HK1134083A

HK1134083A - Processes for the preparation of 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2h)-yl)-n,4-dimethylbenzamide

Info

Publication number: HK1134083A
Application number: HK10101479.6A
Authority: HK
Inventors: Daniel Dukeshereer; Michael Mao; Richard Vonder Embse; Gopichand Yalamanchili; Rajappa Vaidyanathan; Brian Chekal; George Klemm; Ronald Vanderroest; Randy Geurink
Original assignee: 辉瑞产品公司
Priority date: 2006-12-13
Filing date: 2007-12-05
Publication date: 2010-04-16

Description

Preparation method of 3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide

Background

3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide is known to be useful as a therapeutic agent in the treatment of a variety of pathological conditions, including the treatment or prevention of inflammatory and respiratory diseases. The efficacy of 3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide is believed to be related to its ability to inhibit p38 kinase.

It is believed that p38 α kinase can cause or contribute to the effects of diseases such as: usually inflammation; arthritis; neuroinflammation (neuroinflammation); pain; generating heat; pulmonary diseases; cardiovascular diseases; cardiomyopathy; stroke; ischemia; reperfusion injury; renal reperfusion injury; cerebral edema; nerve trauma and brain trauma; neurodegenerative diseases; central nervous system diseases; liver disease and nephritis; gastrointestinal disorders; ulcerative diseases; eye diseases; an ophthalmic disorder; glaucoma, and glaucoma; acute injury and ocular trauma to ocular tissue; diabetes mellitus; diabetic nephropathy; a skin-related disorder; viral and bacterial infections; myalgia due to infection; influenza, influenza; endotoxic shock; toxic shock syndrome; autoimmune diseases; bone resorption diseases; multiple sclerosis; diseases of the female reproductive system; pathological (but non-malignant) conditions such as hepatic hemangiomas (hemangiomas), angiofibromas of the nasopharynx, and avascular osteonecrosis; benign and malignant tumors/neoplasias, including cancers; leukemia; lymphoma; systemic Lupus Erythematosus (SLE); angiogenesis, including neoplasia; and metastatic lesions.

WO03/068,230a1, published on 21/8/2003, describes 3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide, its preparation and use in the treatment of inflammation.

3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide and the close related analog can be prepared by either the racemic (route 1) or chiral (route 2) routes described below.

To make the discovered pathway more efficient and to establish a scalable approach, several variations have been introduced into pathway 1. These changes include not only improved reaction conditions and processing steps (workup procedure) but also new reactions. The sequence of steps 2, 3 and 4 of the discovered pathway, i.e., alkylation, hydrolysis and bromination, was changed to bromination, alkylation and hydrolysis for a variety of reasons. These include avoiding lengthy work-up (such as multiple extractions and concentrations) in each step and achieving higher yields. Route 1 avoids the use of expensive materials where possible.

Route 2 was initiated in order to develop a new chiral route for the preparation of compounds of formula I, eliminating the need for chiral chromatography. Efficient and tunable chiral synthesis was identified by using a selective enzymatic hydrolysis method. Route 2 also avoids the use of expensive materials where possible.

Disclosure of Invention

A first embodiment of the present invention is an improved process for the preparation of compounds of formula I:

the method comprises the following steps:

a) reacting a compound of formula V:

contacting with a halogenating agent in the presence of at least one solvent to produce a compound of formula IV:

b) contacting a compound of formula IV with a substituted benzyl halide (substitated benzylhalide) in the presence of at least one solvent and a base to produce a compound of formula III:

c) contacting a compound of formula III with a base in the presence of at least one solvent to produce a compound of formula II:

d) contacting a compound of formula II with an activating reagent in the presence of at least one solvent, and then contacting the resulting mixture with an amine to produce a compound of formula I;

wherein

X¹、X²、X³、X⁴、X⁵And X⁶Independently is H, halogen or C₁-C₆An alkyl group;

R¹is C₁-C₆An alkyl or aryl group;

R²is H, halogen or C₁-C₆An alkyl group;

R³is halogen or C₁-C₆An alkyl group; and

R⁴is H or C₁-C₆An alkyl group;

R⁵is H, C₁-C₆An alkyl or aryl group; or

R⁴、R⁵And the nitrogen to which they are attached form a morpholine, thiomorpholine, piperidine, pyrrolidine or piperazine ring optionally substituted with 1 or 2 groups independently being C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy C₁-C₄Alkyl radical, C₁-C₄Dihydroxyalkyl or halogen.

A second embodiment of the present invention is an improved process for the preparation of a compound of formula I, said process comprising the steps of:

a) reacting a compound of formula V

With a halogenating agent in the presence of at least one solvent to produce a compound of formula IV:

b) contacting a compound of formula IV with a hydrolase in the presence of a buffer solution to produce a compound of formula X:

c) contacting a compound of formula X with an activating reagent in the presence of at least one solvent, and then contacting the resulting mixture with an amine to produce a compound of formula IX;

d) contacting a compound of formula IX with a substituted benzyl halide in the presence of a base and at least one solvent to produce a compound of formula I;

wherein

R¹is C₁-C₆An alkyl or aryl group;

R²is H, halogen or C₁-C₆An alkyl group;

R³is halogen or C₁-C₆An alkyl group; and

R⁴is H or C₁-C₆An alkyl group;

R⁵is H, C₁-C₆An alkyl or aryl group; or

A third embodiment of the present invention is an improved process for preparing a compound of formula I having the structure,

the method comprises the following steps:

a) reacting a compound of formula V having the structure:

with 1, 3-dibromo-5, 5-dimethylhydantoin in the presence of acetonitrile to produce a compound of formula IV having the following structure:

b) contacting a compound of formula IV with a Bacillus (Bacillus sp.) protease in the presence of a dipotassium hydrogen phosphate buffer solution to produce a compound of formula X having the structure;

c) contacting a compound of formula X with 1, 1' -carbonyldiimidazole in the presence of dimethylformamide and then reacting the resulting mixture with NH in tetrahydrofuran₂CH₃Contacting to produce a compound of formula IX having the structure:

d) contacting a compound of formula IX with a compound having the following structure in the presence of potassium carbonate and N-methylpyrrolidinone:

a fourth embodiment of the present invention provides a novel intermediate selected from the group consisting of:

3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoic acid methyl ester;

(+) -methyl 3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate;

3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide

3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoic acid;

(-) -3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoic acid; and

(-) -1- (5- (1H-imidazole-1-carbonyl) -2-methylphenyl) -3-bromo-4-hydroxy-6-methylpyridin-2 (1H) -one,

or a pharmaceutically acceptable salt thereof.

Detailed Description

The compounds and salts of the present invention can be prepared from materials commonly available in the art.

The term "alkyl" refers to a straight or branched chain hydrocarbon group having 1 to 8 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

The term "aryl" refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may be optionally fused or otherwise attached to other aromatic or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, indanyl, and biphenyl.

The term "group IA metal" is also known as an alkali metal and includes, for example, lithium, sodium, and potassium.

The term "group IIA metal" is also known as an alkaline earth metal and includes, for example, calcium, barium, strontium, magnesium.

