Preparation method of pyridine oxynitride

Abstract

The invention discloses a preparation method of a pyridine nitrogen oxide compound, and particularly discloses a method for preparing a compound as shown in a formula (I) or pharmaceutically acceptable salts and hydrates thereof, which is characterized in that a compound as shown in a formula (I-5) or pharmaceutically acceptable salts thereof is contacted with a compound as shown in a formula (I-6) or pharmaceutically acceptable salts thereof; the method is simple to operate, high in yield and suitable for industrial mass production, and the compound as shown in the formula (I) or pharmaceutically acceptable salts and hydrates of the compound is obtained. # imgabs0 #

Description

Preparation method of pyridine nitrogen oxide compound

[0001] This application claims priority to:

[0002] 1)CN202210629774.5, 2022.06.02;

[0003] 2) CN202310570708.X, 2023.05.19. Technical Field

[0004] The present invention belongs to the field of pharmaceutical chemistry, and in particular relates to a pyridine nitrogen oxide compound and a method for preparing the crystal form thereof. Background Art

[0005] Pain is one of the most common clinical symptoms and the fifth vital sign after respiration, pulse, blood pressure, and body temperature, seriously affecting patients' quality of life. According to statistics, the global analgesic market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023. Among them, acute, moderate, and severe pain mainly relies on opioids, accounting for about two-thirds of the analgesic market share and will grow steadily at a compound annual growth rate of 2.5% in the future. The number of patients with chronic pain, mainly neuropathic pain and arthritis pain, is increasing year by year, and the market is expected to show a compound annual growth rate of approximately 18%, which will be the main driving force for the continued growth of the global pain market in the next decade.

[0006] Research results in recent years have gradually revealed that sodium channel subtype 1.8 (NaV1.8) plays an important role in the occurrence and transmission of pain. NaV1.8 is a voltage-gated sodium channel that is mainly expressed on afferent neurons, including sensory neurons. By controlling the flow of sodium ions into and out of cells, it plays an important role in maintaining the excitability of nociceptive sensory neurons, the firing and persistence of action potentials, and the regulation of pain sensitivity. Patients with activating mutations in NaV1.8 experience paroxysmal pain caused by small fiber neuropathy (damage to Aδ fibers and unmyelinated C-type fibers, which are mainly responsible for pain transmission). Diseases such as chronic inflammation and diabetes can cause increased expression of NaV1.8 or changes in its properties, thereby sensitizing nociceptive neurons and causing various types of pain. NaV1.8 gene knockout mice are insensitive to pain.

[0007] Patent application CN112479996A (published on March 12, 2021) discloses a novel NaV1.8 inhibitor, the general formula of which is Also disclosed are compounds

[0008] The patent application document with application number PCT / CN2022 / 080430 (application date March 11, 2022) discloses the crystalline form A and crystalline form B of compound 7X.

[0009] Summary of the Invention

[0010] The inventors discovered that the synthetic route of compound 7X in patent application CN112479996A is as follows:

[0011] The yield of the second step in this overall route is low, and the third step uses m-CPBA as an oxidant, which contains many impurities, which is not conducive to the quality control of the final compound as a raw material drug and is not suitable for large-scale industrial production.

[0012] Based on this, the inventors developed a new synthesis method, which has higher yield, lower cost, simpler operation, purer product, meets the quality standards of raw materials, and is suitable for large-scale industrial production compared to the methods in the prior art.

[0013] In the first aspect of the present invention, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof. According to an embodiment of the present invention, the method comprises contacting a compound of formula (I-5) or a pharmaceutically acceptable salt thereof with a compound of formula (I-6) or a pharmaceutically acceptable salt thereof to obtain a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof.

[0014] T1 is selected from N or C(R7);

[0015] T2 is selected from N or C(R8);

[0016] T3 is selected from N or C(R9);

[0017] T4 is selected from N or C(R 10 );

[0018] R1, R2, R8, R9 are independently selected from H, halogen, OH, NH2, CN, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, vinyl-C 1-6 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-C 1-6 Alkyl-O-, phenyl-C 1-3 Alkyl-, C 3-6 Cycloalkyl-C1-3 Alkyl-O-, 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-NH-, 5- to 6-membered heteroaryl-C 1-3 Alkyl-, 5- to 6-membered heteroaryl-C 1-3 Alkyl-O- and 5- to 6-membered heteroaryl-C 1- 3 alkyl-NH-, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, vinyl-C 1-6 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-C 1-6 Alkyl-O-, phenyl-C 1-3 Alkyl-, C 3-6 Cycloalkyl-C 1-3 Alkyl-O-, 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-NH-, 5- to 6-membered heteroaryl-C 1- 3-alkyl-, 5- to 6-membered heteroaryl-C 1-3 Alkyl-O- or 5- to 6-membered heteroaryl-C 1-3 Alkyl-NH- is optionally substituted with 1, 2 or 3 R;

[0019] R3, R4, R5, R6, R 10 are independently selected from H, halogen, OH, NH2, SF5, CN, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl- and 3- to 6-membered heterocycloalkyl-C 1-6 Alkyl-, the C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl- or 3- to 6-membered heterocycloalkyl-C1-6 Alkyl - optionally substituted with 1, 2 or 3 R;

[0020] R7 is selected from H, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino is optionally substituted with 1, 2 or 3 R;

[0021] L2 is selected from O, S, NH and CH2, wherein CH2 is optionally substituted with 1 or 2 R, and NH is optionally substituted with R;

[0022] R 13a 、R 13b are independently selected from H, halogen and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R groups;

[0023] R is independently selected from H, D, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and C 1- 6-alkylamino group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino is optionally substituted with 1, 2 or 3 R';

[0024] R' is selected from F, Cl, Br, I, OH, NH2 and CH3;

[0025] The above 3- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0026] In some embodiments of the present invention, the above R is selected from H, D, F, Cl, Br, I, OH, NH2, Me, CF3, CHF2, CH2F, The remaining variables are as defined in the present invention.

[0027] In some embodiments of the present invention, the above R1, R2, R8, and R9 are independently selected from H, halogen, OH, NH2, CN, SF5, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3Alkylamino, vinyl-C 1-3 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl-, 3-6 membered heterocycloalkyl-C 1-3 Alkyl-, 3-6 membered heterocycloalkyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-, phenyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-NH-, pyridyl-C 1-3 Alkyl-, pyrimidinyl-C 1-3 Alkyl-, thienyl-C 1-3 Alkyl-, thiazolyl-C 1-3 Alkyl-, pyrazolyl-C 1-3 Alkyl-, imidazolyl-C 1-3 Alkyl-, pyridyl-C 1-3 Alkyl-O-, pyrimidinyl-C 1-3 Alkyl-O-, thienyl-C 1-3 Alkyl-O-, thiazolyl-C 1-3 Alkyl-O-, pyrazolyl-C 1-3 Alkyl-O-, imidazolyl-C 1-3 Alkyl-O-, pyridyl-C 1-3 Alkyl-NH-, pyrimidinyl-C 1-3 Alkyl-NH-, thienyl-C 1-3 Alkyl-NH-, thiazolyl-C 1-3 Alkyl-NH-, pyrazolyl-C 1-3 Alkyl-NH- and imidazolyl-C 1-3 Alkyl-NH-, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, vinyl-C 1-3 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl-, 3-6 membered heterocycloalkyl-C 1- 3-membered alkyl-, 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-, phenyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-NH-, pyridyl-C 1- 3-alkyl-, pyrimidinyl-C 1-3 Alkyl-, thienyl-C 1-3 Alkyl-, thiazolyl-C 1-3 Alkyl-, pyrazolyl-C1-3 Alkyl-, imidazolyl-C 1-3 Alkyl-, pyridyl-C 1-3 Alkyl-O-, pyrimidinyl-C 1-3 Alkyl-O-, thienyl-C 1-3 Alkyl-O-, thiazolyl-C 1-3 Alkyl-O-, pyrazolyl-C 1-3 Alkyl-O-, imidazolyl-C 1-3 Alkyl-O-, pyridyl-C 1-3 Alkyl-NH-, pyrimidinyl-C 1-3 Alkyl-NH-, thienyl-C 1-3 Alkyl-NH-, thiazolyl-C 1-3 Alkyl-NH-, pyrazolyl-C 1-3 Alkyl-NH- or imidazolyl-C 1-3 Alkyl-NH- is optionally substituted with 1, 2 or 3 R groups, and the remaining variables are as defined herein.

[0028] In some embodiments of the present invention, the above R1, R2, R8, and R9 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, SF5, Me, CF3, CHF2, CH2F, CF3CF2, OCF3, HOCH2CH2O, CH3NHCH2CH2O, (CH3)2NCH2CH2O The remaining variables are as defined in the present invention.

[0029] In some embodiments of the present invention, the above structural unit Selected from The remaining variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above R3, R4, R5, R6, R 10 are independently selected from H, halogen, OH, NH2, SF5, CN, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl- and 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl-, the C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Alkoxy, C3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl- or 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl - optionally substituted with 1, 2 or 3 R groups, with the remaining variables being as defined herein.

[0031] In some embodiments of the present invention, the above R3, R4, R5, R6, R 10 Each independently selected from H, F, Cl, Br, I, OH, NH2, SF5, Me, CF3, CHF2, CH2F, CN, CH(F2)CH3, CD3, OCD3, The remaining variables are as defined in the present invention.

[0032] In some embodiments of the present invention, the above structural unit Selected from The remaining variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the above R 13a 、R 13b are independently selected from H, F, Cl, Br, I and Me, and the remaining variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the compound represented by the above formula (I) or its optical isomers are selected from

[0035] In some embodiments of the present invention, the compound represented by the above formula (I) is selected from The remaining variables are as defined in the present invention.

[0036] In some embodiments of the present invention, the compound represented by formula (I) is selected from The remaining variables are as defined in the present invention.

[0037] In some embodiments of the present invention, the compound represented by formula (I) is selected from The remaining variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the compound represented by the above formula (I-5) or selected from The remaining variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the compound represented by the above formula (I-5) is selected from The remaining variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the compound represented by the above formula (I-6) is selected from The remaining variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the compound represented by the above formula (I-6) is selected from The remaining variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the contacting is carried out in the presence of a condensing agent, and the remaining variables are as defined in the present invention.

[0043] In some embodiments of the present invention, the condensing agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole, and N,N'-carbonyldiimidazole, with the remaining variables being as defined herein. The inventors have discovered that the condensation effect is good under the conditions of these condensing agents.

[0044] In some embodiments of the present invention, the condensing agent is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and the remaining variables are as defined in the present invention. The inventors have found that the condensation effect is better under the conditions of these condensing agents.

[0045] In some embodiments of the present invention, the condensing agent is one of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate or N-methylimidazole, and the remaining variables are as defined in the present invention.

[0046] In some embodiments of the present invention, the condensing agent is a mixture of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole, and the remaining variables are as defined in the present invention.

[0047] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I-5) to the 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is 1:(1.0-2.0), with the remaining variables being as defined herein. The inventors have found that condensation is effective at these ratios.

[0048] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I-5) to the 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is 1:(1.2-1.5), with the remaining variables being as defined herein. The inventors have discovered that these ratios provide better condensation results.

[0049] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-5) to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1:(1.0-2.0), and the remaining variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-5) to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1:(1.1-1.2), and the remaining variables are as defined in the present invention.

[0051] In some embodiments of the present invention, the molar ratio of the N-methylimidazole to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1:(1.2-2.0), and the remaining variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the molar ratio of the N-methylimidazole to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1:(1.4-1.6), and the remaining variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the contacting is performed under alkaline conditions, and the remaining variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the alkaline condition is provided by N,N-diisopropylethylamine, and the remaining variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I-5) to the N,N-diisopropylethylamine is 1:(1.0-5.0), and the remaining variables are as defined in the present invention.

[0056] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I-5) to the N,N-diisopropylethylamine is 1:(2.5-3.0), and the remaining variables are as defined in the present invention.

[0057] In some embodiments of the present invention, the contacting is carried out in a solvent of N,N-dimethylformamide, acetonitrile or dichloromethane, and the remaining variables are as defined in the present invention.

[0058] In some embodiments of the present invention, the contacting is carried out in the presence of N,N-dimethylformamide as the solvent, and the remaining variables are as defined in the present invention.

[0059] In some embodiments of the present invention, the compound represented by the above formula (I-5-A) is obtained by a substitution reaction between the compound represented by the formula (I-2) and the compound represented by the formula (I-3).

[0060] Among them, Rx is selected from C 1-6The remaining variables are as defined in the present invention.

[0061] In some embodiments of the present invention, the compound represented by the above formula (I-2) or its optical isomers are selected from The remaining variables are as defined in the present invention.

[0062] In some embodiments of the present invention, the compound represented by the above formula (I-3) or its optical isomers are selected from The remaining variables are as defined in the present invention.

[0063] In some embodiments of the present invention, the above substitution reaction is carried out in the presence of a base, and the remaining variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the base is selected from Cs2CO3, K2CO3 and K3PO4, and the remaining variables are as defined in the present invention. The inventors have found that the use of the base has a high yield.

[0065] In some embodiments of the present invention, the base is Cs2CO3, and the remaining variables are as defined in the present invention. The inventors have found that the use of Cs2CO3 provides a higher yield.

[0066] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-2) to the Cs2CO3 is 1:(1.3-1.5), and the remaining variables are as defined in the present invention.

[0067] In some embodiments of the present invention, the substitution reaction is carried out in a solvent of N,N-dimethylformamide or tetrahydrofuran, and the remaining variables are as defined in the present invention.

[0068] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I-2) to the compound represented by formula (I-3) is 1:(1.10-1.25), and the remaining variables are as defined in the present invention.

[0069] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I-2) to the compound represented by formula (I-3) is 1:1.15, and the remaining variables are as defined in the present invention.

[0070] In some embodiments of the present invention, the compound represented by formula (I-2) is obtained by esterification of the compound represented by formula (I-1). The remaining variables are as defined in the present invention.

[0071] In some embodiments of the present invention, the compound represented by the above formula (I-1) or its optical isomers are selected from The remaining variables are as defined in the present invention.

[0072] In some embodiments of the present invention, the esterification reaction is carried out in the presence of SOCl2, and the remaining variables are as defined in the present invention.

[0073] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I-1) to the SOCl2 is 1:(1.0-2.0), and the remaining variables are as defined in the present invention.

[0074] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I-1) to the SOCl2 is 1:(1.2-1.5), and the remaining variables are as defined in the present invention.

[0075] In some embodiments of the present invention, the esterification reaction is carried out in ethanol as the solvent, and the remaining variables are as defined in the present invention.

[0076] In some embodiments of the present invention, the ratio of the compound represented by the above formula (I-1) to the ethanol is (1:1672-2090). It should be noted that the ratio here refers to the molar volume ratio (moL:mL), and the remaining variables are as defined in the present invention.

[0077] In some embodiments of the present invention, the above esterification reaction further includes post-treatment, and the remaining variables are as defined in the present invention.

[0078] In some embodiments of the present invention, the post-treatment is performed by adding an aqueous sodium bicarbonate solution, and the remaining variables are as defined in the present invention.

[0079] In another aspect of the present invention, the present invention also provides an intermediate compound or a pharmaceutically acceptable salt thereof. According to an embodiment of the present invention, the structure of the intermediate compound is shown in Compound 5.

[0080] In another aspect of the present invention, the present invention also proposes the use of the compound represented by Compound 5 or a pharmaceutically acceptable salt thereof in the preparation of the compound represented by Compound 7X or an optical isomer thereof.

[0081] In another aspect of the present invention, the present invention also proposes The variables are as defined in the present invention.

[0082] In another aspect of the present invention, the present invention also proposes

[0083] In another aspect of the present invention, the present invention also proposes

[0084] In another aspect of the present invention, a method for preparing compound 1 is provided. According to an embodiment of the present invention, the method comprises subjecting a compound represented by formula (X-1) to a chlorination reaction to obtain compound 1, wherein the chlorination reaction is carried out in a solvent selected from one or more of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid, or ethanesulfonic acid.

[0085] In another aspect of the present invention, a method for preparing compound 1 is provided. According to an embodiment of the present invention, the method comprises subjecting a compound represented by formula (X-1) to a chlorination reaction to obtain compound 1, wherein the chlorination reaction is carried out under the condition that the solvent is concentrated sulfuric acid.

[0086] The inventors discovered that the prior art method for preparing compound 1 uses a Friedel-Crafts alkylation reaction, in which highly toxic carbon tetrachloride is used, and the reaction and post-processing processes are relatively complicated and have a low yield. The method of the present invention is easy to operate, does not use highly toxic reagents, and has a high yield. The inventors also discovered that the chlorination reaction of the present invention needs to be carried out under concentrated sulfuric acid conditions, and does not react or has a low reaction yield under other solvent conditions.

[0087] In some embodiments of the present invention, the above chlorination reaction is carried out in the presence of a chlorination agent, and the remaining variables are as defined in the present invention.

[0088] In some embodiments of the present invention, the chlorination agent is selected from dichlorodimethylhydantoin and N-chlorosuccinimide, and the remaining variables are as defined in the present invention.

[0089] In some embodiments of the present invention, the molar ratio of the compound represented by formula (X-1) to dichlorodimethylhydantoin is 1:(0.5-0.7), and the remaining variables are as defined in the present invention. The inventors have found that at this ratio, the yield of the chlorination reaction is high.

[0090] In some embodiments of the present invention, the molar ratio of the compound represented by formula (X-1) to N-chlorosuccinimide is 1:(1.1-1.6), and the remaining variables are as defined herein. The inventors have found that at this ratio, the yield of the chlorination reaction is higher.

[0091] In some embodiments of the present invention, the chlorination reaction is carried out at a temperature of 55-60° C., with the remaining variables being as defined herein. The inventors have found that within this temperature range, the yield is higher.

[0092] In another aspect of the present invention, the present invention also provides a method for preparing compound 6. According to an embodiment of the present invention, the method comprises subjecting the compound represented by formula (Y-2) to an oxidation reaction and a deprotection reaction to obtain compound 6, The inventors discovered that the prior art method for preparing compound 6 uses nicotinic acid as a starting material, creates a Boc-protected amino group using DPPA and tert-butanol, and then removes the Boc protection to obtain the target product. This method uses relatively expensive DPPA and produces excessive impurities during the reaction. Alternatively, the compound represented by formula (Y-2) is directly oxidized to pyridine using MCPBA. This method easily produces a two-molecule polymerization product with a low yield. The method proposed in the present invention is simple to operate, uses inexpensive raw materials, and facilitates post-processing, making it suitable for large-scale industrial production.

[0093] In some embodiments of the present invention, the compound represented by the above formula (Y-2) is obtained by subjecting the compound represented by the formula (Y-1) to an acylation reaction. The remaining variables are as defined in the present invention.

[0094] Definition and Description

[0095] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0096] The term "contacting" should be understood broadly and may include any method capable of causing a chemical reaction between at least two reactants, such as mixing the two reactants under appropriate conditions. If desired, the reactants to be contacted may be mixed under stirring. The type of stirring is not particularly limited and may, for example, be mechanical stirring, i.e., stirring under the action of a mechanical force.

[0097] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0098] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers with different functional groups that are in dynamic equilibrium at room temperature and can quickly convert into each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0099] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and prolonged biological half-life. All isotopic variations of the compounds of this invention, whether radioactive or not, are encompassed by this invention. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs as well as instances where it does not.

[0100] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.

[0101] In the present invention, "room temperature" refers to a temperature from about 10° C. to about 40° C. In some embodiments, "room temperature" refers to a temperature from about 20° C. to about 30° C.; in other embodiments, "room temperature" refers to 20° C., 22.5° C., 25° C., 27.5° C., etc.

[0102] In the present invention, "room temperature or under heating conditions" means that the reaction is carried out at a certain temperature, which is room temperature or a specific temperature reached by heating. For example, the reaction of preparing the compound of formula (III) from the compound of formula (IV) is carried out at room temperature or under heating conditions, which means that the reaction is carried out at a certain temperature, which is room temperature or a specific temperature reached by heating; for example, the reaction is carried out at room temperature (e.g., 20°C-30°C) or under heating conditions to 30°C-65°C, that is, the reaction is carried out at 20°C-65°C.

[0103] In the context of the present invention, all numerical values ​​disclosed herein are approximate. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, or 10%. Whenever a number having a value of N is disclosed, any number within the value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is expressly disclosed, where "+ / -" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, are disclosed within a numerical range, any value within the disclosed range is expressly disclosed.

[0104] All reaction steps described in the present invention are subjected to post-processing, such as cooling, collection, extraction, filtration, separation, purification, or a combination thereof, after the reaction reaches a certain level, such as when the raw material consumption is greater than 70%, greater than 80%, greater than 90%, or greater than 95%, or after detection that the raw material has been completely consumed. The reaction level can be detected by conventional methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), etc. The reaction solution can be post-processed using conventional methods, for example, by evaporating the reaction solvent under reduced pressure or conventional distillation, collecting the crude product, and directly feeding it into the next reaction; or directly filtering the crude product, and directly feeding it into the next reaction; or standing it, decanting the supernatant to obtain the crude product, and directly feeding it into the next reaction; or selecting an appropriate organic solvent or a combination thereof for purification steps such as extraction, distillation, crystallization, column chromatography, rinsing, and beating.

[0105] Regardless of whether the numerical values ​​of the present invention are modified by the term "about", it should be understood that the numerical values ​​are modified by "about". The term "about" is used to modify a numerical value that differs by 10%. In some embodiments, "about" is used to modify a numerical value that differs by 5%. In some embodiments, "about" is used to modify a numerical value that differs by 3%, 2%, or 1%. It is understood that the error range of the numerical value modified by "about" is the actual or reasonable error range of the numerical value modified by it.

[0106] In each step of the reaction process described in the present invention, the reaction raw materials or other reagents can be added to the reaction system by dropwise addition. Each dropwise addition process and each step of the reaction are carried out under certain temperature conditions, and any temperature suitable for use in each dropwise addition process or each reaction process is included in the present invention. In addition, many similar modifications, equivalent replacements, or temperatures and temperature ranges equivalent to those described in the present invention are considered to be included in the present invention. The present invention provides preferred temperatures or temperature ranges for each dropwise addition process, as well as preferred reaction temperatures for each reaction.

[0107] The solvents used in each reaction step described in the present invention are not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents equivalent to those described in the present invention, solvent combinations, and different ratios of solvent combinations in the art are considered to be within the scope of the present invention. The present invention provides preferred solvents for use in each reaction step.

[0108] The products of each reaction step described in the present invention can be purified by recrystallization under appropriate conditions. The recrystallization solvent used is not particularly limited, and any solvent that can dissolve the crude product to a certain extent and can precipitate crystals under certain conditions is included in the present invention. In addition, many similar modifications, equivalent replacements, or solvents equivalent to those described in the present invention, solvent combinations, and different proportions of solvent combinations in the art are considered to be included within the scope of the present invention. Among them, the solvent can be alcohols, ethers, alkanes, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, acetic acid, water, DMF or a combination thereof. For example, water, acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, DMF, tetrahydrofuran, diethyl ether, isopropyl ether, dioxane, methyl tert-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, acetone, butanone, benzene, toluene, xylene or a combination thereof.

[0109] The content of water in the solvent of the present invention is not particularly limited, that is, the content of water in the solvent does not affect the occurrence of the reaction of the present invention. Any solvent containing a certain amount of water that can be used in the present invention to a certain extent is considered to be the solvent of the present invention. For example, the content of water in the solvent is approximately less than 0.05%, less than 0.1%, less than 0.2%, less than 0.5%, less than 5%, less than 10%, less than 25%, less than 30%, or 0%. In some embodiments, the water content of the solvent is within a certain range, which is more conducive to the reaction; for example, in the step of using ethanol as the reaction solvent, using anhydrous ethanol is more conducive to the reaction. In some embodiments, the water content of the solvent exceeds a certain range, which may affect the reaction (for example, affecting the yield of the reaction), but does not affect the occurrence of the reaction.

[0110] The intermediate compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the above with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. All of these should be considered to be within the scope of protection of the present invention.

[0111] The solvent used in the present invention is commercially available.

[0112] A hyphen ("-") that is not between two letters or symbols indicates the site of attachment of a substituent. For example, C 1-6 Alkylcarbonyl - refers to a C-alkyl group attached to the rest of the molecule through a carbonyl group. 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0113] When the group valence bond is marked with a dotted line When, for example, In the example, the wavy line indicates the point of attachment of the group to the rest of the molecule.

[0114] As used herein, the term "hydrogen" refers to the group -H.

[0115] As used herein, the term "deuterium" refers to the group -D.

[0116] As used herein, the term "hydroxy" refers to the group -OH.

[0117]

[0046] The term "halo" or "halogen" as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0118] As used herein, the term "cyano" refers to the group -CN.

[0119] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1- 3. C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring and a 6-10-membered ring, etc.

[0120] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.

[0121] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-6 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0122] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3Alkyl, etc.; it can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1- Examples of 3 alkyl groups include, but are not limited to, CH3, wait.

[0123] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0124] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0125] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-6 Alkylamino groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0126] Unless otherwise specified, the term “C 1-3"Alkylamino" means an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino groups include C 1-2 , C3 and C2 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0127] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0128] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0129] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0130] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyls, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0131] Unless otherwise specified, the term "3- to 6-membered ring" by itself or in combination with other terms refers to a saturated or unsaturated monocyclic group consisting of 3 to 6 ring atoms, which may be a pure carbon ring or a ring containing heteroatoms. The number of 3-6 refers to the number of atoms forming the ring. Examples of "3- to 6-membered rings" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, cyclopentanonyl, and cyclohexanonyl.

[0132] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0133] Accordingly, the term "heteroaryl ring" as used herein refers to a heteroaryl ring as defined above.

[0134] As used herein, "aryl" or "aromatic" follows Hückel's rule, where the number of π electrons is equal to 4n+2, and n is zero or any positive integer up to 6.

[0135] As used herein, the term "carbonyl" refers to the group -C(O)-, which may also be represented as -CO-.

[0136] The term "amino" as used herein refers to the group -NH2.

[0137] As used herein, the term "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where the event occurs as well as instances where the event does not occur. For example, "optionally substituted alkyl" refers to both unsubstituted alkyl and substituted alkyl, wherein alkyl is as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any substitution pattern that is sterically impractical, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0138] As used herein, the term "substituted" or "substituted by" means that one or more hydrogen atoms on a given atom or group are replaced, for example, by one or more substituents selected from a given substituent group, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are replaced by oxygen. Such combinations are permitted only if the combination of substituents and / or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is stable enough to be isolated from a reaction mixture and the chemical structure of the compound can be determined, and then can be formulated into a formulation that at least has practical utility. For example, in the absence of explicit listing of substituents, the term "substituted" or "substituted" as used herein means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, for example, 1, 2, 3 or 4, substituents independently selected from: deuterium (D), halogen, OH, mercapto, cyano, -CD3, alkyl (preferably C 1-6 Alkyl), alkoxy (preferably C 1-6 Alkoxy), haloalkyl (preferably haloC1-6 alkyl), haloalkoxy (preferably haloC1-6 alkoxy), -C(O)NR a R b and -N(R a )C(O)R b and -C(O)OC 1-4 Alkyl (where R a and R b are each independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4alkyl), carboxyl (COOH), cycloalkyl (preferably 3-8 membered cycloalkyl), heterocyclyl (preferably 3-8 membered heterocyclyl), aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-6 alkyl, OC1-6 alkylphenyl, -C1-6 alkylOH (preferably -C1-4 alkylOH), -C1-6 alkylSH, -C1-6 alkylO-C1-2, C1-6 alkylNH2 (preferably C1-3 alkylNH2), N(C1-6 alkyl)2 (preferably N(C1-3 alkyl)2), NH(C1-6 alkyl) (preferably NH(C1-3 alkyl)), N(C1-6 alkyl)(C1-6 alkylphenyl), NH(C1-6 alkyl C(O)-C1-6 alkyl, C(O)-5-7 membered heteroaryl, C(O)-C1-6 alkylphenyl, C(O)-C1-6 haloalkyl, OC(O)-C1-6 alkyl (preferably OC(O)-C1-3 alkyl), alkylsulfonyl (e.g., -S(O)-C1-6 alkyl), alkylsulfinyl (e.g., -S(O)-C1-6 ... alkyl), -S(O)2-phenyl, -S(O)2-C1-6 haloalkyl, -S(O)2NH2, S(O)2NH(C1-6 alkyl), S(O)2NH(phenyl), -NHS(O)2(C1-6 alkyl), -NHS(O)2(phenyl) and NHS(O)2(C1-6 haloalkyl), wherein said alkyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl are each optionally further substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, cycloalkyl, 3-8 membered heterocyclyl, C1-4 alkyl, C1-4 haloalkyl-, -OC1-4 alkyl, -C1-4 alkylOH, -C1-4 Alkyl, O-C1-4 alkyl, OC1-4 haloalkyl, cyano, nitro, -C(O)-OH, C(O)OC1-6 alkyl, CON(C1-6 alkyl)2, CONH(C1-6 alkyl), CONH2, NHC(O)(C1-6 alkyl), NH(C1-6 alkyl)C(O)(C1-6 alkyl), -SO2(C1-6 alkyl), -SO2(phenyl), -SO2(C1-6 haloalkyl), -SO2NH2, SO2NH(C1-6 alkyl), SO2NH(phenyl), -NHSO2(C1-6 alkyl), -NHSO2(phenyl) and NHSO2(C1-6 haloalkyl). When an atom or group is substituted with a plurality of substituents, the substituents may be the same or different.

[0139] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0140] The present invention uses the following abbreviations:

[0141] SOCl2 represents dichlorothionyl, Cs2CO3 represents cesium carbonate, NaHCO3 represents sodium bicarbonate, K2CO3 represents potassium carbonate, K3PO4 represents potassium phosphate, DMF represents dimethylformamide, THF represents tetrahydrofuran, T3P represents 1-propylphosphoric anhydride, HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, EDCI represents 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride, HOBt stands for 1-hydroxybenzotriazole, CDI stands for N,N'-carbonyldiimidazole, DCM stands for dichloromethane, DIPEA stands for N,N-diisopropylethylamine, DCDMH stands for dichlorodimethylhydantoin, NCS stands for N-chlorosuccinimide, MTBE stands for methyl tert-butyl ether, TCFH stands for N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and NMI stands for N-methylimidazole.

[0142] The volume nV used in the present invention generally refers to n times the volume, which is the ratio of the solvent volume to the weight of the compound used, and the unit is mL / g. For example, the ethanol volume 8V used in Table 3 means that the volume of ethanol is 8 times the volume, that is, the volume of ethanol (mL / ) is 8 times the weight (g) of Compound 1.

[0143] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0144] The present application is described in detail below by way of examples, but this does not necessarily mean that there are any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0145] Unless otherwise specified, the raw materials used in the present invention are commercially available.

[0146] Example 1

[0147] Step 1

[0148] 1) Reaction: Under a slight nitrogen atmosphere, add anhydrous ethanol (38.4 kg, 6.45X) and compound 1 (5.95 kg, 1.0X) to reactor R1 and start stirring. Adjust the temperature of reactor R1 to 0-10°C. Under a slight nitrogen atmosphere, control the temperature of the reactor to 0-20°C. Slowly add thionyl chloride (3.6 kg, 0.61X) dropwise to the reactor. After the addition is complete, heat to 65-75°C and stir for 8-16 hours. Cool to 40-50°C and take a sample for central control testing. After the central control is qualified (purity ratio of compound 1 / (compound 1 + compound 2)) ≤1.0%), proceed to the next step. If the test fails, continue stirring the reaction until the central control is qualified.

[0149] 2) Crystallization: Lower the temperature in the reactor to 15-25°C, add a pre-prepared 10% potassium phosphate (60.0 kg, 10.1X) aqueous solution dropwise, adjust the pH to 6-8, and stir for 3-6 hours.

[0150] 3) Centrifugation 1: The material in the reactor was centrifuged and the filter cake was rinsed with process water (46.5 kg, 7.8X).

[0151] 4) Beating: Add the wet product (7.0 kg, 1.2X) and process water (61.2 kg, 10.3X) into the reactor R1 and stir at 15-25°C for 3-6 hours.

[0152] 5) Centrifugation 2: The material in the reactor is centrifuged and the filter cake is rinsed with process water (42.8 kg, 7.2X) to obtain a wet product. After the wet product passes the test, proceed to the next step.

[0153] 6) Drying: Transfer the wet product to a vacuum oven, control the oven temperature at 30-40°C, and dry under reduced pressure for 24-30 hours. Sample and test for moisture content until acceptable (KF ≤ 0.3%). If unacceptable, extend the drying time until the moisture content is acceptable. This batch yielded 6.1 kg of a white solid, with a yield of 90.4%. 1H NMR (400 MHz, DMSO-d6) δ 8.08–8.01 (m, 1H), 7.89 (d, J = 10.2 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0154] HPLC conditions

[0155] Instrument: High performance liquid chromatograph (UV detector) Agilent 1260

[0156] Column: Waters Xbridge C18 / 4.6×150mm, 3.5μm

[0157] Mobile phase: Mobile phase A, 0.05% formic acid in water, Mobile phase B, 0.05% formic acid in acetonitrile

[0158] Flow rate: 1.0ml / min

[0159] Measurement time: 28 minutes

[0160] Analysis temperature: 35°C

[0161] Detection wavelength: 222nm / 248nm

[0162] Retention time: Compound 1: 10.013 min, Compound 2: 16.029 min

[0163] Table 1

[0164] Steps 2 and 3

[0165] 1) Reaction 1: Under a slight nitrogen atmosphere, compound 2 (6.0 kg, 1.00X) and tetrahydrofuran (44.0 kg, 7.33X) were added to the reactor and stirred. Compound 3 (5.1 kg, 0.85X) and cesium carbonate (10.7 kg, 1.78X) were added, the temperature was lowered to 55-65°C, stirred and reacted for 16 to 24 hours, the temperature was lowered to 15 to 25°C, and a sample was taken for central control testing. After the central control was qualified (the purity ratio of compound 2 / (compound 2 + compound 4 + compound 5) was ≤4.0%), the next step was carried out. If the central control was unqualified, the reaction time was extended until the central control was qualified.

[0166] 2) Reaction 2: Under a slight nitrogen atmosphere, add the prepared lithium hydroxide aqueous solution (35.8 kg, 6.0X) to reactor R1, control the temperature to 55-65°C, and stir the reaction for 8-16 hours. Cool to 15-25°C, and take a sample for in-process control. If the in-process control is qualified (purity ratio of compound 4 / (compound 4 + compound 5) ≤ 1.0%), proceed to the next step. If the in-process control is unqualified, extend the reaction time until it is qualified.

[0167] 3) Acidification: Under nitrogen protection, control the temperature at 0-25°C and slowly add 35% hydrochloric acid (12 kg, 2.0X) dropwise to the reactor R1.

[0168] 4) Extraction: Add methyl tert-butyl ether (21.5 kg, 3.6X) to the reactor. Adjust the reactor temperature to 15-25°C, stir for 0.5-2 hours, let stand for 0.5-2 hours, separate the layers, and transfer the aqueous phase to a steel-plastic composite barrel.

[0169] 5) Washing: Add the prepared 10% sodium chloride aqueous solution (35.35 kg, 5.9X) to the reactor, adjust the reactor temperature to 15-25°C, stir for 0.5-2 hours, let it stand for 0.5-2 hours, separate the layers, and transfer the aqueous phase to a steel-plastic composite barrel.

[0170] 6) Concentration: Control the internal temperature ≤40°C, concentrate the solution in the reactor under reduced pressure to 12-18 L (2-3X), and add anhydrous ethanol (25.0 kg, 4.2X). Control the internal temperature ≤40°C, concentrate the solution in the reactor under reduced pressure to 12-18 L (2-3X), and add anhydrous ethanol (104.0 kg, 17.3X). Control the internal temperature ≤40°C, concentrate the solution in the reactor under reduced pressure to 12-18 L (2-3X), and add anhydrous ethanol (31.5 kg, 5.3X) to reactor R1.

[0171] 7) Crystallization: Control the reactor temperature at 50-60°C, add process water (78.0 kg, 13.0X) dropwise, and stir at this temperature for 1-3 hours. Cool the reaction mixture to 15-25°C for at least 2 hours, and stir at 15-25°C for 1-3 hours.

[0172] 8) Centrifugation: The contents of the reactor were transferred to a centrifuge and the filter cake was washed with a prepared ethanol / process water solution (26.1 kg, 4.3X) of 1:1 (v / v) to obtain 8.60 kg of a wet product. The wet product passed the test and proceeded to the next step.

[0173] 9) Drying: The wet product was transferred to a vacuum oven and dried under reduced pressure at an internal temperature of 40-50°C for at least 18 hours until the product passed the control (KF: 0.3% ≤ 0.3%, EtOH: 0.1% ≤ 0.2%). If the product failed the control, the drying time was extended until the intermediate control passed. Compound 7 (8.18 kg) was obtained as a white solid with a yield of 85.4%.

[0174] 1H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.50(s,1H),7.42–7.32(m,2H),7.12–7.02(m,2H).

[0175] ESI + ,[M+H] + :366.9746,[M+H] + :368.9719

[0176] HPLC conditions

[0177] Instrument: High performance liquid chromatograph (UV detector) Agilent 1260

[0178] Column: Waters Xbridge C18 / 4.6×150mm, 3.5μm

[0179] Mobile phase: Mobile phase A, 0.05% formic acid in water, Mobile phase B, 0.05% formic acid in acetonitrile

[0180] Flow rate: 1.0ml / min

[0181] Measurement time: 28 minutes

[0182] Analysis temperature: 35°C

[0183] Detection wavelength: 222nm / 248nm

[0184] Retention time: Compound 2: 16.029 min, Compound 3: 10.712 min, Compound 4: 18.792 min, Compound 5: 16.232 min.

[0185] Step 4

[0186] 1) Reaction: Under nitrogen, add DCM (56.5 kg, 6.93X) and intermediate compound 5 (8.15 kg, 1.0X) to a dry reactor and start stirring. Add starting material compound 6 (3.95 kg, 0.48X) and HATU (10.2 kg, 1.25X). Maintain the temperature at 20-30°C and add DIPEA (8.5 kg, 1.05X) dropwise to the reactor. After addition, raise the temperature to 25-35°C and stir for 8-16 hours. Take a sample for in-process control testing. If the in-process control passes (compound 5 / (compound 5 + compound 7) purity ratio ≤1.0%), proceed to the next step. If it fails, extend the reaction time until the in-process control passes.

[0187] 2) Washing 1: Cool to 15-25°C, add DCM (27.0 kg, 3.3X) and a prepared 5% K2CO3 aqueous solution (49.0 kg, 6.0X), control the internal temperature at 15-25°C, stir for 0.5-2 hours, let stand for 0.5-2 hours, separate the layers, separate the aqueous phase, and retain the organic phase.

[0188] 3) Wash 2: Add the prepared 7% NaHCO3 aqueous solution (81.0 kg, 9.9X), control the internal temperature at 15-25°C, stir for 0.5-2 hours, let it stand for 0.5-2 hours, separate the layers, separate the aqueous phase, and retain the organic phase. Add the prepared 7% NaHCO3 aqueous solution (83.0 kg, 10.2X), control the internal temperature at 15-25°C, stir for 0.5-2 hours, let it stand for 0.5-2 hours, separate the layers, separate the aqueous phase, and retain the organic phase.

[0189] 4) Wash 3: Add process water (80.0 kg, 9.8X) to the organic phase and add it to reactor R1, controlling the internal temperature at 15-25°C and stirring for 0.5-2 hours. Let it stand for 0.5-2 hours, separate the layers, remove the aqueous phase, and retain the organic phase. Add process water (80.8 kg, 9.9X) to reactor R1, controlling the internal temperature at 15-25°C and stirring for 0.5-2 hours. Let it stand for 0.5-2 hours, separate the layers, remove the aqueous phase, and retain the organic phase.

[0190] 5) Concentration: Transfer the organic phase to a reactor, control the internal temperature to ≤35°C, and concentrate under reduced pressure to 16-24 L (2.0-3.0X). Add acetonitrile (97.0 kg, 11.9X) to reactor R1, control the internal temperature to ≤40°C, and continue to concentrate the solvent under reduced pressure. Concentrate under reduced pressure to 73-81 L (9.0-10.0X). Add acetonitrile (32.8 kg, 4.0X) to reactor R1, control the internal temperature to ≤40°C, and continue to concentrate the solvent under reduced pressure to 73-81 L (9.0-10.0X). Stop concentration.

[0191] 6) Crystallization: Raise the reaction temperature to 50-60°C, add process water (135.2 kg, 16.6X) dropwise to the reactor. Slowly cool to 40-50°C, stir at 40-50°C for 2-4 hours, then lower the internal temperature to 0-10°C and stir for 6-8 hours.

[0192] 7) Centrifugation: Transfer the contents of the reactor to a centrifuge and add process water (17.5 kg, 2.1X) to rinse the filter cake. Sampling and testing are performed. If qualified (IM-A ≤ 0.15%), proceed to the next step. If unqualified, repeat the crystallization operation.

[0193] 8) Drying: The filter cake was transferred to a vacuum oven and dried under reduced pressure at 35-45°C for 18-24 hours until the moisture content (KF ≤ 5.0%) was acceptable. Compound 7 (9.68 kg) was obtained with a yield of 91.4%. Moisture analysis of compound 7 indicated a molar ratio of 1:1 between compound 7 and water. TGA analysis showed a weight loss of 3.5% between 50°C and 150°C, indicating a molar ratio close to 1:1, calculated based on the molecular weight of water.

[0194] ESI + ,[M+H] + :459.0019,[M+H] + :461.0090

[0195] 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.61(s,1H),8.03(s,1H),8.00(ddd,J= 6.3,1.8,1.0Hz,1H),7.48–7.43(m,2H),7.41–7.34(m,3H),7.20–7.15(m,2H).

[0196] HPLC conditions

[0197] Instrument: High performance liquid chromatograph (UV detector) Agilent 1260

[0198] Column: Waters Xbridge C18 / 4.6×150mm, 3.5μm

[0199] Mobile phase: Mobile phase A, 0.05% formic acid in water, Mobile phase B, 0.05% formic acid in acetonitrile

[0200] Flow rate: 1.0ml / min

[0201] Measurement time: 28 minutes

[0202] Analysis temperature: 35°C

[0203] Detection wavelength: 222nm / 248nm

[0204] Retention time: Compound 5: 16.232 min, Compound 6: 1.729 min, Compound 7: 13.976 min.

[0205] Example 2

[0206] Step 1: Add anhydrous ethanol (464 mL, 8.0 v / w) and compound 1 (58.0 g, 278 mmol) to a reaction flask at room temperature and stir to dissolve. Cool to 30-40°C and add SOCl2 (39.6 g, 333 mmol) dropwise. After addition, heat to 55-60°C and react for 4-8 hours. Sampling and control the reaction until satisfactory. Add 10% potassium phosphate solution dropwise to adjust the pH to 6-8 to precipitate the product. Filter and wash the filter cake with water to obtain a wet product. Dry at 30-40°C to obtain compound 2.

[0207] Steps 2, 3: THF (130 mL, 8.0 v / w) was added to a three-necked flask at room temperature, stirring was started, compound 2 (56.2 g, 237 mmol), compound 3 (48.5 g, 272 mmol), Cs2CO3 (100.4 g, 308 mmol), heated to 55-60 ° C for 20-24 hours, sampling and control, after the control was qualified, water (280 mL) and lithium hydroxide monohydrate (24.9 g, 593 mmol) were added at 55-60 ° C for 2-4 hours, sampling and control, after the control was qualified, the temperature was lowered to 20-30 ° C, concentrated hydrochloric acid (101 ml, 1.8 vol) was added dropwise, MTBE (130 mL) was added after the dropwise addition, and stirred for 10-15 minutes. The layers were separated, and the organic phase was washed with 10% sodium chloride solution (280 mL, 5 vol). The organic phase was concentrated under reduced pressure to 2-3 volumes, anhydrous ethanol (280 mL, 5V) was added, and the concentration was continued to 2-3 volumes. Anhydrous ethanol was added to about 10 volumes. Water (504 mL, 9V) was added dropwise at 20-30°C to precipitate a solid, which was filtered to obtain a wet product, which was then dried at 40-50°C to obtain compound 5.

[0208] Synthesis of Step 4: Add DCM (200 ml) and compound 5 (40.0 g, 109 mmol) to a three-necked flask at room temperature and begin stirring. Add HATU (53.8 g, 144 mmol) and compound 6 (19.1 g, 131 mmol). Add DIPEA (42.2 g, 327 mmol) dropwise at 30-35°C until complete. React at 30-35°C for 16 hours. After sampling and control, cool the system to 25-35°C and add more DCM (100 ml). Wash with 5% aqueous potassium carbonate (240 ml, 6 V). Allow to stand and separate. Wash the organic phase twice with 7% aqueous sodium bicarbonate (400 ml, 10 V) and then twice with water (400 ml, 10 V). The organic phase was concentrated under reduced pressure to a residual volume of 3.0-3.5 V. Acetonitrile (480 ml, 12 V) was added and the solvent was replaced twice, followed by concentrating to a residual volume of 10 V. The system was heated to 50-60°C to dissolve the clear solution. Water (560 ml, 14 V) was added dropwise. After completion of the addition, the mixture was kept at 50-60°C for 1 h. The temperature was then lowered to 0-10°C and stirred for 2 h. The wet product was filtered and dried under reduced pressure at 45-50°C to yield compound 7.

[0209] Example 3

[0210] Concentrated sulfuric acid (5 ml, 5 V) was added to the reaction flask. Compound X-1 (1 g, 1.0 eq) was then added at 20-25°C. DCDMH (0.55 eq) was then added portionwise. The temperature was raised to 50-55°C and the reaction was allowed to proceed overnight. After the reaction was qualified, the reaction mixture was cooled to 20-25°C. The reaction mixture was added dropwise to a 20 V ice-water bath. After the addition was complete, the temperature was returned to 20-25°C and stirred for 2 hours. Filter the mixture, wash the filter cake with water, and obtain the wet product. After purification, the mixture was dried at 50-60°C to obtain Compound 1 in a yield of 50-60%.

[0211] Example 4

[0212] Synthesis of Compound Y-2: Add IPA (30.0 ml, 3 V), water (30.0 ml, 3 V), and Y-1 (10.0 g, 106 mmol) to a reaction flask at room temperature and stir to dissolve. Cool to 0-5°C and dropwise add BOC2O (27.8 g, 127 mmol) in IPA (3.0 V). After complete addition, return to room temperature and react for 2-3 hours. Sampling should pass the control. Concentrate the reaction mixture under reduced pressure at 40-50°C, dissolve in MTBE (100 ml), wash once with water (100.0 ml, 10 V), and separate the layers. Concentrate the organic phase to dryness to obtain product Y-2.

[0213] Synthesis of Compound Y-3: Add Y-2 (10 g, 52 mmol) and DCM (100 ml, 10 V) to a reaction flask at room temperature and stir. Cool to 0-10°C and add solid m-CPBA in portions. Return to room temperature (20-25°C) and react overnight. Samples are taken and tested. Wash the flask once with 10% Na₂SO₃ (20 ml, 2 V) and once again with 10% Na₂SO₃ (20 ml, 2 V). Separate the layers, extract the aqueous phase with ethyl acetate (50 ml, 5 V), concentrate the organic phase, add ethyl acetate (100 ml, 10 V), combine the two ethyl acetate phases, and pass through a silica gel pad to obtain a filtrate. Concentrate the filtrate to dryness and dissolve it in 1,4-dioxane (50 ml, 5 V) to obtain a Y-3 solution.

[0214] Synthesis of Compound 6: Y-3 solution (52 mmol) was added to a reaction flask at room temperature. The temperature was controlled at 10-20°C, and HCl / 1,4-Dioxane solution (520 mmol, 10.0 eq.) was added dropwise. After the addition was complete, the mixture was returned to room temperature and reacted for 3-4 hours. Samples were taken to check if the reaction was qualified. A solid precipitated during the reaction, which was filtered to obtain a filter cake. The filter cake was added to a reaction flask, and acetonitrile (50 ml, 5 V) was added. The mixture was slurried at room temperature for 1-2 hours, filtered to obtain a wet product, and dried at 45-50°C to obtain Compound 6.

[0215] Example 5

[0216] Under nitrogen protection, CH3CN (62.2kg) and compound 5 (13.5kg) were added to the dry reactor R1 and stirring was started. Compound 6 (6.5kg) and TCFH (15.5kg) were added. The temperature was controlled at 0-10℃ and NMI (10.5kg) was added dropwise to the reactor. After the temperature was added, the temperature was raised to 25-35℃ and stirred for 2-4 hours. The sample was taken for central control testing and the next step was performed after the central control was qualified. The temperature was controlled at 25-35℃ and the prepared 3% K3PO4 aqueous solution (138kg) was added dropwise. The internal temperature was controlled at 25-35℃ and stirred for 2-4 hours. The contents of the reactor were transferred to a centrifuge for centrifugation and process water (37.1kg) was added to rinse the filter cake. The above wet product and process water (140kg) were added to the reactor R1 and stirred at 35-45℃ for 2-4 hours. The contents of the reactor were transferred to a centrifuge for centrifugation and process water (211.7kg) was added to rinse the filter cake. The wet product and process water (140 kg) were added to reactor R1 and stirred at 35-45°C for 2-4 hours. The contents of the reactor were transferred to a centrifuge and the filter cake was rinsed with process water (185.4 kg). The filter cake was transferred to a vacuum oven and dried under reduced pressure at 35-45°C for 18-24 hours until the moisture content (KF ≤ 5.0%) was acceptable. Compound 7 (15.7 kg) was obtained with a yield of 85%.

[0217] Comparative Example 1

[0218] Keeping other conditions consistent with those in step 1 of Example 2, only the amount of SOCl2 in step 1 was changed, the results are shown in Table 2 below.

[0219] Table 2

[0220] Comparative Example 2

[0221] Keeping other conditions consistent with those in step 1 of Example 2, only the volume of ethanol in step 1 was changed, the results are shown in Table 3 below.

[0222] Table 3

[0223] Comparative Example 3

[0224] Keeping other conditions consistent with those in step 1 of Example 2, only the post-processing operation in step 1 was changed, the results are shown in Table 4 below.

[0225] Table 4

[0226] Comparative Example 4

[0227] Keeping other conditions consistent with those in step 2 of Example 2, only the choice of base in step 2 was changed, the results are shown in Table 5 below.

[0228] Table 5

[0229] Comparative Example 5

[0230] Keeping other conditions consistent with those in step 2 of Example 2, only the choice of solvent in step 2 was changed, the results are shown in Table 6 below.

[0231] Table 6

[0232] Comparative Example 6

[0233] Keeping other conditions consistent with those in step 2 of Example 2, only the selection of cesium carbonate in step 2 was changed, the results are shown in Table 7 below.

[0234] Table 7

[0235] Comparative Example 7

[0236] Keeping other conditions consistent with those in step 2 of Example 2, only the amount of compound 3 in step 2 was changed, the results are shown in Table 7 below.

[0237] Table 8

[0238] Comparative Example 8

[0239] Keeping other conditions consistent with those in step 4 of Example 2, only the type of condensing agent in step 4 was changed, the results are shown in Table 9 below.

[0240] Table 9

[0241] Comparative Example 9

[0242] Keeping other conditions consistent with those in step 4 of Example 2, only the type of solvent in step 4 was changed, the results are shown in Table 10 below.

[0243] Table 10

[0244] Comparative Example 10

[0245] The other conditions were kept consistent with those in step 4 of Example 2, and only the amount of HATU in step 4 was changed. The results are shown in Table 11 below.

[0246] Table 11

[0247] Comparative Example 11

[0248] Keeping other conditions consistent with those in step 4 of Example 2, only the amount of DIPEA in step 4 was changed. The results are shown in Table 12 below.

[0249] Table 12

[0250] Comparative Example 12

[0251] Keeping other conditions consistent with those in step 4 of Example 2, only the post-treatment conditions in step 4 were changed, and the results are shown in Table 13 below.

[0252] Table 13

[0253] Comparative Example 13

[0254] The reaction conditions in Example 3 were screened, and the results are shown in Table 14 below.

[0255] Table 14

[0256] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0257] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt or hydrate thereof, characterized in that: The method comprises contacting a compound represented by formula (I-5) or a pharmaceutically acceptable salt thereof with a compound represented by formula (I-6) or a pharmaceutically acceptable salt thereof to obtain a compound represented by formula (I) or a pharmaceutically acceptable salt or hydrate thereof. T1 is selected from N or C(R7); T2 is selected from N or C(R8); T3 is selected from N or C(R9); T4 is selected from N or C(R 10 ); R1, R2, R8, R9 are independently selected from H, halogen, OH, NH2, CN, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, vinyl-C 1-6 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-C 1-6 Alkyl-O-, phenyl-C 1-3 Alkyl-, C 3-6 Cycloalkyl-C 1-3 Alkyl-O-, 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl-O-, phenyl-C 1- 3-alkyl-O-, phenyl-C 1-3 Alkyl-NH-, 5- to 6-membered heteroaryl-C 1-3 Alkyl-, 5- to 6-membered heteroaryl-C 1-3 Alkyl-O- and 5- to 6-membered heteroaryl-C 1-3 Alkyl-NH-, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, vinyl-C 1-6 Alkyl-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3- 6-cycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-C 1-6 Alkyl-O-, phenyl-C 1-3 Alkyl-, C 3-6 Cycloalkyl-C 1-3 Alkyl-O-, 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-O-, phenyl-C 1-3 Alkyl-NH-, 5- to 6-membered heteroaryl-C 1-3 Alkyl-, 5- to 6-membered heteroaryl-C 1-3 Alkyl-O- or 5- to 6-membered heteroaryl-C 1-3 Alkyl-NH- is optionally substituted with 1, 2 or 3 R; R3, R4, R5, R6, R 10 are independently selected from H, halogen, OH, NH2, SF5, CN, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl- and 3- to 6-membered heterocycloalkyl-C 1-6 Alkyl-, the C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl- or 3- to 6-membered heterocycloalkyl-C 1-6 Alkyl - optionally substituted with 1, 2 or 3 R; R7 is selected from H, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino is optionally substituted with 1, 2 or 3 R; L2 is selected from O, S, NH and CH2, wherein CH2 is optionally substituted with 1 or 2 R, and NH is optionally substituted with R; R 13a 、R 13b are independently selected from H, halogen and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R groups; R is independently selected from H, D, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino is optionally substituted with 1, 2 or 3 R'; R' is selected from F, Cl, Br, I, OH, NH2 and CH3; The above 3- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

2. The method according to claim 1, characterized in that The compound represented by formula (I) is selected from Optionally, the compound represented by formula (I) is selected from Optionally, the compound represented by formula (I) is selected from Optionally, the compound represented by formula (I-5) is selected from Optionally, the compound represented by formula (I-5) is selected from Optionally, the compound represented by formula (I-6) is selected from Optionally, the compound represented by formula (I-6) is selected from 3. The method according to claim 1, characterized in that The contacting is carried out in the presence of a condensing agent; Optionally, the condensing agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole and N,N'-carbonyldiimidazole, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate or N-methylimidazole; Optionally, the condensing agent is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; Optionally, the condensing agent is N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole; Optionally, the molar ratio of the compound represented by formula (I-5) to the 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is 1:(1.0-2.0), optionally 1:(1.2-1.5); Optionally, the molar ratio of the compound represented by formula (I-5) to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1:(1.0-2.0), optionally 1:(1.1-1.2); Optionally, the molar ratio of the N-methylimidazole to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1:(1.2-2.0), optionally 1:(1.4-1.6); Optionally, the contacting is performed under alkaline conditions; