A pharmaceutical intermediate for an androgen receptor antagonist, its preparation method and use

Abstract

The present invention provides a pharmaceutical intermediate for androgen receptor antagonists, its preparation method and uses. The structure of the intermediate is shown in Formula A, wherein each R is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl. It can be started from 2-chloro-5-nitropyridine and prepared through reactions such as Michael addition, hydrolysis decarboxylation, condensation, etc. There are few by-products, and the production scale-up stability and yield are greatly improved. Based on this intermediate, through reactions such as intramolecular ring closure and nitro reduction, various key starting materials for androgen receptor antagonists can be further prepared. The reaction conditions are milder, the product yield is significantly increased, the post-treatment process is simple, and the product purity is relatively high. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and relates to a pharmaceutical intermediate for an androgen receptor antagonist, a preparation method thereof, and a use thereof. Background Art

[0002] Compound 130 is a key starting material for preparing an androgen receptor antagonist. The preparation method disclosed in ZL201280012086.9 is shown in Reaction Route 1: Using 4-(5-nitropyridin-2-yl)butyric acid as a raw material, through reactions such as esterification, amidation, oxazole cyclization, and nitro reduction, the target compound 130 is generated.

[0003]

[0004] Among them, the preparation method of compound 113 is shown in Reaction Route 2: Using 2-chloro-5-nitropyridine as a raw material, through reactions such as nucleophilic substitution, Michael addition, hydrolysis, and decarboxylation, compound 113 is generated.

[0005]

[0006] Currently, the preparation process of compound 130 mainly has the following defects:

[0007] (1) When compound 75 undergoes Michael addition, a by-product with the following structure will be generated:

[0008]

[0009] During the reaction process, if the addition amount of sodium methoxide is too small, the conversion rate of compound 75 is low, and when sodium methoxide is added later, the reaction is too fast, resulting in the generation of a large amount of by-products. Since the by-product is derived from two molecules of methyl acrylate, in order to make compound 75 react completely, a large amount of methyl acrylate needs to be added. However, the addition of excessive methyl acrylate promotes the generation of side reactions.

[0010] In addition, when the applicant prepared samples in the early stage of research (process conditions: 19.4 kg of compound 75, 8.0 kg of methyl acrylate, 0.808 kg of sodium carbonate, 183.5 kg of methanol, reaction temperature about 60 °C; post-treatment: quenched with an aqueous solution, extracted with dichloromethane, washed with saturated brine, and concentrated under reduced pressure to obtain a crude product, and column chromatography of the crude product with a weight ratio of petroleum ether / ethyl acetate of 3.1:1), kilogram-scale production amplification was carried out. However, the purity before column chromatography of this reaction was 91.83% (the sum of the peak area percentages of compound 111 and compound 112), and it was only 92.5% after purification, with basically no purification effect, that is, impurities in this reaction system are difficult to be purified by conventional column chromatography.

[0011] (2) The yield of compound 128 in the preparation of compound 129 through intermolecular cyclization reaction is low, and the usage amount of polyphosphoric acid (PPA) is large. Due to the viscous physical properties of polyphosphoric acid, it can be stirred only at about 160 °C to have good fluidity, and a large amount of saturated sodium bicarbonate is used for quenching the reaction, making the post-treatment of the reaction difficult. In addition, at a temperature of 160 °C, a small part of the mixture undergoes carbonization. Moreover, if the water content in compound 128 is too high, hydrolysis by-product compound 113 will be generated.

[0012] (3) The overall yield of the currently reported route is relatively low, not suitable for scale-up production, and cannot meet the requirements of industrial production.

[0013] Therefore, it is of great significance to develop a method suitable for scale-up production to prepare compound 130. Summary of the Invention

[0014] Problems to be Solved by the Invention

[0015] The object of the present invention is to solve the deficiencies in the prior art and provide a preparation method of a pharmaceutical intermediate for an androgen receptor antagonist with high yield, few by-products, mild reaction conditions, and suitable for production methods.

[0016] Solutions for Solving the Problems

[0017] In the first aspect, the present invention provides a compound of formula A or a pharmaceutically acceptable salt, solvate or tautomer thereof:

[0018]

[0019] Wherein each R is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl.

[0020] Preferably, each R in formula A is independently C1-C6 alkyl.

[0021] More preferably, each R in formula A is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0022] In the second aspect, the present invention provides a preparation method of a compound of formula A, which includes: subjecting compound 113 and a compound of formula B to a condensation reaction to obtain a compound of formula A;

[0023]

[0024] Wherein R in formula B is as defined in formula A.

[0025] Preferably, the molar ratio of compound 113 to the compound of formula B is 1.0:1.0 - 1.5, preferably 1.0:1.0 - 1.2.

[0026] Preferably, the condensation reaction is carried out in the presence of an amide condensing agent.

[0027] More preferably, the amide condensing agent is a carbodiimide condensing agent, an onium salt condensing agent or an organophosphorus condensing agent; wherein, the carbodiimide condensing agent includes DCC, DIC and EDCI; the onium salt condensing agent includes HATU, HBTU, HCTU, TBTU, TSTU, TNTU, BOP, PyBOP and PyAOP; the organophosphorus condensing agent includes DPP-Cl, DECP, DPPA, MPTA and BOP-Cl.

[0028] Preferably, the temperature of the condensation reaction is 0 - 60 °C, preferably 10 - 30 °C.

[0029] In a third aspect, the present invention provides another method for preparing a compound of formula A, which includes: generating a carboxylic acid - carbonic acid mixed anhydride, a carboxylic acid - sulfonic acid mixed anhydride, a carbonyl imidazole or an acyl chloride intermediate from compound 113, and then reacting with a compound of formula B to obtain a compound of formula A;

[0030] (1) The reaction route via the carboxylic acid - carbonic acid mixed anhydride intermediate is as follows:

[0031]

[0032] wherein, R in formula B is defined as in formula A; R X is a C1 - C6 alkyl group, preferably an ethyl group or an isobutyl group;

[0033] (2) The reaction route via the carboxylic acid - sulfonic acid mixed anhydride intermediate is as follows:

[0034]

[0035] wherein, R in formula B is defined as in formula A; R Y is a C1 - C6 alkyl group or a C6 - C 10 aryl group substituted by a C1 - C6 alkyl group or a nitro group, preferably a methyl group, a p - tolyl group or a p - nitrophenyl group;

[0036] (3) The reaction route via the carbonyl imidazole intermediate is as follows:

[0037]

[0038] wherein, R in formula B is defined as in formula A;

[0039] (4) The reaction route via the acyl chloride intermediate is as follows:

[0040]

[0041] Among them, R in formula B is defined in the same way as in formula A; the acyl chloride compound is SOCl2, POCl3 or (COCl)2.

[0042] Furthermore, in the preparation methods described in the second and third aspects, compound 113 is prepared by the following method: compound 75 undergoes a Michael addition reaction with a compound of formula C to form compounds 111 and 112, and then a hydrolysis decarboxylation reaction is carried out to obtain compound 113;

[0043]

[0044] Among them, Ra in formula C is a C1-C6 alkyl group.

[0045] Preferably, Ra in formula C is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0046] More preferably, Ra in formula C is isopropyl or tert-butyl.

[0047] Preferably, the molar ratio of the compound 75 to the compound of formula C is 1.0:1.0 - 2.0, preferably 1.0:1.0 - 1.5.

[0048] Preferably, the Michael addition reaction is carried out in the presence of a base (preferably an inorganic base).

[0049] Preferably, the temperature of the Michael addition reaction is 20 - 120 °C, preferably 50 - 80 °C.

[0050] Preferably, the hydrolysis decarboxylation reaction is carried out in the presence of a base or an acid (preferably an inorganic acid).

[0051] Preferably, the temperature of the hydrolysis decarboxylation reaction is 20 - 120 °C, preferably 40 - 90 °C.

[0052] Furthermore, compound 75 is prepared by the following method: compound 74 undergoes a nucleophilic substitution reaction with dimethyl malonate to obtain compound 75.

[0053]

[0054] Preferably, the nucleophilic substitution reaction is carried out in the presence of a base (preferably an inorganic base).

[0055] Preferably, the molar ratio of the compound 74, dimethyl malonate to the base is 1.0:1.0 - 3.0:1.0 - 5.0, preferably 1.0:1.0 - 2.0:2.0 - 4.0.

[0056] Preferably, the temperature of the nucleophilic substitution reaction is 20 - 100 °C, preferably 30 - 80 °C, more preferably 40 - 60 °C.

[0057] Alternatively, further, in the preparation methods described in the second and third aspects, compound 113 is prepared by the following method: 2-chloro-5-nitropyridine undergoes a substitution reaction with a compound of formula SM to form a compound of formula 111-S, and then a hydrolysis decarboxylation reaction is carried out to obtain compound 113;

[0058]

[0059] Among them, R1 and R2 in formula SM are each independently a C1-C6 alkyl group.

[0060] Preferably, R1 and R2 in formula SM are each independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0061] More preferably, R1 in formula SM is methyl or ethyl, and R2 is tert-butyl

[0062] Preferably, the molar ratio of 2-chloro-5-nitropyridine to the compound of formula SM is 1.0:1.0 - 3.0, preferably 1.0:1.0 - 2.0, more preferably 1.0:1.3 - 1.5.

[0063] Preferably, the substitution reaction is carried out in the presence of a base (preferably an inorganic base).

[0064] Preferably, the molar ratio of 2-chloro-5-nitropyridine to the base is 1.0:1.0 - 5.0, preferably 1.0:1.5 - 3.0, more preferably 1.0:2.0 - 2.5.

[0065] Preferably, the temperature of the substitution reaction is 30 - 100 °C, preferably 40 - 80 °C.

[0066] Preferably, the hydrolysis decarboxylation reaction is carried out in the presence of a base (preferably an inorganic base) or an acid (preferably an inorganic acid).

[0067] Preferably, the temperature of the hydrolysis decarboxylation reaction is 60 - 120 °C, preferably 60 - 80 °C (such as base hydrolysis) or 80 - 110 °C (such as acid hydrolysis).

