Process for the preparation of phenyl-substituted acc inhibitors and intermediates thereof

Abstract

The present invention belongs to the field of medicinal chemistry and relates to a method for preparing a phenyl-substituted ACC inhibitor and an intermediate thereof. Specifically, the present invention relates to a method for preparing (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)benzoic acid of formula (I) or a salt, hydrate, solvate or crystal thereof.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and specifically relates to (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)benzoic acid and intermediates thereof, and a preparation method thereof. BACKGROUND

[0002] Acetyl-CoA carboxylase (ACC) is a biotin enzyme that catalyzes the reaction of acetyl-CoA to produce malonyl-CoA, which is the rate-limiting step of the first phase of fatty acid synthesis. In mammals, ACC exists in the form of two tissue-specific isozymes, ACC1 mainly exists in lipid-generating tissues such as liver and adipose tissue, and ACC2 mainly exists in oxidative tissues such as liver, heart and skeletal muscle. ACC1 and ACC2 are encoded by independent genes, although they exhibit different cellular distribution, but they share 75% overall amino acid sequence identity. In the liver, fatty acid (FA) synthesis and elongation is through ACC1 catalyzing acetyl-CoA to produce malonyl-CoA, thereby promoting the formation of triglycerides and very low density lipoprotein (VLDL). In the heart and skeletal muscle, which have limited capacity for synthesizing fatty acids, malonyl-CoA formed by ACC2 plays a role in regulating FA oxidation [Tong L, Harwood HJ Jr. J Cell Biochem. 2006, 99(6): 1476-1788.].

[0003] Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are considered to be two manifestations of abnormal liver metabolism, and are currently the most common chronic liver disease, and their incidence is rising year by year. Among them, NASH can further develop into cirrhosis and liver cancer, which can cause death caused by liver disease. At present, there is a lack of effective treatment strategy for this kind of disease, and the existing treatment drugs are still insulin sensitizers represented by thiazolidinediones and antioxidants (such as vitamin E), in addition to lipid-lowering drugs, angiotensin receptor antagonists, polyunsaturated fatty acids, etc., and the treatment effect is very limited. In the current research, ACC1 and ACC2 are considered to be drug action targets for treating NAFLD and NASH [Geraldine Harriman, Jeremy Greenwood, Sathesh Bhat, et al. Proc Natl Acad Sci U.S.A. 2016, 113(13): E1796-E1805.].

[0004] CN111484504A provides an ACC inhibitor, which has good inhibitory activity on ACC and is expected to become a therapeutic agent for ACC expression related diseases, such as fibrosis diseases, metabolic diseases, cancers or tissue hyperplasia diseases, with higher efficacy and smaller side effects. The structure is shown as follows:

[0005]

[0006] The application also discloses a synthesis method thereof, but the synthesis step involves a relatively expensive palladium catalyst and a toxic organotin reagent, which is not conducive to process production. A new economic and environmentally friendly process route needs to be explored for process amplification. SUMMARY

[0007] The application provides a new intermediate compound, which has the structure shown in formula (5):

[0008]

[0009] wherein:

[0010] R 1 selected from carboxyl protecting groups.

[0011] In some specific embodiments, R 1 selected from alkyl and silyl groups; further preferably, R 1 selected from C 1-6 alkyl, -Si(C 1-6 alkyl)3 and -Si(phenyl)3; further preferably, R 1 selected from methyl, ethyl, propyl, trimethylsilyl and triphenylsilyl groups.

[0012] Further, the application provides a preparation method of the compound of formula (5), which comprises the following steps: d) subjecting the compound of formula 4 to a dehydration cyclization reaction in the presence of a dehydration reagent to obtain the compound of formula (5), wherein R 1 has the definition described above,

[0013]

[0014] In some specific embodiments, the dehydration reagent in step d) is selected from sulfuric acid, phosphorus pentoxide, dichlorosulfoxide, phosphorus pentachloride and a dehydration reagent combination of triphenylphosphine and hexachloroethane.

[0015] In some specific embodiments, the solvent in step d) is an aprotic solvent; preferably, the solvent is selected from 1-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF) and N,N-dimethylaniline (DMA).

[0016] In some specific embodiments, the reaction temperature in the preparation method of step d) is from 30 °C to 120 °C, preferably from 40 °C to 110 °C, and more preferably from 50 °C to 100 °C.