The term "pharmaceutically acceptable" is used as an adjective in this specification, indicating that the modified noun is suitable for use as, or as part of, a pharmaceutical product.

For the use of the words "comprise" or "including" or "containing" in this patent, including the claims, the words are used on the basis of the following and clear understanding: they are intended to be construed as inclusive and not exclusive, and it is the intention of the applicant that each of these words have such an understanding when interpreting this patent, including the claims.

The following are definitions of various abbreviations used herein:

MHz is Megahertz (Megahertz).

Hz is Hertz (Hertz).

J is the Coupling Constant (Coupling Constant).

m/z is the mass to charge ratio.

DEG C is centigrade.

g is g.

mg is mg.

mmol is millimole.

mL is mL.

μ L is μ L.

M is a mole.

HPLC is high performance liquid chromatography.

"DMAC" is N, N-dimethylacetamide.

"DMAP" is dimethylaminopyridine.

"DMF" is dimethylformamide.

"DMI" is 1, 3-dimethylimidazolidinone (1, 3-dimethyllimidazolidone).

"DMPU" is 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (1, 3-dimethyl-3, 4, 5, 6-tetra-2(1H) -pyrimidinone).

"DMSO" is dimethyl sulfoxide.

"ee" is enantiomeric excess (enatiomer processes).

"HCl" is hydrochloric acid.

"MTBE" is methyl tert-butyl ether (methyl tert-butyl ether).

"NMP" is 1-methyl-2-pyrrolidone.

"TEA" is triethylamine.

"TFA" is trifluoroacetic acid.

"THF" is tetrahydrofuran.

General Synthesis

The present application relates in part to processes for preparing compounds of formula I:

wherein X¹、X²、X³、X⁴、X⁵And X⁶Independently is H, halogen or C₁-C₆An alkyl group; r²Is H, halogen or C₁-C₆An alkyl group; r³Is halogen or C₁-C₆An alkyl group; and R is⁴Is H or C₁-C₆An alkyl group; r⁵Is H, C₁-C₆An alkyl or aryl group; or R⁴、R⁵And the nitrogen to which they are attached form a morpholine, thiomorpholine, piperidine, pyrrolidine or piperazine ring optionally substituted with 1 or 2 groups independently being C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy C₁-C₄Alkyl radical, C₁-C₄Dihydroxyalkyl or halogen.

The compounds of formula I can be prepared by either the racemic (route 1) or chiral (route 2) routes described below.

The compounds of the invention may exist as atropisomers (i.e. chiral rotamers). The present invention includes racemic and resolved atropisomers. In some embodiments, one atropisomer is preferred over the other. In the racemic route, the preferred atropisomers can be separated by chiral column chromatography. In the chiral approach, the need for chiral column chromatography is eliminated by using a selective enzymatic hydrolysis process.

In one embodiment, the present invention provides a process for the preparation of racemic compounds of formula I. Route 1 is presented generally in scheme 1.

Scheme 1

Wherein X¹、X²、X³、X⁴、X⁵And X⁶Independently is H, halogen or C₁-C₆An alkyl group; r¹Is C₁-C₆An alkyl or aryl group; r²Is H, halogen or C₁-C₆An alkyl group; r³Is halogen or C₁-C₆An alkyl group; and R is⁴Is H or C₁-C₆An alkyl group; r⁵Is H, C₁-C₆An alkyl or aryl group; or R⁴、R⁵And the nitrogen to which they are attached form a morpholine, thiomorpholine, piperidine, pyrrolidine or piperazine ring optionally substituted with 1 or 2 groups independently being C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy C₁-C₄Alkyl radical, C₁-C₄Dihydroxyalkyl or halogen.

Preparation of Compounds of formula V-method 1

In one embodiment, the present invention provides a process for preparing a compound of formula V, comprising contacting a compound of formula VI with a compound of formula VII in the presence of at least one solvent.

Wherein R is¹Is C₁-C₆An alkyl or aryl group; r²Is H, halogen or C₁-C₆An alkyl group; and R is³Is halogen or C₁-C₆An alkyl group.

Typically, a compound of formula VI is contacted with a compound of formula VII in the presence of at least one solvent and a base.

The process is typically carried out at a temperature of from about 30 ℃ to about 300 ℃. In one embodiment, the temperature is from about 45 ℃ to about 150 ℃. In another embodiment, the temperature is from about 60 ℃ to about 100 ℃.

The process is typically carried out for a period of about 4 hours to about 60 hours. In one embodiment, the time is from about 2 hours to about 40 hours. In another embodiment, the time is from about 15 hours to about 25 hours.

The solvent is a polar solvent or a non-polar solvent. Examples of useful polar solvents include ethylene glycol and trifluoroethanol. Examples of useful non-polar solvents include dichlorobenzene, xylene, and diphenyl ether. In one embodiment, the solvent is dichlorobenzene, xylene, diphenyl ether, ethylene glycol or trifluoroethanol. In another embodiment, the solvent is trifluoroethanol or ethylene glycol. In another embodiment, the solvent is ethylene glycol.

In one embodiment, the base is an inorganic base or an organic base. In one embodiment, the base is a carbonate, bicarbonate or alkoxide of a group IA or IIA metal, such as potassium carbonate, potassium tert-butoxide or sodium bicarbonate. In one embodiment, the base is, for example, a hindered tertiary amine such as N, N-diisopropylethylamine, Triethylamine (TEA), or Dimethylaminopyridine (DMAP). In one embodiment, the base is potassium carbonate.

Preparation of Compounds of formula V-method 2

In one embodiment, the present invention provides a process for preparing a compound of formula V, comprising contacting a compound of formula VII with a compound of formula VIII.

Typically, the compound of formula VII and the compound of formula VIII are contacted with the compound of formula VIII in the presence of at least one solvent and an acid.

The process is typically carried out at a temperature of from about 0 ℃ to about 250 ℃. In one embodiment, the temperature is from about 5 ℃ to about 100 ℃. In another embodiment, the temperature is from about 15 ℃ to about 60 ℃.

The process is typically carried out for a period of about 0.01 hours to about 10 hours. In one embodiment, the time is from about 0.5 hours to about 7 hours. In another embodiment, the time is from about 1 hour to about 7 hours.

The solvent is a polar solvent or a non-polar solvent. Examples of useful polar solvents include acetic acid, lower alkyl carboxylic acids (lower alkyl carboxylic acids) and dimethylformamide. Examples of useful nonpolar solvents include dioxane, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, toluene, and methylene chloride. In one embodiment, the solvent is dioxane, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, acetic acid or a lower alkyl carboxylic acid, dichloromethane or dimethylformamide. In one embodiment, the solvent is dioxane, tetrahydrofuran, acetic acid, or dichloromethane. In one embodiment, the solvent is dioxane.

In one embodiment, the acid is an organic acid. In another embodiment, the organic acid is a lower alkyl carboxylic acid or substituted lower alkyl carboxylic acid, or a sulfonic acid such as p-toluenesulfonic acid or methanesulfonic acid. In one embodiment, the sulfonic acid is methanesulfonic acid.

