Alternative method for preparing [[[4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid

Abstract

The present invention relates to an alternative method for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt or diastereomer thereof, R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1‑6 Alkyl substituents are substituted; R 2 C 1‑6 Alkyl; R 3 C x H 2x ‑; x is 1, 2, 3, 4, 5, 6 or 7; the compound or its pharmaceutically acceptable salt or diastereomer can be used to prevent and treat viral diseases associated with hepatitis B infection or diseases caused by hepatitis B infection in patients.

Description

Technical Field

[0001] The present invention relates to a method for preparing a compound of formula (Ia),

[0002]

[0003] In particular, the alternative method of the compound of formula (I) or a pharmaceutically acceptable salt or diastereomer thereof,

[0004]

[0005] in

[0006] R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Substitution of alkyl groups;

[0007] R 2 C 1-6 alkyl;

[0008] R 3 For -C x H 2x -;

[0009] x is 1, 2, 3, 4, 5, 6, or 7;

[0010] The compound or its pharmaceutically acceptable salt or diastereomer can be used for preventing and treating viral diseases associated with hepatitis B infection or diseases caused by hepatitis B infection in patients. Background Art

[0011] Patent WO 2015 / 132276 discloses a method for synthesizing compounds of formula (I). However, this synthesis method is not suitable for commercial processes due to a number of reasons, including (i) low overall yield, (ii) expensive starting materials, (iii) cumbersome stereochemical separation and purification of chiral intermediates and final products, and (iv) lack of robustness of the Swern oxidation step.

[0012] A more efficient synthesis method is disclosed in WO 2017 / 140750, which can also be applied on a technical scale and allows higher product yields and stereochemical purity.

[0013] The present invention now discloses a further improved synthetic process for preparing compounds of formula (Ia) and in particular compounds of formula (I), which is suitable for industrial scale, has a further reduced number of steps in the entire process, significantly reduces waste generation, and is therefore more advantageous in terms of overall cost compared to previously described processes.

[0014] The first aspect of the present invention relates to a novel process for preparing a compound of formula (X) or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:

[0015]

[0016] Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7.

[0017] The second aspect of the present invention relates to a novel process for preparing a compound of formula (XVIII) or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof

[0018]

[0019] Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl.

[0020] Compounds of formula (X) and (XIX) are key intermediates in the synthesis and manufacture of the pharmaceutically active compounds of formula (I) described herein.

[0021] The third aspect of the present invention relates to a method for preparing a compound of formula (Ia),

[0022]

[0023] and in particular novel methods of preparing compounds of formula (I) or pharmaceutically acceptable salts or diastereomers thereof,

[0024]

[0025] in

[0026] R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Substitution of alkyl groups;

[0027] R 2 C 1-6 alkyl;

[0028] R 3 For -C x H 2x -;

[0029] x is 1, 2, 3, 4, 5, 6, or 7. DETAILED DESCRIPTION

[0030] definition

[0031] As used herein, the term “C 1-6 "Alkyl" means a saturated, linear or branched alkyl group containing 1 to 6, especially 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. In particular, "C 1-6 The "alkyl" group is methyl or ethyl.

[0032] The term "halogen" denotes fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

[0033] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another.

[0034] The term "pharmaceutical salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and characteristics of the compound of formula I and are formed by suitable nontoxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. Base-addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. Chemically modifying pharmaceutical compounds into salts in order to obtain improved physical and chemical stability, hygroscopicity, fluidity and solubility of the compound is a well-known technology for pharmaceutical chemists. This is described, for example, by Bastin RJ et al. in Organic Process Research & Development, 4, 2000, pp. 427-435 or by Ansel H. et al. in Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457.

[0035] abbreviation

[0036] ACN Acetonitrile

[0037] API Active Pharmaceutical Ingredient

[0038] Boc tert-Butyloxycarbonyl

[0039] (R)-BNP acid (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate

[0040] CPME Cyclopentyl Methyl Ether

[0041] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0042] DCM Dichloromethane

[0043] DIPEA N,N-Diisopropylethylamine

[0044] eq equivalent

[0045] GABA Gamma-aminobutyric acid

[0046] IPA Isopropyl Alcohol

[0047] IPAc Isopropyl acetate

[0048] EtOAc or EA Ethyl acetate

[0049] MEK 2-Butanone

[0050] 2-MeTHF 2-Methyltetrahydrofuran

[0051] MIBK Methyl Isobutyl Ketone

[0052] MSA Methanesulfonic acid

[0053] MTBE Methyl tert-butyl ether

[0054] NBS N-bromosuccinamide

[0055] NMM N-Methylmorpholine

[0056] TEA Triethylamine

[0057] TFA Trifluoroacetic acid

[0058] THF Tetrahydrofuran

[0059] TMP 2,2,6,6-Tetramethylpiperidine

[0060] v / v volume ratio

[0061] V65 2,2'-Azobis-(2,4-dimethylvaleronitrile)

[0062] wt% weight percentage

[0063] The present invention provides methods for preparing compounds of formula (X) as outlined in Scheme 1 and compounds of formula (XVIII) and (I) as outlined in Scheme 2.

[0064] Solution 1

[0065]

[0066] Solution 2

[0067]

[0068] Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 Alkyl; R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; the acid (XV) is (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, (S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, (R)-(–)-3,3′-bis(triphenylsilyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, (R)-(–)-VAPOL hydrogen phosphate, (+)-CSA or (S)-(+)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (R)-(–)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate. Preferably, the acid of formula (XV) acting as a catalyst in step h) is (R)-(-)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate.

[0069] The synthesis includes one or more of the following steps:

[0070] Step a) forming compound (III),

[0071]

[0072] Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7;

[0073] Step b) Compound (III) and compound (IV)

[0074]

[0075] The addition reaction forms urea (V)

[0076]

[0077] Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7;

[0078] Step c) forming a hydantoin of formula (VI) by cyclization reaction of urea (V),

[0079]

[0080] Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7;

[0081] Step d) forming a urea of ​​formula (VIII) by selective reduction of a compound of formula (VI),

[0082]

[0083] Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; R is C 1-6 alkyl;

[0084] Steps e) and f) form a compound of formula (IX) by hydrolysis of a compound of formula (VIII),

[0085]

[0086] Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; R is C 1-6 alkyl;

[0087] Step g) forming a compound of formula (X) by deprotecting a compound of formula (IX),

[0088]

[0089] Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7;

[0090] Step h) forming a compound of formula (XIV) by reacting compounds (XI), (XII) and (XIII) in the presence of acid (XV),

[0091]

[0092] Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl;

[0093] Step i) forming a compound of formula (XVI),

[0094]

[0095] Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl;

[0096] Step j) forming a compound of formula (XVII),

[0097]

[0098] Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 Alkyl; X is halogen, preferably chlorine;

[0099] Step k) forming a compound of formula (XVIII),

[0100]

[0101] Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl;

[0102] Step 1) forming a compound of formula (XIX) by bromination reaction of a compound of formula (XVIII),

[0103]

[0104] Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl;

[0105] Step m) forming a compound of formula (I) by a substitution reaction of a compound of formula (XIX) with a compound of formula (X),

[0106]

[0107] Where R 1is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 Alkyl; R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7.

[0108] The detailed description of the process steps of the present invention is as follows:

[0109] Step a) Formation of compound (III).

[0110] Compound (III) is formed from compound (II) and a suitable reagent, preferably 1,1'-carbonyldiimidazole (CDI), in the presence of a suitable base in a suitable solvent. The conversion is usually carried out under cooling conditions.

[0111] The suitable solvent is selected from 2-MeTHF, THF, IPAc, EA, DCM, DMF, toluene and anisole, in particular, the suitable solvent is anisole.

[0112] The suitable base is selected from Na2CO3, NaOtPent, K2CO3, Na3PO4, K3PO4 and triethylamine (TEA). Preferably, the suitable base is TEA. The reaction rate is controlled at a temperature between -20°C and 40°C, in particular between 0°C and 5°C.

[0113] The suitable reagent is selected from CDI, phosgene, diphosgene, disuccinimidyl carbonate and triphosgene, preferably, the reagent is CDI. The amount of CDI is 1.0 to 2.0 equivalents, especially 1.1 to 1.5 equivalents of the compound of formula (II).

[0114] WO 2017 / 140750 discloses an alternative synthetic route for preparing compound X, which uses a phosgene reagent in the formation of an isocyanate intermediate. The phosgene reagent is selected from phosgene, diphosgene and triphosgene. As is well known in the art, all of these phosgene reagents are highly toxic. The synthetic method according to the present invention avoids the use of any phosgene reagent, but instead uses, for example, CDI in step a).

[0115] Step b) Forming urea (V) by addition reaction of compounds (III) and (IV).

[0116] Urea (V) is synthesized in a suitable organic solvent. The conversion is usually carried out under mild heating conditions.

[0117] The condensation reaction is carried out in a suitable organic solvent selected from 2-MeTHF, THF, IPAc, EA, DMF, anisole, toluene and DCM. In particular, the solvent is anisole.

[0118] The reaction is carried out at a temperature between 0°C and 80°C, in particular between 0°C and 60°C, more in particular between 30°C and 50°C.

[0119] In this synthesis, step b) uses Rather than (As in the previously described synthesis (WO 2017 / 140750)). The sodium compound is much cheaper than the methoxy compound used in the previously described synthesis. The preparation of the ester from the free acid is cumbersome (requiring multiple steps) due to the presence of free NH. Therefore, the sodium salt is much cheaper.

[0120] Step c) cyclization of urea (V) to form hydantoin of formula (VI).

[0121] The compound of formula (VI) is synthesized by cyclization of urea (V) in the presence of a suitable acid in a suitable organic solvent. The conversion is usually carried out under cooling conditions.

[0122] Suitable solvents are selected from 2-MeTHF, IPAc, EA, toluene, DCM, anisole and DMF. Preferably, the solvent is anisole.

[0123] Suitable acidic dehydrating agents are selected from boron trifluoride etherate, phosphoric acid, sulfuric acid, chlorosulfonic acid, trifluoroacetic acid, HBr, HCl, AlCl3, TiCl4, SnCl4, ZrCl4, TMSOTf, pivaloyl chloride, isobutyl chloroformate and oxalyl chloride. Preferably, the acidic dehydrating agent is oxalyl chloride. The reaction is carried out at a temperature between -20°C and 20°C, particularly between -5°C and 5°C.

[0124] Step d) The urea of ​​formula (VIII) is formed by selective reduction of the compound of formula (VI).

[0125] The compound of formula (VIII) is synthesized in the presence of a suitable catalytic Lewis acid and a suitable reducing agent in a suitable solvent. The conversion is carried out under cooling conditions.

[0126] Suitable solvents are selected from THF, 2-MeTHF and cyclopentyl methyl ether, in particular, the solvent is THF or 2-MeTHF or anisole.

[0127] Suitable reducing agents are selected from lithium aluminum hydride, sodium dihydrogen-bis-(2-methoxyethoxy)aluminate, borane dimethyl sulfide, phenylsilane, borane, borane dimethyl sulfide complex and borane tetrahydrofuran complex, and in particular, the reducing agent is borane tetrahydrofuran complex. The amount of borane tetrahydrofuran complex is 1.6-5.0 equivalents of the compound of formula (VI), in particular, 1.6-2.0 equivalents.

[0128] The catalytic Lewis acid is selected from InCl3, YCl3, ZnCl2, Zn(OAc)2, TMSCl, TiCl4, ZrCl4, AlCl3, BF3.THF, and BF3.Et2O, and in particular, the Lewis acid is BF3.Et2O. The amount of BF3.Et2O is 0.05-1.1 equivalents of the compound of formula (VI), in particular, 0.2 equivalents.

[0129] The reaction is carried out at a reaction temperature between -40°C and 40°C, in particular between 10°C and 15°C.

[0130] Usually 4-5 equivalents of borane tetrahydrofuran complex can give 100% conversion, but the reduction selectivity is poor compared with other carbonyl groups. Using a catalytic amount of BF3·Et2O, not only the selectivity is improved, but also the amount of borane tetrahydrofuran complex is reduced from 4-5 equivalents to 1.6-2.0 equivalents.

[0131] Steps e) and f) form a compound of formula (IX) by hydrolysis of a compound of formula (VIII).

[0132] The compound of formula (IX) is synthesized in the presence of a suitable base in a suitable solvent, and then subjected to a work-up procedure.

[0133] Suitable solvents are selected from THF, MeTHF, TBME, toluene, anisole, isopropanol, methanol and ethanol and mixtures thereof with water. In particular, the solvent is a mixture of water and anisole.

[0134] Suitable bases for hydrolysis are selected from LiOH, LiOOH, NaOTMS, KOTMS, KOtBu, NaOH and KOH. In particular, the base is aqueous NaOH solution.

[0135] The reaction is carried out at a temperature between 0°C and 70°C, in particular between 40°C and 60°C.

[0136] The compound of formula (IX) is isolated by a work-up procedure involving phase separation, acidification and isolation of the resulting free acid.

[0137] In one embodiment of the present invention, steps a) to f) are carried out in a single reaction vessel, a so-called one-pot synthesis. This bypasses several purification procedures of the intermediates formed according to steps a) to f), thereby minimizing chemical waste, saving time and simplifying other aspects of the chemical process, such as reducing energy consumption and equipment usage.

[0138] Step g) forming a compound of formula (X) by deprotecting a compound of formula (IX).

[0139] The compound of formula (X) is synthesized in the presence of a suitable acid in a suitable solvent.

[0140] Suitable solvents are selected from DCM, toluene, dioxane, EtOAc, IPAc, IPA, 1-propanol, acetone, MIBK and a mixed solvent of MIBK and acetone. In particular, the solvent is MIBK.

[0141] Suitable acids are selected from TFA, phosphoric acid, MSA, sulfuric acid, HBr and HCl. In particular, the acid is TFA or HCl, and more particularly, the acid is HCl.

[0142] The rate of acid addition is controlled while maintaining the reaction temperature between 0°C and 60°C, in particular, between 20°C and 30°C, while gas evolution can be controlled.

[0143] The amount of the acid is 3-10 equivalents, in particular, 3-4 equivalents, of the compound of formula (IX).

[0144] At the appropriate time, usually after 0.5-2 hours, the reaction is completed by HPLC monitoring. From the reaction mixture, isolate the formula (X) compound in solid form. The formula (X) compound is precipitated in the reaction mixture and separated by filtering and subsequent one or more washing steps, and the one or more washing steps use a solvent in which the reaction has been carried out.

[0145] One aspect of the present invention relates to a synthetic process for preparing a compound of formula (X), said process comprising at least one of steps a) to g).

[0146] Step h) Forming a compound of formula (XIV) by reacting compounds (XI), (XII) and (XIII) in the presence of acid (XV).

[0147] The compound of formula (XIV) is synthesized in the presence of a suitable catalyst in a suitable solvent. The transformation is usually carried out under Dean-Stark water removal conditions (reduced pressure).

[0148] Suitable solvents are selected from methanol, ethanol, IPA, tert-butyl alcohol, 2,2,2-trifluoroethanol, benzene, xylene, anisole, chlorobenzene and toluene, in particular, the solvent is toluene.

[0149] Suitable organic acid catalysts used in the enantioselective Biginelli reaction are selected from (S)-(+)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (R)-(-)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, D-(+)-DTTA, L-DTTA, L-tartaric acid, D-DBTA, (+)-CSA, (S)-(+)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate and (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (R)-(–)-VAPOL hydrogen phosphate, in particular, the organic acid is (R)-(-)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate.

[0150] WO 2017 / 140750 discloses an alternative synthetic route for the preparation of compound (XIX), wherein (S)-(+)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate or (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate is preferably used in the formation and recrystallization of the enantiomeric salt of the compound of formula (XVI). In one embodiment of the present invention, (S)-(+)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate or (R)-(-)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, preferably (R)-(-)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, is used in step h), wherein the compound of formula (XIV) is formed enantiospecifically. In contrast to the teaching of WO2017 / 140750 (where equimolar amounts of (S)-(+)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate or (R)-(-)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate are necessary), the amount of the corresponding 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate required in process step h) according to the present invention is only 0.01 equimolar. Therefore, using the synthesis route according to the present invention, a significant reduction in process waste and costs is possible compared to the methods previously described in the art.

[0151] Step i) forms a compound of formula (XVI).

[0152] The compound of formula (XVI) is synthesized using suitable reagents in a suitable solvent at a suitable pH in the presence of a suitable catalyst.

[0153] Suitable solvents are selected from a mixture of water and two of methanol, ethanol, 2,2,2-trifluoroethanol, toluene, ACN, DMF, EtOAc or dimethyl carbonate, in particular, the solvent is a mixture of water, ethanol and ACN.

[0154] Suitable reagents used in the reaction are selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, formic acid, acetic acid, and in particular, the catalyst is sodium bicarbonate.

[0155] Suitable pH values ​​for the reaction are between 5 and 12, in particular, between 7 and 10.

[0156] Suitable reagents used in the reaction are selected from mCPBA, tBuOOH, urea hydrogen peroxide complex, dibenzoyl peroxide, potassium monopersulfate (oxone) and aqueous hydrogen peroxide solution, and in particular, the reagent is aqueous hydrogen peroxide solution.

[0157] Step j) forms a compound of formula (XVII).

[0158] The compound of formula (XVII) is synthesized using a suitable reagent in a suitable solvent.

[0159] Suitable solvents are selected from toluene, xylene, chlorobenzene, heptane, ACN, dichloromethane, in particular, the solvent is toluene.

[0160] A suitable reagent is selected from oxalyl chloride, PCl5, POCl3, SOCl2 and MsCl, in particular, the reagent is POCl3.

[0161] Step k) forms a compound of formula (XVIII).

[0162] The compound of formula (XVIII) is synthesized using a suitable catalyst and a suitable reagent in a suitable solvent and isolated as a suitable salt, preferably a HBr salt.

[0163] Suitable catalysts are selected from complexes of Xantphos or dppf with palladium(II) salts, in particular the catalyst is XantphosPdCl2.

[0164] A suitable reagent is selected from bromo(thiazol-2-yl)magnesium, thiazol-2-ylboronic acid and bromo(thiazol-2-yl)zinc, in particular, the reagent is bromo(thiazol-2-yl)zinc.

[0165] Suitable solvents are selected from toluene, xylene, chlorobenzene, THF, 2-methyltetrahydrofuran, ACN, dichloromethane, in particular, the solvent is toluene.

[0166] Step 1) forming a compound of formula (XIX) by bromination reaction of a compound of formula (XVIII).

[0167] The compound of formula (XVIII) is synthesized in the presence of a suitable brominating agent in a suitable organic solvent with or without suitable additives. The transformation is usually carried out under heating.

[0168] A suitable brominating agent is selected from NBS, bromine, pyridine tribromide and 1,3-dibromo-5,5-dimethylhydantoin, in particular the brominating agent is NBS.The bromination reaction is carried out at a temperature between 0°C and 80°C, in particular between 35°C and 40°C.

[0169] The reaction is usually carried out in an organic solvent selected from carbon tetrachloride, 1,2-dichloroethane, ACN, acetic acid, fluorobenzene, chlorobenzene and DCM, in particular, the organic solvent is DCM.

[0170] Another aspect of the present invention relates to a synthetic process for preparing a compound of formula (XIX), said process comprising at least one of steps h) to l).

[0171] WO 2017 / 140750 discloses an alternative synthetic route for preparing compound (XIX). However, the synthetic method according to the present invention is estimated to provide (i) >50% waste reduction, (ii) >20% cost reduction and (iii) a significantly shortened process of ≥3 steps compared to the method disclosed in WO 2017 / 140750.

[0172] Step m) forming a compound of formula (I) by a substitution reaction of a compound of formula (XIX) with a compound of formula (X).

[0173] The compound of formula (I) is synthesized in the presence of a suitable base in a suitable organic solvent.

[0174] Suitable bases are selected from TMP, DIPEA, TEA, tripropylamine, N,N-dicyclohexylmethylamine, DBU, NMM, 2,6-lutidine, 1-methylimidazole, 1,2-dimethylimidazole, tetramethylpiperidin-4-ol, Na2CO3, K2CO3, NaHCO3 and tris(2-hydroxyethyl)amine; in particular, the base is TMP or tris(2-hydroxyethyl)amine; and more in particular, the base is tris(2-hydroxyethyl)amine.

[0175] The appropriate pKa and nucleophilicity of the base are directly related to the yield and impurity formation of this step. Both TMP and tris(2-hydroxyethyl)amine can give good yields with high selectivity, but when TMP is used as a base, hydrazine-related impurities may be introduced into the final API.

[0176] Suitable organic solvents are selected from THF, IPAc EtOAc, MTBE, fluorobenzene, chlorobenzene and DCM, in particular, the organic solvent is DCM.

[0177] The substitution reaction is generally carried out at a temperature between 0°C and 40°C, in particular between 10°C and 25°C.

[0178] An effective purification procedure using acid-base workup and recrystallization is required to ensure the purity of the API.

[0179] The purification procedures for the compound of formula (I) include: 1) acid-base post-treatment with a suitable acid and a suitable base in a suitable solvent; and 2) recrystallization in a suitable organic solvent with or without a suitable seed crystal.

[0180] The acid used in the acid-base post-treatment for purifying the compound of formula (I) is selected from HCl, HBr, H2SO4, H3PO4, MSA, toluenesulfonic acid and camphorsulfonic acid, and in particular, the acid is H3PO4. The concentration of the H3PO4 aqueous solution is selected from 15wt% to 60wt%; in particular, the concentration of the H3PO4 aqueous solution is 35wt% to 40wt%. The amount of H3PO4 is necessary and carefully designed to obtain maximum API recovery and minimum impurities.

[0181] The base used in the acid-base work-up for purifying the compound of formula (I) is selected from NaOH, KOH, K2CO3 and Na2CO3, in particular, the base is NaOH.

[0182] Suitable organic solvents for extracting impurities in the acid-base workup for purifying the compound of formula (I) are selected from MTBE, EA, IPAc, butyl acetate, toluene and DCM; in particular, the organic solvent is EA or DCM; more in particular, the solvent is DCM.

[0183] The suitable solvent for recrystallization of the compound of formula (I) is selected from IPA, ethanol, EtOAc, IPAc, butyl acetate, toluene, MIBK, a mixed solvent of acetone and water, a mixed solvent of IPA and water, and a mixed solvent of ethanol and water; in particular, the solvent is a mixed solvent of ethanol and water. The seed amount is 0.1-5wt% of the compound of formula (I), in particular, the seed amount is 1wt%.

[0184] Examples

[0185] Example 1

[0186] Preparation of C15050794-G (Example 1):

[0187]

[0188] The title compound was prepared according to the following scheme:

[0189]

[0190] The production of C15050794-G was carried out in two batches. For C15050794-G17601, 1243.4 kg of C15050794-G anisole solution was obtained from 118.35 kg of C15050794-SM6 and 90.0 kg of C15050794-SM5, with a purity of 92.8%, an assay of 12.6%, an enantiomeric excess of 96.6%, and a yield of 87%. For C15050794-G17602, 1214.6 kg of C15050794-G anisole solution was obtained from 117.35 kg of C15050794-SM6 and 88.9 kg of C15050794-SM5, with a purity of 93.3%, an assay of 12.2%, an enantiomeric excess of 97.5%, and a yield of 83%. The details are summarized in the table below.

[0191] Raw materials used in the preparation of C15050794-G17601

[0192]

[0193]

[0194] Raw materials used in the preparation of C15050794-G17602

[0195]

[0196]

[0197] Plant results for the preparation of C15050794-G

[0198]

[0199] Equipment for the preparation of C15050794-G17601~G17602

[0200]

[0201]

[0202] Detailed process description of C15050794-G

[0203]

[0204]

[0205]

[0206]

[0207] C15050794-G (Example 1):

[0208] MS calculated for C18 H29 N3 O6 [M+Na]+: 406.2, found: 406.4, 1H NMR (300 MHz, CDCl3) δppm 4.50 (br s, 1H), 4.23-4.01 (m, 4H), 3.96 (dd, J=4.7, 11.2 Hz, 1H), 3.66 (s, 2H), 3.01 (dt, J=3.8, 12.8 Hz, 1H), 2.81-2.59 (m, 2H), 1.55-1.42 (m, 9H), 1.37-1.23 (m, 6H), 1.21 (s, 6H)

[0209] Example 2

[0210] Preparation of C15050794-K (Example 2):

[0211]

[0212] The title compound was prepared according to the following scheme:

[0213]

[0214] The production of C15050794-K was carried out in two batches. For C15050794-K17601, 56.75 kg (purity: 100.0%, content: 100.0%, enantiomeric excess %: 99.2%) and 36.70 kg (purity: 100.0%, content: 99.5%, enantiomeric excess %: 99.1%) of C15050794-K were obtained from 1239.0 kg of C15050794-G anisole solution (content: 12.60%), with a yield of 67%. For C15050794-K17602, 54.45 kg (purity: 100.0%, content: 98.6%, enantiomeric excess %: 99.4%) and 50.05 kg (purity: 100.0%, content: 99.6%, enantiomeric excess %: 99.4%) of C15050794-K were obtained from 1214.6 kg of C15050794-G anisole solution (content: 12.20%), with a yield of 78%. Details are summarized in the table below.

[0215] Raw materials used in the preparation of C15050794-K17601

[0216]

[0217] Raw materials used in the preparation of C15050794-K17602

[0218]

[0219]

[0220] Plant results for the preparation of C15050794-K

[0221]

[0222] Equipment for the preparation of C15050794-K17601~K17602

[0223]

[0224]

[0225] Detailed process description of C15050794-K

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234] C15050794-K (Example 2):

[0235] HRMS calculated value for C16 H27 N3 O5 [M+H]+: 341.1951, found value: 341.1976, 1H NMR (600 MHz, chloroform-d) δ ppm 3.90-4.36 (m, 2H), 3.70-3.84 (m, 1H), 3.53-3.63 (m, 1H), 3.46-3.52 (m, 1H), 3.29-3.43 (m, 2H), 3.02 (dd, J=9.1, 4.7 Hz, 1H), 2.36-2.92 (m, 3H), 1.40-1.50 (m, 9H), 1.15-1.30 (m, 6H)

[0236] Example 3

[0237] Preparation of C15050794-SM2 (Example 3):

[0238]

[0239] The title compound was prepared according to the following scheme:

[0240]

[0241] The production of C15050794-SM2 was carried out in one batch. For C15050794-SM2 17601, 157.25 kg of C15050794-SM2 was obtained from 197.20 kg of C15050794-K with a purity of 99.9%, a content of 92.1%, an enantiomeric excess of 99.3%, and a yield of 90%. The details are summarized in the table below.

[0242] Raw materials used in the preparation of C15050794-SM2 17601

[0243]

[0244]

[0245] For C15050794-SM2 Plant results of 17601 preparation

[0246]

[0247] Equipment for the preparation of C15050794-SM2 17601

[0248]

[0249] C15050794-SM2 Detailed process description of 17601

[0250]

[0251]

[0252]

[0253] C15050794-SM2 (Example 3):

[0254] 1H NMR (600 MHz, DMSO-d6) δ ppm 12.10-12.59 (m, 1H), 9.32-9.78 (m, 2H), 3.85-3.95 (m, 1H), 3.75-3.76 (m, 1H), 3.68-3.76 (m, 1H), 3.41-3.47 (m, 1H), 3.23-3.27 (m, 1H), 3.15-3.18 (m, 1H), 3.13-3.30 (m, 2H), 3.13-3.17 (m, 1H), 3.00-3.06 (m, 1H), 2.69-2.79 (m, 1H), 2.66-2.75 (m, 1H), 1.08 (d, J = 7.8 Hz, 6H); HRMS calculated for C11 H19 N3 O3[M+H]+: 241.1426, measured value: 241.1429

[0255] Example 4

[0256] Preparation of 4-(3-fluoro-2-methyl-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Example 4):

[0257]

[0258] The title compound was prepared according to the following scheme:

[0259]

[0260] In a reactor configured for Dean-Stark water removal, a suspension was prepared from thiourea (12.73 g, 167.2 mmol, 1.05 equiv), 3-fluoro-2-methyl-benzaldehyde (22.0 g, 159.3 mmol, 1.00 equiv), and ethyl acetoacetate (24.87 g, 191.1 mmol, 1.20 equiv), (R)-(-)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (1.38 g, 1.59 mmol, 0.01 equiv) and toluene (76.1 g). The mixture was stirred at 80°C jacket temperature under reduced pressure to achieve gentle reflux and Dean-Stark removal of water produced during the reaction over 15-18 h. After the reaction was complete, the suspension was cooled to 15°C and stirred for at least 2 h. The crystals were filtered, washed with pre-cooled toluene (26 g) and dried under reduced pressure at 50° C. The isolated yield was 40.6 g (82%) with an enantiomeric purity of 95%. 1H NMR (600 MHz, DMSO-d6) δ ppm 10.30 (m, 1H), 9.56 (br d, J = 0.8 Hz, 1H), 7.23 (m, 1H), 7.07 (m, 1H), 7.02 (dd, J = 8.1, 0.9 Hz, 1H), 5.43 (d, J = 3.2 Hz, 1H), 3.92 (q, J = 7.1 Hz, 2H), 2.33 (d, J = 1.6 Hz, 3H), 2.32 (d, J = 0.5 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H) HRMS calculated value C15 H17 N2 O2 S [M+H] +: 308.0995, found value: 308.1002

[0261] Example 5

[0262] Preparation of (4S)-4-(3-fluoro-2-methyl-phenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyrimidine-5-carboxylic acid ethyl ester (Example 5):

[0263]

[0264] The title compound was prepared according to the following scheme:

[0265]

[0266] (4S)-4-(3-Fluoro-2-methyl-phenyl)-6-methyl-2-thioxo-3,4-dihydro-1H-pyrimidine-5-carboxylic acid ethyl ester (30 g, 97.3 mmol, 1.0 equiv) suspended in acetonitrile (59.9 g), ethanol (58.95 g), sodium bicarbonate (32.79 g, 389.1 mmol, 4 equiv) and water (390 g) was stirred at room temperature for 30 minutes. The suspension was cooled to 5°C-10°C and hydrogen peroxide (3 wt% aqueous solution, 75.64 g, 778 mmol, 8 equiv) was added over 4 h. Minimal foaming was observed at this addition rate. The resulting suspension was stirred at 5°C-10°C for 15-18 h. After the reaction was complete, water (150 g) was added and the suspension was warmed to 25°C and stirred for an additional 5 h. The crystals were filtered, washed with two portions of 9:1 v / v water / acetonitrile (120 mL total), and dried at 50° C. under reduced pressure. The isolated yield was 25.8 g (90.8%) with a content of approximately 92%. The chiral purity observed in the starting material was retained.

[0267] To recrystallize the material, the crude solid (25.8 g) was dissolved in MeTHF (500 mL), polish filtered, and then partially concentrated under reduced pressure (jacket temperature 30° C.) to about 300 mL. n-Heptane (600 mL) was added over 30 minutes, and the resulting white suspension was cooled to 10° C.-15° C. (internal temperature), filtered and dried. The total yield was 21.4 g (75.3%), with a content of about 100%. The chiral purity was unchanged. 1H NMR (600 MHz, DMSO-d6) δppm 9.20 (d, J = 1.3 Hz, 1H), 7.66 (t, J = 2.3 Hz, 1H), 7.20 (m, 1H), 6.98-7.06 (m, 2H), 5.42 (d, J = 2.6 Hz, 1H), 3.89 (m, 2H), 2.30 (d, J = 1.7 Hz, 3H), 2.29 (d, J = 0.6 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H); HRMS calculated value for C15 H17 N2 O3 [M+H]+: 239.1296, found value: 293.1301

[0268] Example 6

[0269] Preparation of (4S)-2-chloro-4-(3-fluoro-2-methyl-phenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Example 6):

[0270]

[0271] The title compound was prepared according to the following scheme:

[0272]

[0273] (4S)-4-(3-Fluoro-2-methyl-phenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyrimidine-5-carboxylic acid ethyl ester (20 g, 68.4 mmol, 1.0 eq., 92% minimum) was suspended in toluene (43.2 g) and phosphorus oxychloride (34.47 g, 205.3 mmol, 3.0 eq.). Additional toluene (8.7 g) was used to rinse the addition funnel. The white suspension was heated to 100°C (internal temperature) and a yellow solution was obtained after about 15 minutes, which eventually turned into a red solution. The reaction was stirred for 24 h, then diluted with toluene (51.9 g) and cooled to 0°C. This solution was added to a second container containing a vigorously stirred mixture of toluene (51.9 g) and K2HPO4 (5% w / w aqueous solution, 60.0 g) at 0°C over 60 min. The quenching vessel was maintained below 15°C (internal temperature) and the pH was maintained in the range of 7.0-8.5 by co-addition of KOH (48% w / w aqueous solution, 230.3 g) at a variable rate. The addition rate of the KOH solution continued to exceed the dosage of the reaction mixture to maintain the pH range (final pH was about 7.8). The resulting biphasic mixture was warmed to 23°C (jacket temperature) and stirred for 1 h. The lower aqueous layer was removed and the organic layer was washed twice with K2HPO4 (5% w / w aqueous solution, 200 g in total). The organic solution was polish filtered and the filter was rinsed with toluene (17.3 g). The toluene solution was distilled under reduced pressure while maintaining 25°C (jacket temperature), replaced with fresh toluene until free of water and reaching a final volume of 200 mL. This 0.34 M solution of (4S)-2-chloro-4-(3-fluoro-2-methyl-phenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester in toluene was used directly (without correction for assay). 1H NMR (600MHz, DMSO-d6) δppm 9.81-10.33 (m, 1H), 7.16-7.28 (m, 1H), 7.05 (t, J = 9.0 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 5.74 (s, 1H), 3.91 (d, J = 7.1 Hz, 2H), 2.24-2.38 (m, 6H), 0.98 (t, J = 7.1 Hz, 3H); HRMS calculated value C15 H16 Cl F N2 O2 [M + H] +: 310.0898, found value: 310.0884

[0274] Example 7

[0275] Preparation of a solution of bromo(thiazol-2-yl)zinc in THF (Example 7):

[0276]

[0277] The title compound was prepared according to the following scheme:

[0278]

[0279] Under inert atmosphere, zinc (21.9 g, 335 mmol, 1.1 equivalents) was loaded into the reactor containing THF (200 mL) and the feed port was rinsed with additional THF (50 mL). Under vigorous stirring at 23 ° C (internal temperature), TMSCl (1.7 g, 15.2 mmol, 0.05 equivalent) was slowly added over about 25 minutes, and the feed tube was rinsed with THF (10 mL). Vigorous stirring was continued for 30 minutes, then 2-bromothiazole (50 g, 304.8 mmol, 1.0 equivalents) was added over 2 h, and the feed tube was rinsed with THF (10 mL). Stirring was continued and the 2-bromothiazole starting material of the reaction was monitored by GC analysis to determine whether it was completely consumed. If necessary, the reaction was heated to reflux to complete the conversion. The solution of bromine (thiazole-2-yl) zinc in THF can be filtered at ambient temperature under an inert atmosphere to remove residual zinc, or directly used without filtration. The volume was adjusted by addition of THF to reach a final volume of 305 mL, giving a 1 M stock solution that was stable at room temperature when stored under an inert atmosphere.

[0280] Example 8

[0281] Preparation of (4S)-4-(3-fluoro-2-methyl-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester hydrobromide (Example 8):

[0282]

[0283] The title compound was prepared according to the following scheme:

[0284]

[0285] A reactor under an inert atmosphere was charged with a solution of (4S)-2-chloro-4-(3-fluoro-2-methyl-phenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (21.26 g, 68.41 mmol, 1.0 equiv) in toluene (0.36 M solution, total volume 200 mL), followed by a portion of a 1 M solution of bromo(thiazol-2-yl)zinc in THF (6.8 mL, 0.1 equiv), followed by the addition of the catalyst dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (1.03 g, 1.4 mmol, 0.02 equiv) as a solid, and the addition port was rinsed with THF (8.9 g). The resulting red solution was heated to 70° C. (internal temperature). The remaining 1M solution of bromo(thiazol-2-yl)zinc in THF (130 mL, 1.9 equiv) was added by an infusion pump over 2 h, and the feed tube was rinsed with THF (8.9 g). The reaction was stirred for another 1 h, at which point the reaction was usually complete. The reaction was quickly worked up by cooling to 23 ° C (jacket temperature), then washed with aqueous citric acid solution (13.14 g citric acid dissolved in 100 g water), followed by two washes with water (200 mL in total). The organic solution was partially concentrated to a volume of 60 mL under reduced pressure, then acetonitrile (157.2 g) was added and the reaction mixture was concentrated to 60 mL again. Acetonitrile (125.8 g) was added and the resulting mixture was finely filtered. The filtered acetonitrile solution was warmed to 65 ° C, and then an aqueous HBr solution (11.53 g 48% w / w aqueous solution, 68.4 mmol, 1.0 equiv) was added. Water was removed by distillation under reduced pressure (75°C-85°C jacket temperature), and the solvent was replaced with acetonitrile. The reaction was concentrated to a minimum volume (about 40 mL), and toluene (100 mL) was then added over 20 minutes (jacket temperature 85°C). The resulting slurry was stirred for 1 h, then cooled to 0°C over 3 h, stirred for 1 h, and the off-white to brown solid was separated by filtration. The solid was washed with three portions of 5:1 toluene:acetonitrile (total volume 40 mL), and then dried under reduced pressure at 50°C to provide 18.78 g (yield of 67.7% over two steps) of the title compound. (Note: The yield is corrected by the content (92%) of (4S)-4-(3-fluoro-2-methyl-phenyl)-6-methyl-2-thio-3,4-dihydro-1H-pyrimidine-5-carboxylic acid ethyl ester starting material).1H NMR (600 MHz, DMSO-d6) δppm 10.18-12.25 (m, 1H), 8.23 ​​(m, 1H), 8.18 (m, 1H), 7.23-7.29 (m, 1H), 7.18-7.22 (m, 1H), 7.08-7.15 (m, 1H), 5.91 (m, 1H), 3.85-4.05 (m, 2H), 2.49 (m, 3H), 2.43 (d, J=1.7 Hz, 3H), 1.04 (t, J=7.1 Hz, 3H); HRMS calculated value for C18 H18 F N3 O2 S [M+H]+: 360.1177, found value: 360.1181.

[0286] Example 9

[0287] Preparation of 3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propionic acid (Example 9):

[0288]

[0289] The title compound was prepared according to the following scheme:

[0290]

[0291] Step 1) Preparation of (4S)-6-(bromomethyl)-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 10-b):

[0292] A 10 L flask equipped with a mechanical stirrer, a thermometer and a nitrogen bubbler was charged with a solution of (4S)-4-(3-fluoro-2-methyl-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (706 mmol, compound 10-a) from step 1) in DCM (4.0 L). To the reaction mixture heated to 32°C-37°C, NBS (125.6 g, 706 mmol) was added in portions while maintaining the temperature at 35°C-40°C. After 0.5 h, another batch of NBS (12.6 g, 70.6 mmol) was added to the reaction mixture, which was carefully monitored by HPLC until the conversion was >95%. The resulting solution of compound 10-b was cooled to 10°C-20°C and used directly in the next step. MS m / e=436.1 / 438.0 [M+H] + .

[0293] Step 2) Preparation of 3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propionic acid (Example 9):

[0294] A 10 L flask equipped with a mechanical stirrer, a thermometer, and a nitrogen bubbler was charged with a solution of (4S)-6-(bromomethyl)-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester in DCM from the last step. 3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propionic acid hydrochloride (193 g, 635 mmol, purity: 91.6 wt %, Example 3) was added to the reaction mixture cooled to 10-20° C., followed by triethanolamine (329 g, 2.33 mol) in DCM (350 mL) in portions at 25° C. The reaction mixture was stirred at 20-30° C. for 16 hours. Water (1.25 L) was then added to the resulting reaction mixture and the aqueous layer was adjusted to pH = 3-4 using H3PO4 (85 wt%). After phase separation, the organic phase was washed with acidic water (1.25 L, pH = 2-3 H3PO4 solution). After phase separation, the organic phase was extracted once with H3PO4 aqueous solution (35 wt%, 1980 g) and H3PO4 aqueous solution (35 wt%, 990 g). The combined aqueous layer was extracted with DCM (500 mL). DCM (2.0 L) was added to the aqueous layer cooled to 0°C-10°C. The aqueous layer was then adjusted to pH = 3-4 with NaOH aqueous solution (50 wt%, 770 g). After phase separation, the organic phase was washed with water (1.5 L) and filtered through diatomaceous earth (25 g), and then concentrated to about 500 mL in vacuo. The residue was diluted with ethanol (500 mL) and concentrated to about 500 mL in vacuo, and the process was repeated once more. The residue is then diluted with ethanol (1700mL) again and heated to 70 ℃-80 ℃ until all solids dissolve. Water (2.20L) is added to the previous solution by an addition funnel while maintaining an internal temperature between 60 ℃ and 78 ℃. The reaction mixture is then cooled to 55 ℃ over 2 hours and maintained at 50 ℃-55 ℃ for 1 hour, then cooled to 25 ℃ over 3 hours and stirred for another 1 hour at 25 ℃. Solids are collected by filtration and washed with ethanol / water (v / v=1 / 1, 250g). The wet cake is dried in a vacuum oven (45 ℃-55 ℃ / about 0.1Mpa is blown into nitrogen) for 35 hours to obtain product example 9 (260.0g, purity: 99.1%, chiral purity: 99.8%, yield: 61.5%), which is a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δ12.35(s,1H),9.60(s,1H),8.01(d,J=3.2Hz,2H),7.93(d,J=3.2Hz,2H),7.15-7.19(m, 1H),7.01-7.05(m,2H),5.89(s,1H),3.87-4.00(m,4H),3.62-3.73(m,2H),3.33-3.39(m,1 H),3.27(d,J=14.0Hz,1H),3.16(d,J=14.0Hz,1H),2.93-3.00(m,2H),2.77-2.82(m,2H),2 .45(t,J=1.6Hz,3H),2.15(d,J=11.2Hz,1H),2.02(d,J=11.2Hz,1H),1.03-1.08(m,9H);MS m / e=599.6[M+H] + .

[0295] Example 10

[0296] H3PO4 concentration and equivalent screening in the acid-base post-treatment of step 1)

[0297] The amount of H3PO4 in the acid-base post-treatment of step 1) is necessary and carefully designed to obtain maximum API recovery and minimum impurities. The concentration and equivalent of H3PO4 in step 2) of Example 9 were screened according to Table 1. The main impurity was Impurity 2 shown below.

[0298]

[0299] After the initial H3PO4 solution wash (pH=3-4 and pH=2-3), the purity of the organic layer was product / impurity 2 (Rt (杂质) =19.4 min) =71.9 / 1.38 (peak area %), selected examples of further extraction using different H3PO4 concentrations and equivalents were tested and are shown in Table 1.

[0300] Table 1. H3PO4 concentration and equivalent screening

[0301]

[0302] The above studies were tested using the following HPLC parameters shown in Table 2.

[0303] Table 2. HPLC parameters

[0304]

[0305]

[0306] According to the results shown in Table 1, the amount of H3PO4 in the acid-base post-treatment of step m) is directly related to the recovery rate of API and the amount of impurities. Therefore, the specific concentration of H3PO4 is 35wt% to 40wt% and 10-15 equivalents of the compound of formula (XVIII).

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt or diastereomer thereof, in R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Substitution of alkyl groups; R 2 C 1-6 alkyl; R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6, or 7; The method comprises one or more of the following steps: Step a) forming compound (III), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7, wherein the formation of compound (III) is carried out with CDI in a solvent in the presence of a base; Step b) Compound (III) and compound (IV) The addition reaction forms urea (V) Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Step c) forming a hydantoin of formula (VI) by cyclization reaction of urea (V), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Step d) forming a urea of ​​formula (VIII) by selective reduction of a compound of formula (VI), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Steps e) and f) form a compound of formula (IX) by hydrolysis of a compound of formula (VIII), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Step g) forming a compound of formula (X) by deprotecting the compound of formula (IX), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Step h) forming a compound of formula (XIV) by reacting compounds (XI), (XII) and (XIII) in the presence of acid (XV), Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl, wherein the acid (XV) is (R)-(-)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate; Step i) forming a compound of formula (XVI), Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl; Step j) forming a compound of formula (XVII), Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 Alkyl; X is halogen; Step k) forming a compound of formula (XVIII), Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl; Step 1) forming a compound of formula (XIX) by bromination reaction of a compound of formula (XVIII), Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 alkyl; Step m) forming a compound of formula (I) by a substitution reaction of a compound of formula (XIX) with a compound of formula (X), Where R 1 is phenyl, which is unsubstituted or substituted by one, two or three independently selected from halogen and C 1-6 Alkyl substituents are substituted; R 2 C 1-6 Alkyl; R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7.

2. The method according to claim 1, wherein R 1 is chlorofluorophenyl, methylchlorophenyl or fluoromethylphenyl; R 2 is methyl or ethyl; R 3 For -C x H 2x -, wherein x is 3; or a pharmaceutically acceptable salt or diastereomer thereof.

3. The method according to claim 1 or 2, which is used for synthesizing or a pharmaceutically acceptable salt or diastereomer thereof.

4. A method for preparing a compound of formula (X) or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, in R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6, or 7; The method comprises one or more of the following steps: Step a) forming compound (III), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7, wherein the formation of compound (III) is carried out with CDI in a solvent in the presence of a base; Step b) Compound (III) and compound (IV) The addition reaction forms urea (V) Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Step c) forming a hydantoin of formula (VI) by cyclization reaction of urea (V), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Step d) forming a urea of ​​formula (VIII) by selective reduction of a compound of formula (VI), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Steps e) and f) form a compound of formula (IX) by hydrolysis of a compound of formula (VIII), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7; Step g) forming a compound of formula (X) by deprotecting the compound of formula (IX), Where R 3 For -C x H 2x -; x is 1, 2, 3, 4, 5, 6 or 7.

5. The method according to claim 4, wherein R 3 For -C x H 2x -, where x is 3.

6. The method according to claim 4, wherein compound (X) is in the form of a pharmaceutically acceptable salt or diastereomer thereof.

7. The method according to any one of claims 1 to 6, characterized in that The formation of compound (III) in step a) is carried out with CDI in the presence of a base in a solvent, wherein the solvent is selected from 2-MeTHF, THF, IPAc, EA, DCM, DMF, toluene and anisole.

8. The method of claim 7, wherein the base is selected from the group consisting of Na2CO3, sodium tert-amylate, NaHCO3, K2CO3, Na3PO4, K3PO4 and triethylamine.

9. The method according to any one of claims 1 to 8, characterized in that The formation of the hydantoin of formula (VI) in step c) is carried out in the presence of an acid in an organic solvent, wherein the solvent is selected from 2-MeTHF, IPAc, EA, toluene, DCM, anisole and DMF.

10. The method of claim 9, wherein the acid is selected from the group consisting of boron trifluoride etherate, phosphoric acid, sulfuric acid, chlorosulfonic acid, trifluoroacetic acid, HBr, HCl, AlCl3, TiCl4, SnCl4, ZrCl4, TMSOTf, pivaloyl chloride, isobutyl chloroformate and oxalyl chloride.

11. The method according to any one of claims 1 to 10, characterized in that In step d), the formation of the urea of ​​formula (VIII) is carried out in the presence of a catalytic Lewis acid and a reducing agent, wherein the catalytic Lewis acid is selected from InCl3, YCl3, ZnCl2, Zn(OAc)2, TMSCl, TiCl4, ZrCl4, AlCl3, BF3·THF and BF3·Et2O.

12. The method according to claim 11, wherein the reducing agent is selected from the group consisting of lithium aluminum hydride, sodium dihydrogen-bis-(2-methoxyethoxy)aluminate, borane dimethyl sulfide, phenylsilane, borane, borane dimethyl sulfide complex and borane tetrahydrofuran complex.

13. The method according to any one of claims 1 to 12, characterized in that The compound of formula (IX) is synthesized in the presence of a solvent selected from THF, MeTHF, TBME, toluene, anisole, isopropanol, methanol and ethanol and mixtures thereof with water.

14. The method according to any one of claims 1 to 13, characterized in that The formation of the compound of formula (X) in step g) is carried out in the presence of HCl in a solvent.

15. The method according to claim 14, wherein the solvent is selected from DCM, toluene, dioxane, EtOAc, IPAc, IPA, 1-propanol, acetone, MIBK and a mixed solvent of MIBK and acetone.

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