[0068] Furthermore, the compound of formula SM is prepared by the following method: a compound of formula SM1 undergoes a Michael addition reaction with a compound of formula SM2 to obtain a compound of formula SM;

[0069]

[0070] Preferably, the molar ratio of the compound of formula SM1 to the compound of formula SM2 is 1:0.5-5.0, preferably 1:0.8-3.0.

[0071] Preferably, the Michael addition reaction is carried out in the presence of a base (preferably an inorganic base).

[0072] Preferably, the temperature of the Michael addition reaction is 20-120°C, preferably 20-60°C, more preferably 30-50°C.

[0073] In a fourth aspect, the present invention provides use of a compound of formula A in the preparation of compound 129 (whose chemical name is 2-(3-(5-nitropyridin-2-yl)propyl)oxazole).

[0074] Specifically, the present invention provides a method for preparing compound 129, comprising: subjecting a compound of formula A to an intramolecular ring-closure reaction to obtain compound 129;

[0075]

[0076] wherein each R is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl.

[0077] Preferably, each R in formula A is independently a C1-C6 alkyl group.

[0078] More preferably, each R in formula A is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0079] Preferably, the intramolecular ring-closure reaction is carried out in the presence of a cyclization condensation agent.

[0080] More preferably, the cyclization condensation agent is polyphosphoric acid or Eaton's reagent, preferably polyphosphoric acid.

[0081] Preferably, the temperature of the intramolecular ring-closure reaction is 100-160°C, preferably 110-140°C.

[0082] Furthermore, compound 129 prepared by the above method was subjected to nitro reduction reaction to obtain compound 130 (whose chemical name is 6-(3-(oxazol-2-yl)propyl)pyridin-3-amine).

[0083]

[0084] Preferably, the reduction system for the nitro reduction reaction is Fe powder reduction, catalytic hydrogenation reduction or hydrazine hydrate reduction under acidic conditions; for the catalytic hydrogenation reduction, transition metals such as palladium, platinum, nickel, copper or their alloys are used as catalysts, and hydrogen is used as the reducing agent. When performing catalytic hydrogenation reduction, a carrier is used to support the catalyst, such as activated carbon, microporous silica gel, activated alumina, etc.

[0085] Preferably, the compound 130 prepared by the above method is further salted with an acid.

[0086] Preferably, the acid is formic acid, hydrochloric acid, acetic acid, phosphoric acid, methanesulfonic acid, maleic acid, tartaric acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, benzoic acid, benzenesulfonic acid or p-toluenesulfonic acid;

[0087] More preferably, the acid is 1,5-naphthalenedisulfonic acid.

[0088] In a fifth aspect, the present invention provides the use of the compound of formula A in the preparation of the compound 130.

[0089] Specifically, the present invention provides a method for preparing the compound 130, which includes:

[0090] 1) The compound 75 undergoes a Michael addition reaction with the compound of formula C to generate the compound 111 and the compound 112, and then a hydrolysis decarboxylation reaction is carried out to obtain the compound 113;

[0091] 2) The compound 113 undergoes a condensation reaction with the compound of formula B to obtain the compound of formula A;

[0092] 3) The compound of formula A undergoes an intramolecular cyclization reaction to obtain the compound 129;

[0093] 4) The compound 129 undergoes a nitro reduction reaction to obtain the compound 130;

[0094]

[0095] Wherein, each R is independently hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, preferably a C1-C6 alkyl group, more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group; Ra is a C1-C6 alkyl group, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, more preferably an isopropyl group or a tert-butyl group;

[0096] In step 1), the conditions for the Michael addition reaction and the hydrolysis decarboxylation reaction are as described in the third aspect;

[0097] In step 2), the conditions for the condensation reaction are as described in the second aspect;

[0098] In step 3), the conditions for the intramolecular cyclization reaction are as described in the fourth aspect;

[0099] The conditions for the nitro reduction reaction in step 4) are as described in the fourth aspect;

[0100] Alternatively, compound 113 in step 2) is prepared by the following method:

[0101] 1') 2-Chloro-5-nitropyridine undergoes a substitution reaction with a compound of formula SM to form a compound of formula 111-S, and then a hydrolysis decarboxylation reaction is carried out to obtain compound 113;

[0102]

[0103] Among them, R1 and R2 in formula SM are each independently a C1-C6 alkyl group, preferably R1 and R2 are each independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, more preferably R1 is methyl or ethyl, and R2 is tert-butyl;

[0104] The conditions for the substitution reaction and the hydrolysis decarboxylation reaction in step 1') are as described in the third aspect.

[0105] Preferably, compound 130 prepared by the above method is further salted with an acid.

[0106] Preferably, the acid is formic acid, hydrochloric acid, acetic acid, phosphoric acid, methanesulfonic acid, maleic acid, tartaric acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, benzoic acid, benzenesulfonic acid or p-toluenesulfonic acid;

[0107] More preferably, the acid is 1,5-naphthalenedisulfonic acid.

[0108] Effects of the Invention

[0109] Compared with the prior art, the present invention has the following advantages:

[0110] 1) The present invention surprisingly finds that by using an intramolecular ring closure (forming an oxazole ring) to replace the intermolecular ring closure in the prior art, the reaction conditions can be made milder (the reaction temperature is reduced, the reaction materials are reduced, and the post-treatment is simplified), and the product yield is significantly increased (taking the route from compound 113 to compound 130, the total three-step reaction yield of 7.8% in ZL201280012086.9 is increased to the total two-step reaction yield of more than 60% in the present invention);

[0111] 2) When performing the Michael addition reaction on compound 75, the present invention uses a bulky acrylic acid alkyl ester (such as isopropyl acrylate or tert-butyl acrylate) to replace methyl acrylate in the prior art, which can reduce by-products 111-P and 111-P-A, and significantly reduce the dosage of the acrylic acid alkyl ester. The post-treatment does not require column chromatography purification, and the reaction can be carried out under mild conditions of a weak base (such as potassium carbonate or sodium carbonate), greatly improving the production scale-up stability and yield;

[0112] 3) When preparing compound 113, the present invention also provides a brand-new route based on the formula SM compound, opening up new ideas and methods for preparing drug intermediates for androgen receptor antagonists; in this method, the generation ratio of the bimolecular acrylate addition by-product SM-IP during the Michael addition reaction is low. Even if a small amount of the bimolecular acrylate addition by-product SM-IP is generated, it will not further react with 2-chloro-5-nitropyridine, and the impurities will not be transferred to the subsequent products, making it easier to separate and purify;

[0113] 4) After preparing compound 130, the present invention uses an acid to form a salt with it, which can convert the liquid free base into a solid acid addition salt, facilitating transfer and storage; in addition, after the intramolecular ring closure and nitro reduction reactions, purification is not required, and only one-step salt formation is needed to make the product purity reach 99.6%. BRIEF DESCRIPTION OF THE DRAWINGS

[0114] Figure 1 It is the HPLC spectrum of compound 129 synthesized in Example 4.

[0115] Figure 2 It is the HPLC spectrum of the 1,5-naphthalenedisulfonate salt of compound 130 synthesized in Example 5.

[0116] Figure 3 It is the 1 1H-NMR spectrum of the 1,5-naphthalenedisulfonate salt of compound 130 synthesized in Example 5.

[0117] Figure 4 It is the GC spectrum of the formula SM compound synthesized in Example 7.

[0118] Figure 5 It is the GC spectrum of intermediate compound 111-S synthesized in Example 8.

[0119] Figure 6 It is the GC spectrum of compound 113 synthesized in Example 8. DETAILED DESCRIPTION OF THE INVENTION

[0120] <Compound of formula A>

[0121] The present invention provides a compound of formula A or a pharmaceutically acceptable salt, solvate or tautomer thereof, which is used as a pharmaceutical intermediate for androgen receptor antagonists;

[0122]

[0123] wherein each R can independently be hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl.

[0124] In one embodiment of the present invention, each R in the compound of formula A can independently be C1-C6 alkyl.

[0125] In a specific embodiment of the present invention, each R in the compound of formula A can independently be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0126] In a more specific embodiment of the present invention, R in the compound of formula A can be methyl.

[0127] <Preparation method of the compound of formula A>

[0128] First, the present invention provides a preparation method (Method A) of the compound of formula A.

[0129] Method A may include: condensing compound 113 with a compound of formula B to obtain the compound of formula A;

[0130]

[0131] wherein R in formula B is as defined in formula A.

[0132] In one embodiment of the present invention, the molar amount of the compound of formula B in Method A can be slightly in excess of that of compound 113.

[0133] In a specific embodiment of the present invention, the molar ratio of compound 113 to the compound of formula B in Method A can be 1.0:1.0 - 1.5, such as 1.0:1.0, 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5 or any other ratio.

[0134] In a more specific embodiment of the present invention, the molar ratio of compound 113 to the compound of formula B in Method A can be 1.0:1.0.

[0135] In one embodiment of the present invention, the condensation reaction in Method A can be carried out in the presence of an amide condensing agent.

[0136] Unless otherwise specified, the term "amide condensing agent" means a chemical reagent that facilitates the dehydration condensation reaction between a carboxylic acid and an amine, including (but not limited to) carbodiimide condensing agents, onium salt condensing agents, and organophosphorus condensing agents.

[0137] In a specific embodiment of the present invention, the condensation reaction in Method A can be carried out in the presence of a carbodiimide condensing agent. The carbodiimide condensing agents include (but not limited to) dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).

[0138] In addition, those of ordinary skill in the art can also add any kind of acylation catalyst or activator when using carbodiimide condensing agents, such as 4-dimethylaminopyridine (DMAP), 4-(pyrrolidin-1-yl)pyridine (4-PPY), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu or NHS), N-hydroxyphthalimide (NHPI), N-hydroxy-1,8-naphthalimide (NHNI), etc.

[0139] In a specific embodiment of the present invention, the condensation reaction in Method A can be carried out in the presence of an onium salt condensing agent. The onium salt condensing agents include (but not limited to) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(succinimid-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximid-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP), and (7-azabenzotriazol-1-yloxy)tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyAOP).

[0140] In a specific embodiment of the present invention, the condensation reaction in Method A can be carried out in the presence of an organophosphorus condensing agent. The organophosphorus condensing agent includes (but is not limited to) diphenylphosphinic chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenyl phosphorazidate (DPPA), methylphosphonyl azide (MPTA), and bis(2-oxooxazolidin-3-yl)phosphinic chloride (BOP-Cl).