[0017] In some specific embodiments, the preparation method of the compound of formula (I) or its salt, hydrate, solvate or crystal further comprises the steps of c-1) condensation reaction of the compound of formula 1 with the compound of formula 2 in the presence of a condensation reagent and a base to obtain the compound of formula 3, c-2) deprotection of the group of formula 3 under acid conditions to obtain the compound of formula 4,

[0018]

[0019] wherein R 1 having the definitions described above, R 2 , R 3 is selected from an acetal protecting group and a thioacetal protecting group, each independently selected from C 1-10 alkyloxy and C 1-10 alkylthio, or R 2 , R 3 are combined to form a cyclic acetal or a cyclic thioacetal structure.

[0020] In some specific embodiments, R 2 , R 3 are each independently selected from C 1-6 alkyloxy and C 1-6 alkylthio, or R 2 , R 3 are combined to form a cyclic acetal or a cyclic thioacetal structure; further preferably, R 2 , R 3 are each independently a substituent C 1-6 alkyloxy; more preferably, R 2 , R 3 are each independently C 1-3 alkyloxy.

[0021] In some specific embodiments, the condensation reagent in step c-1) is selected from one or more of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), 1,1'- carbonyldiimidazole (CDI), 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 4-dimethylaminopyridine (DMAP).

[0022] In some specific embodiments, the base in step c-1) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicycloundec-7-ene, 2,6-dimethylpyridine, 4-dimethylaminopyridine, imidazole, sodium carbonate, potassium carbonate, cesium carbonate, preferably triethylamine, diisopropylethylamine, sodium carbonate and potassium carbonate.

[0023] In some specific embodiments, the solvent in step c-1) is an aprotic solvent; preferably, the solvent is selected from the group consisting of dichloromethane, diethyl ether, isopropyl ether, methyl tert-butyl ether, butyl ether, ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile, propionitrile, N,N-dimethylformamide (DMF), hexamethylphosphoramide and dimethylsulfoxide; further preferably, the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane and N,N-dimethylformamide (DMF).

[0024] In some specific embodiments, the acid in step c-2) is a protic acid, a Lewis acid, further, the acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, formic acid, acetic acid, oxalic acid, phthalic acid, trichloroacetic acid and trifluoroacetic acid; further preferably from the group consisting of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid and trifluoroacetic acid.

[0025] In some specific embodiments, the molar ratio of the compound of formula 1 and the acid in step c-2) is from 1:1 to 1:6, preferably from 1:1.2 to 1:6, further preferably from 1:1.5 to 1:5.

[0026] Further, the present application provides a process for preparing a compound of formula (5), which comprises the following steps:

[0027]

[0028] c-1) condensation reaction of the compound of formula 1 with the compound of formula 2 in the presence of a condensing reagent and a base to obtain a compound of formula 3, c-2) deprotection of the protecting group of the compound of formula 3 under acid conditions to obtain a compound of formula 4;

[0029] d) anhydrous cyclization reaction of the compound of formula 4 in the presence of a dehydrating reagent to obtain a compound of formula 5;

[0030] wherein R 1 , R 2 , R 3 have the definitions described above.

[0031] The present application also provides a compound of formula 1,

[0032]

[0033] wherein:

[0034] R 1 is selected from carboxyl protecting groups.

[0035] In some specific embodiments, R 1 is selected from alkyl and silyl groups; further preferably, R 1 is selected from C 1-6 alkyl, -Si(C 1-6 alkyl)3 and -Si(phenyl)3; further preferably, R 1 is selected from methyl, ethyl, propyl, trimethylsilyl and triphenylsilyl.

[0036] Further, the present application provides a method for preparing the compound of formula 1, which comprises the following steps:

[0037]

[0038] e) subjecting the compound of formula 1-1 to a formylation reaction in the presence of an N-substituted amide and a catalyst to obtain the compound of formula 1-2;

[0039] f) subjecting the compound of formula 1-2 to an oxidation reaction to obtain the compound of formula 1;

[0040] wherein:

[0041] R 1 has the definition described above.

[0042] In some specific embodiments, in step e), the compound of formula 1-1 is subjected to a formylation reaction in the presence of an N-substituted amide and an acyl chloride, the N-substituted amide is selected from mono-substituted formamide and di-substituted formamide, preferably di-substituted formamide, further preferably N,N-dimethylformamide; the acyl chloride is selected from phosphorus oxychloride, dichlorosulfoxide, oxalyl chloride, acetyl chloride and propionyl chloride, preferably phosphorus oxychloride.

[0043] In some specific embodiments, in the method of step e), the reaction temperature is -10°C to 100°C, preferably -10°C to 90°C, further preferably 0°C to 80°C.