Synthesis of Compounds of formula VIII

A process for preparing a compound of formula VIII comprises contacting madumyl acid (Meldrum's acid) with diketene (diketene) in the presence of a base and at least one solvent.

The following procedure is analogous to that described in the literature: kang, J; kim, Y; park, M; lee, c.; the procedures reported in Kim, W.synthetic Communications (1984), 14(3), 265-9.

The process is typically carried out at a temperature of from about 0 ℃ to about 100 ℃. In one embodiment, the temperature is from about 5 ℃ to about 50 ℃. In another embodiment, the temperature is from about 20 ℃ to about 25 ℃.

The process is typically carried out for a period of about 0.01 hours to about 25 hours. In one embodiment, the time is from about 0.5 hours to about 10 hours. In another embodiment, the time is from about 1 hour to about 5 hours.

In one embodiment, the base is an organic base or an inorganic base. Examples of useful inorganic bases include carbonates, bicarbonates or alkoxides of group IA or group IIA metals, such as potassium carbonate, potassium tert-butoxide and sodium bicarbonate. Examples of useful organic bases include Triethylamine (TEA), Dimethylaminopyridine (DMAP), and N, N-diisopropylethylamine. In one embodiment, the base is potassium carbonate, TEA or DMAP. In another embodiment, the base is TEA.

Step 1 halogenation

In one embodiment, the present invention provides a process for preparing a compound of formula IV comprising contacting a compound of formula V with a halogenating agent.

Typically, the compound of formula V is contacted with a halogenating agent in the presence of at least one solvent.

The process is typically carried out at a temperature of from about-40 ℃ to about 50 ℃. In one embodiment, the temperature is from about-15 ℃ to about 20 ℃. In another embodiment, the temperature is from about-10 ℃ to about 10 ℃.

The process is typically carried out for a period of about 0.5 hours to about 10 hours. In one embodiment, the time is from about 1.5 hours to about 5 hours. In one embodiment, the time is from about 1 hour to about 3 hours.

In one embodiment, the solvent is a polar solvent. Examples that may be used include acetonitrile, acetic acid or acetic acid with a co-solvent (co-solvent) such as water or a lower alkyl alcohol. In one embodiment, the solvent is, for example, acetonitrile, acetic acid, or acetic acid containing a co-solvent such as water or a lower alkyl alcohol. In one embodiment, the solvent is an acetic acid/water solution. In another embodiment, the solvent is acetonitrile.

The halogenating agent may be pure or in solution. In one embodiment, the halogenating agent is a brominating or chlorinating agent. In one embodiment, the brominating or chlorinating agent is, for example, phenyl triethyl ammonium tribromide (phenyl trimethyl lammonium tribromide), 1, 3-dibromo-5, 5-dimethylhydantoin, N-bromosuccinimide, pyridinium bromide, perbromide, bromine, dibromotriphenylphosphine, bromine chloride, N-bromohydantoin, N-bromocaprolactam, N-chlorosuccinimide, sodium hypochlorite, chlorine, sulfuryl chloride, copper bromide, phosphorus pentachloride, or tert-butyl hypochlorite. In one embodiment, the brominating or chlorinating agent is 1, 3-dibromo-5, 5-dimethylhydantoin, bromine chloride, or chlorine. In another embodiment, the brominating agent is bromine. In another embodiment, the brominating reagent is 1, 3-dibromo-5, 5-dimethylhydantoin.

The halogenation may be carried out in the presence of an acid. In one embodiment, the acid is an organic acid or an inorganic acid. Examples of useful acids include tetrafluoroboric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, sulfuric acid, and phosphoric acid. In one embodiment, the acid is tetrafluoroboric acid.

Step 2-benzylation

In one embodiment, the present invention provides a method of preparing a compound of formula III, comprising contacting a compound of formula IV with a substituted benzyl halide.

Wherein X¹、X²、X³、X⁴、X⁵And X⁶Independently is H, halogen or C₁-C₆An alkyl group; r¹Is C₁-C₆An alkyl or aryl group; r²Is H, halogen or C₁-C₆An alkyl group; r³Is halogen or C₁-C₆An alkyl group.

Typically, the compound of formula IV is contacted with a substituted benzyl halide in the presence of at least one solvent and a base.

The process is typically carried out at a temperature of from about 0 ℃ to about 200 ℃. In one embodiment, the temperature is from about 15 ℃ to about 100 ℃. In another embodiment, the temperature is from about 25 ℃ to about 75 ℃.

The process is typically carried out for a period of about 0.5 hours to about 40 hours. In one embodiment, the time is from about 1 hour to about 10 hours. In another embodiment, the time is from about 1 hour to about 5 hours.

In one embodiment, the substituted benzyl halide is:

wherein halogen is chlorine, bromine or iodine; and X²、X³、X⁴、X⁵And X⁶Independently is H, halogen or C₁-C₆An alkyl group. In one embodiment, the halogen-substituted benzyl halide is, for example, 2, 4-difluorobenzyl bromide, 2, 3-difluorobenzyl bromide, 2, 5-difluorobenzyl bromide, 2, 4-difluorobenzyl chloride, 2, 3-difluorobenzyl chloride, or 2, 5-difluorobenzyl chloride. In another embodiment, the halogen-substituted benzyl halide is 2, 4-difluorobenzyl chloride. In another embodiment, the halogen-substituted benzyl halide is 2, 4-difluorobenzyl bromide.

In one embodiment, the solvent is a polar aprotic solvent. In one embodiment, the polar aprotic solvent is, for example, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), 1, 3-Dimethylimidazolidinone (DMI), or 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU). In another embodiment, the polar aprotic solvent is N, N-dimethylformamide. In another embodiment, the solvent is N-methylpyrrolidone.

In one embodiment, the base is an organic base or an inorganic base. Examples of useful inorganic bases include carbonates, bicarbonates or alkoxides of group IA or group IIA metals, such as potassium carbonate, potassium tert-butoxide and sodium bicarbonate. Examples of useful organic bases include Triethylamine (TEA), Dimethylaminopyridine (DMAP), and N, N-diisopropylethylamine. In one embodiment, the base is potassium carbonate, potassium tert-butoxide, or sodium bicarbonate. In another embodiment, the base is potassium carbonate.

Step 3-hydrolysis

In one embodiment, the present invention provides a process for preparing a compound of formula II comprising contacting a compound of formula III with a base.

Typically, the compound of formula III is contacted with a base in the presence of at least one solvent.

The process is typically carried out at a temperature of from about 10 ℃ to about 100 ℃. In one embodiment, the temperature is from about 20 ℃ to about 80 ℃. In another embodiment, the temperature is from about 40 ℃ to about 75 ℃.

The process is typically carried out for a period of about 0.5 hours to about 40 hours. In one embodiment, the time is about 1 hour to 10 hours. In another embodiment, the time is from about 1 hour to about 5 hours.

In one embodiment, the base is an inorganic base. Examples of useful inorganic bases include group IA or IIA metal hydroxide bases or carbonate bases such as potassium hydroxide, lithium hydroxide, cesium hydroxide, and sodium hydroxide. In one embodiment, the base is potassium hydroxide, lithium hydroxide, cesium hydroxide, or sodium hydroxide. In one embodiment, the base is sodium hydroxide.