[0141] Regarding the dosage of the condensing agent, those of ordinary skill in the art can adjust its specific dosage according to the selection of different types of condensing agents. For example, in an embodiment of the present invention, the condensation reaction in Method A can be carried out in the presence of EDCI and HOBt. Among them, the molar ratio of compound 113, EDCI, and HOBt can be 1.0:0.5-1.5:0.5-1.5. Another example, in a specific embodiment of the present invention, the molar ratio of compound 113, EDCI, and HOBt can be 1.0:1.2:0.5.

[0142] In an embodiment of the present invention, the condensation reaction in Method A can be carried out under the condition of 0-60 °C.

[0143] In a specific embodiment of the present invention, the condensation reaction in Method A can be carried out under the condition of 10-30 °C.

[0144] In another specific embodiment of the present invention, the condensation reaction in Method A can be carried out at room temperature.

[0145] In an embodiment of the present invention, the condensation reaction in Method A can be carried out in an organic solution.

[0146] Unless otherwise specified, the term "organic solvent" means a chemical reagent that is liquid under normal temperature and pressure conditions, has strong volatility, and can dissolve some water-insoluble substances (such as oils, waxes, resins, rubbers, dyes, etc.), including (but not limited to) aromatic hydrocarbons, heteroaromatic hydrocarbons, aliphatic hydrocarbons, cycloaliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, glycol derivatives, phenols, nitriles, amides, sulfones, sulfoxides or any mixture thereof. Among them, the aromatic hydrocarbon solvents are selected from at least one of benzene, toluene and xylene; the heteroaromatic hydrocarbon solvents are selected from pyridine; the aliphatic hydrocarbon solvents are selected from at least one of pentane, hexane, heptane and octane; the cycloaliphatic hydrocarbon solvents are selected from at least one of cyclopentane and cyclohexane; the halogenated hydrocarbon solvents are selected from at least one of dichloromethane, chloroform, chlorobenzene and dichlorobenzene; the alcohol solvents are selected from at least one of methanol, ethanol, isopropanol, tert-butanol, tert-pentanol, tert-hexanol, benzyl alcohol, ethylene glycol and glycerol; the ether solvents are selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether and propylene oxide; the ester solvents are selected from at least one of methyl acetate, ethyl acetate, isopropyl acetate, dimethyl phthalate and propyl acetate; the ketone solvents are selected from at least one of acetone, methyl butyl ketone and methyl isobutyl ketone; the glycol derivative solvents are selected from at least one of ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether; the phenol solvents are selected from at least one of phenol and p-cresol; the nitrile solvents are selected from at least one of acetonitrile and propionitrile; the amide solvents are selected from at least one of N,N-dimethylformamide and N,N-dimethylacetamide; the sulfone solvents are selected from at least one of dimethyl sulfone, phenyl ethyl sulfone, diethyl sulfone, diphenyl sulfone and sulfolane; the sulfoxide solvents are selected from at least one of dimethyl sulfoxide, diethyl sulfoxide and benzyl sulfoxide.

[0147] In a specific embodiment of the present invention, the condensation reaction in Method A can be carried out in a halogenated hydrocarbon solvent.

[0148] In a specific embodiment of the present invention, the condensation reaction in Method A can be carried out in dichloromethane (DCM).

[0149] Second, the present invention also provides a method for preparing a compound of formula A (Method B).

[0150] Method B may include: generating a carboxylic acid-carbonic acid mixed anhydride from Compound 113 and then reacting it with a compound of formula B to obtain a compound of formula A;

[0151]

[0152] wherein, R in formula B is defined in the same way as in formula A; R X can be a C1-C6 alkyl group.

[0153] In a specific embodiment of the present invention, R X may be ethyl.

[0154] In another specific embodiment of the present invention, R X may be isobutyl.

[0155] Third, the present invention further provides a method for preparing a compound of formula A (Method C).

[0156] Method C may include: first generating a carboxylic acid-sulfonic acid mixed anhydride from compound 113, and then reacting it with a compound of formula B to obtain a compound of formula A;

[0157]

[0158] wherein R in formula B is defined in the same manner as in formula A; R Y may be a C1-C6 alkyl group or a C6-C aryl group substituted with a C1-C6 alkyl group or a nitro group 10 aryl.

[0159] In a specific embodiment of the present invention, R Y may be methyl.

[0160] In another specific embodiment of the present invention, R Y may be p-tolyl.

[0161] In yet another specific embodiment of the present invention, R Y may be p-nitrophenyl.

[0162] Fourth, the present invention further provides a method for preparing a compound of formula A (Method D).

[0163] Method D may include: first generating carbonyl imidazole from compound 113, and then reacting it with a compound of formula B to obtain a compound of formula A;

[0164]

[0165] wherein R in formula B is defined in the same manner as in formula A.

[0166] Fifth, the present invention further provides a method for preparing a compound of formula A (Method E).

[0167] Method E may include: first generating an acyl chloride intermediate from compound 113, and then reacting it with a compound of formula B to obtain a compound of formula A;

[0168]

[0169] wherein R in formula B is defined in the same manner as in formula A.

[0170] In a specific embodiment of the present invention, the acyl chloride compound may be thionyl chloride (SOCl2).

[0171] In another specific embodiment of the present invention, the acyl chloride compound may be phosphorus oxychloride (POCl3).

[0172] In yet another specific embodiment of the present invention, the acyl chloride compound may be oxalyl chloride ((COCl)2).

[0173] <Preparation method of Compound 113>

[0174] First, the present invention provides a preparation method of Compound 113 (Method F).

[0175] Method F may include: performing a Michael addition reaction between Compound 75 and Compound C of formula C to generate Compound 111 and Compound 112, and then performing a hydrolysis and decarboxylation reaction to obtain Compound 113;

[0176]

[0177] Among them, Ra in formula C may be a C1-C6 alkyl group.

[0178] In an embodiment of the present invention, Ra in formula C may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0179] In a specific embodiment of the present invention, Ra in formula C may be isopropyl.

[0180] In another specific embodiment of the present invention, Ra in formula C may be tert-butyl.

[0181] Experiments show that when Ra in Compound C of formula C is isopropyl or tert-butyl with a large steric hindrance, less by-product with the structure of formula 111-P is generated. Speculating from the structure, it may be attributed to the fact that the alkyl group with a large steric hindrance is not conducive to the further Michael addition reaction between Compound 112 and Compound C of formula C. In addition, by-product 111-P can be further hydrolyzed to form an acid with the structure of formula 111-P-A under the subsequent hydrolysis and decarboxylation reaction conditions. The by-product formation routes in the Michael addition reaction and the hydrolysis and decarboxylation reaction are as follows:

[0182]

[0183] Most of Compound 111 generated from the reaction of Compound 75 and Compound C of formula C under the Michael addition reaction conditions will undergo decarboxylation in situ to form Compound 112, and Compound 112 will further react with Compound C of formula C to form by-product 111-P, which forms by-product 111-P-A in the next hydrolysis and decarboxylation reaction.

[0184] In addition, experiments found that when isopropyl acrylate or tert-butyl acrylate was used to synthesize compound 113, the intermediate compounds 111 and 112 were more prone to decarboxylation, and the reaction conversion rate was higher. Moreover, since the generation of by-product 111-P was reduced, the dosage of isopropyl acrylate or tert-butyl acrylate could be correspondingly reduced, resulting in significant improvements in various aspects such as the number of impurities, purity, and yield of the reaction from compound 75 to compound 113.

[0185] In one embodiment of the present invention, the molar ratio of compound 75 to the compound of formula C in method F can be 1.0:1.0 - 2.0, such as 1.0:1.0, 1.0:1.2, 1.0:1.4, 1.0:1.6, 1.0:1.8, 1.0:2.0 or any other ratio.

[0186] In a specific embodiment of the present invention, the molar ratio of compound 75 to the compound of formula C in method F can be 1.0:1.0 - 1.5, such as 1.0:1.0, 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5 or any other ratio.

[0187] In a specific embodiment of the present invention, the molar ratio of compound 75 to the compound of formula C in method F can be 1.0:1.05.

[0188] In one embodiment of the present invention, the Michael addition reaction in method F can be carried out in the presence of a base, which includes (but is not limited to) organic bases and inorganic bases. In addition, both strong bases and weak bases can catalyze the Michael addition reaction in method F.

[0189] In a specific embodiment of the present invention, the Michael addition reaction in method F can be carried out in the presence of an inorganic base, which includes (but is not limited to) ammonia water, alkali metal hydrides (such as NaH), alkali metal hydroxides (such as LiOH, NaOH, KOH, CsOH), alkali metal carbonates (such as Na2CO3, K2CO3, Cs2CO3), alkali metal bicarbonates (such as NaHCO3), alkaline earth metal hydrides (such as CaH2) and alkaline earth metal hydroxides (Mg(OH)2, Ca(OH)2, Ba(OH)2).

[0190] In a more specific embodiment of the present invention, the Michael addition reaction in method F can be carried out in the presence of an alkali metal carbonate (such as Na2CO3).

[0191] Regarding the amount of base, those of ordinary skill in the art can adjust its specific amount according to the selection of different types of bases, and it is usually a catalytic amount. For example, in one embodiment of the present invention, the molar ratio of compound 75 to the base can be 1.0:0.05 - 1.0. Again, in a specific embodiment of the present invention, the molar ratio of compound 75 to the base can be 1.0:0.1 - 0.8. Also, in a more specific embodiment of the present invention, the molar ratio of compound 75 to the base can be 1.0:0.5.

[0192] In one embodiment of the present invention, the Michael addition reaction in method F can be carried out under the condition of 20 - 120 °C.

[0193] In a specific embodiment of the present invention, the Michael addition reaction in method F can be carried out under the condition of 50 - 80 °C.

[0194] In a more specific embodiment of the present invention, the Michael addition reaction in method F can be carried out under the condition of 60 - 65 °C.

[0195] In one embodiment of the present invention, the Michael addition reaction in method F can be carried out in an organic solution.

[0196] In a specific embodiment of the present invention, the Michael addition reaction in method F can be carried out in an alcohol solvent.

[0197] In a specific embodiment of the present invention, the Michael addition reaction in method F can be carried out in methanol (MeOH).

[0198] In one embodiment of the present invention, the hydrolysis decarboxylation reaction in method F can be carried out in the presence of a base, which includes (but is not limited to) organic bases (such as alkali metal salts of alcohols, organolithium compounds, lithium amide compounds, and amine compounds containing amino groups) and inorganic bases (such as NaOH and LiOH). In ZL201280012086.9, LiOH was used to catalyze hydrolysis, but LiOH is extremely hygroscopic and corrosive. An acid can be used to replace LiOH, which not only avoids the hygroscopicity and corrosiveness problems of LiOH, but also can reduce costs.

[0199] In another embodiment of the present invention, the hydrolysis decarboxylation reaction in method F can be carried out in the presence of an acid, which includes (but is not limited to) organic acids (such as trifluoroacetic acid, formic acid, acetic acid, salicylic acid, oxalic acid, malonic acid, succinic acid, benzoic acid, tartaric acid, and citric acid) and inorganic acids (such as carbonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, orthocarbonic acid, hydrosulfuric acid, nitrous acid, silicic acid, and sulfurous acid).

[0200] In a specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out in the presence of an inorganic acid.

[0201] In a more specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out in the presence of sulfuric acid.

[0202] In an embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out under the condition of 20 - 120 °C.

[0203] In a specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out under the condition of 40 - 90 °C.

[0204] In a more specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out under the condition of 60 - 70 °C.

[0205] In an embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out in an organic solution.

[0206] In a specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out in an ether solvent.

[0207] In a specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out in tetrahydrofuran (THF).

[0208] Second, the present invention also provides a preparation method of compound 113 (Method G).

[0209] Method G may include: 2-chloro-5-nitropyridine (Compound 74) undergoes a substitution reaction with a compound of formula SM to generate a compound of formula 111-S, and then undergoes a hydrolysis decarboxylation reaction to obtain compound 113;

[0210]

[0211] Wherein, R1 and R2 in the formula SM are each independently a C1-C6 alkyl group.

[0212] In an embodiment of the present invention, R1 and R2 in the formula SM are each independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0213] In a specific embodiment of the present invention, R1 in the formula SM is methyl and R2 is tert-butyl.

[0214] In another specific embodiment of the present invention, R1 in the formula SM is ethyl and R2 is tert-butyl.

[0215] In one embodiment of the present invention, the molar ratio of 2-chloro-5-nitropyridine to the compound of formula SM in Method G can be 1.0:1.0 - 3.0, such as 1.0:1.0, 1.0:1.5, 1.0:2.0, 1.0:2.5, 1.0:3.0 or any other ratio.

[0216] In a specific embodiment of the present invention, the molar ratio of 2-chloro-5-nitropyridine to the compound of formula SM in Method G can be 1.0:1.0 - 2.0, such as 1.0:1.0, 1.0:1.2, 1.0:1.4, 1.0:1.6, 1.0:1.8, 1.0:2.0 or any other ratio.

[0217] In a more specific embodiment of the present invention, the molar ratio of 2-chloro-5-nitropyridine to the compound of formula SM in Method G can be 1.0:1.3 - 1.5, preferably 1.0:1.5.

[0218] In one embodiment of the present invention, the substitution reaction in Method G can be carried out in the presence of a base, which includes (but is not limited to) organic bases and inorganic bases.

[0219] In a specific embodiment of the present invention, the substitution reaction in Method G can be carried out in the presence of an inorganic base, which includes (but is not limited to) alkali metal hydroxides (such as KOH), alkaline earth metal hydroxides (Ba(OH)2), alkali metal alkoxides (such as NaOEt), alkali metal carbonates (such as K2CO3) and alkali metal bicarbonates (such as KHCO3).

[0220] In a more specific embodiment of the present invention, the substitution reaction in Method G can be carried out in the presence of an alkali metal alkoxide (such as NaOEt).

[0221] In another more specific embodiment of the present invention, the substitution reaction in Method G can be carried out in the presence of an alkali metal carbonate (such as K2CO3).

[0222] In one embodiment of the present invention, the molar ratio of 2-chloro-5-nitropyridine to the base in Method G can be 1.0:1.0 - 5.0, such as 1.0:1.0, 1.0:2.0, 1.0:3.0, 1.0:4.0, 1.0:5.0 or any other ratio.

[0223] In a specific embodiment of the present invention, the molar ratio of 2-chloro-5-nitropyridine to the base in Method G can be 1.0:1.5 - 3.0, such as 1.0:!1.5, 1:2.0, 1:2.5, 1:3.0 or any other ratio.

[0224] In a more specific embodiment of the present invention, the molar ratio of 2-chloro-5-nitropyridine to the base in Method G can be 1.0:2.0 - 2.5, preferably 1.0:2.2.

[0225] In a more specific embodiment of the present invention, the molar ratio of 2-chloro-5-nitropyridine to the base in Method G can be 1.0:1.0 - 1.5, preferably 1.0:1.1.

[0226] In one embodiment of the present invention, the substitution reaction in Method G can be carried out under the conditions of 30 - 100 °C.

[0227] In a specific embodiment of the present invention, the substitution reaction in Method G can be carried out under the conditions of 40 - 80 °C.

[0228] In a more specific embodiment of the present invention, the substitution reaction in Method G can be carried out under the conditions of 50 - 60 °C.

[0229] In a more specific embodiment of the present invention, the substitution reaction in Method G can be carried out under the conditions of 40 - 45 °C.

[0230] In one embodiment of the present invention, the substitution reaction in Method G can be carried out in an organic solution.

[0231] In a specific embodiment of the present invention, the substitution reaction in Method G can be carried out in an amide solvent.

[0232] In a specific embodiment of the present invention, the substitution reaction in Method G can be carried out in N,N-dimethylformamide (DMF).

[0233] In a specific embodiment of the present invention, the substitution reaction in Method G can be carried out in an ether solvent.

[0234] In a specific embodiment of the present invention, the substitution reaction in Method G can be carried out in tetrahydrofuran.

[0235] In one embodiment of the present invention, the hydrolysis and decarboxylation reaction in Method G can be carried out in the presence of a base, which includes (but is not limited to) organic bases (such as alkali metal salts of alcohols, organolithium compounds, lithium amide compounds, and amine compounds containing amino groups) and inorganic bases (such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and alkaline earth metal hydroxides).

[0236] In a specific embodiment of the present invention, the hydrolysis and decarboxylation reaction in Method G can be carried out in the presence of an inorganic base.

[0237] In a more specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out in the presence of sodium hydroxide.

[0238] In one embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out in an organic solution.

[0239] In a specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out in an alcohol solvent.

[0240] In a specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method F can be carried out in methanol (MeOH).

[0241] In another embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out in the presence of an acid, which includes (but is not limited to) organic acids (such as trifluoroacetic acid, formic acid, acetic acid, salicylic acid, oxalic acid, malonic acid, succinic acid, benzoic acid, tartaric acid, and citric acid) and inorganic acids (such as carbonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, orthocarbonic acid, hydrosulfuric acid, nitrous acid, silicic acid, and sulfurous acid).

[0242] In a specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out in the presence of an inorganic acid.

[0243] In a more specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out in the presence of sulfuric acid.

[0244] In one embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out under the condition of 60 - 120 °C.

[0245] In a specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out under the condition of 80 - 110 °C.

[0246] In a more specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out under the condition of 95 - 100 °C.

[0247] In another specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out under the condition of 60 - 80 °C.

[0248] In another more specific embodiment of the present invention, the hydrolysis decarboxylation reaction in Method G can be carried out under the condition of 65 - 70 °C.

[0249] <Preparation Method of Compound 75>

[0250] The present invention provides a preparation method of compound 75 (Method H).

[0251] Method H may include: a nucleophilic substitution reaction of compound 74 with dimethyl malonate to obtain compound 75.

[0252]

[0253] In one embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out in the presence of a base, which includes (but is not limited to) organic bases (such as alkali metal salts of alcohols, alkyllithium compounds, lithium amide compounds, and amine compounds containing amino groups) and inorganic bases (such as NaH, LiOH, NaOH, KOH, CsOH, Li2CO3, Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, Na3PO4, Na2HPO4, NaH2PO4, K3PO4, K2HPO4, and KH2PO4).

[0254] In a specific embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out in the presence of an inorganic base (such as NaH, LiOH, NaOH, KOH, CsOH, Li2CO3, Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, Na3PO4, Na2HPO4, NaH2PO4, K3PO4, K2HPO4, and KH2PO4).

[0255] In a more specific embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out in the presence of an alkali metal carbonate (such as Li2CO3, Na2CO3, K2CO3, and Cs2CO3, preferably Na2CO3, K2CO3, and Cs2CO3, more preferably K2CO3).

[0256] In one embodiment of the present invention, the molar ratio of compound 74, dimethyl malonate to the base in Method H can be 1.0:1.0 - 3.0:1.0 - 5.0.

[0257] In a specific embodiment of the present invention, the molar ratio of compound 74, dimethyl malonate to the base in Method H can be 1.0:1.0 - 2.0:2.0 - 4.0.

[0258] In a more specific embodiment of the present invention, the molar ratio of compound 74, dimethyl malonate to the base in Method H can be 1.0:2.0:2.0.

[0259] In one embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out under the condition of 20 - 120 °C.

[0260] In a specific embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out under the condition of 30 - 80 °C.

[0261] In a more specific embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out under the condition of 40 - 60 °C.

[0262] In an embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out in an organic solvent.

[0263] In a specific embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out in an amide solvent.

[0264] In a specific embodiment of the present invention, the nucleophilic substitution reaction in Method H can be carried out in N,N - dimethylformamide (DMF).

[0265] <Preparation Method of Compound of Formula SM>

[0266] The present invention provides a preparation method (Method I) of a compound of formula SM.

[0267] Method I may include: a Michael addition reaction between a compound of formula SM1 and a compound of formula SM2 to obtain a compound of formula SM;

[0268]

[0269] In an embodiment of the present invention, the molar ratio of the compound of formula SM1 to the compound of formula SM2 in Method I can be 1:0.5 - 5.0, such as 1:0.5, 1:1.0, 1:2.0, 1:3.0, 1:4.0, 1:5.0 or any other ratio.