[0044] In some specific embodiments, in step f), the compound of formula 1-2 is subjected to an oxidation reaction in the presence of an acid and an oxidizing agent, the acid is selected from formic acid, acetic acid, trifluoroacetic acid, potassium dihydrogen phosphate, preferably potassium dihydrogen phosphate; in some specific embodiments, in step f), the oxidizing agent is selected from one or a combination of hydrogen peroxide, potassium permanganate, sodium chlorite, sodium bromite, sodium hypochlorite, sodium hypobromite, potassium dichromate and the like, preferably sodium chlorite.

[0045] In some embodiments, a reaction solvent is included in step f), and the solvent is selected from one or more of dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, and 2-methyltetrahydrofuran.

[0046] In some embodiments, the reaction temperature in the preparation method of step f) is from 10 °C to 100 °C, preferably from 20 °C to 90 °C, and more preferably from 30 °C to 80 °C.

[0047] The present application also provides a preparation method of the compound of formula 1-1, comprising the following steps:

[0048]

[0049] 1) reacting a compound of formula SM-A with N,N'-carbonyldiimidazole (CDI) and a compound of formula SM-B in dichloromethane to produce a compound of formula (Int-B);

[0050] 2) reacting a compound of formula Int-B with potassium tert-butoxide in solvent 1,4-dioxane to cyclize to produce a compound of formula Int-C;

[0051] 3) condensing the carboxyl group of a compound of formula Int-C with an alcohol to produce a compound of formula 1-1.

[0052] In another aspect, the present application also provides the use of a compound of formula (5) or a salt thereof as an intermediate in the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a specific embodiment, the use of a compound of formula (5a) as an intermediate in the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided,

[0053]

[0054] In some embodiments, the present application provides a preparation method of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of using a compound of formula (5) or a salt thereof according to the present application. In some specific embodiments, the preparation method of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present application, wherein the compound of formula (5) or a salt thereof is prepared by the above preparation method.

[0055] In some specific embodiments, the present application provides a preparation method of a compound of formula (I) or a salt, hydrate, solvate or crystal thereof, wherein the method comprises the following steps:

[0056]

[0057] 1) condensation reaction of the compound of formula 1a with the compound of formula 2a to obtain the compound of formula 3a; and deprotection of the group under acid condition to obtain the compound of formula 4a;

[0058] 2) dehydrating condensation of the compound of formula 4a to obtain the compound of formula 5a;

[0059] 3) reaction of the compound of formula 5a with the compound of formula 6a under base condition to obtain the compound of formula 7a;

[0060] 4) hydrolysis reaction of the compound of formula 7a under base condition to obtain the compound of formula (I);

[0061] The compound of formula 1a is prepared by the preparation method of the present application, and the compound of formula 2a and the compound of formula 6a are commercially available or synthesized by conventional means.

[0062] The present application provides a preparation method of the compound of formula (I) or a salt, hydrate, solvate or crystal thereof, which uses a new intermediate as a raw material to perform cyclization reaction to generate an oxazole ring, overcomes the use of expensive palladium catalyst and toxic organotin reagent in the prior art for introducing the oxazole ring, greatly reduces the cost, is easy to operate, is environmentally friendly, and can meet the production and application on an industrial scale.

[0063] Term explanation

[0064] 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 application belongs.

[0065] The "leaving group" of the present application has the general meaning in the art, and refers to a group that can be easily replaced, an active functional group on a molecule that is replaced by a molecule when a new bond is formed. Groups having this function are well known to those skilled in the art, and specific examples can be further referred to manuals of organic synthesis commonly used in the art. For example, the leaving group can be a halogen atom, an amino group, an alkoxy group, an acyloxy group, an aryloxy group, a heteroaryloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a hydroxyl group, an active ester of a hydroxyl group, such as a carboxylate, a sulfonate, a phosphate, or a borate.

[0066] The "carboxyl protecting group" of the present application refers to a suitable group known in the art for amino protection, for example, the carboxyl protecting group can be (C 1-10 alkyl or aryl)trisilane, such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and the like; can be C 1-10 alkyl or substituted alkyl, such as methyl, tert-butyl, allyl, trityl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), and the like; can be (C 1-10alkyl or aryl)acyl, for example formyl, acetyl, trifluoroacetyl, benzoyl, and the like; can be (C 1-6 alkyl or C 6-10 aryl) sulfonyl, for example methylsulfonyl, ethylsulfonyl, benzylsulfonyl, and the like; can be (C 1-6 alkyl or C 6-10 aryloxy)carbonyl, for example methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2-biphenylyl-2-propyloxycarbonyl, t-butyloxycarbonyl, phenoxycarbonyl, t-butyloxycarbonyl; can also be C 1-6 alkyl or C 6-10 aryl, for example methoxy, ethoxy, phenoxy, trimethylsilyl ethoxy, and the like.

[0067] "Alkyl" of the present application refers to straight-chained or branched saturated hydrocarbon groups. Suitable alkyl groups are substituted or unsubstituted C 1-10 alkyl, for example methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl, and the like.

[0068] "Alkoxy" of the present application refers to -O-alkyl. Suitable alkoxy groups according to the present application are C 1-10 alkoxy, such as C 1-8 alkoxy, C 1-7 alkoxy, C 1-6 alkoxy, C 1-5 alkoxy, C 1-4 alkoxy, C 1-3 alkoxy, including methoxy, ethoxy, propoxy, isopropoxy, isobutyloxy, sec-butyloxy, and the like.

[0069] "Halogen" of the present application refers to fluorine, chlorine, bromine, iodine.

[0070] "Aryl" of the present application refers to aromatic systems which can comprise a single ring or multiple condensed rings, for example, bi- or tri-cyclic rings, wherein at least a portion of the condensed rings form a conjugated aromatic system, which is a 5- to 50-membered ring, preferably about 6 to about 12-membered ring. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthyl.

[0071] "Heteroaryl" of the present application refers to aromatic systems which are aromatic monocyclic or multiple condensed rings, for example, bi- or tri-cyclic rings, at least one carbon atom of which is replaced by a heteroatom, O, S, N. Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridinyl, quinazolinonyl, pyrrolyl, imidazolonyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, and the like.

[0072] The "salts" of the present application can be any salt, and in particular, a pharmaceutically acceptable salt. In this context, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a compound of the present application formed from the reaction of a compound of the present application with a "base" or "basic reagent" of the present application, which can be selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfamic acid, nitric acid, p-toluenesulfonic acid, benzenesulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, acetic acid, ethanedioic acid, phenylacetic acid, propanoic acid, propanedioic acid, trifluoroacetic acid, succinic acid, glycolic acid, stearic acid, ascorbic acid, pamoic acid, hydroxymaleic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, ethanedisulfonic acid, oxalic acid, isethionic acid, citric acid, D-gluconic acid, lactic acid, L-malic acid, succinic acid, L-tartaric acid, fumaric acid, alpha-ketoglutaric acid, hippuric acid, maleic acid, D-tartaric acid, methanesulfonic acid, or the like. "Pharmaceutically acceptable salts" of the compounds of the present application can be synthesized from a compound of the present application that contains a basic or acidic moiety by conventional chemical methods. Generally, the salt can be prepared by dissolving the free base in a suitable solvent, such as water, ethanol or methanol, and passing a gas saturated with the desired salt or a solution of the desired salt through the solution, or by reacting the free base in a suitable solvent with the desired salt or a solution of the desired salt.

[0073] A "basic reagent" of the present application refers to a compound capable of deprotonating a hydroxyl or amino group. Examples of bases include, but are not limited to, (C 1-6 alkyl)oxides ((C 1-6 alkyl)OM), wherein (C 1-6 alkyl)oxides include, but are not limited to, MeO-, EtO-, n-PrO-, i-PrO-, t-BuO-, i-AmO- (isoamyl oxide), and the like, and wherein M is an alkali metal cation, such as Li + , Na + , K + , and the like. The alcohol solvent includes (C 1-6 alkyl)OH, such as, for example, methanol, ethanol, n-propanol, isopropanol, t-butanol, isoamyl alcohol, and the like. Non-alkoxy bases can also be used, such as sodium hydroxide, potassium hydroxide, sodium hydride, sodium hexamethyldisilylamide, lithium hexamethyldisilylamide, lithium diisopropylamide, calcium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), Grignard reagents such as (C 1-6 alkyl)Mg(halogen), which include, but are not limited to, methylmagnesium chloride, methylmagnesium bromide, t-butylmagnesium chloride, t-butylmagnesium bromide, and the like.

[0074] The "acetal protecting groups" of the present application are appropriate groups known in the art for acetal protection. For example: dimethyl acetal, diethyl acetal, diisopropyl acetal, ethylene glycol acetal, propylene glycol acetal, and the like; the "thioacetal protecting groups" of the present application are appropriate groups known in the art for thioacetal protection. For example: dimethyl thioacetal, diethyl thioacetal, ethylene glycol thioacetal, propylene glycol thioacetal, and the like.

[0075] The term "solvate" means a form of the compounds of the present application that forms a complex with solvent molecules in either the solid or liquid state. Hydrates are a special form of solvate where the solvent is water. Within the scope of the present application, solvates preferably are hydrates.

[0076] The term "crystalline" refers to various solid forms of the compounds of the present application, including crystalline forms, amorphous.

[0077] "Hydrogen", "carbon", "oxygen" in the compounds of the present application include all isotopes of these atoms. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, isotopes of carbon include 13 C and 14 C, isotopes of oxygen include 16 O and 18 O, and the like. DETAILED DESCRIPTION

[0078] The following representative examples are presented in order to more fully illustrate the application and are not intended to limit the scope of the application. The materials used in the following examples are commercially available unless otherwise stated.

[0079] Example 1 Preparation of 3-(3-(ethoxycarbonyl)phenyl)-5-methyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylic acid

[0080]

[0081] Step 1: Preparation of ethyl 2-(3-(3-(ethoxycarbonyl)phenyl)ureido)-4- methylthiophene-3-carboxylate

[0082]

[0083] Into a 100 L reactor, add dichloromethane (79.5 kg), 2-amino-4-methyl- thien-3-carboxylic acid ethyl ester (6.0 kg) and N'N-carbonyldiimidazole (5.777 kg), protect with nitrogen, react at 20-25 °C overnight, after the reaction is completed, add triethylamine (3.605 kg) at 25 °C, add 3-aminobenzoic acid ethyl ester methyl sulfonate (9.309 kg), react at 20-25 °C overnight, after the reaction is completed, slowly add the reaction solution into heptane in batches, stir the reaction solution for 0.5-1 h after the addition is completed, centrifuge, wash with water, pulp the wet product with water, pulp for 2 h at 10-20 °C, centrifuge, wash with water, dry the solid at 70±5 °C with air blowing to obtain the title compound, total 9.68 kg, yield 79.40%.

[0084] Step 2: Preparation of 3-(5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin- 3(4H)-yl)benzoic acid

[0085]

[0086] Into a 100 L reactor, add 1,4-dioxane (33.08 kg) and 2-(3-(3-(ethoxycarbonyl) phenyl)ureido)-4-methylthiophene-3-carboxylic acid ethyl ester (3.2 kg), heat and control the temperature at 50±5 °C to stir until 2-(3-(3-(ethoxycarbonyl)phenyl)ureido)-4- methylthiophene-3-carboxylic acid ethyl ester is completely dissolved, then add potassium tert-butoxide (2.38 kg) at 50±5 °C, react for 0.5 h, after the reaction is completed, add purified water, react for 0.5 h, stop the reaction, slowly add hydrochloric acid in batches, adjust the pH to 2-3, crystallize at 35±5 °C for more than 1 h, crystallize at 15±5 °C for more than 8 h, centrifuge, wash with water, repeat the above feeding and post-treatment in another two 100 L reactors, combine the solids obtained three times, dry at 70 °C with air blowing for more than 8 h to obtain the title compound, total 7.00 kg, yield 90.90%.

[0087] Step 3: Preparation of 3-(5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin- 3(4H)-yl)benzoic acid ethyl ester

[0088]

[0089] Into a 100 L reactor, add N,N dimethylformamide (39.7 kg), 3-(5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)benzoic acid (6.98 kg) and N'N-carbonyldiimidazole (5.62 kg), protect with nitrogen, react at 35±5°C for 2 h, add anhydrous ethanol to the reaction solution, react at 35±5°C overnight, after the reaction is completed, slowly add the reaction solution into water in batches, after adding, stir at 15±5°C for more than 3 h, centrifuge, wash with water, and dry at 70°C for more than 8 h. The title compound is obtained, a total of 6.62 kg, with a yield of 96.79%.

[0090] Step 4: 3-(6-formyl-5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)benzoic acid ethyl ester

[0091]

[0092] Into a 100 L reactor, add N,N dimethylformamide (62.12 kg), cool to 0±5°C, drop phosphorus oxychloride (6.11 kg), maintain the temperature below 5°C, after the drop is completed, maintain the temperature and stir for 0.5 h, then add 3-(5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)benzoic acid ethyl ester (6.58 kg), after the addition is completed, maintain the temperature and stir for 0.5 h, then warm to 25±5°C and stir for 0.5 h, then warm to 60±5°C and react for 2 h, during the reaction, solid is precipitated, after the reaction is completed, slowly add the reaction solution into water in batches, after adding, stir at 10±5°C for more than 1 h, centrifuge, pulp with water for more than 0.5 h, make the solid neutral, centrifuge, wash with water, and dry at 70°C for more than 8 h. The title compound is obtained, a total of 6.42 kg, with a yield of 90.0%.

[0093] Step 5: 3-(3-(ethoxycarbonyl)phenyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylic acid

[0094]

[0095] In a 100 L reactor, dimethyl sulfoxide (14.124 kg) was added, 3-(6-formyl-5- methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)benzoic acid ethyl ester (2.14 kg) was added in 30±5 °C with stirring and dissolved completely, tetrahydrofuran (11.42 kg) was added, water (6.42 kg) was stirred, the reaction liquid became turbid, sodium dihydrogen phosphate (2.868 kg) solid was stirred for 20 min, then sodium chlorite (2.70 kg) in water (10.70 kg) was added dropwise, the temperature was maintained below 60 °C, after the addition was completed, the temperature was maintained and stirred at 40±5 °C, the reaction was monitored for completion, the reaction was stopped, the reaction liquid was pumped into water for crystallization, after the addition was completed, it was stirred at 10±5 °C for 8 h or more, centrifuged, washed with water, the above feeding and post-treatment were repeated in another two 100 L reactors, the solid was dried at 70 °C with air blowing for 8 h or more. The title compound was obtained, a total of 5.84 kg, with a yield of 87.1 %.

[0096] 1 H NMR (500 MHz, DMSO-d6) δ 12.77 (s, 2H), 8.00 (d, 1H), 7.91 (s, 1H), 7.65-7.59 (m, 2H), 4.34 (dd, 2H), 2.70 (s, 3H), 1.33 (t, 3H). ESI-MS [M+H] + m / z: 375.1.

[0097] Example 2 Preparation of 3-(5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3- d]pyrimidin-3(2H)-yl)benzoic acid ethyl ester

[0098]

[0099] Step 1 : 3-(5-methyl-2,4-dioxo-6-((2-oxoethyl)carbamoyl)-1,2-dihydrothieno[2,3- d]pyrimidin-3(4H)-yl)benzoic acid ethyl ester

[0100]

[0101] In a 100 L reactor, acetonitrile (11.455 kg), 3-(3-(ethoxycarbonyl)phenyl)-5- methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylic acid (2.90 g), EDCI (1.783 kg), HOBt (0.733 kg) and triethylamine (1.175 kg) were stirred and dissolved, then aminoacetaldehyde diethyl acetal (1.239 kg) was added. The temperature was controlled at 65-70 °C, and the reaction was monitored by HPLC. After the reaction was completed, the reaction solution was cooled to T = 25 ± 5 °C, and a prepared methyl sulfonic acid (2.234 kg) water (7.250 kg) solution was added dropwise, with the internal temperature controlled at 20-30 °C. After the addition was completed, the temperature was increased to 35-40 °C, and the reaction was monitored by HPLC. Then the temperature was decreased to 20 ± 10 °C, and the reaction solution was added to 10 times the volume of ethyl acetate (26.158 kg). The organic layer was washed with 5 times the volume of saturated brine 3 times, with the temperature controlled at 20 ± 10 °C. The third time, the water was removed by standing for a long time. The organic layer was dried over anhydrous sodium sulfate (2.900 kg) and rotary evaporated. The solid was dissolved in 10 times the volume of dichloromethane (38.425 kg) and slowly added dropwise to 20 times the volume of heptane (39.672 kg) to crystallize. After stirring at room temperature for 30 min, the solid was obtained by centrifugation. The solid was vacuum dried at 40 ± 5 °C for 12 h or more to obtain the title compound solid, 3.680 kg.

[0102] 1 H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.55 (s, 1H), 8.36 (t, 1H), 8.01-8.02 (m, 1H), 7.94 (s, 1H), 7.61-7.66 (m, 2H), 4.32-4.37 (m, 2H), 4.06 (d, 2H), 2.67 (s, 3H), 1.32-1.35 (m, 3H). ESI-MS [M+H] + m / z: 416.1.

[0103] Step 2: 3-(5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)- yl)benzoic acid ethyl ester

[0104]

[0105] In a 100 L reactor, add 3-(5-methyl-2,4-dioxo-6-((2-oxoethyl)carbamoyl)- 1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)benzoic acid ethyl ester (2.460 kg), 1 -methyl-2-pyrrolidinone (15.173 kg), triphenylphosphine (3.106 kg), and hexachloroethane (2.797 kg), and start heating and stirring. Heat to 75±5°C, and monitor the reaction by HPLC until completion. Cool to 25±5°C, and add the reaction solution to 15 volumes of ethyl acetate (33.284 kg). Wash with 10 volumes of water (24.600 kg) twice, remove the water layer, and reserve the organic layer. After rotary evaporation of the organic layer, add ethanol (1.941 kg) and triethylamine (1.798 kg), and stir at 25±5°C for 20±10 min. Slowly add to 30 volumes of water (73.800 kg) to crystallize. After stirring for 10±10 min, remove the solid by filtration. Add 15 volumes of dichloromethane (48.893 kg) to the filtrate, adjust the pH to 1-3 with concentrated hydrochloric acid (about 1.2 L), stir for 10±10 min, and separate the layers. After rotary evaporation of the organic layer, add 5 volumes of methanol (7.929 kg), heat to 60±10°C, stir for 20±10 min, cool to 10±5°C, and crystallize for 30 min or more. Centrifuge, rinse the crude product with methanol, and dry at 70±5°C for 12 hours or more to obtain the title compound as a crude product. The remaining portion is reacted and treated according to the same procedure.

[0106] The crude product obtained in the above step (1.500 kg) is recrystallized using a mixture of N,N-dimethylformamide (5.700 kg) and ethyl acetate (10.820 kg). Start heating and stirring, heat to 75±5°C until the solid is completely dissolved, cool, control the external temperature at 40°C until the solid precipitates, control the external temperature at 0°C, and stir at 5±5°C for 2 hours or more. Filter the solid, and dry at 70±5°C for 12 hours or more to obtain the title compound as a semi-finished product with a yield of 96.67%.

[0107] The title compound as a semi-finished product (1.450 kg) is recrystallized using methanol (11.470 kg). Heat to 60±5°C and stir for 2 hours or more, cool to 5±5°C, and stir for 2 hours or more. Filter the solid, and dry at 70±5°C for 12 hours or more to obtain the title compound as a finished product (1.230 kg) with a yield of 84.83%.

[0108] 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.19 (s, 1H), 8.02 (d, 1H), 7.93 (s, 1H), 7.66-7.61 (m, 2H), 7.37 (s, 1H), 4.35 (dd, 2H), 2.74 (s, 3H), 1.34 (t, 3H). ESI-MS [M+H] + m / z: 398.1.

[0109] Example 3. Preparation of (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)- yl)benzoic acid

[0110]

[0111] Step 1. Preparation of (R)-ethyl 3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)- yl)benzoate

[0112]

[0113] Into a 30 L reactor, was placed 1-methyl-2-pyrrolidinone (5.184 kg), ethyl 3-(5-methyl-6-(oxazol-2-yl)-2,4-dioxa-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (1.008 kg), (R)-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro-2H-pyran (0.800 kg), and potassium carbonate (0.386 kg). The mixture was stirred and purged with nitrogen for 3 times, then heated to 120-130 °C under nitrogen protection. The reaction was monitored by HPLC until completion. The reaction mixture was cooled to T = 25 ± 5 °C. Into a 100 L reactor, was placed ethyl acetate (18.184 kg). The reaction mixture was added into the 100 L reactor, stirred, and then water (20.160 kg) was added. After stirring for 20-30 min, the mixture was allowed to stand and separate into layers. The aqueous layer was removed, and the organic layer was retained. Water (10.080 kg) was added, and the mixture was stirred for 20-30 min. The mixture was allowed to stand and separate into layers. The aqueous layer was removed, and the organic layer was retained. The organic layer was concentrated under reduced pressure using a 50 L rotary evaporator to remove ethyl acetate. After no obvious solvent was evaporated, the rotary evaporation was continued under reduced pressure. Ethanol (4.362 kg) was added into the rotary flask, and the mixture was rotated without vacuum until no solid adhered to the wall. The suspension was transferred into a 50 L reactor and stirred. The rotary flask was rinsed with ethanol (2.000 kg) and transferred into the 50 L reactor. The mixture was heated to 70 ± 5 °C, and then cooled to 20-30 °C. Filtration was started, and the filter cake was rinsed with ethanol (0.795 kg). The solid was dried at 50 ± 5 °C for 12 h or longer to give the title compound as a solid, 0.959 kg, in 59.86% yield.

[0114] 1 H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.06 (d, 1H), 7.86 (s, 1H), 7.69 (t, 1H), 7.56 (d, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 7.33-7.30 (m, 1H), 7.06-7.01 (m, 2H), 5.35 (m, 1H), 4.36 (m, 2H), 4.14 (d, 1H), 4.04 (m, 1H), 3.80 (s, 3H), 3.63-3.60 (m, 2H), 3.46-3.42 (m, 1H), 3.33-3.25 (m, 2H), 2.79 (s, 3H), 1.72-1.65 (m, 2H), 1.38-1.31 (m, 5H). ESI-MS [M+H] + m / z: 632.2.

[0115] Step 2: Preparation of (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin- 3(4H)-yl)benzoic acid

[0116]

[0117] Step 2: Preparation of (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin- 3(4H)-yl)benzoic acid

[0118] Step 2: Preparation of (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin- 3(4H)-yl)benzoic acid

[0119] Step 2: Preparation of (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin- 3(4H)-yl)benzoic acid

[0120] Step 3: Purification of (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin- 3(4H)-yl)benzoic acid

[0121] The weighed ethanol (10.150 kg) and water (3.220 kg) were added into a 100 L reaction kettle, the crude product (0.731 kg) was added, heated and stirred to dissolve, T = 80 ± 5 °C, weighed activated carbon (0.037 kg) was added, and stirring was continued for 20-30 min, then filtered to remove insoluble solids to obtain a filtrate. The filtrate was transferred to a 100 L reaction kettle, cooled to room temperature, and stirred to crystallize for more than 8 hours, then filtered to obtain a solid, which was air-dried at 70 ± 5 °C until the ethanol residue was not more than 1.0%, then crushed and sieved to obtain 0.630 kg of the title compound product, with a yield of 86.18%.

[0122] 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.25 (s, 1H), 8.04 (d, 1H), 7.83 (d, 1H), 7.67 (t, 1H), 7.52 (t, 2H), 7.42 (s, 1H), 7.32 (t, 1H), 7.04 (dd, 2H), 5.35-5.32 (m, 1H), 4.17-4.14 (m, 1H), 4.04-3.98 (m, 1H), 3.80 (s, 3H), 3.62-3.59 (m, 2H), 3.44-3.41 (m, 1H), 3.31-3.24 (m, 2H), 2.79 (s, 3H), 1.72-1.65 (m, 2H), 1.30-1.24 (m, 2H). ESI-MS [M+H] + m / z: 604.2.

[0123] Although the present application has been described in detail above, those skilled in the art understand that various modifications and changes can be made to the present application without departing from the spirit and scope of the present application. The scope of the rights of the present application is not limited to the detailed description above, but should be attributed to the claims.

Claims

1. A compound of formula 5 or a salt thereof, where R 1 Selected from C 1-6 alkyl.

2. A method for preparing a compound of formula 5 or a salt thereof according to claim 1, comprising the step of d) subjecting a compound of formula 4 to a dehydration cyclization reaction in the presence of a dehydrating agent to obtain a compound of formula 5, in, R 1 Selected from C 1-6 alkyl.

3. The method for preparing the compound of formula 5 or a salt thereof according to claim 2, wherein the dehydrating agent is selected from sulfuric acid, phosphorus pentoxide, thionyl chloride, phosphorus pentachloride, and a dehydrating agent combination of triphenylphosphine and hexachloroethane; and the solvent is selected from 1-methyl-2-pyrrolidone, N,N-dimethylformamide, and N,N-dimethylaniline.

4. The method for preparing a compound of formula 5 or a salt thereof according to claim 2 or 3, further comprising the steps of: c-1) reacting a compound of formula 1 with a compound of formula 2 in the presence of a condensation reagent and a base to obtain a compound of formula 3; and c-2) deprotecting the compound of formula 3 under acidic conditions to obtain a compound of formula 4. in, R 1 Selected from C 1-6 Alkyl; R 2 、R 3 Each independently selected from C 1-6 Alkyloxy and C 1-6 Alkylmercapto, or R 2 、R 3 Combined to form a cyclic acetal or cyclic thioacetal structure.

5. The method for preparing a compound of formula 5 according to claim 4 or a salt thereof, wherein in step c-1), the condensation reagent is selected from one or more of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 1,1'-carbonyldiimidazole, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and 4-dimethylaminopyridine; and the base is selected from triethylamine, diisopropylethylamine, pyridine, 1,8-, diazabicycloundec-7-ene, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, sodium carbonate, potassium carbonate, and cesium carbonate.

6. The method for preparing the compound of formula 5 or a salt thereof according to claim 4, wherein in step c-2), the acid is selected from hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid and trifluoroacetic acid.

7. The method for preparing the compound of formula 5 or a salt thereof according to claim 5, wherein in step c-2), the acid is selected from hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid and trifluoroacetic acid.

8. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, The method comprises the following steps: 1) the compound of formula 1a undergoes a condensation reaction with the compound of formula 2 to obtain a compound of formula 3a; Then, the protecting group is removed under acidic conditions to obtain a compound of formula 4a; 2) the compound of formula 4a is subjected to dehydration condensation to obtain the compound of formula 5a; 3) the compound of formula 5a and the compound of formula 6a are reacted under alkaline conditions to obtain a compound of formula 7a; and 4) The compound of formula 7a is hydrolyzed under alkaline conditions to obtain the compound of formula (I).

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