In one embodiment, the solvent is a solvent. In another embodiment, the solvent comprises a mixture of two or more solvents. In one embodiment, the solvent is, for example, water with or without a water-miscible organic co-solvent, examples of which are lower alkyl alcohols, Tetrahydrofuran (THF), acetone, acetonitrile, N-dimethylformamide, or Dimethylsulfoxide (DMSO). In one embodiment, the solvent is water. In one embodiment, the solvent comprises acetonitrile and water.

In another embodiment, the compound of formula III may be hydrolyzed under non-aqueous conditions with a proteolytic enzyme or nucleophile.

Step 4-amidation

In one embodiment, the present invention provides a process for preparing a compound of formula I, comprising reacting a compound of formula II with a suitable activating reagent, and then contacting the resulting mixture with a suitable primary or secondary amine to produce the compound of formula I.

Typically, the compound of formula II is contacted with an activating reagent in the presence of at least one solvent, and the resulting mixture is then contacted with an amine.

The process is typically carried out at a temperature of from about 0 ℃ to about 50 ℃. In one embodiment, the temperature is from about 1 ℃ to about 25 ℃. In another embodiment, the temperature is from about 5 ℃ to about 15 ℃.

The process is typically carried out for a period of about 0.01 hours to about 35 hours. In one embodiment, the time is from about 0.5 hours to about 10 hours. In another embodiment, the time is from about 1 to about 5 hours.

The activating agent is an agent that activates a carboxylic acid. Activation means increasing the electrophilicity of the carboxylic acid, thereby increasing its reactivity towards nucleophilic attack. In one embodiment, the activating reagent is carbonyldiimidazole, dicyclohexylcarbodiimide, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phenyltriethylammonium tribromide, pyridinium bromide, perbromide, bromine, dibromotriphenylphosphine, bromine chloride, N-bromohydantoin, or N-bromocaprolactam. In one embodiment, the activating reagent is carbonyldiimidazole, dicyclohexylcarbodiimide, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, or phosphorus pentachloride. In one embodiment, the activating reagent is oxalyl chloride. In another embodiment, the activating reagent is carbonyldiimidazole.

The solvent is a polar solvent or a non-polar solvent. Examples of useful polar solvents include dimethylformamide, acetic acid and lower alkyl carboxylic acids. Examples of useful nonpolar solvents include dichloroethane, tetrahydrofuran, dioxane, methyl tert-butyl ether, diethyl ether, and toluene. In one embodiment, the solvent is, for example, dimethylformamide, dichloroethane, tetrahydrofuran, dioxane, methyl tert-butyl ether or toluene. In one embodiment, the solvent is dimethylformamide, dichloroethane, tetrahydrofuran, or dioxane. In another embodiment, the solvent is dichloroethane. In one embodiment, the solvent is dimethylformamide.

In one embodiment, the amine is HNR⁴R⁵Wherein R is⁴Is H or C₁-C₆Alkyl radical(ii) a And R is⁵Is H, C₁-C₆An alkyl or aryl group; or R⁴、R⁵And the nitrogen to which they are attached form a morpholine, thiomorpholine, piperidine, pyrrolidine or piperazine ring optionally substituted with 1 or 2 groups independently being C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy C₁-C₄Alkyl radical, C₁-C₄Dihydroxyalkyl, or halogen. In one embodiment, R⁴Is H. In one embodiment, R⁵Is C₁-C₆An alkyl group. In one embodiment, the amine is methylamine. Typically, the amine is combined with a solvent prior to addition. In one embodiment, the solvent is methanol, ethanol, tetrahydrofuran, or water. In another embodiment, the solvent is methanol, tetrahydrofuran, or water. In one embodiment, the solvent is tetrahydrofuran. In one embodiment, the amine is a solution of methylamine in tetrahydrofuran.

Optionally, an acid may be used to cause the (work up) reaction. In one embodiment, the acid is an organic acid or an inorganic acid. Examples of useful acids include acetic acid, citric acid, HCl, and sulfuric acid. In one embodiment, the acid is acetic acid, citric acid, HCl, or sulfuric acid. In one embodiment, the acid is HCl, acetic acid, or sulfuric acid. In one embodiment, the acid is HCl.

The compounds of formula I can be isolated by filtration or by standard extraction or evaporation methods.

One skilled in the art will recognize an alternative to using a mixed anhydride intermediate such as a lower alkyl carboxylic anhydride intermediate or an acyl imidazole intermediate instead of an acyl chloride intermediate to prepare the product. The mixed anhydride intermediate can be synthesized using a typical alkyl chloroformate in the presence of a typical hindered amine base. Acylimidazole intermediates can be synthesized using reagents such as carbonyldiimidazole.

The order of the steps may be rearranged in several possible ways. In one embodiment, the hydrolysis and amidation may be performed prior to the benzylation step.

In another embodiment, the invention provides a process for preparing an enantiomerically enriched mixture or only a single enantiomer of a compound of formula I according to pathway 2. Route 2 is presented generally in scheme 2.

Scheme 2

The compounds of formulae V and IV can be prepared as previously described in scheme 1.

Step 1-protease reaction

In one embodiment, the present invention provides a method of preparing a compound of formula X, comprising contacting a compound of formula IV with a hydrolase.

Wherein R is¹Is C₁-C₆Alkyl or aryl, R²Is H, halogen or C₁-C₆Alkyl, and R³Is halogen or C₁-C₆An alkyl group.

Typically, the compound of formula IV is contacted with a hydrolase in the presence of a buffer solution.

The process is typically carried out at a temperature of from about 5 ℃ to about 80 ℃. In one embodiment, the temperature is from about 10 ℃ to about 60 ℃. In another embodiment, the temperature is from about 20 ℃ to about 40 ℃.

The process is typically carried out for a period of about 5 hours to about 100 hours. In one embodiment, the time is from about 25 hours to about 75 hours. In another embodiment, the time is from about 30 hours to about 60 hours.

The process is typically carried out at a pH of about 6 to about 12. In one embodiment, the pH is from about 8 to about 11. In another embodiment, the pH is from about 9 to about 10. In another embodiment, the pH is about 9.

In one embodiment, the buffer solution is an inorganic buffer solution. In another embodiment, the buffer solution is, for example, a potassium phosphate buffer solution or an inorganic bicarbonate buffer. In one embodiment, the buffer solution is a dipotassium hydrogen phosphate buffer solution. Typically, the molar concentration of the buffer solution is about 1M.

In one embodiment, a suitable enzyme solution is a hydrolase such as a lipase or a protease. In one embodiment, the hydrolase enzyme produces an excess of the (-) enantiomer of the compound of formula X. In one embodiment, particularly useful hydrolases are those that produce the (-) enantiomer at least 80% enantiomeric excess (enantiomeric excess).In another embodiment, particularly useful hydrolases are those that produce the (-) enantiomer in at least 85% enantiomeric excess. In another embodiment, particularly useful hydrolases are those that produce an enantiomeric excess of the (-) enantiomer of at least 90%. In another embodiment, particularly useful hydrolases are those that produce an enantiomeric excess of the (-) enantiomer of at least 95%. In another embodiment, particularly useful hydrolases are those that produce an enantiomeric excess of the (-) enantiomer of at least 99%. In one embodiment, the hydrolase is a Bacillus protease solution (BNovozyme，Bagsvaerd，Denmark)。

In one embodiment, the hydrolase enzyme produces a compound of formula X as a racemic mixture. In another embodiment, the hydrolase enzyme produces an excess of the (+) enantiomer of the compound of formula X.

In one embodiment, the (-) enantiomer of the compound of formula X is preferred. The (+) enantiomer of the compound of formula IV may be isolated and removed. The (+) enantiomer may be recycled to the racemic mixture by thermal isomerization in a typical aprotic organic solvent at a temperature of about 100 ℃ to about 300 ℃.

Typically, the (+) enantiomer of the compound of formula IV is contacted with a high boiling aprotic solvent, a halogenated or substituted aromatic or aliphatic solvent.

The high boiling aprotic solvent, halogenated or substituted aromatic or aliphatic solvent may be chlorobenzene, anisole, dioxane, NMP, N-dimethylformamide or dimethylsulfoxide.

The process is typically carried out at a temperature of from about 0 ℃ to about 200 ℃. In one embodiment, the temperature is from about 75 ℃ to about 150 ℃. In another embodiment, the temperature is from about 100 ℃ to about 140 ℃.

The process is typically carried out for a period of about 30 hours to about 200 hours. In one embodiment, the time is from about 20 hours to about 100 hours. In another embodiment, the time is from about 50 hours to about 75 hours.

Step 3 amidation

In one embodiment, the present invention provides a process for preparing a compound of formula IX, comprising reacting a compound of formula X with a suitable activating reagent, and then contacting the resulting mixture with a suitable primary or secondary amine to produce a compound of formula IX.

Wherein X¹Is H, halogen or C₁-C₆An alkyl group; r²Is H, halogen or C₁-C₆An alkyl group; r³Is halogen or C₁-C₆An alkyl group; and R is⁴Is H or C₁-C₆An alkyl group; r⁵Is H, C₁-C₆An alkyl or aryl group; or R⁴、R⁵And the nitrogen to which they are attached form a morpholine, thiomorpholine, piperidine, pyrrolidine or piperazine ring optionally substituted with 1 or 2 groups independently being C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy C₁-C₄Alkyl radical, C₁-C₄Dihydroxyalkyl or halogen.

In one embodiment, the compounds of formulae X and IX are the (-) enantiomer.

Typically, the compound of formula X is contacted with an activating reagent in the presence of at least one solvent, and the resulting mixture is then contacted with an amine.

The process is typically carried out at a temperature of from about 0 ℃ to about 100 ℃. In one embodiment, the temperature is from about 10 ℃ to about 50 ℃. In one embodiment, the temperature is from about 15 ℃ to about 30 ℃.

The process is typically carried out for a period of about 0.1 hour to about 10 hours. In one embodiment, the time is from about 0.5 hours to about 5 hours. In another embodiment, the time is from about 1 hour to about 3 hours.

In one embodiment, the activating reagent is carbonyldiimidazole, dicyclohexylcarbodiimide, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phenyltriethylammonium tribromide, pyridinium bromide, perbromide, bromine, dibromotriphenylphosphine, bromine chloride, N-bromohydantoin, or N-bromocaprolactam. In one embodiment, the activating reagent is carbonyldiimidazole, dicyclohexylcarbodiimide, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, or phosphorus pentachloride. In one embodiment, the activating reagent is oxalyl chloride. In another embodiment, the activating reagent is carbonyldiimidazole.

In one embodiment, the amine is HNR⁴R⁵Wherein R is⁴Is H or C₁-C₆An alkyl group; and R is⁵Is H, C₁-C₆An alkyl or aryl group; or R⁴、R⁵And the nitrogen to which they are attached form an optionally unsubstituted or 1 or 2 radicalA group-substituted morpholine ring, thiomorpholine ring, piperidine ring, pyrrolidine ring or piperazine ring, said group being independently C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy C₁-C₄Alkyl radical, C₁-C₄Dihydroxyalkyl, or halogen. In one embodiment, R⁴Is H. In one embodiment, R⁵Is C₁-C₆An alkyl group. In one embodiment, the amine is methylamine. Typically, the amine is combined with a solvent prior to addition. In one embodiment, the solvent is methanol, ethanol, tetrahydrofuran, or water. In another embodiment, the solvent is methanol, tetrahydrofuran, or water. In one embodiment, the solvent is tetrahydrofuran. In one embodiment, the amine is methylamine in tetrahydrofuran.

Optionally, an acid may be used to initiate the reaction. In one embodiment, the acid is an organic acid or an inorganic acid. Examples of useful acids include acetic acid, citric acid, HCl, and sulfuric acid. In one embodiment, the acid is acetic acid, citric acid, HCl, or sulfuric acid. In one embodiment, the acid is HCl, acetic acid, or sulfuric acid. In one embodiment, the acid is HCl.

Step 4-benzylation

In one embodiment, the present invention provides a process for preparing a compound of formula I, comprising contacting a compound of formula IX with a substituted benzyl halide.

In one embodiment, the compounds of formula IX and I are the (-) enantiomer.

Typically, the compound of formula IX is contacted with a substituted benzyl halide in the presence of a base and at least one solvent.

The process is typically carried out at a temperature of from about 0 ℃ to about 200 ℃. In one embodiment, the temperature is from about 25 ℃ to about 100 ℃. In another embodiment, the temperature is from about 50 ℃ to about 75 ℃.

The process is typically carried out for a period of about 0.5 hours to about 20 hours. In one embodiment, the time is from about 1 hour to about 10 hours. In another embodiment, the time is from about 2 hours to about 4 hours.

In one embodiment, the substituted benzyl halide is:

wherein halogen is chlorine, bromine or iodine; and X²、X³、X⁴、X⁵And X⁶Independently is H, halogen or C₁-C₆An alkyl group. In one embodiment, the halogen-substituted benzyl halide is, for example, 2, 4-difluorobenzyl bromide, 2, 3-difluorobenzyl bromide, 2, 5-difluorobenzyl bromide, 2, 4-difluorobenzyl chloride, 23-difluorobenzyl chloride or 2, 5-difluorobenzyl chloride. In another embodiment, the halogen-substituted benzyl halide is 2, 4-difluorobenzyl chloride. In another embodiment, the halogen-substituted benzyl halide is 2, 4-difluorobenzyl bromide.

In one embodiment, the base is an organic base or an inorganic base. Examples of useful inorganic bases include carbonates, bicarbonates or alkoxides of group IA or group IIA metals, such as potassium carbonate, potassium tert-butoxide and sodium bicarbonate. Examples of useful organic bases include Triethylamine (TEA) or Dimethylaminopyridine (DMAP); and hindered amines such as N, N-diisopropylethylamine. In one embodiment, the base is potassium carbonate, potassium tert-butoxide, or sodium bicarbonate. In another embodiment, the base is potassium carbonate.

In one embodiment, the solvent is a polar aprotic solvent. In one embodiment, the polar aprotic solvent is, for example, N-dimethylformamide (N, N-dimethylformamide), N-Dimethylacetamide (DMAC) or N-methylpyrrolidone (NMP), 1, 3-Dimethylimidazolidinone (DMI), 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU). In another embodiment, the polar aprotic solvent is N, N-dimethylformamide. In another embodiment, the solvent is N-methylpyrrolidone.

In one embodiment, the product is purified by trituration or precipitation with a suitable solvent and/or co-solvent system. In one embodiment, the solvent is methanol, 1-butanol, ethanol, ethyl acetate, or 2-propanol. In one embodiment, the solvent is methanol, ethanol or ethyl acetate. In one embodiment, the solvent is methanol.

Those skilled in the art will appreciate that the order of steps may occur in an alternative order. Scheme 6 depicts some possible sequences.

Scheme 6

Sequence 1: halogenation, hydrolysis and amidation. Sequence 2: hydrolysis, halogenation, amidation. Sequence 3: hydrolysis, amidation, halogenation. Sequence 4: starting with 3-amino-4-methylbenzoic acid, amidation, halogenation. Note that the final step in all these processes is the benzylation step.

In one embodiment, the present invention provides novel intermediates. In one embodiment, the compound is selected from:

3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide;

3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoic acid;

(-) -1- (5- (1H-imidazole-1-carbonyl) -2-methylphenyl) -3-bromo-4-hydroxy-6-methylpyridin-2 (1H) -one;

or a pharmaceutically acceptable salt thereof.

The compounds of the invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, salts of the compound may be advantageous due to one or more physical properties of the salt, such as enhanced drug stability under different conditions of temperature and humidity, or a desired solubility in water or oil. In some cases, salts of the compounds may also be used as an aid/auxiliary means for isolating, purifying, and/or resolving the compounds.

Non-toxic pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, pyrophosphoric, hydrobromic and nitric acids, or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethanesulfonic, salicylic and stearic acids. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium ions. Those skilled in the art will recognize a variety of non-toxic pharmaceutically acceptable salts.

The compounds described herein may exist as atropisomers, i.e., chiral rotamers. These compounds may be, for example, racemates, chiral non-racemic or diastereomers. In these cases, the single enantiomer, i.e. the optically active form, can be obtained by asymmetric synthesis or by resolution of the racemate. Resolution of the racemate may be accomplished by conventional methods such as crystallization in the presence of a resolving agent; chromatography using, for example, a chiral HPLC column; thermal or kinetic resolution; or producing diastereomers using a resolving agent to give a racemic mixture, separating the diastereomers by chromatography or selective crystallization, and removing the resolving agent to yield the original compound in enantiomerically enriched form. Any of the above methods can be repeated or combined to increase the enantiomeric purity of the compound.

The compounds described herein may exist as atropisomers, i.e., chiral rotamers. The present invention includes racemic atropisomers and resolved atropisomers. The following scheme shows in general the compounds (Z) which can be present as atropisomers and also the two possible atropisomers (A) and (B) thereof. The scheme also shows each of the atropisomers (A) and (B) of the Fischer projection formula. In this scheme, R³And X¹Having the same definition as described for formula I, R_p’Is R²Substituent in the definition, R_pIs CONR⁴R⁵And D represents a substituted benzyloxy group.

When enriched in one enantiomer, it is present in a higher amount than the other enantiomer, and the degree of enrichment can be defined by the expression enantiomeric excess ("ee"), defined as 100(2x-1), where x is the molar fraction of the predominant enantiomer in the enantiomeric mixture (e.g., 20% ee corresponds to a ratio of 60: 40 enantiomers).

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The following examples are merely illustrative and do not limit the remainder of the disclosure in any way.

Example 1

Schemes 7 and 8 depict the overall synthesis described in example 1.

Scheme 7

Scheme 8

The racemic procedure for the preparation of (-) -3- [ 3-bromo-4- [ (2, 4-difluorobenzyl) oxy ] -6-methyl-2-oxopyridin-1 (2H) -yl ] -N, 4-dimethylbenzamide (1) is as follows:

synthesis of 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzene Using Pyranone 6 Methyl formate (5)：

4-hydroxy-6-methyl pyrone (6) (1.18kg, 9.34mol), methyl 3-amino-4-methylbenzoate (7) (1.0kg, 6.21mol), catalyst K₂CO₃(102gm, 0.74mol) and 2L trifluoroethanol were mixed and heated to 80-87 ℃ under nitrogen and held for 22 hours. After the reaction was complete, the mixture was cooled to 65 ℃, 11.3L ethyl acetate was added and the solution was gradually cooled to 5-10 ℃. The product was collected and washed with 2L of ethyl acetate to give methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate in about 55% isolated yield (isolatedyield).

Alternatively, methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (5) can be prepared as follows using 5- (1-hydroxy-3-oxobutylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (8).

A mixture of methyl 3-amino-4-methylbenzoate (7) (2.0g, 12.1mmol) and 5- (1-hydroxy-3-oxobutylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (8) (3.86g, 16.94mmol, 1.4 equiv.) in dioxane (20mL) was heated to reflux for 5 minutes and cooled to 50 ℃. The mixture was then treated with 1.16g of methanesulfonic acid and heated at reflux for 5 minutes. Liquid chromatography showed the reaction (cyclization) to be essentially complete. The mixture was poured into 60mL of crushed ice-water and stirred for 1.5 hours. The precipitate was filtered, washed with water and air dried to give 2.47g (75% yield) of product.

The above steps are described in the literature: kang, J; kim, Y; park, M; lee, c.; variations of the steps described in Kim, w.synthetic Communications (1984), 14(3), 265-9. Basically, reaction of madumyl acid with diketene in dichloromethane in the presence of TEA at 20-25 ℃ for 2 hours yielded 80% of 5- (1-hydroxy-3-oxobutylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (8).

Process for preparing methyl 3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate Synthesis of

A suspension of methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (5) (1.6kg, 5.85mol) in 6.4L acetic acid/1.6L water was cooled to 15 ℃. A solution of 973g of bromine in 1.6L of acetic acid was prepared and added slowly to the reaction via the dropping funnel. During the addition of bromine, a white precipitate formed after the mixture became homogeneous. After the addition was complete, the mixture was stirred for a further 15 minutes. The mixture was diluted with 16L of water; the product was filtered and washed with 12L of water followed by 9.6L of cold acetonitrile (0-5 ℃). The solid was dried, yielding 1.85kg (90%) of product.¹H NMR(300MHz，DMSO-d₆)δ1.80(s，3H)，2.04(s，3H)，3.86(s，3H)，6.15(s，1H)，7.59(d，J＝8.1Hz)，7.73(s，1H)，7.98(d，J＝8.1，1H)，11.6(bs，1H)。C₁₅H₁₄BrNO₄Analytical calculation of (a): c, 51.16; h, 4.01; and N, 3.98. Experimental values: c, 50.83; h, 4.02; and N, 4.00.

3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzene Synthesis of methyl ester of acid (3)

Methyl 3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (4) (1.9kg, 5.4mol), N-dimethylformamide (4.8L) and powdered K were combined under nitrogen₂CO₃(1.1kg, 8.1mol) were mixed together and heated to 55 ℃.2, 4-difluorobenzyl chloride (964g, 5.9mol) was added at a rate which maintained the temperature below 65 ℃. After addition, the mixture was heated at 65 ℃ for 3.5 hours. After 3 hours the reaction was complete, 19L of water was added and the reaction mixture was cooled to 20-25 ℃. The solid was filtered and washed with 15L of water. The crude product was then purified by trituration in refluxing methanol (4L). The mixture was cooled and the solid was filtered, yielding 2.32kg (90%) of product.¹H NMR(300MHz，CDCl₃)δ1.90(s，3H)，2.11(s，3H)，3.87(s，3H)，5.25(s，2H)，6.11(s，1H)，6.88(dt，J＝4.8，1.8Hz，1H)，6.96(t，J＝4.8Hz，1H)，7.42(d，J＝6Hz，1H)，7.59(q，J＝4.8Hz，1H)，7.74(s，1H)，8.02(d，J＝6Hz，1H)。C₂₂H₁₈BrF₂NO₄Analytical calculation of (a): c, 55.25; h, 3.79; and N, 2.93. Experimental values: c, 55.34; h, 3.83; and N, 3.14.

3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzene Preparation of acid (2)

Methyl 3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (3) (3.4kg, 7.1mol), 2.5M NaOH (3.1L.7.8mol), CH₃CN (12L) and 8.6L of water were mixed together and heated to 60 ℃. Once the mixture became homogeneous, the mixture was stirred for another hour. The reaction mixture was cooled to 20 ℃ and then treated with 865ml of concentrated HCl at a rate such that the temperature was maintained below 25 ℃.After the HCl addition was complete, the mixture was stirred for an additional hour. The product was filtered and washed with 12L CH₃CN was washed and dried to yield 2.87kg (87%) of the adduct.¹H NMR(300MHz，CD₃OD)δ7.87(dd，J＝7.8，1.6Hz，1H)，7.82(d，J＝1.8Hz，1H)，7.69(q，J＝8.1Hz，1H)，7.57(d，J＝8.1Hz，1H)，7.09(dt，J＝2.2，8.6Hz，1H)，6.7(s，1H)，5.4(s，2H)，2.14(s，3H)，2.02(s，3H)(d，J＝2.4Hz，1H)，3.94(s，3H)，2.15(s，3H)，1.91(s，3H)。ES-HRMS m/z 464.0275(C₂₁H₁₇BrF₂NO₄M + H calcd of 464.0304). C₂₁H₁₆BrF₂NO₄Analytical calculation of (a): c, 54.33; h, 3.47; and N, 3.02. Experimental values: c, 54.40; h, 3.42; and N, 3.17.

(-)3- (4- (2, 4-Difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethyl Preparation of phenylbenzamides (1)

3- (4- (2, 4-Difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoic acid (2) (1.4kg, 3.0mol) was suspended in 7L of tetrahydrofuran containing 28ml of N, N-dimethylformamide and cooled to 5 ℃. Oxalyl chloride (368ml, 4.22mol) was added to the reactor at a rate such that the temperature remained below 10 ℃ and the evolution of gas was controlled. After addition of oxalyl chloride, the reaction mixture was allowed to warm to room temperature. The reaction was complete when the mixture became homogeneous. The reaction mixture was discharged into a separate vessel and left to stand. 40% methylamine (4.4L, 50.3mol) and 2.6L water were added to the reactor and cooled to below 5 ℃. The reaction mixture is then added to the cooled methylamine solution at a rate which maintains the temperature below 15 ℃. Once the addition was complete, the mixture was allowed to warm to room temperature and stirring was continued for 30 minutes. 12.6L of water was added to the mixture and stirring was continued for one hour. The product was filtered and washed with 10L of water, yielding 1.25kg (90%).¹H NMR(300MHz，DMSO-d₆)δ7.95(bs，1H)，7.88(dd，J＝1.2，5.7Hz，1H)，7.68(q，J＝5.1Hz，1H)，7.64(d，J＝1.2Hz，1H)，7.46(d，J＝6.0Hz，1H)，7.36(bs，1H)，7.29(dt，J＝1.8，7.8Hz，1H)，7.16(dt，J＝1.8，76.0Hz，1H)，6.70(s，1H)，6.18(s，1H)，5.33(s，2H)，3.32(s，3H)，1.97(s，3H)，1.88(s，3H)。C₂₁H₁₇BrF₂N₂O₃+0.66EtOH+0.1H₂Analytical calculation of O: c, 54.11; h, 4.30; and N, 5.65. Experimental values: c, 54.03; h, 4.59; n, 5.79.

Then using a chiral stationary phase such as Chiralcel OJ^TMOrAD^TM(Daicel chemical Industries, Japan) using methanol or ethanol as a mobile phase, the racemic product 3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide (1) produced was chromatographed to isolate the corresponding (-) -3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide (1).

Example 2

Scheme 9 depicts the overall synthesis described in example 2.

Scheme 9

Following the development of the method for racemic 3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide, a method for the direct preparation of (-) -3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide has been developed, which is described below:

step 1

4-hydroxy-6-methyl pyrone (6) (6.71kg, 53.2mol), methyl-3-amino-4-methyl benzoate (7) (4.50kg, 27.2mol), catalyst K₂CO₃(0.54kg, 3.91mol), acetonitrile (6.14L) and ethylene glycol (6.14L) were combined under nitrogen and the acetonitrile was removed by vacuum distillation. The reaction is stirred at 65 ℃ for 18-24 hours. After the reaction, the mixture was cooled to 25 ℃. A1: 1 acetonitrile/water solution (6.14L each) was added to the mixture. The mixture was stirred for 90 minutes and cooled to 0 ℃. The product was collected, washed with 1: 1 acetonitrile/water (3.4L each) and dried to give methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (5) in 60% isolated yield.

Step 2

A solution of 1, 3-dibromo-5, 5-dimethylhydantoin (1.375kg, 4.81mol) in acetonitrile (11.5L) was added to a solution of methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (5) (2.50kg, 9.15mol) in acetonitrile (4.8L). The solution is added at a rate such that the temperature below-10 ℃ is maintained for 90 to 180 minutes. After completion of the reaction part of the acetonitrile (about 6L) was removed via distillation. The product was precipitated by adding water (7.9L) and filtered to yield 2.90kg (90%) of methyl 3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (4).

Step 3

Methyl (±) -3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (4) (1kg, 2.84mol) was mixed with 1M dipotassium hydrogen phosphate buffer (dipotassium hydrogen phosphate (3.05kg, 17.5mol) and water (16.4L)) and warmed to 25 ℃. The pH of the solution was adjusted to 9.1 with 10% NaOH solution (ca. 4.2L) and then addedEnzyme (Novozyme, Bagsvaerd, Denmark) and warmed to 30 ℃. After stirring for about 40-45 hours, the solution was adjusted to pH 6.0 using 6N HCl (2.3L) and stirred for 30 minutes. The precipitate obtained was the following ester: the unreacted enantiomer of methyl (+) -3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (423mg) was isolated by filtration and washed with water. The aqueous filtrate was washed with 5.0L of dichloromethane. It is then precipitated by further acidification with 2.1L of 6N HCl and the optically active acid is isolated by filtration: (-) -3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoic acid (10). After drying, 1.3kg (80% of theory) of product are obtained.

Step 4

(-) -3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoic acid (10) (1.50kg, 4.44mol), 1' -carbonyldiimidazole (1.08kg, 6.66mol) and N, N-dimethylformamide (3mL) were mixed together at ambient temperature. Once the activation reaction was deemed complete, a 2M methylamine solution in tetrahydrofuran (5.5L, 11.1mol) was added at such a rate that the temperature remained below 30 ℃. As the reaction reached completion, the mixture became homogeneous. A1N hydrochloric acid solution (15.4kg) was added to reach pH 3 or less. Acidification to precipitate the product. The product was filtered, washed with water and dried overnight at 60 ℃ under vacuum to give (-) -3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide (9) (1.56kg, 4.44mol, 97% pure).

Step 5

3- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide (9) (1kg, 2.85mol), potassium carbonate (0.43kg, 3.11mol), 1-methyl-2-pyrrolidone (4.0L) and 2, 4-difluorobenzyl bromide (0.71kg, 3.42mol) were mixed together and heated at 30 ℃ for 2 hours. The reaction mixture was diluted with water (12.5L) over a period of 30 to 60 minutes and then stirred for 30 to 60 minutes. The product was filtered and washed with water. (-) -3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide (1) was obtained (1.36kg, 95% pure, > 99% ee).

The product was then purified. (-) -3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide (1) (4.0kg, 8.4mol) and methanol (13L) were mixed together, brought to 60 ℃ and stirred for 1H. The product was filtered and washed with ambient temperature methanol (3.0L) to give (-) -3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide (1) (2.9kg, 6.1mol, 98.4% pure).

The above detailed description of the embodiments is intended only to acquaint others skilled in the art with the invention, its principles, and its practical application so that others skilled in the art may modify and apply the invention in its numerous forms, as may be best suited to the requirements of a particular application. The present invention is therefore not limited to the above-described embodiments and may be variously modified.

Claims

1. A process for preparing a compound of formula I:

the method comprises the following steps:

a) reacting a compound of formula V:

c) contacting a compound of formula X with an activating reagent in the presence of at least one solvent, and then contacting the resulting mixture with an amine to produce a compound of formula IX:

wherein the content of the first and second substances,

R¹is C₁-C₆An alkyl or aryl group;

R²is H, halogen or C₁-C₆An alkyl group;

R³is halogen or C₁-C₆An alkyl group; and

R⁴is H or C₁-C₆An alkyl group;

R⁵is H, C₁-C₆An alkyl or aryl group; or

R⁴、R⁵And the nitrogen formation to which they are attached is optionally not takenA morpholine ring, thiomorpholine ring, piperidine ring, pyrrolidine ring or piperazine ring, substituted or unsubstituted with 1 or 2 groups independently being C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy C₁-C₄Alkyl radical, C₁-C₄Dihydroxyalkyl or halogen.

2. The method of claim 1, wherein the compound of formula V:

the preparation method comprises the following steps: reacting a compound of formula VI:

with a compound of formula VII:

in the presence of at least one solvent and a base,

wherein

R¹Is C₁-C₆An alkyl or aryl group;

R²is H, halogen or C₁-C₆An alkyl group; and

R³is halogen or C₁-C₆An alkyl group.

3. The method of claim 1, wherein the compound of formula V:

the preparation method comprises the following steps: reacting a compound of formula VII:

with a compound of formula VIII:

in the presence of at least one solvent and an acid,

wherein

R¹Is C₁-C₆An alkyl or aryl group;

R²is H, halogen or C₁-C₆An alkyl group; and

R³is halogen or C₁-C₆An alkyl group.

4. The method according to claim 1, wherein the compound of formula I is (-) -3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide or a pharmaceutically acceptable salt thereof.

5. The process as claimed in claim 4, wherein (-) -3- (4- (2, 4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) -N, 4-dimethylbenzamide is present in 80% enantiomeric excess.

6. The process of claim 1, wherein the halogenating agent in step a is phenyl triethyl ammonium tribromide, 1, 3-dibromo-5, 5-dimethylhydantoin, N-bromosuccinimide, pyridinium bromide, perbromide, bromine, dibromotriphenylphosphine, bromine chloride, N-bromohydantoin, N-bromocaprolactam, N-chlorosuccinimide, sodium hypochlorite, chlorine, sulfuryl chloride, copper bromide, phosphorus pentachloride, or tert-butyl hypochlorite.

7. The process of claim 1, wherein the solvent in step a is acetonitrile, acetic acid or acetic acid containing a co-solvent such as water, a lower alkyl alcohol or dioxane.

8. The method of claim 1, wherein the hydrolase in step b is a lipase or a protease.

9. The method of claim 1, wherein the buffer solution in step b is a dipotassium hydrogen phosphate buffer solution or an inorganic bicarbonate buffer solution.

10. The process of claim 1, wherein the activating reagent in step c is 1, 1' -carbonyldiimidazole, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phenyltriethylammonium tribromide, pyridinium bromide, perbromide, bromine, dibromotriphenylphosphine, bromine chloride, N-bromohydantoin, or N-bromocaprolactam.

11. The process of claim 1, wherein the solvent in step c is dimethylformamide, dichloroethane, tetrahydrofuran, dioxane, methyl tert-butyl ether, or toluene.

12. The process of claim 1, wherein the amine in step c is HNR⁴R⁵Wherein R is⁴Is H and R⁵Is C₁-C₆An alkyl group.

13. The process of claim 1, wherein the substituted benzyl halide in step d is:

wherein

Halogen is chlorine, bromine or iodine;

X¹、X²、X³、X⁴、X⁵and X⁶Independently is H, halogen or C₁-C₆An alkyl group.

14. The process of claim 1, wherein the solvent in step d is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, 1, 3-dimethylimidazolidinone, or 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone.

15. The process of claim 1, wherein the base in step d is potassium carbonate, potassium tert-butoxide, sodium bicarbonate, triethylamine, dimethylaminopyridine or N, N-diisopropylethylamine.

16. The method of claim 1, wherein the solvent is dichlorobenzene, xylene, diphenyl ether, ethylene glycol or trifluoroethanol.

17. The process of claim 2, wherein the base is potassium carbonate, potassium tert-butoxide, sodium bicarbonate, N-diisopropylethylamine, triethylamine, or dimethylaminopyridine.

18. The process of claim 3, wherein the solvent is dioxane, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, acetic acid or a lower alkyl carboxylic acid, dichloromethane or dimethylformamide.

19. The method of claim 3, wherein the acid is a sulfonic acid.

20. A process for preparing a compound of formula I having the structure:

the method comprises the following steps:

a) reacting a compound of formula V having the structure:

b) contacting the compound of formula IV with bacillus protease in the presence of potassium phosphate buffer to produce a compound of formula X having the structure:

d) reacting a compound of formula IX with a compound having the structure:

in the presence of potassium carbonate and N-methylpyrrolidone.