flow and low vacuum until constant mass. 7-(8-Chloronaphthalen-1-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4( 1H )-one was obtained as a pale yellow solid (77 g, 225 mmol, 95% yield).

Mp: 237.5 - 237.6℃ (dec.).

¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 2.35 (br d, J = 16.4 Hz, 1H), 2.51 - 2.59 (m, 1H), 3.05 - 3.16 (m, 1H), 3.36 - 3.45 (m , 1H), 3.57 (br d, J = 17.0 Hz, 1H), 3.94 (d, J = 17.5 Hz, 1H), 7.27 - 7.36 (m, 1H), 7.39 - 7.48 (m, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.59 (dd, J = 7.4, 1.4 ㎐, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.85 - 7.96 (m, 1H), 11.68 - 12.50 (br s, 1H).

¹³ C NMR (126 MHz, DMSO-d ₆ ) δ ppm 21.6, 49.7, 53.5, 109.8, 119.7, 125.5, 126.5, 127.3, 129.1, 129.3, 130.1, 137.5, 148.3, 150.1, 161.9, 172.9, 174.9.

HRMS (ESI) Calculated for C ₁₇ H ₁₅ CIN ₃ OS: 344.0624 [M+H] ⁺ , Found: 344.0779.

Example 8

Step (b')

7-(8-Chloronaphthalen-1-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(lH)-one (10 g, 29.0 mmol, 1.0 equiv) was placed in a 250 mL 3-necked round-bottom flask. MeOH (100 mL) was then added. Then, a 1 N aqueous solution of sodium hydroxide (77 mL, 77.0 mmol, 2.66 equiv) was added. Stirring was continued until a homogeneous solution was obtained. Then, 2-iodopropane (5.2 mL, 50.0 mmol, 1.7 equiv) was added to the solution. The reaction was then allowed to react at 40 °C until the starting material area was less than 3.0 area % (approximately 36 h). The reaction mixture was cooled to 5 °C and 2 N aqueous HC1 (45 mL, 90 mmol, 3 equiv) was added slowly. The solid formed upon addition was then collected by filtration and washed with water (100 mL). The solid was dried to constant mass to give 7-(8-chloronaphthalen-1-yl)-2-(isopropylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one as an off-white solid (9.6 g, 24.7 mmol, 85% yield).

Mp: 225.8 - 225.9℃

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.62 (s, 1H), 7.91 (dd, J = 8.2, 1.3 Hz, 1H), 7.73 (dd, J = 8.2, 1.1 Hz, 1H), 7.58 ( dd, J = 7.5, 1.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.36 (dd, J = 7.6, 1.2 Hz, 1H), 3.96 (d, J = 17.1 ㎐, 1H), 3.86 (hept, J = 6.9 Hz, 1H), 3.73 (dt, J = 17.1,2.1 ㎐, 1H), 3.45 (dd, J = 12.5, 5.5 ㎐, 1H), 3.06 (ddd, J= 11.8, 10.0, 4.1 ㎐, 1H), 2.72 (dt , J = 15.7, 7.3 Hz, 1H), 2.46 (d, J = 16.7 Hz, 1H), 1.43 - 1.25 (m, 6H).

¹³ C NMR (101 ㎒, DMSO- d ₆ ) δ 162.3, 158.0, 155.3, 148.5, 137.5, 130.0, 129.4, 129.0, 127.3, 126.3, 125.4, 125.1, 119.2, 115.2, 57.4, 50.1, 36.1, 23.1, 23.0, 22.2.

HRMS (ESI) Calculated for C ₂₀ H ₂₁ CIN ₃ OS: 386.1094 [M+H] ⁺ , Found: 386.1092

Example 9

Step (c')

7-(8-Chloronaphthalen-1-yl)-2-(isopropylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (12 g, 31 mmol, 1.0 equiv) was placed in a 250 mL 3-necked round-bottom flask. MeOH (60 mL) was then added. The reaction mixture was cooled to 0 °C, and sodium methoxide solution (7 mL, 34 mmol, 1.1 equiv, 4.5 M in MeOH) was slowly added. Sodium tungstate (1.0 g, 3.1 mmol, 0.1 equiv) was then added to the reaction mixture, followed by the slow addition of hydrogen peroxide (32 mL, 310. mmol, 10 equiv, 30% in water). Afterwards, the reactants were reacted at 20°C until the starting material area became less than 1.0 area% (approximately 16 h). Water (120 mL) and 2-MeTHF (120 mL) were added to the reaction mixture. The mixture was cooled to 5°C, and 20% w/v aqueous acetic acid (120 mL) was slowly added. After the addition was complete, sodium carbonate was slowly added until pH = 8 (gas evolution). The aqueous phase was discarded, and the organic phase was washed with brine. The organic phase was concentrated under reduced pressure, and 2-MeTHF (36 mL) was added. Heptane (120 mL) was added slowly, and after filtration and drying, 7-(8-chloronaphthalen-1-yl)-2-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one was obtained as an off-white solid (12.5 g, 28.2 mmol, 91% yield).

Mp: 195.5 - 195.6℃.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.66 (s, 1H), 7.92 (dd, J = 8.2, 1.3 Hz, 1H), 7.76 (dd, J = 8.3, 1.1 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.45 (t, J -7.8 Hz, 1H), 7.39 (dd, J = 7.6, 1.2 Hz, 1H), 4.19 (d, J = 17.2 Hz, 1H), 3.99 (dt, J = 17.4, 1.8 Hz, 1H) , 3.90 - 3.75 (m, J = 6.8 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.20 (ddd, J= 12.0, 10.1, 4.1 Hz, 1H), 2.97 (ddd, J = 16.7, 10.3, 6.3 Hz, 1H), 2.74 - 2.65 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H).

¹³ C NMR (101 ㎒, DMSO- d ₆ ) δ 168.6, 163.7, 160.4, 148.2, 137.5, 130.1, 129.3, 129.1, 127.3, 126.4, 125.4, 125.4, 119.4, 117.8, 57.5, 51.0, 49.8, 22.8, 15.1, 15.0.

HRMS (ESI) Calculated for C ₂₀ H ₂₁ CIN ₃ O ₃ S: 418.0992 [MH] ⁺ , Found: 418.0991.

Example 10

Step (d')

( S )-(1-Methylpyrrolidin-2-yl)methanol (230 mg, 2.0 mmol, 2.0 equiv) was placed in a 20 mL vial. THF (2.4 mL) was then added. The reaction was cooled to 0 °C.

Potassium tert -butoxide (450 mg, 4 mmol, 4.0 equiv) was then added at the same temperature. 7-(8-Chloronaphthalen-1-yl)-2-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (418 mg, 1.0 mmol, 1.0 equiv) in THF (2.4 mL) was added slowly at 0 °C. The reaction was then reacted at 20 °C until the starting material area was less than 1.0 area % (approximately 16 h). The reaction mixture was cooled to 0 °C and 10 w/w% AcOH in THF (4 mL) was added slowly. Methanol (4 mL) was then added and the insoluble material was filtered off. The filtrate was concentrated to remove most of the solvent, and ethyl acetate (10 mL) was added. The organic phase was washed with brine, dried over MgSO ₄ and filtered. The volatiles were removed, and the crude product (400 mg) was stirred in n -heptane (8 mL) for 16 h at 20 °C. The solid product was filtered to obtain ( S )-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one as an off-white solid (310 mg, 0.72 mmol, 72% yield).

Mp: 140.9-141.0℃

¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.51 - 1.61 (m, 1H), 1.66 (br d, J = 8.21 Hz, 2H), 1.84 - 1.94 (m, 1H), 2.14 - 2.25 (m , 1H), 2.33 (s, 3H), 2.42 (m, 1H), 2.52 - 2.60 (m, 1H), 2.62 - 2.72 (m, 1H), 2.90 - 2.98 (m, 1H), 3.01 - 3.09 (m, 1H), 3.42 - 3.48 ( m, 1H), 3.63 - 3.70 (m, 1H), 3.88 (d, J - 16.97 Hz, 1H), 4.16-4.27 (m, 2H), 7.34(d, J = 7.12 Hz, 1H), 7.40-7.46 (m, 1 H), 7.51 (t, J = 7.94 ㎐, 1 H), 7.57 (dd, J = 7.39, 1.37 Hz, 1 H), 7.72 (d, J = 7.67 Hz, 1H), 7.90 (dd, J = 8.21, 1.10 Hz, 1H), 12.2 (br s, 1H).

¹³ C NMR (126 ㎒, DMSO- d ₆ ) δ ppm 163.6, 157.8, 156.0, 148.6, 137.6, 130.0, 129.4, 129.0, 127.3, 126.4, 125.5, 125.1, 119.2, 112.4, 69.6, 63.7, 57.5, 57.3, 50.4, 41.6, 28.4, 23.1,22.2.

HRMS (ESI) Calculated for C ₂₃ H ₂₆ CIN ₄ O ₂ : 425.1744 [M+H] ⁺ , Found: 425.1902.

Example 11

Steps (e') and (f')

( S )-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (3.0 g, 7.06 mmol, 1 equiv), tribasic potassium phosphate (3.0 g, 14.12 mmol, 2 equiv), and dibasic potassium phosphate (1.2 g, 7.06 mmol, 1 equiv) were placed in a 100 mL reactor, and MeCN (30.0 mL) was added. The reaction was stirred at 0 °C, and bis(trifluoromethanesulfonyl)aniline (4.5 g, 12.71 mmol, 1.8 equiv) was slowly added to the reaction mixture. The reaction was then reacted at 0°C until the starting material area was less than 5 area% (approximately 24 h). Then, tribasic potassium phosphate (1.5 g, 7.06 mmol, 1 eq) was added to the same mixture, followed by ( S )-2-(piperazin-2-yl)acetonitrile dihydrochloride (g, 8.47 mmol, 1.2 eq). The reaction was then reacted at 20°C until the triflate intermediate area was less than 0.5 area% (approximately 16 h). To the mixture was added 30.0 mL of water. The phases were separated, and the organic phase was concentrated to dryness, and then diluted with 9.0 mL of DMAc. Then 3.0 mL of water was added, and the mixture was seeded with the final crystalline product (1% w/w). The mixture was stirred for 10 h, after which 9.0 mL of water was slowly added over 3 h. The slurry was stirred at rt until the black color of the forming liquid was less than 1 area %. The crystalline solid was then filtered, washed with 6.0 mL of water and then dried under nitrogen flow and low vacuum at T below 45 °C until constant mass and KF NMT 10%. 2-( (S) -4-(7-(8-chloronaphthalen-1-yl)-2-(( (S) -1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile was obtained as an off-white solid (2.6 g, 4.94 mmol, 70% yield).

Mp: 60.3 - 60.4℃.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.52 - 1.73 (m, 3H), 1.84 - 1.96 (m, 1H), 2.13 (q, J = 8.67 Hz, 1H), 2.32 (d, J = 1.77 ㎐, 3H), 2.44 - 2.49 (m, 1H), 2.61 - 2.83 (m, 5H), 2.85 - 2.98 (m, 3H), 3.07 (br s, 3H), 3.37 (br s, 2H), 3.42 - 3.51 (m, 1H) ), 3.72 (s, 1H), 3.85 (br d, J = 12.38 ㎐, 1H) 4.01 (ddd, J = 10.48, 6.69, 3.28 ㎐, 1H), 4.17 (br d, J = 17.43 ㎐, 1H), 4 24 (dd, J = 10.74, 4.93 ㎐, 1H) 7.31 (ddd , J = 7.58, 3.41, 0.88 Hz, 1H), 7.43 (t, J = 7.83 Hz, 1H), 7.52 (t, J = 7.71 Hz, 1H), 7.57 (dd, J = 7.58, 1.26 Hz, 1H), 7.72 ( d, J = 8.08 Hz, 1H), 7.87 - 7.95 (m, 1H).

¹³ C NMR (101 ㎒, DMSO- d ₆ ) δ ppm 21.2, 22.5, 25.6, 28.5, 41.2, 44.6, 47.6, 50.0, 51.0, 51.6, 56.9, 58.6, 63.4, 68.7, 108.2, 118.7, 118.8, 124.6, 124.9, 125.9, 126.8, 128.5, 128.8, 129.5, 137.0, 148.0, 162.1, 163.8, 165.6.

HRMS (ESI) Calculated for C ₂₉ H ₃₅ CIN ₇ O: 532.2592 [M+H] ⁺ , Found: 532.2706.

Example 12

Step (g')

Acetonitrile (1093.0 kg) was added to a 3000 L glass lined reactor. Next, MR84916 (81.6 kg, mass corrected to HPLC assay wt % 68.1 kg, 128.0 mol, 1.0 eq) was added to the reactor. The mixture was concentrated under reduced pressure (P ≤ -0.06 MPa) at a temperature below 45 °C until 3 to 4 vol (204 to 272 L) remained. Acetonitrile (268.0 kg) was then added to the mixture at a temperature below 45 °C. The mixture was concentrated under reduced pressure (P ≤ -0.06 MPa) at a temperature below 45 °C until 3 to 4 vol (204 to 272 L) remained. The mixture was sampled to determine that the moisture content was less than 0.3% (actual 0.1%) as determined by Karl-Fischer analysis. The mixture was cooled to a temperature of 10 to 25°C (actual 16.5°C). Acetonitrile (163.9 kg) was added to a separate 3000 L Hastelloy reactor. The mixture was sampled to determine that the moisture content was less than 0.3% (actual 0.02%). Sodium 2-fluoroacrylate (25.0 kg, 218 mol, 1.7 eq) was added to the Hastelloy reactor under nitrogen protection at a temperature of 10 to 20°C. It was determined that the sodium 2-fluoroacrylate was finely powdered prior to addition. The reactor walls were rinsed with acetonitrile (13.7 kg). A 50 w/w% solution of propylphosphonic anhydride in ethyl acetate (124.7 kg, 192 mol, 1.5 eq) was added to the sodium 2-fluoroacrylate solution in a Hastelloy reactor at 10 to 20°C under nitrogen protection. The mixture was stirred at 10 to 20°C for more than 2 hours. The mixture containing MR84916 in a 3000 L glass lined reactor was slowly added to the mixture containing 2-fluoroacrylate in a 3000 L Hastelloy reactor at 10 to 20°C. The 3000 L glass lined reactor containing MR84916 was rinsed with acetonitrile (18.2 kg) and transferred to the Hastelloy reactor with the acrylate. The reaction was allowed to proceed at 10 to 20 °C (14.5 to 18.0 °C) and after 1 h, the mixture was sampled every 1 to 3 h for HPLC purity analysis until the area % of MR84916/(MR84916 + MRTX849) was less than 0.4% (0.3% observed at 5 h 1 min). The mixture was adjusted to pH 8 to 9 using potassium carbonate solution (348.3 kg) prepared from potassium carbonate (41.6 kg) and purified water (307.2 kg) at a temperature of 10 to 30 °C. The mixture was continued to be stirred for an additional 0.5 h and then the pH was retested for confirmation (actual pH 8). The mixture was adjusted to a temperature of 25 to 35 °C, stirring was discontinued and the layers were allowed to settle before separation. The aqueous phase was transferred and retained. The mixture was washed with potassium phosphate tribasic solution prepared from potassium phosphate tribasic (50.1 kg) and purified water (204.4 kg) at a temperature of 25 to 35°C. The mixture was stirred for an additional 0.5 to 3 h at a temperature of 25 to 35°C and allowed to stand before separation. The aqueous phase was transferred and retained. The aqueous layers were combined and extracted with 2-MeTHF (175.9 kg). The mixture was stirred for an additional 20 to 30 min at a temperature of 25 to 35°C and the layers were allowed to stand before separation. The organic fractions were combined and the combined mixture was then concentrated under reduced pressure (P ≤ -0.06 MPa) at a temperature of up to 45°C until 2 to 3 vol (136 to 204 L) remained. Isopropanol (429.2 kg) was added to the mixture at a temperature of up to 45°C. (136 to 204 L) The mixture was concentrated at a temperature below 45°C under reduced pressure (P ≤ -0.06 MPa) until 2 to 3 vol remained. Isopropanol (320.1 kg) was added to the mixture at a temperature below 45°C. The mixture was circulated through a CUNO filtration system. The CUNO filter was then rinsed with isopropanol (106.9 kg) and added to the reactor. The mixture was concentrated at a temperature below 45°C under reduced pressure (P ≤ 0.06 MPa) until 4.5 to 5.5 vol (306 to 374 L) remained. The mixture was sampled to ensure that the acetonitrile residue remaining was less than 1.5% (actual 0.05%). The mixture was adjusted to a temperature of 33 to 38°C (actual 35.3°C). Purified water (170.0 kg) was added to the mixture at 33 to 38°C. Form 2 seed crystals (0.2 kg) were added to the mixture at a temperature of 33 to 38°C. The mixture was maintained at this temperature and stirred for 2 to 3 hours. The mixture was slowly cooled to 15 to 20°C. The mixture was maintained at this temperature and stirred for 6 to 10 hours. Purified water (170.0 kg) was added to the reactor at a temperature of 15 to 20°C. The mixture was slowly cooled to -3 to 7°C (actual 4.8°C). The mass was stirred at -3 to 7°C for crystallization and after 8 hours the mixture was sampled every 3 to 5 hours until the mother liquor assay wt% of MRTX849 was less than 0.7% or the difference between two consecutive samples was less than 0.1 wt% (observed 0.7 wt%). The mixture was filtered using a stainless steel centrifuge. Purified water (102.6 kg) and isopropanol (16.4 kg) were added to a 3000 L Hastelloy-lined reactor and then transferred to a stainless steel centrifuge to rinse the filter cake. The wet filter cake was swept with nitrogen for 6 to 8 hours and dried in a rotary cone dryer at T below 40 °C until the moisture content was below 1% as determined by Karl-Fischer analysis. After drying was complete, the solid was cooled to 20 to 30 °C. Isopropanol (368.4 kg) was added to a 1000 L glass-lined reactor and stirring was then started. The solid from the filter cake was added to the 1000 L reactor and the mixture was heated to a temperature of 55 to 60 °C (actual 57.2 °C). The mixture was maintained at this temperature and stirred until the solid was completely dissolved as confirmed by visual inspection. The mixture was then filtered through a filtration system heated to 55-60°C into a 1000 L Hastelloy reactor (T _jacket = preheated to 55-60°C). The mixture was maintained at 55-60°C. n -Heptane (80.5 kg) was added to the reactor passing through the filter first for rinsing. The mixture was stirred in the reactor for 0.5 h. After the solids were completely dissolved, the mixture was cooled to a temperature of 43-47°C. Isopropanol (5.5 kg) and n-heptane (1.3 kg) were added through a capsule filter to a 20 L 4-necked flask, and Form 2 seed crystals (MRTX849 Form 2, 0.8 kg) maintained at a temperature of 20-25°C were added to prepare a seed slurry. The mixture was stirred until uniformly mixed and then it was recycled through the wet mill. Prior to adding the slurry feed to the reactor, the reactor was checked to ensure that the MRTX849 was completely dissolved and no precipitation occurred. The Form 2 seed slurry was then added to a 1000 L Hastelloy reactor at a temperature of 43 to 47 °C. The mixture was stirred at 43 to 47 °C for 3 to 4 hours. The mixture was then cooled to a temperature of 28 to 32 °C and stirred at that temperature (actual 30.6 °C) for 4 to 5 hours. After that time, the mixture was cooled to 18 to 22 °C and stirred for 4 to 5 hours (actual 20.9 °C). The mixture was then cooled to -3 to 7 °C (actual 3.5 °C) while stirring. After 12 hours, the supernatant of the mixture was sampled every 3 to 5 hours to check the assay wt % of MRTX849 in the mother liquor and ensure that the level was less than or equal to 1.2% or, alternatively, that the difference between samples was less than or equal to 0.2%. During crystallization, nitrogen was intermittently bubbled through the bottom port of the reactor. Upon checking the mother liquor, the assay wt % of MRTX849 was found to be 1.0%. The mixture was recirculated through the wet mill at -3 to 10°C, and the batch temperature can be expected to rise by 2 to 3°C during this process. The solids were sampled for particle size until the D(90) was less than 100 μm (actually 22 μm). The mixture was maintained at -3 to 7°C for 0.5 to 1 hour. The mixture was then filtered through a stainless steel Nutsche filter. The reactor walls were rinsed with a mixed solvent system of n-heptane (15.9 kg) and isopropanol (74.1 kg) through a liquid material filter. The wet mill was then rinsed with this rinsing liquid, transferred to the reactor, and then discharged through a filter to rinse the filter cake. The above operation was repeated once more using a mixed solvent of n-heptane (15.9 kg) and isopropanol (74.2 kg). Due to the small particle size from the wet milling, the filtration appeared to be very slow. The solid inside the filter was swept with nitrogen at T- _jacket =20 to 30°C for 8 to 10 hours and then dried at T-jacket =35 to 45°C until the isopropanol residue was less than 6300 ppm (actual 3488 ppm) and the n -heptane residue was less than 3500 ppm (not detected, LOD 432 ppm) as measured by GC. After drying was complete, the solid was cooled to a temperature of 20 to 30°C. The solid was sieved until the appearance of the product was uniform and free of blocking. The working area RH% should be less than 50%. The product (MRTX849) was obtained as an off-white solid (51.1 kg, mass corrected for assay wt% 50.0 kg, 100.4 assay wt%, 64.7% yield).

Mp: 128.3 - 128.4℃.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.56 - 1.77 (m, 3H), 1.96 (br dd, J = 11.87, 7.58 Hz, 1H), 2.20 (dd, J = 8.21,2.40 Hz, 1H ), 2.37 (d, J = 3.54 Hz, 3H), 2.72 (br d, J = 1.77 Hz, 1H), 2.91 - 3.03 (m, 2H), 3.04 - 3.23 (m, 4H), 3.28 (br dd, J = 13.77, 3.66 Hz, 1H), 3.33 - 3.63 (m, 4H), 3.73 - 3.86 (m, 1H), 3.89 - 3.98 (m, 1H), 3.99 - 4.15 (m, 3H), 4.17 - 4.36 (m, 2H), 5.22 - 5.41 (m, 1H), 5.42 - 5.50 (m, 1H), 7.34 - 7.44 (m, 1H), 7.46 - 7.53 (m, 1H), 7.58 (q, J = 7.58 Hz, 1H), 7.63 (dt, J = 7.45, 1.07 Hz, 1H), 7.75 - 7.83 (m, 1H), 7.93 - 8.00 (m, 1H).

¹³ C NMR (101 ㎒, DMSO- d ₆ ) δ ppm 22.5, 25.0, 25.3, 25.5, 26.8, 28.5, 41.2, 47.5, 50.0, 57.0, 58.4, 58.7, 63.4, 68.9, 99.5, 108.6, 118.1, 118.8, 124.7, 124.9, 125.9, 126.9, 128.5, 128.9, 129.5, 137.0, 148.0, 155.5 (d, J = 266.39 Hz), 161.0 (d, J = 11.71 ㎐), 162.0, 164.3, 165.9.

¹⁹ F NMR (376 ㎒, DMSO-d ₆ ) 8 ppm -106.4.

HRMS (ESI) Calculated for C ₃₂ H ₃₆ CIFN ₇ O ₂ : 604.2603 [M+H] ⁺ , Found: 604.2690.

Selective isolation of MRTX849 as a tartrate salt:

3.5 L of ethanol was added to a reactor charged with MRTX849 (875 g) and stirred until completely dissolved. In a separate reactor IM, 1.59 L of THF and 0.24 kg of L-tartaric acid were added to prepare L-tartaric acid in THF and heated to 35-40°C. The tartaric acid solution prepared above was added to the ethanol reaction mixture of MRTX849 at 45-50°C. MRTX849 free base seed (60 mg) was added at 45-50°C and precipitate formation was observed slowly. The slurry was stirred at 45-50°C for at least 1 hour, filtered, washed with cold ethanol and dried under vacuum at 40°C for 24 hours.

While the invention has been described with reference to specific embodiments thereof, it will be understood that further modifications are possible and that the present application is intended to cover any modification, use, or adaptation of the invention which follows the principles of the invention and which comes within known or customary practice to which the invention pertains and which includes such departures from the teachings of the present disclosure as can be applied to the essential features set forth above and which are within the scope of the appended claims.

Claims (109)

As a method for synthesizing adagrasip,
a) A compound having the following structure:

By reacting with a compound of the following structure in the presence of a base and a polar solvent:

A method for synthesizing adagrasib, comprising the step of producing a final compound of step (a) having the following structure:
A method for synthesizing adagrasib in claim 1, wherein the base is selected from the group consisting of methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate. A method for synthesizing adagrasib, wherein in claim 1, the base is MeONa. A method for synthesizing adagrasib in claim 1, wherein the polar solvent is selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), N- methylpyrrolidone (NMP), and an alcohol having the chemical formula R-OH, wherein R is alkyl, allyl or aryl. A method for synthesizing adagrasib in claim 1, wherein the polar solvent is MeOH. In paragraph 1, step (b):
b) A method for synthesizing adagrasib, further comprising the step of reacting the final compound of step (a) with a derivative of phosgene in the presence of an acid and a polar aprotic solvent to produce the final compound of step (b) having the following structure:
A method for synthesizing adagrasib in claim 6, wherein the phosgene derivative is selected from the group consisting of phosgene, diphosgene, triphosgene, thiophosgene, and 1,1'-carbonyldiimidazole. A method for synthesizing adagrasib in claim 7, wherein the derivative of phosgene is triphosgene. A method for synthesizing adagrasib in claim 6, wherein the acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. A method for synthesizing adagrasib in claim 9, wherein the mineral acid is hydrogen chloride. A method for synthesizing adagrasib in claim 6, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. A method for synthesizing adagrasib in claim 11, wherein the polar aprotic solvent is 2-MeTHF. In paragraph 6, step (c):
c) The final compound of step (b) is prepared in the presence of a base and a polar aprotic solvent. A method for synthesizing adagrasib, further comprising the step of reacting with a compound of step (c) to produce a final compound having the following structure:
A method for synthesizing adagrasib in claim 13, wherein the base is selected from the group consisting of iso -propoxide, tert -butoxide and tert -amylate. A method for synthesizing adagrasib in claim 14, wherein the base is tert -amylate. A method for synthesizing adagrasib in claim 13, wherein the base is sodium tert -amylate. A method for synthesizing adagrasib in claim 13, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. A method for synthesizing adagrasib in claim 17, wherein the polar aprotic solvent is 2-MeTHF. In paragraph 13, step (d):
d) further comprising a step of reacting the final product of step (c) with an activator in the presence of an additive, a polar aprotic solvent and a base to produce the final compound of step (d) having the following structure:
, wherein LG is a leaving group, a method for synthesizing adagrasib. A method for synthesizing adagrasib in claim 19, wherein the activator is selected from the group consisting of sulfonyl halides R-SO ₂ X (wherein R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, or Br), anhydrides (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride), and organic triflate reagents R ^l -N-Tf2 (wherein R ¹ is phenyl, 5-chloro-2-pyridine, or 2-pyridine). A method for synthesizing adagrasib in claim 20, wherein the activator is bis(trifluoromethanesulfonyl)aniline. A method for synthesizing adagrasib in claim 19, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. A method for synthesizing adagrasib in claim 19, wherein the polar aprotic solvent is MeCN. A method for synthesizing adagrasib in claim 19, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 24, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. A method for synthesizing adagrasib in claim 25, wherein the inorganic base is tribasic potassium phosphate or dibasic potassium phosphate. In paragraph 19, step (e):
e) a method for synthesizing adagrasib, further comprising the step of reacting the final compound of step (d) with a base in the presence of ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and at least one polar aprotic solvent to produce the final compound of step (e) having the following structure:
A method for synthesizing adagrasib in claim 27, wherein the base is an organic base. A method for synthesizing adagrasib in claim 28, wherein the organic base is selected from the group consisting of DIPEA, Et ₃ N, DABCO, and DBU. A method for synthesizing adagrasib in claim 27, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 30, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. A method for synthesizing adagrasib in claim 27, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. A method for synthesizing adagrasib in claim 33, wherein the polar aprotic solvent comprises MeCN. In paragraph 27, step (f):
f) A method for synthesizing adagrasib, further comprising the step of reacting the final compound of step (e) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. In claim 34, the coupling agent is propylphosphonic anhydride (T3P®), carbonyldiimidazole (CDI), carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-( N',N' -dimethylamino)propylcarbodiimide hydrochloride (EDC.HCl)), phosphonium ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)), and uronium ( O -(benzotriazol-1-yl)- N,N,N',N' -tetramethyluronium hexafluorophosphate (HBTU), O -(7-azabenzotriazol-1-yl)- A method for synthesizing adagrasib, wherein the adagrasib is selected from the group consisting of N,N,N',N' -tetramethyluronium hexafluorophosphate (HATU). A method for synthesizing adagrasib in claim 34, wherein the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP. A method for synthesizing adagrasib in claim 34, wherein the base is an organic base. A method for synthesizing adagrasib in claim 37, wherein the organic base is selected from the group consisting of DIPEA, Et ₃ N, DABCO, and DBU. A method for synthesizing adagrasib in claim 34, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 39, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. As a method for synthesizing adagrasip,
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;
a step of generating; and
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;
- A step of forming - in the above formula, LG is a leaving group;
- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;
a step of generating; and
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- in the presence of bases and polar aprotic solvents.

And react with
Steps to generate;
- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;
- A step of generating - where LG is a leaving group;
- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;
a step of generating; and
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- reacted with a derivative of phosgene in the presence of acid and polar solvent.
Steps to generate;
- in the presence of bases and polar aprotic solvents. And react with
Steps to generate;
- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;
- A step of generating - where LG is a leaving group;
- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;
a step of generating; and
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- in the presence of base and polar solvent. And react with
Steps to produce the following compound:

- A step of reacting a derivative of phosgene in the presence of an acid and a polar solvent to produce the following compound:

- In the presence of an alkali salt and a polar aprotic solvent among alkoxides Steps for producing the following compound by reacting:

- reacting with an activator in the presence of an additive, a polar aprotic solvent and a base;
- A step of generating - where LG is a leaving group;
- reacting ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a base in the presence of at least one polar aprotic solvent;
a step of generating; and
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
a') A compound having the following structure:

By reacting with a compound of the following structure in the presence of a base and a polar solvent:

A method comprising the step of producing a final compound of step (a') having the following structure:
A method for synthesizing adagrasib in claim 47, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 48, wherein the inorganic base is selected from the group consisting of methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate, or an ammonium salt or alkali salt thereof. A method for synthesizing adagrasib in claim 49, wherein the ammonium salt or alkali salt is selected from the group consisting of lithium, sodium, and potassium. A method for synthesizing adagrasib in claim 49, wherein the inorganic base is sodium methoxide. A method for synthesizing adagrasib in claim 47, wherein the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol having the formula R-OH, wherein R is alkyl, allyl or aryl. A method for synthesizing adagrasib in claim 52, wherein the polar solvent is MeOH. In paragraph 47, step (b'):
b') further comprising a step of reacting the final compound of step (a') with an alkylating agent or an arylating agent using a base in the presence of a polar solvent to produce a final compound having the following structure:
, wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl, a method for synthesizing adagrasib. A method for synthesizing adagrasib in claim 54, wherein the alkylating agent or arylating agent is selected from the group consisting of aryl halide or alkyl halide R-X (wherein R is methyl, ethyl, isopropyl, or benzyl, and X is Cl, Br, I, alkyl sulfonate, aryl sulfonate, triflate, or nonaflate), di-alkyl sulfates, and carbonates. A method for synthesizing adagrasib, wherein the alkylating agent in claim 55 is 2-iodopropane. A method for synthesizing adagrasib in claim 54, wherein the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol having the formula R-OH, wherein R is alkyl, allyl or aryl. A method for synthesizing adagrasib in claim 57, wherein the polar solvent is MeOH. A method for synthesizing adagrasib in claim 50, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 59, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate, or ammonium salts or alkali salts thereof. A method for synthesizing adagrasib in claim 60, wherein the ammonium salt or alkali salt is selected from the group consisting of lithium, sodium, and potassium. In paragraph 54, step (c'):
c') A method for synthesizing adagrasib, further comprising the step of reacting the final compound of step (b') with an oxidizing agent in the presence of a polar aprotic solvent and optionally a catalyst and a base to produce the final compound of step (c') having the following structure:
A method for synthesizing adagrasib in claim 62, wherein the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide, and urea hydrogen peroxide. A method for synthesizing adagrasib in claim 63, wherein the oxidizing agent is hydrogen peroxide. A method for synthesizing adagrasib in claim 62, wherein the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate. A method for synthesizing adagrasib in claim 65, wherein the catalyst is sodium tungstate. A method for synthesizing adagrasib in claim 62, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP. A method for synthesizing adagrasib in claim 67, wherein the polar aprotic solvent is 2-propanol. A method for synthesizing adagrasib in claim 62, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 69, wherein the inorganic base is selected from the group consisting of methoxide, ethoxide, iso -propoxide, tert -butoxide and tert -amylate, or an ammonium salt or alkali salt thereof. A method for synthesizing adagrasib in claim 70, wherein the ammonium salt or alkali salt is selected from the group consisting of lithium, sodium, and potassium. A method for synthesizing adagrasib in claim 70, wherein the base is sodium methoxide. In paragraph 63, step (d'):
d') A method for synthesizing adagrasib, further comprising the step of reacting the final product of step (c') with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce the final compound of step (d') having the following structure:
A method for synthesizing adagrasib in claim 73, wherein the base is an alkoxide selected from the group consisting of iso -propoxide, tert -butoxide and tert -amylate, or an ammonium salt or alkali salt thereof. A method for synthesizing adagrasib in claim 74, wherein the alkali salt is selected from the group consisting of lithium, sodium, and potassium. A method for synthesizing adagrasib in claim 74, wherein the alkoxide is potassium tert -butoxide. A method for synthesizing adagrasib in claim 73, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. A method for synthesizing adagrasib in claim 77, wherein the polar aprotic solvent is THF. In paragraph 73, step (e'):
e') further comprising a step of reacting the final product of step (d') with an activator in the presence of a base, an additive and a polar aprotic solvent to produce the final compound of step (e') having the following structure:
, wherein LG is a leaving group, a method for synthesizing adagrasib. A method for synthesizing adagrasib in claim 79, wherein the activator is selected from the group consisting of sulfonyl halides R-SO ₂ X (wherein R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, or Br), anhydrides (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride), and organic triflate reagents R ^l -N-Tf2 (wherein R ¹ is phenyl, 5-chloro-2-pyridine, or 2-pyridine). A method for synthesizing adagrasib in claim 80, wherein the activator is bis(trifluoromethanesulfonyl)aniline. A method for synthesizing adagrasib in claim 81, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 82, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate or an ammonium salt or alkali salt thereof. A method for synthesizing adagrasib in claim 83, wherein the inorganic base is tribasic potassium phosphate or dibasic potassium phosphate. A method for synthesizing adagrasib in claim 81, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. A method for synthesizing adagrasib in claim 85, wherein the polar aprotic solvent is MeCN. In paragraph 79, step (f'):
f') A method for synthesizing adagrasib, further comprising the step of reacting the final product of step (e') with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and a polar aprotic solvent to produce the final compound of step (f') having the following structure:
A method for synthesizing adagrasib in claim 87, wherein the base is an organic base. A method for synthesizing adagrasib in claim 88, wherein the organic base is selected from the group consisting of DIPEA, Et ₃ N, DABCO, and DBU. A method for synthesizing adagrasib in claim 87, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 90, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate or an ammonium salt or alkali salt thereof. A method for synthesizing adagrasib in claim 91, wherein the inorganic base is tribasic potassium phosphate or dibasic potassium phosphate. A method for synthesizing adagrasib in claim 87, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. A method for synthesizing adagrasib in claim 93, wherein the polar aprotic solvent is MeCN. In paragraph 87, step (g'):
g') A method for synthesizing adagrasib, further comprising the step of reacting the final compound of step (f') with sodium 2-fluoroacrylic acid (or the corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. In claim 95, the coupling agent is selected from the group consisting of propylphosphonic anhydride (T3P®), carbonyldiimidazole (CDI), carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-( N',N' -dimethylamino)propylcarbodiimide hydrochloride (EDC.HCl)), phosphonium ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)) and uronium ( O- (benzotriazol-1-yl)- N,N,N',N' -tetramethyluronium hexafluorophosphate (HBTU), O- (7-azabenzotriazol-1-yl)- A method for synthesizing adagrasib, wherein the adagrasib is selected from the group consisting of N,N,N',N' -tetramethyluronium hexafluorophosphate (HATU). A method for synthesizing adagrasib in claim 95, wherein the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP. A method for synthesizing adagrasib in claim 95, wherein the base is an organic base. A method for synthesizing adagrasib in claim 98, wherein the organic base is selected from the group consisting of DIPEA, Et ₃ N, DABCO, and DBU. A method for synthesizing adagrasib in claim 95, wherein the base is an inorganic base. A method for synthesizing adagrasib in claim 100, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. As a method for synthesizing adagrasip,
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- - In the above formula, LG is a leaving group - is reacted with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent.
Steps to generate;
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.
- A step of generating - where LG is a leaving group;
- reacting with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent
Steps to generate;
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- - In the above formula, R is methyl, ethyl, isopropyl, or benzyl - reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent.
Steps to generate;
- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.
- A step of generating - where LG is a leaving group;
- reacting with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent
Steps to generate;
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- - In the above formula, R is methyl, ethyl, isopropyl, or benzyl - reacted with an oxidizing agent in the presence of a polar aprotic solvent.
Steps to generate;
- was reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent.
Steps to generate;
- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.
- A step of generating - where LG is a leaving group;
- reacting with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent
Steps to generate;
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
- By reacting with an alkylating agent or an arylating agent using a base in the presence of a polar solvent.
- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;
- A step of reacting with an oxidizing agent in the presence of a polar aprotic solvent to produce the following compound:

- was reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent.
Steps to generate;
- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.
- A step of generating - where LG is a leaving group;
- reacting with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent
Steps to generate;
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. As a method for synthesizing adagrasip,
-

in the presence of base and polar solvent. And react with
Steps to generate;
- By reacting with an alkylating agent or an arylating agent using a base in the presence of a polar solvent.
- a step of producing - wherein R in the above formula is methyl, ethyl, isopropyl, or benzyl;
- reacted with an oxidizing agent in the presence of a polar aprotic solvent.
Steps to generate;
- was reacted with ( S )-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent.
Steps to generate;
- reacting with an activator in the presence of a base, an additive and a polar aprotic solvent.
- A step of generating - in the above formula, LG is a leaving group;
- reacting with a base, ( S )-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent
Steps to generate;
- A method for synthesizing adagrasib, comprising the step of reacting 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib. A compound selected from the group consisting of:


; and
.