Processes and intermediates for the synthesis of adagrasib

Abstract

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

Description

[Technical field]

[0001] The present invention relates to a new and improved synthetic route for the synthesis of adagrasib. [Background technology]

[0002] Kirsten Rat Sarcoma 2 viral oncogene homolog (KRas) is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch that cycles between inactive (GDP-bound) and active (GTP-bound) states and transmits upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancies 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 lead to 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 at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, 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).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations of KRas in various tumor types have made KRas a highly attractive target for the pharmaceutical industry in cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas for the treatment of cancer, KRas inhibitors have yet to demonstrate sufficient safety and / or efficacy to gain regulatory approval (see, e.g., McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] 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, also known as adagrasib) has the following structure:

[0006] [ka]

[0007] Adaglasib is described, for example, in Example 478 of WO 2019 / 099524.

[0008] Although WO 2019 / 099524 describes methods for making adagrasib, there is a need in the art for new and improved synthetic routes to make adagrasib. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2019 / 099524 [Non-patent literature]

[0010] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.13:394-401 [Non-Patent Document 2] Der et al.,(1982)Proc.Natl Acad.Sci.USA 79(11):3637-3640 [Non-Patent Document 3] Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428 [Non-Patent Document 4] Dogan et al.,(2012)Clin Cancer Res.18(22);6169-6177, published online 2012 Sep 26.doi:10.1158 / 1078-0432.CCR-11-3265 [Non-Patent Document 5] McCormick(2015)Clin Cancer Res.21(8):1797-1801 Summary of the Invention

[0011] The present invention, in one embodiment, provides a new and improved method for making adagrasib.

[0012] In one embodiment, the present invention provides a method of synthesizing adagrasib, the method comprising: a) reacting a compound of the following structure:

[0013] [ka] A compound of the following structure:

[0014] [ka] Reacting in the presence of a base and a polar solvent to give the following structure: The method includes the step of producing a final compound of step (a) having the following structure:

[0015] [ka]

[0016] In one embodiment, step (a) is carried out at a temperature of from about 20°C to about 120°C.

[0017] In one embodiment, the method of the present invention further comprises step (b): b) reacting the final compound of step (a) with a derivative of phosgene in the presence of an acid and a polar aprotic solvent to obtain a compound of the following structure: The method further comprises the step of producing a final compound of step (b) having the following structure:

[0018] [ka]

[0019] In one embodiment, step (b) is carried out at a temperature of from about 0°C to about 120°C.

[0020] In one embodiment, the method further comprises step (c): c) reacting the final compound of step (b) with a base and a polar aprotic solvent;

[0021] [ka] This is reacted with The method further comprises the step of producing a final compound of step (c) having the following structure:

[0022] [ka]

[0023] In one embodiment, step (c) is carried out at a temperature of from about 0°C to about 120°C.

[0024] In one embodiment, the method further comprises step (d): d) reacting the final compound of step (c) with an activating agent in the presence of an additive, a polar aprotic solvent and a base to obtain a compound of the following structure:

[0025] [ka] wherein LG is a leaving group.

[0026] In one embodiment, step (d) is carried out at a temperature of from about -20°C to about 70°C.

[0027] In one embodiment, the method of the present invention further comprises step (e): e) 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 one or more polar aprotic solvents to produce the final compound of step (e) having the following structure:

[0028] [ka]

[0029] In one embodiment, the method of the present invention further comprises step (f): f) 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.

[0030] In one embodiment, step (f) is carried out at a temperature of about -10°C to about 50°C.

[0031] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0032] [ka] 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.

[0033] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0034] [ka] where LG is a leaving group, with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and one or more polar aprotic solvents to produce:

[0035] [ka] and

[0036] [ka] 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.

[0037] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0038] [ka] with an activating agent in the presence of an additive, a polar aprotic solvent and a base,

[0039] [ka] wherein LG is a leaving group;

[0040] [ka] with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and one or more polar aprotic solvents to produce

[0041] [ka] 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.

[0042] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0043] [ka] in the presence of a base and a polar aprotic solvent

[0044] [ka] to produce

[0045] [ka] is reacted with an activating agent in the presence of an additive, a polar aprotic solvent and a base to produce:

[0046] [ka] wherein LG is a leaving group;

[0047] [ka] with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and one or more polar aprotic solvents to produce

[0048] [ka] 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.

[0049] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0050] [ka] with a derivative of phosgene in the presence of an acid and a polar solvent to produce

[0051] [ka] in the presence of a base and a polar aprotic solvent

[0052] [ka] to produce

[0053] [ka] with an activating agent in the presence of an additive, a polar aprotic solvent and a base,

[0054] [ka] wherein LG is a leaving group;

[0055] [ka] with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and one or more polar aprotic solvents to produce

[0056] [ka] 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.

[0057] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0058] [ka] in the presence of a base and a polar solvent.

[0059] [ka] to produce

[0060] [ka] with a derivative of phosgene in the presence of an acid and a polar solvent to produce

[0061] [ka] in the presence of a base and a polar aprotic solvent

[0062] [ka] to produce

[0063] [ka] with an activating agent in the presence of an additive, a polar aprotic solvent and a base,

[0064] [ka] wherein LG is a leaving group;

[0065] [ka] with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and one or more polar aprotic solvents;

[0066] [ka] 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.

[0067] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0068] [ka] in the presence of MeONa and MeOH

[0069] [ka] reacting with:

[0070] [ka] with triphosgene in the presence of hydrogen chloride and 2-MeTHF to produce

[0071] [ka] in the presence of sodium tert-amylate and 2-MeTHF

[0072] [ka] and reacting the compound with

[0073] [ka] with bis(trifluoromethanesulfonyl)aniline in the presence of tripotassium phosphate KPO and dipotassium phosphate KHPO in MeCN to produce

[0074] [ka] with tripotassium phosphate in the presence of (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride, 2-MeTHF and MeCN to produce

[0075] [ka] with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

[0076] In another embodiment, the present invention provides an alternative route for the synthesis of adagrasib. Thus, in one embodiment, the present invention provides a method for the synthesis of adagrasib, comprising: a')

[0077] [ka] in the presence of a base and a polar solvent.

[0078] [ka] to give the following structure: The method comprises the step of producing a final compound of step (a') having the following structure:

[0079] [ka]

[0080] In one embodiment, step (a') is carried out at a temperature of from about 0°C to about 100°C.

[0081] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (b'): b') reacting the final compound of step (a') with an alkylating or arylating agent and a base in the presence of a polar solvent to obtain a compound of the following structure:

[0082] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl.

[0083] In one embodiment, step (b') is carried out at a temperature of about 20°C to about 120°C.

[0084] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (c'): c') 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 give a compound of the following structure:

[0085] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl.

[0086] In one embodiment, step (c') is carried out at a temperature of from about 0° C. to about 120° C. 。

[0087] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (d'): d') reacting the final compound 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 structure:

[0088] [ka]

[0089] In one embodiment, step (d') is carried out at a temperature of about -20°C to about 50°C.

[0090] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (e'): e') reacting the final compound of step (d') with an activating agent in the presence of a base, an additive and a polar aprotic solvent to obtain a compound of the following structure:

[0091] [ka] wherein LG is a leaving group.

[0092] In one embodiment, step (e') is carried out at about -20°C. ~ It is carried out at a temperature of about 70°C.

[0093] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (f'): f') 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:

[0094] [ka]

[0095] In one embodiment, step (f') is carried out at a temperature of about 20°C to about 120°C.

[0096] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (g'): g') 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.

[0097] In one embodiment, step (g') is carried out at a temperature of about -10°C to about 50°C.

[0098] In one embodiment, the present invention provides

[0099] [ka] 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.

[0100] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0101] [ka] wherein LG is a leaving group, with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0102] [ka] 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.

[0103] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0104] [ka] with an activating agent in the presence of a base, an additive and a polar aprotic solvent,

[0105] [ka] wherein LG is a leaving group;

[0106] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0107] [ka] 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.

[0108] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0109] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl, with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce

[0110] [ka] with an activating agent in the presence of a base, an additive and a polar aprotic solvent,

[0111] [ka] wherein LG is a leaving group;

[0112] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0113] [ka] 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.

[0114] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0115] [ka] 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

[0116] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce

[0117] [ka] with an activating agent in the presence of a base, an additive and a polar aprotic solvent,

[0118] [ka] wherein LG is a leaving group;

[0119] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0120] [ka] 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.

[0121] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0122] [ka] with an alkylating or arylating agent and a base in the presence of a polar solvent,

[0123] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl;

[0124] [ka] with an oxidizing agent in the presence of a polar aprotic solvent, and optionally a catalyst and a base,

[0125] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl;

[0126] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce

[0127] [ka] with an activating agent in the presence of a base, an additive and a polar aprotic solvent,

[0128] [ka] wherein LG is a leaving group;

[0129] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent;

[0130] [ka] 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.

[0131] In one embodiment 、 The present invention provides a method for synthesizing adagrasib, comprising:

[0132] [ka] in the presence of a base and a polar solvent.

[0133] [ka] to give the following structure: producing the final compound of step (a'),

[0134] [ka] with an alkylating or arylating agent and a base in the presence of a polar solvent,

[0135] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl;

[0136] [ka] with an oxidizing agent in the presence of a polar aprotic solvent, and optionally a catalyst and a base,

[0137] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl;

[0138] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce

[0139] [ka] with an activating agent in the presence of a base, an additive and a polar aprotic solvent,

[0140] [ka] wherein LG is a leaving group;

[0141] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0142] [ka] 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.

[0143] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0144] [ka] in the presence of MeONa and MeOH

[0145] [ka] to produce

[0146] [ka] with 2-iodopropane and sodium hydroxide in the presence of methanol to produce

[0147] [ka] with sodium methoxide, sodium tungstate and hydrogen peroxide in the presence of 2-propanol to produce

[0148] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of potassium tert-butoxide and THF to produce

[0149] [ka] with bis(trifluoromethanesulfonyl)aniline in the presence of tripotassium phosphate KPO and dipotassium phosphate KHPO in MeCN to produce

[0150] [ka] with tripotassium phosphate, (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride and MeCN to produce

[0151] [ka] with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

[0152] In another embodiment, the present invention provides

[0153] [ka]

[0154] [ka] The present invention provides new intermediate compounds such as DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0155] The present invention relates to new synthetic routes for the synthesis of adagrasib, as well as novel intermediates used in the provided routes.