[0270] In a specific embodiment of the present invention, the molar ratio of the compound of formula SM1 to the compound of formula SM2 in Method I can be 1:0.8 - 3.0, such as 1:0.8, 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0 or any other ratio.

[0271] In a more specific embodiment of the present invention, the molar ratio of the compound of formula SM1 to the compound of formula SM2 in Method I can be 1:0.8.

[0272] In an embodiment of the present invention, the Michael addition reaction in Method I can be carried out in the presence of a base, and the base includes (but is not limited to) organic bases and inorganic bases. In addition, both strong bases and weak bases can catalyze the Michael addition reaction in Method I.

[0273] In a specific embodiment of the present invention, the Michael addition reaction in Method I can be carried out in the presence of an inorganic base, which includes (but is not limited to) alkali metal hydroxides (such as KOH), alkaline earth metal hydroxides (Ba(OH)2), alkali metal alkoxides (such as NaOMe), alkali metal carbonates (such as K2CO3), and alkali metal bicarbonates (such as KHCO3).

[0274] In a more specific embodiment of the present invention, the Michael addition reaction in Method I can be carried out in the presence of an alkali metal carbonate (such as K2CO3).

[0275] Regarding the dosage of the base, those of ordinary skill in the art can adjust its specific dosage according to the selection of different base types, and it is usually a catalytic amount. For example, in an embodiment of the present invention, the molar ratio of the compound of formula SM1 to the base can be 1.0:0.05 - 1.0. Another example, in a specific embodiment of the present invention, the molar ratio of the compound of formula SM1 to the base can be 1.0:0.1 - 0.8.

[0276] In addition, when using an inorganic base, in order to accelerate the rate of the Michael addition reaction, those of ordinary skill in the art can add a catalytic amount of a phase transfer catalyst (PTC), which includes (but is not limited to) quaternary ammonium salt compounds, crown ether compounds, and polyethylene glycol compounds; among them, the quaternary ammonium salt compounds include (but are not limited to) tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium hydrogensulfate (TBAHS), tetramethylammonium chloride (TMAC), tetramethylammonium bromide (TMAB), tetramethylammonium hydroxide (TMAH), tetramethylformamide (TMAF), tetramethylacetate (TMAA), benzyltrimethylammonium hydroxide (BTMAH), cetyltrimethylammonium chloride (CTAC), and cetyltrimethylammonium bromide (CTAB); the crown ether compounds include (but are not limited to) 15-crown-5 and 18-crown-6; the polyethylene glycol compounds include (but are not limited to) polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800.

[0277] In an embodiment of the present invention, the Michael addition reaction in Method I can be carried out under the condition of 20 - 120 °C.

[0278] In a specific embodiment of the present invention, the Michael addition reaction in Method I can be carried out under the condition of 20 - 60 °C.

[0279] In a more specific embodiment of the present invention, the Michael addition reaction in Method I can be carried out under the condition of 30 - 50 °C.

[0280] In one embodiment of the present invention, the Michael addition reaction in Method I can be carried out in an organic solvent.

[0281] In a specific embodiment of the present invention, the Michael addition reaction in Method I can be carried out in an aromatic hydrocarbon solvent.

[0282] In a specific embodiment of the present invention, the Michael addition reaction in Method I can be carried out in toluene (Tol).

[0283] In another embodiment of the present invention, the Michael addition reaction in Method I can be carried out under solvent-free conditions.

[0284] In another specific embodiment of the present invention, an excess of the compound of formula SM2 (such as dimethyl malonate) can be added and used as both a raw material and a solvent.

[0285] <Preparation Use of Compound A>

[0286] The present invention provides a method for preparing Compound 129 (Method J).

[0287] Method J may include: carrying out an intramolecular cyclization reaction on the compound of formula A to obtain Compound 129;

[0288]

[0289] Wherein each R is independently hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group or a phenyl group.

[0290] In one embodiment of the present invention, each R in formula A is independently a C1-C6 alkyl group.

[0291] In a specific embodiment of the present invention, each R in formula A is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0292] In a more specific embodiment of the present invention, R in formula A is methyl.

[0293] In one embodiment of the present invention, the intramolecular cyclization reaction in Method J can be carried out in the presence of a cyclizing condensing agent.

[0294] In a specific embodiment of the present invention, the intramolecular cyclization reaction in Method J can be carried out in the presence of polyphosphoric acid (PPA).

[0295] In another specific embodiment of the present invention, the intramolecular cyclization reaction in Method J can be carried out in the presence of Eaton's reagent.

[0296] Regarding the dosage of the cyclization condensing agent, those of ordinary skill in the art can appropriately adjust the dosage of the cyclization condensing agent in combination with the reaction temperature and the fluidity of the reaction system. For example, in one embodiment of the present invention, the intramolecular cyclization reaction in Method J can be carried out in the presence of PPA, wherein the molar ratio of the compound of Formula A to PPA can be 1:1 - 12. Again, in a specific embodiment of the present invention, the molar ratio of the compound of Formula A to PPA can be 1:5 - 10.

[0297] In one embodiment of the present invention, the intramolecular cyclization reaction in Method J can be carried out under the condition of 100 - 160 °C.

[0298] In a specific embodiment of the present invention, the intramolecular cyclization reaction in Method J can be carried out under the condition of 110 - 140 °C.

[0299] In a more specific embodiment of the present invention, the intramolecular cyclization reaction in Method J can be carried out under the condition of 125 - 135 °C.

[0300] In addition, those of ordinary skill in the art can add a solvent to the reaction system according to the reaction needs.

[0301] On this basis, the present invention further provides a method for preparing compound 130 (Method K).

[0302] Method K may include: carrying out a nitro reduction reaction on compound 129 to obtain compound 130.

[0303]

[0304] In one embodiment of the present invention, the reduction system for the nitro reduction reaction in Method K can be hydrazine hydrate reduction.

[0305] In another embodiment of the present invention, the reduction system for the nitro reduction reaction in Method K can be catalytic hydrogenation reduction.

[0306] In a specific embodiment of the present invention, the reduction system for the nitro reduction reaction in Method K can be Pd / C - H₂ reduction.

[0307] In yet another embodiment of the present invention, the reducing agent for the nitro reduction reaction in Method K can be Fe powder reduction under acidic (preferably inorganic acid) conditions.

[0308] In another specific embodiment of the present invention, the reduction system for the nitro reduction reaction in Method K can be Fe - HCl reduction.

[0309] In one embodiment of the present invention, the nitro reduction reaction in Method K can be carried out in an organic solvent.

[0310] In a specific embodiment of the present invention, the nitro reduction reaction in Method K can be carried out in an alcohol solvent.

[0311] In a specific embodiment of the present invention, the nitro reduction reaction in Method K can be carried out in methanol (MeOH).

[0312] The compound 130 obtained by Method K can be further salted with an acid to form a solid, which is beneficial to purification and material transfer. The selection of the acid for salting can refer to the 68 acids disclosed in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" ISBN: 978 - 3 - 906 - 39051 - 2. For example, those skilled in the art can select formic acid, hydrochloric acid, acetic acid, phosphoric acid, methanesulfonic acid, maleic acid, tartaric acid, 2 - naphthalenesulfonic acid, 1,5 - naphthalenedisulfonic acid, benzoic acid, benzenesulfonic acid or p - toluenesulfonic acid, etc.

[0313] In a specific embodiment of the present invention, compound 130 can be salted with 1,5 - naphthalenedisulfonic acid to form the 1,5 - naphthalenedisulfonate of compound 130.

[0314] In a more specific embodiment of the present invention, the molar ratio of compound 130 to 1,5 - naphthalenedisulfonic acid in the 1,5 - naphthalenedisulfonate of compound 130 can be 2:1.

[0315] <Preparation method of compound 130>

[0316] In summary, the present invention completely provides a preparation method of compound 130 (Method L).

[0317] Method L may include:

[0318] 1) Compound 75 undergoes a Michael addition reaction with Compound C of formula C to generate Compound 111 and Compound 112, and then undergoes a hydrolysis decarboxylation reaction to obtain Compound 113;

[0319] 2) Compound 113 undergoes a condensation reaction with Compound B of formula B to obtain Compound A of formula A;

[0320] 3) Compound A of formula A undergoes an intramolecular cyclization reaction to obtain Compound 129;

[0321] 4) Compound 129 undergoes a nitro reduction reaction to obtain Compound 130;

[0322]

[0323] Wherein, each R can independently be hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and Ra can be a C1-C6 alkyl group.

[0324] In one embodiment of the present invention, each R can independently be a C1-C6 alkyl group, and Ra can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0325] In a specific embodiment of the present invention, each R can independently be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and Ra can be tert-butyl.

[0326] In a more specific embodiment of the present invention, R can be methyl and Ra can be tert-butyl.

[0327] In one embodiment of the present invention, the conditions for the Michael addition reaction and the hydrolysis decarboxylation reaction in step 1) are as described in Method F.

[0328] In one embodiment of the present invention, the conditions for the condensation reaction in step 2) are as described in Method A.

[0329] In one embodiment of the present invention, the conditions for the intramolecular cyclization reaction in step 3) are as described in Method J.

[0330] In one embodiment of the present invention, the conditions for the nitro reduction reaction in step 4) are as described in Method K.

[0331] In addition, in Method L, compound 113 in step 2) can also be prepared by other methods. For example, it can be prepared by the following method:

[0332] 1') 2-Chloro-5-nitropyridine undergoes a substitution reaction with a compound of formula SM to form a compound of formula 111-S, and then undergoes a hydrolysis decarboxylation reaction to obtain compound 113;

[0333]

[0334] Wherein, R1 and R2 in formula SM are each independently a C1-C6 alkyl group.

[0335] In one embodiment of the present invention, R1 and R2 in formula SM are each independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0336] In a specific embodiment of the present invention, R1 in formula SM is methyl or ethyl, and R2 is tert-butyl;

[0337] In one embodiment of the present invention, the conditions for the substitution reaction and the hydrolysis decarboxylation reaction in step 1') are as described in Method G.

[0338] Compound 130 obtained by Method L can also be further salified with an acid.

[0339] In one embodiment of the present invention, compound 130 can be salified with formic acid, hydrochloric acid, acetic acid, phosphoric acid, methanesulfonic acid, maleic acid, tartaric acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, benzoic acid, benzenesulfonic acid, or p-toluenesulfonic acid.

[0340] In a specific embodiment of the present invention, compound 130 can be salified with 1,5-naphthalenedisulfonic acid to form 1,5-naphthalenedisulfonic acid salt of compound 130.

[0341] In a more specific embodiment of the present invention, the molar ratio of compound 130 to 1,5-naphthalenedisulfonic acid in the 1,5-naphthalenedisulfonic acid salt of compound 130 may be 2:1.

[0342] The technical solutions of the present invention will be further described below with reference to the accompanying drawings and specific examples. Unless otherwise specified, the instruments, consumables, and reagents used in the following examples can all be obtained through conventional commercial means.

[0343] HPLC detection condition 1:

[0344] Chromatographic column: C18 150*4.6mm, 5μm; detection wavelength: 220nm; flow rate: 1.0ml / min; column temperature: 25°C; sample preparation: take an appropriate amount of the test sample, dissolve it in acetonitrile, and dilute it to a solution of approximately 1.0mg / mL; mobile phase: mobile phase A is 0.02% v / v trifluoroacetic acid in water, and mobile phase B is acetonitrile; the gradient program is shown in Table 1.

[0345] Table 1 Gradient elution table

[0346] Time (min) A (% v / v) B (% v / v) 0 90 10 1.0 90 10 8.0 0 100 13.0 0 100 13.01 90 10 15.0 90 10

[0347] HPLC detection condition 2:

[0348] High performance liquid chromatograph, Agilent 1200; chromatographic column: Poroshell 120EC-C18 (4.6 mm × 50 mm × 2.7 μm); detection wavelength: 220 nm; flow rate: 1.0 ml / min; column temperature: 30°C; mobile phase: mobile phase A: 0.05% v / v trifluoroacetic acid in water, mobile phase B: acetonitrile; gradient program as shown in Table 2.

[0349] Table 2 Gradient elution table

[0350] Time (min) A% (V / V) B% (V / V) 0 95 5 5.00 5 95 6.67 5 95 6.70 95 5 8.33 95 5

[0351] GC detection conditions:

[0352] Gas chromatograph: Agilent-7820A; Chromatographic column: DB-1701 (30m × 0.32mm × 0.25μm); Injector temperature: 260°C; Detector temperature: 280°C; Column oven: Hold at 50°C for 1 minute, then increase the temperature to 280°C at a rate of 10°C per minute, and hold for 3 minutes; Gas flow mode: Constant flow; Column flow rate: 1 mL / min; Split ratio: 30 / 1; Hydrogen flow rate: 30 mL / min; Air flow rate: 400 mL / min; Tail gas purge flow rate (nitrogen): 25 mL / min; Stop time: 27 min.

[0353] Unless otherwise specified, the above HPLC and GC calculations of the impurity contents and the main peak purity (peak area percentage %) are both performed by the area normalization method.

[0354] Example 1: Synthesis of dimethyl 2-(5-nitropyridin-2-yl)malonate (Compound 75)

[0355]

[0356] Add dimethylformamide (500 mL) to a 1000 mL reactor, start stirring, then add dimethyl malonate (220 g, 1.665 mol, 2.0 eq), then add potassium carbonate (229 g, 2.5 mol, 2.0 eq), and finally add 2-chloro-5-nitropyridine (130 g, 0.82 mol, 1.0 eq) to the system. Heat the temperature to 55 - 60°C and react until HPLC shows that the remaining raw material is less than 0.5%. Cool to room temperature and prepare for quenching.

[0357] Add concentrated hydrochloric acid (500 g) and water (1 kg) to another reactor, stir evenly to form dilute hydrochloric acid, and drop the reaction solution into the above dilute hydrochloric acid. After dropping, stir for 2 hours, filter by suction, slurry the filter cake with water for 1 - 2 hours, filter by suction, centrifuge, and dry the filter cake until the water content < 1.0%. Discharge the product. A total of 172 g of yellow solid is obtained, with a yield of about 82.5% and an HPLC purity of about 95.5% (HPLC detection condition 1, the retention time of Compound 75 is about 7.5 min).

[0358] 1 1H-NMR (400 MHz, CDCl3): δ 9.38 (d, 1H, J = 2.2 Hz), 8.51 (dd, 1H, J = 2.4 Hz, 8.6 Hz), 7.39 (d, 1H, J = 8.6 Hz), 5.10 (s, 1H), 3.82 (s, 6H).

[0359] 1313C-NMR (100 MHz, CDCl3): δ 166.93, 158.75, 144.81, 131.98, 124.52, 60.12, 53.53.

[0360] LC-MS: m / z 255.0 [M+H] + .

[0361] Example 2: Synthesis of 4-(5-nitropyridin-2-yl)butyric acid (Compound 113)

[0362]

[0363] Add methanol (1 L), tert-butyl acrylate (92 g, 0.716 mol, 1.05 eq), Compound 75 (174 g, 0.684 mol, 1.0 eq), and anhydrous sodium carbonate solid (34 g, 0.32 mol, 0.5 eq) to the reactor. After purging with nitrogen, heat to 60 - 65 °C for reaction. Stop the reaction when the area percentage of Compound 75 monitored by HPLC is < 3%, and cool to room temperature. Adjust the pH to about 5 with dilute hydrochloric acid, and concentrate the methanol under reduced pressure to obtain 225 g of a mixture of Compounds 111 and 112. The peak area percentages of Compound 111 and Compound 112 detected by HPLC are approximately 12.39% and 85.10% respectively, and the peak area percentage of Compound 75 is approximately 2.51% (HPLC detection condition 1. The retention times of each compound are as follows: Compound 111 is about 10.3 min, Compound 112 is about 9.1 min, and Compound 75 is about 6.9 min; the [M+H] + is as follows: Compound 111 is 383.1; Compound 112 is 325.1).

[0364] Add tetrahydrofuran (400 mL) and the mixture of Compounds 111 and 112 (225 g) to the reactor. Add dilute sulfuric acid prepared from concentrated sulfuric acid (200 g) and water (500 g), heat to 60 - 70 °C, and react until no raw materials remain. Cool to 20 - 30 °C, adjust the pH to about 8 - 9 with ammonia water, add methyl tert-butyl ether (600 mL), stir, let it stand for liquid separation, and collect the aqueous phase. Add methyl tert-butyl ether (300 mL) to the aqueous phase, let it stand for liquid separation, and collect the aqueous phase. Add dilute sulfuric acid prepared from concentrated sulfuric acid (78 g) and water (186 g) to the aqueous phase, stir evenly, filter, and dry the filter cake at 70 °C to obtain 92 g of solid. The total yield of the two-step reaction is approximately 64.0%. The HPLC purity is approximately 93.4% (HPLC detection condition 1, the retention time of Compound 113 is about 6.4 min).

[0365] 11H-NMR (400 MHz, CDCl3): δ 9.37 (d, 1H, J = 2.3 Hz), 8.41 (dd, 1H, J = 2.5 Hz, 8.6 Hz), 7.39 (d, 1H, J = 8.5 Hz), 3.02 (t, 2H, J = 7.6 Hz), 2.46 (t, 2H, J = 7.1 Hz), 2.14 (quintet, 2H, J = 7.3 Hz).

[0366] 13 13C-NMR (100 MHz, CDCl3): δ 178.30, 167.91, 144.88, 142.97, 131.78, 123.34, 37.24, 33.20, 24.24.

[0367] LC-MS: m / z 211.1 [M+H] + 。

[0368] Example 3: Synthesis of N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide (Compound of Formula A, where R is methyl)

[0369]

[0370] Add dichloromethane (800 mL) and Compound 113 (95.0 g, 0.452 mol, 1.0 eq) to a reactor, control the temperature at 0 - 10 °C, add HOBT (31.0 g, 0.229 mol, 0.5 eq), then add EDCI (102.0 g, 0.532 mol, 1.2 eq), then dropwise add aminoacetaldehyde dimethyl acetal (48.0 g, 0.457 mol, 1.0 eq), and finally dropwise add triethylamine (69.0 g, 0.682 mol, 1.5 eq), control the temperature at 0 - 10 °C. After dropping, turn off the cooling cycle, and let it rise to room temperature naturally. After reacting for 2 hours, there is no raw material left. Add saturated sodium bicarbonate solution (475.0 g) to the reaction solution, separate the layers, wash the organic phase with saturated ammonium chloride aqueous solution (475.0 g), collect the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 112.0 g of a brown solid, with a yield of about 83.3%. The HPLC purity is about 91.8% (under HPLC detection condition 1, the retention time of Compound A is about 6.07 min).

[0371] 11H-NMR (400 MHz, CDCl3): δ 9.35 (d, 1H, J = 2.5 Hz), 8.39 (dd, 1H, J = 2.6 Hz, 8.5 Hz), 7.39 (d, 1H, J = 8.5 Hz), 5.94 (br.s, 1H), 4.39 (t, 1H, J = 5.1 Hz), 3.42 (t, 2H, J = 5.4 Hz), 3.40 (s, 6H), 2.99 (t, 2H, J = 7.4 Hz), 2.27 (t, 2H, J = 7.1 Hz), 2.13 (quintet, 2H, J = 7.2 Hz).

[0372] 13 13C-NMR (100 MHz, CDCl3): δ 172.36, 168.28, 144.49, 131.37, 123.18, 116.49, 102.40, 54.09, 40.68, 37.08, 35.13, 24.98.

[0373] LC-MS: m / z 298.1 [M+H] + 。

[0374] Example 4: Synthesis of 2-(3-(5-nitropyridin-2-yl)propyl)oxazole (Compound 129)

[0375]

[0376] Add polyphosphoric acid (295.0 g) to a reactor, heat up to 125 - 135 °C, and add the compound of formula A prepared in Example 3 (30.0 g, 0.101 mol, 1.0 eq) in batches. After the addition is complete, cool the reaction mixture after reacting for about 60 min. Pour the reaction solution into water (1500 g), adjust the pH to about 8 - 9 with potassium hydroxide, add ethyl acetate (300.0 g), stir for 1 h, filter, let the filtrate stand for liquid separation, collect the organic phase, control the temperature at 40 - 50 °C, concentrate the organic phase to obtain 17.2 g of the target product, with a yield of about 73.1% and an HPLC purity of about 81.6% (under HPLC detection condition 1, the retention time of Compound 129 is about 6.97 min, as Figure 1 shown).

[0377] 11H-NMR (400 MHz, CDCl3): δ 9.36 (d, 1H, J = 2.6 Hz), 8.39 (dd, 1H, J = 2.7 Hz, 8.6 Hz), 7.57 (s, 1H), 7.37 (d, 1H, J = 8.5 Hz), 7.02 (s, 1H), 3.02 (t, 2H, J = 7.4 Hz), 2.87 (t, 2H, J = 7.3 Hz), 2.29 (quintet, 2H, J = 7.4 Hz).

[0378] 13 13C-NMR (100 MHz, CDCl3): δ 144.43, 138.28, 131.18, 126.64, 123.04, 116.45, 36.98, 27.04, 25.95.

[0379] LC-MS: m / z 234.0 [M+H] + .

[0380] The experimental results show that when using the compound of formula A as the raw material and preparing compound 129 through an intramolecular cyclization reaction with milder conditions (reaction temperature is 125 - 135 °C), the yield can be as high as 73.1%, achieving unexpected technical effects. While in ZL201280012086.9, the intermolecular cyclization reaction has a low yield (only 20.1%), harsh process conditions (reaction temperature needs to reach 160 °C), and is prone to carbonization.

[0381] The present invention has also used Eaton's reagent to catalyze the intramolecular cyclization reaction, but it shows an obvious scale-up effect. When the feed is 10 g, the yield is 71.4%, but when scaled up to 100 g, the yield decreases to 38%, and when further scaled up to 320 g, the yield further decreases to 26%. After analysis, it may be attributed to the formation of an ester between methanesulfonic acid in Eaton's reagent and the generated alcohol, further methylating the N atom on the pyridine ring in the product, and then forming a quaternary ammonium methanesulfonate. Using polyphosphoric acid instead of P2O5 / CH3SO3H can solve this problem.

[0382] Example 5: Synthesis of 6-(3-(oxazol-2-yl)propyl)pyridin-3-amine (Compound 13)

[0383]

[0384] Add methanol (80.0 g) and Compound 129 (20.0 g, 85.6 mmol, 1.0 eq) prepared by the method of Reference Example 4 into the reactor. After stirring and dissolving, add activated carbon (2.0 g) and ferric chloride (0.2 g). Heat up to 40 - 50 °C, and dropwise add hydrazine hydrate (16.0 g). After the addition is complete, stir at 60 - 70 °C for 5 hours. Filter, control the temperature at 40 - 50 °C, and concentrate the reaction solution until it is nearly dry. Cool down to 20 - 30 °C, add 10 wt% sodium carbonate solution (80 g) and dichloromethane (80 mL), and stir for 0.5 h. Let it stand for liquid separation, collect the organic phase. Add dichloromethane (60 mL) to the aqueous phase, stir for 0.5 h, let it stand for liquid separation, collect the organic phase. Add dichloromethane (40 mL) to the aqueous phase, stir for 0.5 h, let it stand for liquid separation, collect the organic phase. Combine the organic phases and concentrate to obtain 19.8 g of an oily substance (crude product of Compound 130).

[0385] 1 1H-NMR (400 MHz, CDCl3): δ 8.03 (d, 1H, J = 1.6 Hz), 7.54 (s, 1H), 7.00 (s, 1H), 6.93 (m, 2H), 3.58 (br.s, 2H), 2.80 (t, 2H, J = 7.5 Hz), 2.75 (t, 2H, J = 7.7 Hz), 2.16 (quintet, 2H, J = 7.5 Hz).

[0386] 13 13C-NMR (100 MHz, CDCl3): δ 140.58, 138.26, 136.82, 134.25, 126.81, 122.92, 122.59, 116.51, 36.30, 27.46, 27.23.

[0387] LC-MS: m / z 204.1 [M + H] + 。

[0388] Dissolve the crude product of Compound 130 in ethanol (100 mL), start stirring, and dropwise add 1,5-naphthalenedisulfonic acid solution (37 g) (11 g of 1,5-naphthalenedisulfonic acid dissolved in 26 g of ethanol) at room temperature. After the addition is complete, stir at room temperature for 2 h. Filter, and wash the filter cake with ethanol (5 mL). Place the filter cake in the drying oven and dry until the moisture content < 1.0%, then discharge to obtain 13.6 g of a solid. The total yield of the two-step reaction is about 45.7%, and the HPLC purity is about 99.6% (HPLC detection condition 1, retention time is about 5.12 min, as Figure 2 shown).

[0389] 1 The 1H-NMR spectrum is as Figure 3As shown, the results showed that the molar ratio of the free compound 130 and 1,5-naphthalene disulfonic acid constituting the acid addition salt was 2:1.

[0390] The experimental results show that the process impurities in the entire preparation process from compound 75 to compound 130 can be removed by simply using 1,5-naphthalene disulfonic acid and compound 130 to form a salt in one step, which greatly facilitates industrial production.

[0391] Example 6: Synthesis of 6-(3-(oxazol-2-yl)propyl)pyridin-3-amine (Compound 130)

[0392] Compound 129 was prepared by the method in Example 4 and purified using a silica gel column with an eluent of (petroleum ether:ethyl acetate = 26:9 to 13:18, w / w) to give a light yellow solid with an HPLC purity of approximately 99.9%.

[0393] Methanol (500 mL) and purified compound 129 (35 g, 150 mmol, 1.0 eq) were added to the reactor, stirred and dissolved, and then 10 wt% palladium on carbon (3.5 g) was added. The atmosphere was purged with nitrogen three times, then replaced with hydrogen three times. The internal temperature was maintained at 25-35°C and the pressure was 0.2 MPa. The reaction was continued for 10 h, during which hydrogen was added to maintain the pressure. After the reaction was complete, the atmosphere was purged with nitrogen three times. The reaction solution was filtered through a pad of celite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain 27.5 g of a brown oil with a yield of approximately 90.2% and an HPLC purity of approximately 99.3% (HPLC detection condition 1).

[0394] Example 7: Synthesis of 3-(tert-butyl)1,1-dimethyl 1,1,3-propanetriate (Formula SM compound, wherein R1 is methyl and R2 is tert-butyl)

[0395]

[0396] Take tert-butyl acrylate (Compound of Formula SM1, 1500 g, 11.7 mol, 1.0 eq), dimethyl malonate (Compound of Formula SM2, 4638 g, 35.1 mol, 3.0 eq, which also serves as a reaction reagent and solvent here), potassium carbonate (161.7 g, 1.2 mol, about 0.1 eq) and tetrabutylammonium hydrogen sulfate (39.8 g), keep the reaction at 30 - 50 °C for 8 h, and monitor the disappearance of tert-butyl acrylate by GC, then perform post-treatment. Add saturated sodium chloride aqueous solution (1.5 L) to the reaction solution for washing, stir and separate the layers, collect the organic phase, concentrate under reduced pressure, then add toluene (4 L), stir evenly, wash the toluene with 1 mol / L sodium hydroxide aqueous solution (1.2 L x 2), and let it stand for layer separation. Collect the toluene layer, remove the solvent, and obtain 3049.4 g of the crude product of the compound of Formula SM, with a yield of about 100% (containing a small amount of toluene), and the GC purity is about 87.1% (the toluene was integrated, and the peak area percentage of toluene is about 9.85%, as Figure 4 shown).

[0397] In addition, the GC chromatogram also shows that there is about 2.3% of the bimolecular addition product SM-IP, that is, the ratio of the product to the bimolecular addition product SM-IP is about 38:1. However, even if the bimolecular addition product SM-IP is formed, it does not need to be purified and can directly proceed to the next reaction (for example, the substitution reaction of the compound of Formula SM with 2-chloro-5-nitropyridine in Example 8), because SM-IP cannot react with 2-chloro-5-nitropyridine, and the generated Compound 111-S is significantly different from SM-IP and can be automatically removed by post-treatment.

[0398] Example 8: Synthesis of Compound 113 (R1 is methyl and R2 is tert-butyl in Formula SM)

[0399]

[0400] Take DMF (1416 g), the compound of formula SM (1231.3 g, 4.7 mol, 1.5 eq), and potassium carbonate (980.7 g, 7.1 mol, 2.2 eq). Add 2-chloro-5-nitropyridine (500 g, 3.2 mol, 1.0 eq) in batches at 25 - 40 °C, then add tetrabutylammonium bromide (20.3 g). Heat the mixture to 50 - 60 °C and react for 6 h. After the reaction solution is cooled, it is added dropwise to a mixed solution of water (1500 g), methyl tert-butyl ether (1110 g), and glacial acetic acid (662.3 g). Control the temperature at 20 - 30 °C. After the addition is complete, stir for 15 min and let it stand for liquid separation. The organic phase is washed with water (1000 g) once again. The aqueous phases are combined and extracted with methyl tert-butyl ether (1110 g) once. The organic phases are combined. The organic phase is added dropwise with an aqueous sodium bicarbonate solution (1000 g). After the addition is complete, stir for 15 min and let it stand for liquid separation. The organic phase is washed with water (1000 g) 3 times. The solvent is removed from the organic phase to obtain compound 111-S (1754 g). The yield exceeds the standard, and the HPLC purity is about 93.1% (HPLC detection condition 2, as Figure 5 shown).

[0401] Take the above compound 111-S (1205.91 g), add 50 wt% sulfuric acid aqueous solution (about 2 kg), heat to 95 - 100 °C, and react for 1 - 2 h. Add water (5000 g), heat to 70 - 80 °C, and perform vacuum distillation. Add water equivalent to the volume of the distillate at any time and react for 8 h. Cool to 0 - 25 °C, add dropwise ammonia water to adjust the pH to 3 - 4. After the addition is complete, control the temperature at 15 - 25 °C. Centrifuge, wash the filter cake with water and dry it to obtain compound 113 (583 g). The yield is about 88%, and the HPLC purity is about 97.9% (HPLC detection condition 2, as Figure 6 shown).

[0402] Example 9: Synthesis of 3-(tert-butyl)-1,1-diethyl-1,1,3-propanetricarboxylate (compound of formula SM, where R1 is ethyl and R2 is tert-butyl)

[0403]

[0404] Add toluene (2 L) and diethyl malonate (Compound of Formula SM2, 750 g, 4.7 mol, 0.8 eq) into the reactor. Start stirring, and add potassium carbonate (650 g, 4.7 mol, 0.8 eq) through the feeding port. Control the temperature at 10 - 20 °C, and dropwise add tert-butyl acrylate (Compound of Formula SM1, 780.3 g, 6.1 mol, 1.0 eq) into the reactor. Heat to 45 - 50 °C and react for 5 h (detected by GC, the raw material Compound of Formula SM2 has completely reacted, the purity of Compound of Formula SM is about 91.07%, and there is 5.75% of the bimolecular addition product SM-IP). After cooling to 10 - 15 °C, centrifuge and filter to remove the salt, then wash the filter cake with toluene. The filtrate is distilled under normal pressure to recover toluene. The residue is transferred into a distillation still and subjected to vacuum rectification to obtain the product Compound of Formula SM (980 g, light yellow oil), with a yield of about 72.5%, a GC purity of about 95.42%, and the GC spectrum also shows that there is about 1.31% of the bimolecular addition product SM-IP, that is, the ratio of the product to the bimolecular addition product SM-IP is about 73:1.

[0405] Example 10: Synthesis of Compound 113 (R1 is ethyl and R2 is tert-butyl in Formula SM)

[0406]

[0407] Add tetrahydrofuran (1 L) into the reactor, and then add sodium ethoxide (142 g, 2.1 mol, 1.1 eq). Start stirring, cool to maintain the internal temperature of the reaction at 15 - 25 °C, and dropwise add Compound of Formula SM (808.0 g, 2.8 mol, 1.5 eq). After the addition is completed, keep the temperature at 20 - 25 °C and react for 2 h. Then add 2-chloro-5-nitropyridine (300 g, 1.9 mol, 1.0 eq) at 20 - 30 °C, and then heat and keep the temperature at 40 - 45 °C and react for 8 h (the percentage of peak area detected by HPLC: 2-chloro-5-nitropyridine is about 0.45%, and Compound 111-S is about 93.74%). Raise the temperature to 75 - 85 °C, distill to recover tetrahydrofuran to obtain the crude product of Compound 111-S. Add methanol and 2 M aqueous sodium hydroxide solution, control the temperature at 65 - 70 °C, and react for 4 h. Then distill off methanol under normal pressure, adjust the pH to 5 - 6 with 2 M hydrochloric acid, add toluene (900 kg), stir for 30 min, and let it stand for 1 h to separate layers. Collect the toluene layer and distill it under reduced pressure to obtain the residue. Add the residue to a 4 M hydrochloric acid solution in dioxane (1230 g), start stirring and raise the temperature to 20 - 25 °C, stir for 4 h, centrifuge, wash with dioxane, and vacuum dry the filter cake at 55 - 60 °C for 24 h to obtain Compound 113 (291.5 kg, brownish-yellow solid), with a total yield of about 68% and an HPLC purity of about 98.63% (HPLC detection condition 2).

Claims

1. A compound of formula A: Among them, Each R is independently a C1-C6 alkyl group.

2. The compound of formula A according to claim 1, wherein R is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

3. The method for preparing the compound of formula A according to claim 1, which comprises: Compound 113 undergoes a condensation reaction with a compound of formula B to obtain a compound of formula A; wherein, R is defined as in any one of claims 1-2; The molar ratio of the compound 113 to the compound of formula B is 1.0:1.0 - 1.5; The condensation reaction is carried out in the presence of an amide condensing agent; The temperature of the condensation reaction is 0 - 60 °C.

4. The preparation method according to claim 3, characterized in that The compound 113 is prepared by the following method: Compound 75 undergoes a Michael addition reaction with a compound of formula C to generate compound 111 and compound 112, and then undergoes a hydrolysis decarboxylation reaction to obtain compound 113; wherein, Ra in formula C is a C1-C6 alkyl group; The molar ratio of the compound 75 to the compound of formula C is 1.0:1.0 - 2.0; The Michael addition reaction is carried out in the presence of a base; The temperature of the Michael addition reaction is 20 - 120 °C; The hydrolysis decarboxylation reaction is carried out in the presence of a base or an acid; The temperature of the hydrolysis decarboxylation reaction is 20 - 120 °C.

5. The preparation method according to claim 4, characterized in that, The Ra is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

6. The preparation method according to claim 5, characterized in that, The Ra is selected from isopropyl or tert-butyl.

7. The preparation method according to claim 4, characterized in that The compound 75 is prepared by the following method: Compound 74 undergoes a nucleophilic substitution reaction with dimethyl malonate to obtain compound 75; The nucleophilic substitution reaction is carried out in the presence of a base; The molar ratio of the compound 74, dimethyl malonate to the base is 1.0:1.0 - 3.0:1.0 - 5.0; The temperature of the nucleophilic substitution reaction is 20 - 100 °C.

8. The preparation method according to claim 3, characterized in that The compound 113 is prepared by the following method: 2-chloro-5-nitropyridine undergoes a substitution reaction with a compound of formula SM to generate a compound of formula 111-S, and then undergoes a hydrolysis decarboxylation reaction to obtain compound 113; wherein, R1 and R2 in formula SM are each independently a C1-C6 alkyl group; The molar ratio of the 2-chloro-5-nitropyridine to the compound of formula SM is 1.0:1.0 - 3.0; The substitution reaction is carried out in the presence of a base; The molar ratio of the 2-chloro-5-nitropyridine to the base is 1.0:1.0 - 5.0; The temperature of the substitution reaction is 30 - 100 °C; The hydrolysis decarboxylation reaction is carried out in the presence of a base or an acid; The temperature of the hydrolysis decarboxylation reaction is 60 - 120 °C.

9. The preparation method according to claim 8, wherein The R1 and R2 are each independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

10. The preparation method according to claim 9, wherein, The R1 is methyl or ethyl, and R2 is tert-butyl.

11. The preparation method according to claim 8, characterized in that The compound of formula SM is prepared by the following method: A compound of formula SM1 undergoes a Michael addition reaction with a compound of formula SM2 to obtain a compound of formula SM; wherein, R1 and R2 are as defined in any one of claims 8-10; the molar ratio of the compound of formula SM1 to the compound of formula SM2 is 1:0.5 - 5.0; the Michael addition reaction is carried out in the presence of a base; the temperature of the Michael addition reaction is 20 - 120 °C.

12. Use of the compound of formula A according to claim 1 in the preparation of 2-(3-(5-nitropyridin-2-yl)propyl)oxazole.

13. A method for preparing 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, comprising: The compound of formula A undergoes an intramolecular cyclization reaction to obtain compound 129, which is 2-(3-(5-nitropyridin-2-yl)propyl)oxazole; wherein each R is independently a C1-C6 alkyl group; the intramolecular cyclization reaction is carried out in the presence of a cyclization condensing agent; the temperature of the intramolecular cyclization reaction is 100 - 160 °C.

14. The preparation method according to claim 13, wherein The R is a C1-C6 alkyl group.

15. According to the preparation method of claim 13, the R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

16. A method for preparing 6-(3-(oxazol-2-yl)propyl)pyridin-3-amine, which comprises: The compound of formula A undergoes an intramolecular cyclization reaction to obtain 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, and 2-(3-(5-nitropyridin-2-yl)propyl)oxazole then undergoes a nitro reduction reaction to obtain compound 130, which is 6-(3-(oxazol-2-yl)propyl)pyridin-3-amine; wherein each R is independently a C1-C6 alkyl group; the intramolecular cyclization reaction is carried out in the presence of a cyclization condensing agent; the temperature of the intramolecular cyclization reaction is 100 - 160 °C; the reduction system for the nitro reduction reaction is catalytic hydrogenation reduction or hydrazine hydrate reduction.

17. Use of the compound of formula A according to claim 1 in the preparation of 6-(3-(oxazol-2-yl)propyl)pyridin-3-amine.

18. A preparation method of 6-(3-(oxazol-2-yl)propyl)pyridin-3-amine, which comprises: 1) The compound 75 undergoes a Michael addition reaction with the compound of formula C to generate compounds 111 and 112, and then undergoes a hydrolysis decarboxylation reaction to obtain compound 113; 2) Compound 113 undergoes a condensation reaction with the compound of formula B to obtain the compound of formula A; 3) The compound of formula A undergoes an intramolecular cyclization reaction to obtain compound 129; 4) Compound 129 undergoes a nitro reduction reaction to obtain compound 130, which is 6-(3-(oxazol-2-yl)propyl)pyridin-3-amine; wherein each R is independently a C1-C6 alkyl group; Ra is a C1-C6 alkyl group; the conditions of the Michael addition reaction and the hydrolysis decarboxylation reaction in step 1) are as defined in claim 4; the conditions of the condensation reaction in step 2) are as defined in claim 3; the conditions of the intramolecular cyclization reaction in step 3) are as defined in claim 13; the conditions of the nitro reduction reaction in step 4) are as defined in claim 16; alternatively, compound 113 in step 2) is prepared by the following method: 1’) 2-Chloro-5-nitropyridine undergoes a substitution reaction with the compound of formula SM to generate the compound of formula 111-S, and then undergoes a hydrolysis decarboxylation reaction to obtain compound 113; Among them, R1 and R2 in formula SM are each independently a C1-C6 alkyl group; The conditions of the substitution reaction and the hydrolysis decarboxylation reaction described in step 1') are as defined in claim 8.

19. The preparation method according to claim 18, characterized in that, The Ra is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

20. The preparation method according to claim 18, characterized in that, The R1 and R2 are each independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

21. The preparation method according to claim 18, wherein The R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

22. The preparation method according to claim 19, characterized in that, The Ra is isopropyl or tert-butyl.

23. The preparation method according to claim 20, characterized in that, The R1 is methyl or ethyl, and R2 is tert-butyl.

24. The preparation method according to claim 16 or 18, characterized in that, The preparation method further includes salifying compound 130 with 1,5-naphthalenedisulfonic acid.

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