[0156] While there are known methods of synthesizing adagrasib (see WO 2019 / 099524), the synthesis provided by the present invention is much improved in that it has fewer steps, provides higher isolated yields and higher or similar overall purity.

[0157] The new and improved synthesis of MRTX849-adagrasib-features five high-yielding steps that introduce valuable building blocks late in the process.

[0158] The previous synthesis of adagrasib involved the sequential introduction of two expensive chiral moieties in steps 1 and 2. Using the new approach, these two moieties are introduced towards the end of the synthesis, thus significantly improving the cost-effectiveness of production.

[0159] The new route also eliminates both the Boc and Cbz protecting groups, avoiding the use of protective steps, saving time and resources for the introduction and removal of protecting groups, making the route environmentally friendly.

[0160] This new route avoids the major cost factor of palladium catalysis. The increasingly expensive palladium is used in two of the six steps, which has dramatically increased costs. The new procedure disclosed is completely transition metal-free.

[0161] 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 mentioned herein are incorporated by reference.

[0162] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing a glycine to cysteine ​​amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Glyl2Cys.

[0163] 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.

[0164] As used herein, the term "adagrasib" refers to the 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:

[0165] [ka]

[0166] Adaglasib is described, for example, in Example 478 of WO 2019 / 099524.

[0167] The term "adagrasib" encompasses all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.

[0168] In one embodiment, the term "adagrasib" includes salts of the above compounds, for example, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; 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 salts of the formula --NRZ-. wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0169] Whenever this application refers to a chemical compound, unless specifically stated otherwise, the compound includes all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.

[0170] "LG" refers to a leaving group and has the meaning conventionally associated with the term "leaving group" in synthetic organic chemistry, i.e., an atom or group displaceable under alkylation or nucleophilic aromatic substitution conditions. The term "leaving group" includes, but is not limited to, halogens, such as chlorine and bromide; alkanesulfonyloxy, 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 selected to be chemically less reactive than the reactive group bromine to ensure proper reaction (unless, of course, the similarly reactive leaving group is bromine).

[0171] 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.

[0172] The term "alkyl" is intended to mean a straight or branched aliphatic group having 1 to 12 carbon atoms, alternatively 1 to 8 carbon atoms, alternatively 1 to 6 carbon atoms. Other examples of alkyl groups have 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 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.

[0173] The term "alkenyl" is intended to mean an unsaturated linear or branched aliphatic group having one or more carbon-carbon double bonds and having 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0174] The term "alkynyl" is intended to mean an unsaturated linear or branched aliphatic group having one or more carbon-carbon triple bonds and having 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0175] The terms "alkylene", "alkenylene", or "alkynylene", as used herein, are intended to mean, respectively, an alkyl, alkenyl, or alkynyl group, as defined above, that is located between and serves to connect two other chemical groups. 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.

[0176] As used herein, the term "carbocycle" is intended to mean a cycloalkyl or aryl moiety.

[0177] The term "cycloalkyl" is intended to mean a saturated or unsaturated monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group having about 3 to 15 carbons, alternatively 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, 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.

[0178] The term "heteroalkyl" is intended to mean a saturated or unsaturated, straight-chain or branched aliphatic group, in which one or more carbon atoms in the group are replaced by a heteroatom independently selected from the group consisting of O, S, and N.

[0179] The term "aryl" is intended to mean a monocyclic, bicyclic, tricyclic, or polycyclic aromatic moiety, e.g., a C6-C14 aromatic moiety, e.g., containing 1-3 aromatic rings. Alternatively, the aryl group is a C6-C10 aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0180] The term "aralkyl" or "arylalkyl" is intended to mean a group that includes 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 portions may be, independently, optionally substituted or unsubstituted. Alternatively, the aralkyl group is (C1-C6)alkyl(C6-C10)aryl, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. For brevity, when described as "arylalkyl", this term and its related terms are intended to indicate the order of the groups in a compound as "aryl-alkyl". Similarly, "alkyl-aryl" is intended to indicate the order of the groups in a compound as "alkyl-aryl".

[0181] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound and exhibits minimal or no undesired toxicological effects.Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), 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 pharma- ceutically acceptable quaternary salts known to those of skill in the art, specifically including quaternary ammonium salts of the formula --NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion that includes chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0182] As used herein, the term "mineral acid" (or "inorganic acid") refers to any acid derived from an inorganic compound that dissociates in water to produce a hydrogen ion (H+). Non-limiting examples of mineral acids include hydrogen halides of the general formula HX, where X is F, Cl, Br, or I, nitric acid, phosphoric acid, sulfuric acid, boric acid, and perchloric acid.

[0183] As used herein, the term "organic acid" refers to any organic compound with acidic properties. Non-limiting examples of organic acids include sulfonic acids of general formula RSO3H, where R can be alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, as defined above, and carboxylic acids (having one or several carboxylic acid moieties) of general formula RCOH, where R can be alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, 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.

[0184] Synthesis scheme In one embodiment, the present invention provides a method of synthesizing adagrasib, the method comprising: a) reacting a compound of the following structure:

[0185] [ka] A compound of the following structure:

[0186] [ka] Reacting in the presence of a base and a polar solvent to give the following structure: The method includes the step of producing a final compound of step (a) having the following structure:

[0187] [ka]

[0188] In one embodiment, step (a) is carried out at a temperature of from about 20°C to about 120°C.

[0189] In one embodiment, the method of the present invention further comprises step (b): b) reacting the final compound of step (a) with a derivative of phosgene in the presence of an acid and a polar aprotic solvent to obtain a compound of the following structure: The method further comprises the step of producing a final compound of step (b) having the following structure:

[0190] [ka]

[0191] In one embodiment, step (b) is carried out at a temperature of from about 0°C to about 120°C.

[0192] In one embodiment, the method further comprises step (c): c) reacting the final compound of step (b) with a base and a polar aprotic solvent;

[0193] [ka] to give the following structure: The method further comprises the step of producing a final compound of step (c) having the following structure:

[0194] [ka]

[0195] In one embodiment, step (c) is carried out at a temperature of from about 0°C to about 120°C.

[0196] In one embodiment, the method further comprises step (d): d) reacting the final compound of step (c) with an activating agent in the presence of an additive, a polar aprotic solvent and a base to obtain a compound of the following structure:

[0197] [ka] wherein LG is a leaving group.

[0198] In one embodiment, step (d) is carried out at a temperature of from about -20°C to about 70°C.

[0199] In one embodiment, the method of the present invention further comprises step (e): (e) (e) further comprising 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 one or more polar aprotic solvents to produce the final compound of step (e) having the following structure:

[0200] [ka]

[0201] In one embodiment, the method of the present invention further comprises step (f): f) 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.

[0202] In one embodiment, step (f) is carried out at a temperature of about -10°C to about 50°C.

[0203] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0204] [ka] 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.

[0205] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0206] [ka] where LG is a leaving group, with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and one or more polar aprotic solvents to produce

[0207] [ka] 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.

[0208] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0209] [ka] is reacted with an activating agent in the presence of an additive, a polar aprotic solvent and a base to produce:

[0210] [ka] wherein LG is a leaving group;

[0211] [ka] with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and one or more polar aprotic solvents;

[0212] [ka] 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.

[0213] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0214] [ka] in the presence of a base and a polar aprotic solvent

[0215] [ka] to produce

[0216] [ka] with an activating agent in the presence of an additive, a polar aprotic solvent and a base,

[0217] [ka] wherein LG is a leaving group;

[0218] [ka] with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and one or more polar aprotic solvents;

[0219] [ka] 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.

[0220] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0221] [ka] with a derivative of phosgene in the presence of an acid and a polar solvent to produce

[0222] [ka] in the presence of a base and a polar aprotic solvent

[0223] [ka] to produce

[0224] [ka] with an activating agent in the presence of an additive, a polar aprotic solvent and a base,

[0225] [ka] wherein LG is a leaving group;

[0226] [ka] with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and one or more polar aprotic solvents to produce

[0227] [ka] 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.

[0228] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0229] [ka] in the presence of a base and a polar solvent.

[0230] [ka] reacting with

[0231] [ka] with a derivative of phosgene in the presence of an acid and a polar solvent to produce:

[0232] [ka] in the presence of a base and a polar aprotic solvent

[0233] [ka] reacting with:

[0234] [ka] with an activating agent in the presence of an additive, a polar aprotic solvent and a base,

[0235] [ka] wherein LG is a leaving group;

[0236] [ka] with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof and one or more polar aprotic solvents to produce:

[0237] [ka] 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.

[0238] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0239] [ka] and reacting in the presence of MeONa and MeOH to produce

[0240] [ka] with triphosgene in the presence of hydrogen chloride and 2-MeTHF' to produce

[0241] [ka] in the presence of sodium tert-amylate and 2-MeTHF

[0242] [ka] and reacting the compound with

[0243] [ka] with bis(trifluoromethanesulfonyl)aniline in the presence of tripotassium phosphate KPO and dipotassium phosphate KHPO in MeCN to produce:

[0244] [ka] with tripotassium phosphate in the presence of (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride, 2-MeTHF and MeCN to produce

[0245] [ka] with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

[0246] In another embodiment, the present invention provides an alternative route for the synthesis of adagrasib. Thus, in one embodiment, the present invention provides a method for the synthesis of adagrasib, comprising: a')

[0247] [ka] in the presence of a base and a polar solvent.

[0248] [ka] to give the following structure: The method comprises the step of producing a final compound of step (a') having the following structure:

[0249] [ka]

[0250] In one embodiment, step (a') is carried out at a temperature of from about 0°C to about 100°C.

[0251] In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising steps (b'): b') reacting the final compound of step (a') with an alkylating or arylating agent together with a base in the presence of a polar solvent to obtain the compound of the following structure:

[0252] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl.

[0253] In one embodiment, step (b') is carried out at a temperature of about 20°C to about 120°C.

[0254] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (c'): c') 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 give a compound of the following structure:

[0255] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl.

[0256] In one embodiment, step (c') is carried out at a temperature of from about 0°C to about 120°C.

[0257] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (d'): d') reacting the final compound 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:

[0258] [ka]

[0259] In one embodiment, step (d') is carried out at a temperature of about -20°C to about 50°C.

[0260] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising: Process (e'), e') reacting the final compound of step (d') with an activating agent in the presence of a base, an additive and a polar aprotic solvent to obtain a compound of the following structure:

[0261] [ka] wherein LG is a leaving group.

[0262] In one embodiment, step (e') is carried out at a temperature of about -20°C to about 70°C.

[0263] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising step (f'): f) reacting the final compound 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 structure:

[0264] [ka]

[0265] In one embodiment, step (f') is carried out at a temperature of about 20°C to about 120°C.

[0266] In one embodiment, the present invention provides a method for synthesizing adagrasib, the method comprising the steps of (g'): g') 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.

[0267] In one embodiment, step (g') is carried out at a temperature of about -10°C to about 50°C.

[0268] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0269] [ka] 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.

[0270] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0271] [ka] wherein LG is a leaving group, with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0272] [ka] 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.

[0273] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0274] [ka] with an activating agent in the presence of a base, an additive and a polar aprotic solvent,

[0275] [ka] wherein LG is a leaving group;

[0276] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0277] [ka] 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.

[0278] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0279] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl, with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce:

[0280] [ka] with an activating agent in the presence of a base, an additive and a polar aprotic solvent,

[0281] [ka] wherein LG is a leaving group;

[0282] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0283] [ka] 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.

[0284] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0285] [ka] 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

[0286] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce

[0287] [ka] with an activating agent in the presence of a base, an additive and a polar aprotic solvent,

[0288] [ka] wherein LG is a leaving group;

[0289] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0290] [ka] 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.

[0291] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0292] [ka] with an alkylating or arylating agent and a base in the presence of a polar solvent to give:

[0293] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl;

[0294] [ka] with an oxidizing agent in the presence of a polar aprotic solvent, and optionally a catalyst and a base,

[0295] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl;

[0296] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce:

[0297] [ka] is reacted with an activating agent in the presence of a base, an additive, and a polar aprotic solvent to produce:

[0298] [ka] wherein LG is a leaving group;

[0299] [ka] with a base, (S)-2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof, and a polar aprotic solvent to produce

[0300] [ka] 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.

[0301] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising:

[0302] [ka] in the presence of a base and a polar solvent.

[0303] [ka] to give the following structure: producing the final compound of step (a'),

[0304] [ka] with an alkylating or arylating agent and a base in the presence of a polar solvent to give:

[0305] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl;

[0306] [ka] with an oxidizing agent in the presence of a polar aprotic solvent, and optionally a catalyst and a base,

[0307] [ka] wherein R is methyl, ethyl, isopropyl, or benzyl;

[0308] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce:

[0309] [ka] is reacted with an activating agent in the presence of a base, an additive, and a polar aprotic solvent to produce:

[0310] [ka] wherein LG is a leaving group;

[0311] [ka] reacting 2-(piperazin-2-yl)acetonitrile or an inorganic or organic salt thereof with a polar aprotic solvent to produce:

[0312] [ka] 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.

[0313] In one embodiment, the present invention provides a method of synthesizing adagrasib, comprising:

[0314] [ka] in the presence of MeONa and MeOH

[0315] [ka] to produce

[0316] [ka] with 2-iodopropane and sodium hydroxide in the presence of methanol to produce

[0317] [ka] with sodium methoxide, sodium tungstate and hydrogen peroxide in the presence of 2-propanol to produce

[0318] [ka] with (S)-(1-methylpyrrolidin-yl)methanol in the presence of potassium tert-butoxide and THF to produce

[0319] [ka] with bis(trifluoromethanesulfonyl)aniline in the presence of tripotassium phosphate KPO and dipotassium phosphate KHPO in MeCN to produce

[0320] [ka] with tripotassium phosphate, (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride and MeCN to produce

[0321] [ka] with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

[0322] In one embodiment, in step (a), 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), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), and an alcohol having the formula R-OH, where R is alkyl, allyl, or aryl.

[0323] In one embodiment, in step (a), the polar solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and alcohols having the formula R-OH, where R can be, but is not limited to, alkyl, allyl, or aryl.

[0324] In one embodiment, in step (a), the polar solvent is methanol (MeOH).

[0325] In one embodiment, in step (a), the base is selected from the group consisting of methoxide, ethoxide, iso-propoxide, tert-butoxide and tert-amylate.

[0326] In one embodiment, in step (a), the base includes one or more of the following, but is not limited to: methoxide, ethoxide, iso-propoxide, tert-butoxide, and tert-amylate.

[0327] In one embodiment, in step (a), the base is sodium methoxide.

[0328] In one embodiment, in step (b), the phosgene derivative is selected from the group consisting of phosgene, disphosgene, triphosgene, thiophosgene and 1,1'-carbonyldiimidazole.

[0329] In one embodiment, in step (b), the phosgene derivatives include one or more of the following, but are not limited to: phosgene, disphosgene, triphosgene, thiophosgene, and 1,1'-carbonyldiimidazole.

[0330] In one embodiment, in step (b), the phosgene derivative is triphosgene.

[0331] In one embodiment, in step (b), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0332] In one embodiment, in step (b), the polar aprotic solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0333] In one embodiment, in step (b), the polar aprotic solvent is 2-MeTHF.

[0334] In one embodiment, in step (b), the mineral acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

[0335] In one embodiment, in step (b), the mineral acid includes one or more of the following, but is not limited to: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

[0336] In one embodiment, in step (b), the mineral acid is hydrogen chloride.

[0337] In one embodiment, in step (c), the base is a bulky alkoxide selected from the group consisting of iso-propoxide, tert-butoxide, and tert-amylate.

[0338] In one embodiment, in step (c), the base is a bulky alkoxide, including but not limited to one or more of the following: iso-propoxide, tert-butoxide, and tert-amylate.

[0339] In one embodiment, in step (c), the base is sodium tert-amylate.

[0340] 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.

[0341] In one embodiment, in step (c), the polar aprotic solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0342] In one embodiment, in step (c), the polar aprotic solvent is 2-MeTHF.

[0343] In one embodiment, in steps (d) and (e), the activating agent is a sulfonyl halide R-SO2X, where 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 1 -N-Tf2 (where R 1 is phenyl, 5-chloro-2-pyridine, 2-pyridine.

[0344] In one embodiment, in steps (d) and (e), the activating agent includes one or more of the following, but is not limited to: sulfonyl halides R-SO2X, where 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, anhydrides (such as trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride), and organic triflate agents R 1 -N-Tf2 (where R 1 is phenyl, 5-chloro-2-pyridine, 2-pyridine).

[0345] In one embodiment, in step (d), the activating agent is bis(trifluoromethanesulfonyl)aniline.

[0346] In one embodiment, in steps (d) and (e), the base is an inorganic base.

[0347] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphoric acids).

[0348] In one embodiment, inorganic bases include, but are not limited to, one or more of the following: carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

[0349] In one embodiment, an inorganic base is used in combination with an alkali salt selected from the group consisting of lithium, sodium and potassium.

[0350] In one embodiment, an inorganic base is used along with an alkali salt, including, but not limited to, one or more of the following: lithium, sodium, and potassium.

[0351] In one embodiment, in step (d), the base is potassium phosphate tribasic and dibasic.

[0352] 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.

[0353] In one embodiment, in steps (d) and (e), the polar aprotic solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0354] In one embodiment, in step (d), the polar aprotic solvent is MeCN.

[0355] In one embodiment, in step (e), the polar aprotic solvent is MeCN.

[0356] 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).

[0357] In one embodiment, in step (f), 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), phosphonium hexafluorophosphate, ... 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)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)).

[0358] In one embodiment, in step (f), the base is an organic base.

[0359] In one embodiment, the inorganic base is It is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0360] In one embodiment, in step (f), the base is an inorganic base.

[0361] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

[0362] 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.

[0363] In one embodiment, in step (f), the solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

[0364] In one embodiment, in steps (a') and (b'), 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, where R is alkyl, allyl, or aryl.

[0365] In one embodiment, in steps (a') and (b'), the polar solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and alcohols having the formula R-OH, where R can be, but is not limited to, alkyl, allyl, or aryl.

[0366] In one embodiment, in step (a'), the polar solvent is MeOH.

[0367] In one embodiment, in step (a'), the base is selected from the group consisting of methoxide, ethoxide, iso-propoxide, tert-butoxide and tert-amylate.

[0368] In one embodiment, in step (a'), the base includes one or more of the following, but is not limited to: methoxide, ethoxide, iso-propoxide, tert-butoxide, and tert-amylate.

[0369] In one embodiment, in step (a'), the base is sodium methoxide.

[0370] In one embodiment, in step (b'), the alkylating or arylating agent is selected from the group consisting of aryl or alkyl halides RX, where R is methyl, ethyl, isopropyl, or benzyl, and X is Cl, Br, I, alkyl sulfonate, aryl sulfonate, triflate, or nonaflate, dialkyl sulfate, and dialkyl carbonate.

[0371] In one embodiment, in step (b'), the alkylating or arylating agent includes one or more of the following, but is not limited to: aryl halides, alkyl halides RX (wherein R can be, but is not limited to, methyl, ethyl, isopropyl, or benzyl, and X can be, but is not limited to, Cl, Br, I, alkyl sulfonate, aryl sulfonate, triflate, or nonaflate), dialkyl sulfate, and dialkyl carbonate.

[0372] In one embodiment, the alkylating agent is 2-iodopropane.

[0373] In one embodiment, in step (b'), the base is an inorganic base.

[0374] In one embodiment, the inorganic base is selected from the group consisting of hydroxides, carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

[0375] In one embodiment, inorganic bases include, but are not limited to, one or more of the following: hydroxides, carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

[0376] In one embodiment, an inorganic base is used in combination with an alkali salt selected from the group consisting of lithium, sodium and potassium.

[0377] In one embodiment, in step (b'), the base is sodium hydroxide.

[0378] In one embodiment, in step (c'), the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide, and urea hydrogen peroxide.

[0379] In one embodiment, in step (c'), the oxidizing agent includes one or more of the following, but is not limited to: peracid (such as metachloroperbenzoic acid or peracetic acid), oxone, bleach, hydrogen peroxide, and urea hydrogen peroxide.

[0380] In one embodiment, in step (c'), the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate.

[0381] In one embodiment, in step (c'), the catalyst includes one or more of the following, but is not limited to: sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate.

[0382] In one embodiment, in step (c'), the catalyst is sodium tungstate.

[0383] In one embodiment, in step (c'), the base is selected from the group consisting of methoxide, ethoxide, iso-propoxide, tert-butoxide and tert-amylate.

[0384] In one embodiment, in step (c'), the base includes one or more of the following, but is not limited to: methoxide, ethoxide, iso-propoxide, tert-butoxide, and tert-amylate.

[0385] In one embodiment, in step (c'), the ammonium or alkali salt is selected from the group consisting of lithium, sodium, and potassium.

[0386] In one embodiment, in step (c'), the ammonium or alkali salt includes one or more of the following, but is not limited to: lithium, sodium, and potassium.

[0387] In one embodiment, in step (c'), the base is sodium methoxide.

[0388] 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.

[0389] In one embodiment, in step (c'), the polar aprotic solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0390] In one embodiment, in step (d'), the base is a bulky alkoxide selected from the group consisting of iso-propoxide, tert-butoxide, and tert-amylate.

[0391] In one embodiment, in step (d'), the base is a bulky alkoxide, including but not limited to one or more of the following: iso-propoxide, tert-butoxide, and tert-amylate.

[0392] In one embodiment, in step (d'), the base is potassium tert-butoxide.

[0393] 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.

[0394] In one embodiment, in step (d'), the polar aprotic solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0395] In one embodiment, in step (d'), the polar aprotic solvent is THF.

[0396] In one embodiment, in steps (e') and (f), the activating agent is a sulfonyl halide R-SO2X, where R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, or Br, anhydrides (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride), and an organic triflate reagent R 1 -N-Tf2 (where R 1 is phenyl, 5-chloro-2-pyridine, 2-pyridine.

[0397] In one embodiment, in steps (e') and (f), the activating agent includes one or more of the following, but is not limited to: sulfonyl halides R-SO2X (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), anhydrides (such as trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride), and organic triflate reagents R 1 -N-Tf2 (where R 1 is phenyl, 5-chloro-2-pyridine, or 2-pyridine).

[0398] In one embodiment, the activating agent in steps (e') and / or (f') is bis(trifluoromethanesulfonyl)aniline.

[0399] In one embodiment, in steps (e') and (f'), the base is an inorganic base.

[0400] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphoric acids).

[0401] In one embodiment, inorganic bases include, but are not limited to, one or more of the following: carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

[0402] In one embodiment, an inorganic base is used in combination with an alkali salt selected from the group consisting of lithium, sodium and potassium.

[0403] In one embodiment, an inorganic base is used along with an alkali salt, including, but not limited to, one or more of the following: lithium, sodium, and potassium.

[0404] In one embodiment, in step (e'), the inorganic base is potassium phosphate tribasic and dibasic.

[0405] 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.

[0406] In one embodiment, in steps (e') and (f'), the polar aprotic solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0407] In one embodiment, in steps (e') and (f'), the polar aprotic solvent is MeCN.

[0408] 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).

[0409] In one embodiment, in step (g'), the coupling agent is selected from the group consisting of T3P®, CDI, carbodiimides (e.g., DCC, DIG, EDC.HCl), BOP, PyBOP, HBTU, HATU.

[0410] In one embodiment, in step (g'), the base is an organic base.

[0411] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0412] In one embodiment, in step (g'), the base is an inorganic base.

[0413] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

[0414] 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, IPAc, and NMP.

[0415] In one embodiment, in step (g'), the solvent includes one or more of the following, but is not limited to: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

[0416] The following examples are intended to illustrate further certain embodiments of the present invention and are not intended to limit the scope of the invention.

[0417] Example 1 Step (a)

[0418] [ka]

[0419] Methyl 1-(8-chloronaphthalen-1-yl)-5-hydroxy-1,2,3,6-tetrahydropyridine-4-carboxylate (75 g, 236 mmol, 1.0 equiv.) was charged to 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 in one portion to the reaction at 20° C. Following this, the reaction was reacted at 60° C. until the starting material area was ≦1.0 area % (approximately 4 hours). The mixture was cooled to 20° C. and then purified water (750 mL) was added. The mixture was filtered through a celite pad and transferred to a clan reactor. 2N hydrochloric acid solution was added slowly to the reaction at 15-25°C until pH = 4-5. A large amount of precipitation was observed upon addition of the hydrochloric acid solution. The solid was then filtered off and reslurried in purified water (375 mL) followed by a second filtration. The solid was dried to constant mass under nitrogen flow and low vacuum at T < 45°C. 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).

[0420] Mp: 237.5~237.6℃ (decomposition).

[0421] 1 H NMR(500MHz,DMSO-d6)δ ppm2.35(br d,J=16.4Hz,1H),2.51-2.59(m,1H),3.05-3.16(m,1H),3.36-3.45(m,1H),3.57(br d,J=17.0Hz,1H),3.94(d,J=17.5Hz,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=7.4,1.4Hz,1H),7.74(d,J=7.7Hz,1H),7.85-7.96(m,1H),11.68-12.50(br s,1H).

[0422] 13 C NMR (126MHz, DMSO-d6) δ ppm21.6,49.7,53.5,109.8,119.7,125.5,126.5,127.3,129.1,129.3,130.1,137.5,148.3,150.1,161.9,172.9,174.9.

[0423] HRMS(ESI)C 17 H 15 Calculated for ClNO: 344.0624 [M+H] + , Actual value: 344.0779.

[0424] Example 2 Process (b)

[0425] [ka]

[0426] 7-(8-Chloro-naphthalen-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 charged to a 400 mL EasyMax reactor followed by 2-MeTHF (200 mL) and the reaction was stirred at 25° C. Then 4N hydrogen chloride in dioxane (7.3 mL, 29 mmol, 1.0 equiv.) was charged. Triphosgene (8.6 g, 29 mmol, 1.0 equiv.) was added to the reaction at 25° C. Following this, the reaction was allowed to react at 25° C. until the starting material area was ≦0.5 area % (approximately 24 hours). The mixture was cooled to 15° C. and then purified water (50 mL) was added. 1N sodium hydroxide solution was added slowly to the reaction mass at 15-25°C with stirring until pH = 5-6. Following this, the mixture was stirred for 10 minutes at a temperature of 15°C and the layers were allowed to settle and then 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 then volatiles were removed from the slurry. The solid was dried to constant mass under a stream of nitrogen and low vacuum at T < 45°C. 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).

[0427] Mp: 200.7~200.8℃ (decomposition).

[0428] 1 H NMR(500MHz,DMSO-d6)δ ppm2.54(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=7.7Hz,1H),7.53(t,J= 7.9Hz,1H),7.57(dd,J=7.4,1.4Hz,1H),7.74(d,J=7.7Hz,1H),7.91(dd,J=8.2,1.1Hz,1H),13.39(m,1H).

[0429] 13C NMR (126MHz, DMSO-d6) δ ppm164.5,151.3,148.3,147.4,137.5,130.1,129.3,129.1,127.3,126.4,125.5,125.4,119.5,104.4,57.1,49.8,22.3.

[0430] HRMS(ESI)C 17 H 14 Calculated for ClN2O3: 346.0514 [M+H] + , Actual value: 346.0668.

[0431] Example 3 Process (c)

[0432] [ka]

[0433] 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 charged into an 8 mL vial, followed by the addition of 2-MeTHF (1.0 mL). The reaction mixture was stirred at 20 °C. Then, (S)-(1-methylpyrrolidin-2-yl)methanol (41 μL, 0.35 mmol, 1.2 equiv) was added. Subsequently, sodium tert-amylate (160 mg, 0.87 mmol, 5.0 equiv) was added to the reaction mixture. Subsequently, the reaction was carried out at 60 °C until the starting material area became ≤0.5 area% (about 16 h). The mixture was cooled to 20 °C, and 1.0 mL of 10% w / w aqueous citric acid 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 again. After adding 1.0 mL of fresh 2-MeTHF, the pH of the aqueous solution was adjusted to neutral (6.5 < pH < 7.5). The organic phase was taken, while the neutral aqueous phase was back-extracted with 0.5 mL of fresh 2-MeTHF. After concentrating the combined organic phase to half, 1.0 mL of heptane was added. After removing the volatile substances, the solid was dried under a nitrogen stream and low vacuum at T ≤ 45 °C until a constant mass was obtained. (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).

[0434] M.p. 140.9~141.0 °C.

[0435] 11H NMR (500 MHz, DMSO-d6) 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).

[0436] 13 13C NMR (126 MHz, DMSO-d6) 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.

[0437] HRMS (ESI) C 23 H 26 Calculated for C21H19N4O2: 425.1744 [M + H] + , found: 425.1902.

[0438] Example 4 Steps (d) and (e)

[0439]

Chemical Structure

[0440] (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), tripotassium phosphate (3.0 g, 14.12 mmol, 2 equiv) and dipotassium phosphate (1.2 g, 7.06 mmol, 1 equiv) were charged to a 100 mL reactor followed by MeCN (30.0 mL). The reaction was stirred at 0° C. and bis(trifluoromethanesulfonyl)aniline (4.5 g, 12.71 mmol, 1.8 equiv) was added slowly to the reaction mixture. Following this, the reaction was allowed to react at 0° C. until the starting material area was ≦5 area % (approximately 24 hours). To the same mixture was then added tripotassium phosphate (1.5 g, 7.06 mmol, 1 equiv.) followed by (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (g, 8.47 mmol, 1.2 equiv.). Following this, the reaction was allowed to react at 20° C. until the triflate intermediate area was ≦0.5 area % (approximately 16 h). 30.0 mL of water was added to the mixture. A phase cut was performed and the organic phase was concentrated to dryness and then diluted with 9.0 mL of DMAc. 3.0 mL of water was then added and the mixture was seeded with the final crystalline product (1% w / w). The mixture was stirred for 10 h and then 9.0 mL of water was slowly added over 3 h. The slurry was stirred at room temperature until the supernatant assayed ≦1 area %. The crystalline solid was then filtered and washed with 6.0 mL of water, and the solid was then dried under nitrogen flow and low vacuum at T≦45° C. to constant weight 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).

[0441] Mp:60.3~60.4℃.

[0442] 11H NMR (400 MHz, DMSO-d6) 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 Hz, 1H), 4.17 (br d, J = 17.4 Hz, 1H), 4.24 (dd, J = 10.7, 4.9 Hz, 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).

[0443] 13 13C NMR (101 MHz, DMSO-d6) 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.

[0444] HRMS (ESI) C 29 H 35 alculated for C + lN7O: 532.2592 [M + H]

[0445] Example 5 Step (f)

[0446]

Chemical Structure

[0447] Acetonitrile (1093.0 kg) was added to a 3000 L glass-lined reactor. MR84916 (81.6 kg, 68.1 kg corrected by HPLC assay wt%, 128.0 mol, 1.0 equiv.) was then added to the reactor. The mixture was concentrated under reduced pressure (P≦-0.06 MPa) at a temperature below ≦45° C. until 3-4 volumes (204-272 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 3-4 volumes (204-272 L) remained. The mixture was sampled to confirm that the water content was less than 0.3% (actual 0.1%) as determined by Karl Fischer analysis. The mixture was cooled to a temperature of 10-25° C. (actual 16.5° C.). Acetonitrile (163.9 kg) was added to another 3000 L Hastelloy reactor. The mixture was sampled to ensure that the moisture content was less than 0.3% (actually 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 10-20 °C. It was ensured that the sodium 2-fluoroacrylate was in fine powder form before addition. The reactor walls were rinsed with acetonitrile (13.7 kg). A 50 w / w% solution of propylphosphosphonic anhydride in ethyl acetate (124.7 kg, 192 mol, 1.5 eq) was added to the sodium 2-fluoroacrylate solution in the Hastelloy reactor under nitrogen protection at a temperature of 10-20 °C. The mixture was stirred for not less than 2 hours at a temperature of 10-20 °C. The mixture containing MR84916 in the 3000 L glass-lined reactor was slowly added to the mixture containing 2-fluoroacrylate in the 3000 L Hastelloy reactor at a temperature of 10-20° C. The 3000 L glass-lined reactor containing MR84916 was rinsed with acetonitrile (18.2 kg), which was transferred to the Hastelloy reactor along with the acrylate.The reaction was allowed to proceed at 10-20°C (14.5-18.0°C) and the mixture was sampled for HPLC purity analysis every 1-3 hours until after 1 hour the area % of MR84916 / (MR84916+MRTX849) was less than 0.4% (0.3% was observed at 5 hours 1 minute). At a temperature of 10-30°C, the mixture was adjusted to pH 8-9 using potassium carbonate solution (348.3 kg) prepared from potassium carbonate (41.6 kg) and purified water (307.2 kg). The mixture was kept stirring for another 0.5 hours and then the pH was retested to confirm (actually pH 8). The mixture was adjusted to a temperature of 25-35°C, stirring was stopped and the layers were allowed to settle and then separated. The aqueous phase was removed and kept. This phase was washed at a temperature of 25-35°C using tripotassium phosphate solution prepared from tripotassium phosphate (50.1 kg) and purified water (204.4 kg). The mixture was stirred for an additional 0.5-3 h, allowed to settle, and then allowed to separate at a temperature of 25-35 °C. The aqueous phase was removed and kept. The aqueous layers were combined and extracted with 2-MeTHF (175.9 kg). The mixture was stirred for an additional 20-30 min, allowed to settle, and then allowed to separate at a temperature of 25-35 °C. The organic fractions were combined, and the combined mixture was then concentrated under reduced pressure (P ≦ -0.06 MPa) at a temperature of ≦ 45 °C until 2-3 volumes (136-204 L) remained. Isopropanol (429.2 kg) was added to the mixture at a temperature of ≦ 45 °C. The mixture was concentrated under reduced pressure (P ≦ -0.06 MPa) at a temperature of ≦ 45 °C until 2-3 volumes (136-204 L) remained. Isopropanol (320.1 kg) was added to the mixture at a temperature of ≦ 45 °C. The mixture was circulated through a CUNO filtration system. Isopropanol (106.9 kg) was then used to rinse the CUNO filter and added to the reactor. The mixture was concentrated under reduced pressure (P≦-0.06 MPa) at a temperature of ≦45° C. until 4.5-5.5 volumes (306-374 L) remained. The mixture was sampled to confirm that the residual acetonitrile residue was less than 1.5% (actually 0.05%). The mixture was adjusted to a temperature of 33-38° C. (actually 35.3° C.). Purified water (170.0 kg) was added to the mixture at 33-38° C. Form 2 seed crystals (0.2 kg) were added to the mixture at a temperature of 33-38° C. The mixture was maintained at this temperature and stirred for 2-3 hours.The mixture was slowly cooled to 15-20°C. The mixture was maintained at this temperature and stirred for 6-10 hours. Purified water (170.0 kg) was added to the reactor at a temperature of 15-20°C. The mixture was slowly cooled to -3-7°C (actually 4.8°C). The mass was stirred at -3-7°C for crystallization and after 8 hours the mixture was sampled every 3-5 hours until the mother liquor assay wt% of MRTX849 was less than 0.7% or the difference between two consecutive samples was ≦0.1 wt% (0.7 wt% observed). The mixture was filtered through 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 6-8 hours and dried in a rotary cone dryer at T ≤ 40 °C until the moisture content was 1% or less as determined by Karl Fischer analysis. After drying was complete, the solids were cooled to 20-30 °C. Isopropanol (368.4 kg) was added to a 1000 L glass-lined reactor and then the agitator was started. The solids from the filter cake were added to the 1000 L reactor and the mixture was heated to a temperature of 55-60 °C (actually 57.2 °C). The mixture was maintained at this temperature and agitated until a visual check confirmed that the solids were completely dissolved. The mixture was then passed through a filtration system heated to 55-60 °C into a 1000 L Hastelloy reactor (T ≤ 40 °C). ジャケット= 55-60°C). The mixture was held at 55-60°C. n-Heptane (80.5 kg) was added to the reactor and passed through the filter first for rinsing. The mixture was stirred in the reactor for 0.5 hours. After the solids were completely dissolved, the mixture was cooled to a temperature of 43-47°C. A seed slurry was prepared by adding isopropanol (5.5 kg) and n-heptane (1.3 kg) through a capsule filter to a 20 L four-neck flask, followed by the addition of Form 2 seed crystals (MRTX849 Form 2, 0.8 kg) held at a temperature of 20-25°C. The mixture was stirred until homogeneously mixed and then recirculated it through a wet mill. Prior to adding the slurry feed to the reactor, the reactor was checked to ensure complete dissolution and no precipitation of MRTX849 had occurred. Following this, the Form 2 seed slurry was added to a 1000 L Hastelloy reactor at a temperature of 43-47°C. The mixture was stirred at 43-47°C for 3-4 hours. The mixture was then cooled to a temperature of 28-32°C and stirred at that temperature (actually 30.6°C) for 4-5 hours. After this, the mixture was cooled to 18-22°C and stirred for 4-5 hours (actually 20.9°C). The mixture was then cooled to -3-7°C (actually 3.5°C) with stirring. After 12 hours, the mixture supernatant was sampled every 3-5 hours to check the assay weight % of MRTX849 in the mother liquor and when the level was below 1.2% or when the difference between samples was below 0.2%. Nitrogen was bubbled intermittently through the bottom port of the reactor during crystallization. Checking the mother liquor showed that the assay weight % of MRTX849 was 1.0%. The mixture was recirculated through a wet mill at -3-10°C and the batch temperature can be expected to increase by 2-3°C during this process. The solids were sampled for particle size until D(90) was 100 μm or less (actually 22 μm). The mixture was held at -3 to 7°C for 0.5 to 1 hour. The mixture was then filtered through a stainless steel Nutsche filter. The walls of the reactor 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 these rinses, which were transferred to the reactor and then discharged into the filter to rinse the filter cake. The above procedure was repeated once more using a mixed solvent of n-heptane (15.9 kg) and isopropanol (74.2 kg). Filtration was observed to be very slow as a result of the small particle size from the wet mill. The solids in the filter were collected by filtration at T. ジャケット = 20-30°C for 8-10 hours with a nitrogen sweep, then run until isopropanol residuals were below 6300 ppm (actual 3488 ppm) and n-heptane residuals were below 3500 ppm (not detected, LOD 432 ppm) as measured by GC. ジャケット = 35-45°C. After drying was complete, the solid was cooled to a temperature of 20-30°C. The solid was sieved until the product was uniform in appearance and not blocking. The operating area RH% should be below 50%. The product (MRTX849) was obtained as an off-white solid (51.1 kg, 50.0 kg corrected for assay weight%, 100.4 assay weight%, 64.7% yield).

[0448] Mp:128.3~128.4℃.

[0449] 11H NMR (400 MHz, DMSO-d6) 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 dd, 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).

[0450] 13 13C NMR (101 MHz, DMSO-d6) 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 Hz), 162.0, 164.3, 165.9.

[0451] 19 19F NMR (376 MHz, DMSO-d6) δ ppm -106.4.

[0452] HRMS (ESI) C 32 H 36 Calculated for CIFN7O2: 604.2603 [M + H] + , found: 604.2690.

[0453] Example 6 Optional isolation of MRTX849 as the tartrate salt: 3.5 L of ethanol was added to the reactor charged with MRTX849 (875 g) and stirred until completely dissolved. In a separate reactor, 1 M L-tartaric acid in THF was prepared by adding 1.59 L of THF and 0.24 kg of L-tartaric acid 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.

[0454] MRTX849 free base species (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 h, then filtered, washed with cold ethanol, and dried in vacuum at 40° C. for 24 h.

[0455] Example 7 Step (a')

[0456] [ka]

[0457] Methyl 1-(8-chloronaphthalen-1-yl)-5-hydroxy-1,2,3,6-tetrahydropyridine-4-carboxylate (75 g, 236 mmol, 1.0 equiv.) was charged to 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 in one portion to the reaction at 20° C. Following this, the reaction was reacted at 60° C. until the starting material area was ≦1.0 area % (approximately 4 hours). The mixture was cooled to 20° C. and then purified water (750 mL) was added. The mixture was filtered through a celite pad and transferred to a clan reactor. 2N hydrochloric acid solution was added slowly to the reaction at 15-25°C until pH = 4-5. A large amount of precipitation was observed upon addition of the hydrochloric acid solution. The solid was then filtered off and reslurried in purified water (375 mL) followed by a second filtration. The solid was dried to constant mass under nitrogen flow and low vacuum at T < 45°C. 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).

[0458] Mp: 237.5~237.6℃ (decomposition).

[0459] 1 H NMR(500MHz,DMSO-d6)δ ppm2.35(br d,J=16.4Hz,1H),2.51-2.59(m,1H),3.05-3.16(m,1H),3.36-3.45(m,1H),3.57(br d,J=17.0Hz,1H),3.94(d,J=17.5Hz,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=7.4,1.4Hz,1H),7.74(d,J=7.7Hz,1H),7.85-7.96(m,1H),11.68-12.50(br s,1H).

[0460] 13 C NMR (126MHz, DMSO-d6) δ ppm21.6,49.7,53.5,109.8,119.7,125.5,126.5,127.3,129.1,129.3,130.1,137.5,148.3,150.1,161.9,172.9,174.9.

[0461] HRMS(ESI)C 17 H 15 Calculated for ClNO: 344.0624 [M+H] + , Actual value: 344.0779.

[0462] Example 8 Process (b')

[0463] [ka]

[0464] 7-(8-chloronaphthalen-1-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (10 g, 29.0 mmol, 1.0 equiv.) was charged to a 250 mL three-neck round bottom flask. MeOH (100 mL) was then added. 1N aqueous sodium hydroxide (77 mL, 77.0 mmol, 2.66 equiv.) was then added. Stirring was continued until a homogenous solution was obtained. 2-iodopropane (5.2 mL, 50.0 mmol, 1.7 equiv.) was then added to the solution. Following this, the reaction was allowed to react at 40° C. until the starting material area was ≦3.0 area % (approximately 36 hours). The reaction mixture was cooled to 5° C. and 2N aqueous HCl (45 mL, 90 mmol, 3 equiv.) was slowly added. The solid that 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).

[0465] M.p.: 225.8~225.9 °C.

[0466] 1 1H NMR (400 MHz, DMSO-d6) 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 Hz, 1H), 3.86 (hept, J = 6.9 Hz, 1H), 3.73 (dt, J = 17.1, 2.1 Hz, 1H), 3.45 (dd, J = 12.5, 5.5 Hz, 1H), 3.06 (ddd, J = 11.8, 10.0, 4.1 Hz, 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).

[0467] 13 13C NMR (101 MHz, DMSO-d6) 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.

[0468] HRMS (ESI) C 20 H 21 Calculated for C + , H 1 13 20 Example 9 Step (c’)

[0470]

Chemical Structure

[0471] 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 charged to a 250 mL three-neck 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 added slowly. 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). Following this, the reaction was allowed to react at 20° C. until the starting material area was ≦1.0 area % (approximately 16 hours). To the reaction mixture was added water (120 mL) and 2-MeTHF (120 mL). The mixture was cooled to 5° C. and 20% w / v aqueous acetic acid (120 mL) was added slowly. After the addition was complete, sodium carbanate was added slowly to 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 then added slowly to give, after filtration and drying, 7-(8-chloronaphthalen-1-yl)-2-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one as an off-white solid (12.5 g, 28.2 mmol, 91% yield).

[0472] Mp: 195.5~195.6℃.

[0473] 1H NMR(400MHz,DMSO-d6)δ 13.66(s,1H),7.92(dd,J=8.2,1.3Hz,1H),7.76(dd,J=8.3,1.1Hz,1H),7.61-7.50(m,2H) ,7.45(t,J-7.8Hz,1H),7.39(dd,J=7.6,1.2Hz,1H),4.19(d,J=17.2Hz,1H),3.99(dt,J=1 7.4,1.8Hz,1H),3.90-3.75(m,J=6.8Hz,1H),3.61-3.51(m,1H),3.20(ddd,J=12.0,10.1, 4.1Hz, 1H), 2.97 (ddd, J=16.7, 10.3, 6.3Hz, 1H), 2.74-2.65 (m, 1H), 1.26 (d, J=6.9Hz, 6H).

[0474] 13 C NMR(101MHz,DMSO-d6)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.

[0475] HRMS(ESI)C 20 H 21 Calculated for ClN3O3: 418.0992 [M+H] + , Actual value: 418.0991.

[0476] Example 10 Process (d')

[0477] [ka]

[0478] (S)-(1-methylpyrrolidin-2-yl)methanol (230 mg, 2.0 mmol, 2.0 equiv) was charged to a 20 mL vial. THF (2.4 mL) was then added. The reaction was cooled to 0° C.

[0479] 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) dissolved in THF (2.4 mL) was added slowly at 0° C. Following this, the reaction was allowed to react at 20° C. until the starting material area was ≦1.0 area % (about 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 layer was washed with brine, dried over MgSO4, 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 off to give (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).

[0480] Mp: 140.9~141.0℃.

[0481] 11H NMR (500 MHz, DMSO-d6) 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, 1H), 7.51 (t, J = 7.94 Hz, 1H), 7.57 (dd, J = 7.39, 1.37 Hz, 1H), 7.72 (d, J = 7.67 Hz, 1H), 7.90 (dd, J = 8.21, 1.10 Hz, 1H), 12.2 (br s, 1H).

[0482] 13 13C NMR (126 MHz, DMSO-d6) 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.

[0483] HRMS (ESI) C 23 H 26 Calculated for C21H19N4O2: 425.1744 [M + H]+ + , Found: 425.1902.

[0484] Example 11 Steps (e’) and (f’)

[0485]

Chemical Structure

[0486] (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), tripotassium phosphate (3.0 g, 14.12 mmol, 2 equiv) and dipotassium phosphate (1.2 g, 7.06 mmol, 1 equiv) were charged to a 100 mL reactor followed by MeCN (30.0 mL). The reaction was stirred at 0° C. and bis(trifluoromethanesulfonyl)aniline (4.5 g, 12.71 mmol, 1.8 equiv) was added slowly to the reaction mixture. Following this, the reaction was allowed to react at 0° C. until the starting material area was ≦5 area % (approximately 24 hours). To the same mixture was then added tripotassium phosphate (1.5 g, 7.06 mmol, 1 equiv.) followed by (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (g, 8.47 mmol, 1.2 equiv.). Following this, the reaction was allowed to react at 20° C. until the triflate intermediate area was ≦0.5 area % (approximately 16 h). 30.0 mL of water was added to the mixture. A phase cut was performed and the organic phase was concentrated to dryness and then diluted with 9.0 mL of DMAc. 3.0 mL of water was then added and the mixture was seeded with the final crystalline product (1% w / w). The mixture was stirred for 10 h and then 9.0 mL of water was slowly added over 3 h. The slurry was stirred at room temperature until the supernatant assayed ≦1 area %. The crystalline solid was then filtered and washed with 6.0 mL of water, and the solid was then dried under nitrogen flow and low vacuum at T≦45° C. to constant weight 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).

[0487] Mp:60.3~60.4℃.

[0488] 11H NMR (400 MHz, DMSO-d6) 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 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 = 12.38 Hz, 1H), 4.01 (ddd, J = 10.48, 6.69, 3.28 Hz, 1H), 4.17 (br d, J = 17.43 Hz, 1H), 4.24 (dd, J = 10.74, 4.93 Hz, 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).

[0489] 13 13C NMR (101 MHz, DMSO-d6) 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.

[0490] HRMS (ESI) C 29 H 35 alculated for C + lN7O: 532.2592 [M + H], found: 532.2706.

[0491] Example 12 Step (g’)

[0492]

Chemical Structure

[0493] Acetonitrile (1093.0 kg) was added to a 3000 L glass-lined reactor. MR84916 (81.6 kg, 68.1 kg corrected by HPLC assay wt%, 128.0 mol, 1.0 equiv.) was then added to the reactor. The mixture was concentrated under reduced pressure (P≦-0.06 MPa) at a temperature below ≦45° C. until 3-4 volumes (204-272 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 3-4 volumes (204-272 L) remained. The mixture was sampled to confirm that the water content was less than 0.3% (actual 0.1%) as determined by Karl Fischer analysis. The mixture was cooled to a temperature of 10-25° C. (actual 16.5° C.). Acetonitrile (163.9 kg) was added to another 3000 L Hastelloy reactor. The mixture was sampled to ensure that the moisture content was less than 0.3% (actually 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 10-20 °C. It was ensured that the sodium 2-fluoroacrylate was in fine powder form before addition. The reactor walls were rinsed with acetonitrile (13.7 kg). A 50 w / w% solution of propylphosphosphonic anhydride in ethyl acetate (124.7 kg, 192 mol, 1.5 eq) was added to the sodium 2-fluoroacrylate solution in the Hastelloy reactor under nitrogen protection at a temperature of 10-20 °C. The mixture was stirred for not less than 2 hours at a temperature of 10-20 °C. The mixture containing MR84916 in the 3000 L glass-lined reactor was slowly added to the mixture containing 2-fluoroacrylate in the 3000 L Hastelloy reactor at a temperature of 10-20° C. The 3000 L glass-lined reactor containing MR84916 was rinsed with acetonitrile (18.2 kg), which was transferred to the Hastelloy reactor along with the acrylate.The reaction was allowed to proceed at 10-20°C (14.5-18.0°C) and the mixture was sampled for HPLC purity analysis every 1-3 hours until after 1 hour the area % of MR84916 / (MR84916+MRTX849) was less than 0.4% (0.3% was observed at 5 hours 1 minute). At a temperature of 10-30°C, the mixture was adjusted to pH 8-9 using potassium carbonate solution (348.3 kg) prepared from potassium carbonate (41.6 kg) and purified water (307.2 kg). The mixture was kept stirring for another 0.5 hours and then the pH was retested to confirm (actually pH 8). The mixture was adjusted to a temperature of 25-35°C, stirring was stopped and the layers were allowed to settle and then separated. The aqueous phase was removed and kept. This phase was washed at a temperature of 25-35°C using tripotassium phosphate solution prepared from tripotassium phosphate (50.1 kg) and purified water (204.4 kg). The mixture was stirred for an additional 0.5-3 h, allowed to settle, and then allowed to separate at a temperature of 25-35 °C. The aqueous phase was removed and kept. The aqueous layers were combined and extracted with 2-MeTHF (175.9 kg). The mixture was stirred for an additional 20-30 min, allowed to settle, and then allowed to separate at a temperature of 25-35 °C. The organic fractions were combined, and the combined mixture was then concentrated under reduced pressure (P ≦ -0.06 MPa) at a temperature of ≦ 45 °C until 2-3 volumes (136-204 L) remained. Isopropanol (429.2 kg) was added to the mixture at a temperature of ≦ 45 °C. The mixture was concentrated under reduced pressure (P ≦ -0.06 MPa) at a temperature of ≦ 45 °C until 2-3 volumes (136-204 L) remained. Isopropanol (320.1 kg) was added to the mixture at a temperature of ≦ 45 °C. The mixture was circulated through a CUNO filtration system. Isopropanol (106.9 kg) was then used to rinse the CUNO filter and added to the reactor. The mixture was concentrated under reduced pressure (P≦-0.06 MPa) at a temperature of ≦45° C. until 4.5-5.5 volumes (306-374 L) remained. The mixture was sampled to confirm that the residual acetonitrile residue was less than 1.5% (actually 0.05%). The mixture was adjusted to a temperature of 33-38° C. (actually 35.3° C.). Purified water (170.0 kg) was added to the mixture at 33-38° C. Form 2 seed crystals (0.2 kg) were added to the mixture at a temperature of 33-38° C. The mixture was maintained at this temperature and stirred for 2-3 hours.The mixture was slowly cooled to 15-20°C. The mixture was maintained at this temperature and stirred for 6-10 hours. Purified water (170.0 kg) was added to the reactor at a temperature of 15-20°C. The mixture was slowly cooled to -3-7°C (actually 4.8°C). The mass was stirred at -3-7°C for crystallization and after 8 hours the mixture was sampled every 3-5 hours until the mother liquor assay wt% of MRTX849 was less than 0.7% or the difference between two consecutive samples was ≦0.1 wt% (0.7 wt% observed). The mixture was filtered through 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 6-8 hours and dried in a rotary cone dryer at T ≤ 40 °C until the moisture content was 1% or less as determined by Karl Fischer analysis. After drying was complete, the solids were cooled to 20-30 °C. Isopropanol (368.4 kg) was added to a 1000 L glass-lined reactor and then the agitator was started. The solids from the filter cake were added to the 1000 L reactor and the mixture was heated to a temperature of 55-60 °C (actually 57.2 °C). The mixture was maintained at this temperature and agitated until a visual check confirmed that the solids were completely dissolved. The mixture was then passed through a filtration system heated to 55-60 °C into a 1000 L Hastelloy reactor (T ≤ 40 °C). ジャケット= 55-60°C). The mixture was held at 55-60°C. n-Heptane (80.5 kg) was added to the reactor and passed through the filter first for rinsing. The mixture was stirred in the reactor for 0.5 hours. After the solids were completely dissolved, the mixture was cooled to a temperature of 43-47°C. A seed slurry was prepared by adding isopropanol (5.5 kg) and n-heptane (1.3 kg) through a capsule filter to a 20 L four-neck flask, followed by the addition of Form 2 seed crystals (MRTX849 Form 2, 0.8 kg) held at a temperature of 20-25°C. The mixture was stirred until homogeneously mixed and then recirculated it through a wet mill. Prior to adding the slurry feed to the reactor, the reactor was checked to ensure complete dissolution and no precipitation of MRTX849 had occurred. Following this, the Form 2 seed slurry was added to a 1000 L Hastelloy reactor at a temperature of 43-47°C. The mixture was stirred at 43-47°C for 3-4 hours. The mixture was then cooled to a temperature of 28-32°C and stirred at that temperature (actually 30.6°C) for 4-5 hours. After this, the mixture was cooled to 18-22°C and stirred for 4-5 hours (actually 20.9°C). The mixture was then cooled to -3-7°C (actually 3.5°C) with stirring. After 12 hours, the mixture supernatant was sampled every 3-5 hours to check the assay weight % of MRTX849 in the mother liquor to see when the level was below 1.2% or when the difference between samples was below 0.2%. Nitrogen was bubbled intermittently through the bottom port of the reactor during crystallization. A check of the mother liquor showed that the assay weight % of MRTX849 was 1.0%. The mixture was recirculated through a wet mill at -3-10°C and the batch temperature can be expected to increase by 2-3°C during this process. The solids were sampled for particle size until D(90) was 100 μm or less (actually 22 μm). The mixture was held at -3 to 7°C for 0.5 to 1 hour. The mixture was then filtered through a stainless steel Nutsche filter. The walls of the reactor 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 these rinses, which were transferred to the reactor and then discharged into the filter to rinse the filter cake. The above procedure was repeated once more using a mixed solvent of n-heptane (15.9 kg) and isopropanol (74.2 kg). Filtration was observed to be very slow as a result of the small particle size from the wet mill. The solids in the filter were collected by filtration at T. ジャケット = -20 to -30 °C for 8 to 10 hours with nitrogen sweep, then T until isopropanol residuals were below 6300 ppm (actual 3488 ppm) and n-heptane residuals were below 3500 ppm (not detected, LOD 432 ppm) as measured by GC. ジャケット =-35 to -45°C. After drying was complete, the solid was cooled to a temperature of 20 to 30°C. The solid was sieved until the product was uniform in appearance and not blocking. The operating area RH% should be below 50%. The product (MRTX849) was obtained as an off-white solid (51.1 kg, 50.0 kg corrected for assay weight%, 100.4 assay weight%, 64.7% yield).

[0494] Mp:128.3~128.4℃.

[0495] 11H NMR (400 MHz, DMSO-d6) 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).

[0496] 13 13C NMR (101 MHz, DMSO-d6) 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 Hz), 162.0, 164.3, 165.9.

[0497] 19 19F NMR (376 MHz, DMSO-d6) δ ppm -106.4.

[0498] HRMS (ESI) C 32 H 36 Calculated for CIFN7O2: 604.2603 [M + H] + , found: 604.2690.

[0499] Optional isolation of MRTX849 as the tartrate salt: 3.5 L of ethanol was added to the reactor charged with MRTX849 (875 g) and stirred until completely dissolved. In a separate reactor, 1 M L-tartaric acid in THF was prepared by adding 1.59 L of THF and 0.24 kg of L-tartaric acid and heated to 35-40 °C. The above prepared tartaric acid solution 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, then filtered, washed with cold ethanol, and dried in vacuum at 40 °C for 24 hours.

[0500] While the invention has been described in relation to particular embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention generally in accordance with the principles of the invention, within known or customary practice in the art to which the invention pertains, which may be applied to the essential features described above, and which include departures from the present disclosure that fall within the scope of the appended claims.

Claims

1. A method for synthesizing adagrav, a) Compounds with the following structure, 【Chemistry 1】 Compounds with the following structure, 【Chemistry 2】 The reaction is carried out in the presence of a base and a polar solvent to produce the following structure: 【Transformation 3】 A method comprising the step of producing a final compound of step (a) having the above.

2. The method according to claim 1, wherein the base is optionally selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide and tert-amilate, and the base is MeONa.

3. Step (b): b) The final compound from step (a) is reacted with a phosgene derivative in the presence of an acid and a polar aprotic solvent to obtain the following structure: 【Chemistry 4】 The method according to claim 1, further comprising the step of producing the final compound of step (b) having the above.

4. The method according to claim 3, wherein the derivative of phosgene is selected from the group consisting of phosgene, disphosgene, triphosgene, thiophosgene, and 1,1'-carbonyldiimidazole, and optionally the derivative of phosgene is triphosgene.

5. The method according to claim 3 or 4, wherein the acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and optionally the mineral acid is hydrogen chloride.

6. Step (c): c) The final compound of step (b) in the presence of a base and a polar aprotic solvent 【Transformation 5】 When reacted with this, the following structure is formed: 【Transformation 6】 The method according to claim 3, further comprising the step of producing the final compound of step (c) having the above.

7. The method according to claim 6, wherein the base is selected from the group consisting of isopropoxide, tert-butoxide and tert-amilate, optionally the base is tert-amilate, and optionally the base is sodium tert-amilate.

8. The method according to claim 3, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP, and optionally the polar aprotic solvent is 2-MeTHF.

9. Step (d): d) The final compound from step (c) is reacted with an activator in the presence of an additive, a polar aprotic solvent, and a base to form the following structure: 【Transformation 7】 (In the formula, LG is a leaving group.) The method according to claim 6, further comprising the step of producing the final compound of step (d) having the above.

10. The method according to claim 9, wherein the base is an inorganic base, optionally selected from the group consisting of carbonates, bicarbonates, and phosphates, and optionally the inorganic base is tripotassium phosphate or dipotassium phosphate.

11. Step (e): e) The final compound from step (d) is reacted with a base in the presence of (S)-2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt and one or more polar aprotic solvents to form the following structure: 【Transformation 8】 The method according to claim 9, further comprising the step of producing a final compound of step (e) having the above.

12. Step (f): The method according to claim 11, further comprising the step of reacting the final compound of step (e) with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

13. The binder is propylphosphonic anhydride (T3P®), carbonyl diimidazole (CDI), carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC.HCl)), phosphonium ((benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) The method according to claim 12, selected from the group consisting of (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and uronium (O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)). 【Request Item 14】 【Chemistry 9】 A method for synthesizing adaglaci, comprising reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglaci.

15. A method for synthesizing adagrav, 【Chemistry 10】 (wherein LG is a leaving group) is reacted with a base in the presence of S-2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and one or more polar aprotic solvents. 【Chemistry 11】 The process of generating, and 【Chemistry 12】 A method for synthesizing adaglacib according to claim 14, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

16. A method for synthesizing adagrav, 【Chemistry 13】 This is reacted with an activator in the presence of an additive, a polar aprotic solvent, and a base. 【Chemistry 14】 The process of generating (wherein LG is a leaving group), 【Chemistry 15】 This is reacted with a base in the presence of (S)-2-(piperazine-2-yl)acetonitrile or its inorganic or organic salt, and one or more polar aprotic solvents. 【Chemistry 16】 The process of generating, and 【Chemistry 17】 A method for synthesizing adaglacib according to claim 15, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

17. A method for synthesizing adagrav, [Chemistry 18] in the presence of a base and a polar aprotic solvent 【Chemistry 19】 Respond with: 【Chemistry 20】 The process of generating; 【Chemistry 21】 The activator is reacted with an additive, a polar aprotic solvent, and a base. 【Chemistry 22】 The process of generating (wherein LG is a leaving group); 【Chemistry 23】 This is reacted with a base in the presence of S-2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and one or more polar aprotic solvents. 【Chemistry 24】 The process of generating; and 【Chemistry 25】 A method for synthesizing adaglacib according to claim 16, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

18. A method for synthesizing adagrav, 【Chemistry 26】 This is reacted with a phosgene derivative in the presence of an acid and a polar solvent. 【Chemistry 27】 The process of generating 【Chemistry 28】 in the presence of a base and a polar aprotic solvent 【Chemistry 29】 And it will react, 【Transformation 30】 The process of generating 【Chemistry 31】 Reacting with an activator in the presence of an additive, a polar aprotic solvent, and a base: 【Chemistry 32】 The process of generating (wherein LG is a leaving group), 【Transformation 33】 (S)-2-(piperazine-2-yl)acetonitrile or its inorganic or organic salt, and one or more polar aprotic solvents are reacted with a base. 【Transformation 34】 The process of generating, and 【Chemistry 35】 A method for synthesizing adaglacib according to claim 17, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

19. A method for synthesizing adagrav, 【Transformation 36】 It is reacted with a base and a polar solvent, 【Chemistry 37】 The process of generating 【Transformation 38】 This is reacted with a phosgene derivative in the presence of an acid and a polar solvent. 【Chemistry 39】 The process of generating 【Chemistry 40】 under the presence of an alkali salt of an alkoxide and a polar aprotic solvent 【Chemistry 41】 And it will react, 【Chemistry 42】 The process of generating 【Chemistry 43】 The activator is reacted with an additive, a polar aprotic solvent, and a base. 【Chemistry 44】 A process of generating (wherein LG is a leaving group); 【Chemistry 45】 (S)-2-(piperazine-2-yl)acetonitrile or its inorganic or organic salt, and one or more polar aprotic solvents are reacted with a base. 【Chemistry 46】 The process of generating, and 【Chemistry 47】 A method for synthesizing adaglacib according to claim 18, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

20. A method for synthesizing adagrav, a') Compounds with the following structure, 【Chemistry 48】 Compounds with the following structure, 【Chemistry 49】 The reaction is carried out in the presence of a base and a polar solvent. The following structure: [Transformation 50] A method for synthesizing adaglab, comprising the step of producing the final compound of step (a') having the above.

21. Step (b'); b') The final compound from step (a') is reacted with an alkylating agent or arylating agent and a base in the presence of a polar solvent to obtain the following structure: 【Chemistry 51】 The method according to claim 20, further comprising the step of producing the final compound of step (b') having (wherein R is methyl, ethyl, isopropyl, or benzyl).

22. The method according to claim 21, wherein the alkylating agent or arylating agent is optionally selected from the group consisting of aryl halides or alkyl halides R-X (wherein R is methyl, ethyl, isopropyl, or benzyl, and X is Cl, Br, I, alkyl sulfonate, aryl sulfonate, triflate, or nonaflate), dialkyl sulfate, and dialkyl carbonate, and the alkylating agent is optionally 2-iodopropane.

23. The method according to claim 1, wherein the polar solvent is optionally 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 alcohols having the formula R-OH (wherein R is alkyl, allyl, or aryl), and the polar solvent is MeOH.

24. The method according to claim 21, wherein the base is an inorganic base, optionally selected from the group consisting of hydroxides, carbonates, bicarbonates, and phosphates, or ammonium salts or alkali salts thereof, and optionally selected from the group consisting of lithium, sodium, and potassium.

25. Process (c'): c') The final compound from step (b') is reacted with an oxidizing agent in a polar aprotic solvent, and optionally in the presence of a catalyst and a base, to obtain the following structure: 【Chemistry 52】 The method according to claim 21, further comprising the step of producing the final compound of step (c') having the above.

26. The method according to claim 25, wherein the oxidizing agent is selected from the group consisting of peracids, oxone, bleaching agents, hydrogen peroxide, and hydrogen peroxide urea, and optionally the oxidizing agent is hydrogen peroxide.

27. The method according to claim 25 or 26, wherein the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium bisulfate, and optionally the catalyst is sodium tungstate.

28. The method according to claim 25, 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, and optionally the polar aprotic solvent is 2-propanol.

29. The method according to any one of claims 20 and 25 to 28, wherein the base is an inorganic base, optionally selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, and tert-amilate, or ammonium salts or alkali salts thereof, optionally selected from the group consisting of lithium, sodium, and potassium, and optionally selected from the group consisting of sodium methoxide.

30. Step (d'): d') The final compound from step (c') is reacted with (S)-(1-methylpyrrolidine-2-yl)methane in the presence of a base and a polar aprotic solvent to obtain the following structure: 【Chemistry 53】 The method according to claim 25, further comprising the step of producing the final compound of step (d') having the above.

31. The method according to claim 30, wherein the base is an alkoxide selected from the group consisting of isopropoxide, tert-butoxide, and tert-amilate, or ammonium salts or alkali salts thereof, optionally the alkali salt is selected from the group consisting of lithium, sodium, and potassium, or the alkoxide is potassium tert-butoxide.

32. The method according to claim 30 or 31, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP, and optionally the polar aprotic solvent is THF.

33. Process (e'): e') The final compound from step (d') is reacted with an activator in the presence of a base, an additive, and a polar aprotic solvent to form the following structure: 【Chemistry 54】 The method according to claim 30, further comprising the step of producing a final compound of step (e') having (wherein LG is a leaving group).

34. The activator is a halogenated sulfonyl R-SO ２ X (wherein R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, or Br), anhydride (trifluoromethanesulfonic acid anhydride and nonafluorobutanesulfonic acid anhydride), and organic triflate reagent R １ -N-Tf2 (in the formula, R １ The method according to any one of claims 9, 10, and 33, wherein the activator is optionally selected from the group consisting of phenyl, 5-chloro-2-pyridine, or 2-pyridine, and is bis(trifluoromethanesulfonyl)aniline.

35. The activator is bis(trifluoromethanesulfonyl)aniline, i) The base is an inorganic base, optionally selected from the group consisting of carbonates, bicarbonates, and phosphates or their ammonium or alkali salts, and optionally the inorganic base is tripotassium phosphate or dipotassium phosphate; and / or ii) The method according to claim 33, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP, and optionally the polar aprotic solvent is MeCN.

36. Process (f'): f) The final compound from step (e') is reacted with a base, (S)-2-(piperazine-2-yl)acetonitrile or its inorganic or organic salt and a polar aprotic solvent to form the following structure: 【Transformation 55】 The method according to claim 33, further comprising the step of producing a final compound of step (f') having the above.

37. The method according to claim 36, wherein the base is an inorganic base, optionally selected from the group consisting of carbonates, bicarbonates, and phosphates or ammonium salts or alkali salts thereof, and optionally the inorganic base is tripotassium phosphate or dipotassium phosphate.

38. The method according to any one of claims 9, 10, 11, 36, and 37, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP, and optionally the polar aprotic solvent is MeCN.

39. Process (g'): The method according to claim 36, further comprising the step of reacting the final compound of step (f') with sodium 2-fluoroacrylate (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglasib.

40. The binder is propylphosphonic anhydride (T3P®), carbonyl diimidazole (CDI), carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC.HCl)), phosphonium ((benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP)). The method according to claim 39, selected from the group consisting of (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and uronium (O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)).

41. The method according to any one of claims 12, 13, 39, and 40, 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.

42. The aforementioned base is an organic base, and optionally the organic base is DIPEA, Et ３ The method according to claim 11, selected from the group consisting of N, DABCO, and DBU.

43. The method according to claim 11, wherein the base is an inorganic base, and optionally the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

44. A method for synthesizing adagrav, 【Transformation 56】 (wherein R is methyl, ethyl, isopropyl, or benzyl) is reacted with (S)-(1-methylpyrrolidine-2-yl)methanol in the presence of a base and a polar aprotic solvent. 【Chemistry 57】 The process of generating 【Transformation 58】 This is reacted with an activator in the presence of a base, an additive, and a polar aprotic solvent. 【Chemistry 59】 The process of generating (wherein LG is a leaving group); 【Transformation 60】 Reacting with a base, (S)-2-(piperazine-2-yl)acetonitrile or its inorganic or organic salt and a polar aprotic solvent, 【Chemistry 61】 The process of generating 【Transformation 62】 A method for synthesizing adaglacib according to claim 16, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

45. A method for synthesizing adagrav, 【Transformation 63】 (wherein R is methyl, ethyl, isopropyl, or benzyl) is reacted with an oxidizing agent in the presence of a polar aprotic solvent. 【Chemistry 64】 The process of generating 【Transformation 65】 This was reacted with (S)-(1-methylpyrrolidine-2-yl)methanol in the presence of a base and a polar aprotic solvent. 【Chemical Formula 66】 The process of generating 【Transformation 67】 This is reacted with an activator in the presence of a base, an additive, and a polar aprotic solvent. 【Transformation 68】 The process of generating (wherein LG is a leaving group), 【Transformation 69】 This is reacted with a base, (S)-2-(piperazine-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent. 【Transformation 70】 The process of generating 【Chemistry 71】 A method for synthesizing adaglacib according to claim 44, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

46. A method for synthesizing adagrav, 【Chemistry 72】 This is reacted with an alkylating agent or arylating agent and a base in the presence of a polar solvent. 【Transformation 73】 A step of producing (wherein R is methyl, ethyl, isopropyl, or benzyl); 【Chemistry 74】 This is reacted with an oxidizing agent in the presence of a polar aprotic solvent. 【Chemistry 75】 The process of generating 【Transformation 76】 This was reacted with (S)-(l-methylpyrrolidine-2-yl)methanol in the presence of a base and a polar aprotic solvent. 【Chemical 77】 The process of generating 【Transformation 78】 This is reacted with an activator in the presence of a base, an additive, and a polar aprotic solvent. 【Transformation 79】 The process of generating (wherein LG is a leaving group), 【Chemistry 80】 Reacting with a base, (S)-2-(piperazine-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent, 【Chemistry 81】 The process of generating 【Chemistry 82】 A method for synthesizing adaglacib according to claim 45, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

47. A method for synthesizing adagrav, 【Chemistry 83】 It is reacted with a base and a polar solvent, 【Chemical 84】 The process of generating; 【Chemical 85】 This is reacted with an alkylating agent or arylating agent and a base in the presence of a polar solvent. 【Chemical 86】 A step of producing (wherein R is methyl, ethyl, isopropyl, or benzyl); 【Chemistry 87】 It is reacted with an oxidizing agent in the presence of a polar aprotic solvent, 【Chemical 88】 The process of generating; 【Chemistry 89】 This was reacted with (S)-(1-methylpyrrolidine-2-yl)methanol in the presence of a base and a polar aprotic solvent. [Chemical 90] The process of generating; 【Chemistry 91】 This is reacted with an activator in the presence of a base, an additive, and a polar aprotic solvent. 【Chemistry 92】 The process of generating (wherein LG is a leaving group); 【Chemistry 93】 This is reacted with a base, (S)-2-(piperazine-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent. 【Chemical 94】 The process of generating; 【Chemical 95】 A method for synthesizing adaglacib according to claim 46, comprising the step of reacting with 2-fluoroacrylic acid (or the corresponding alkali salt or metal salt) and a binder in the presence of a solvent and optionally a base to produce adaglacib.

48. A compound selected from the group consisting of the following: 【Chemistry 96】 【Chemistry 97】 【Chem.98】

Images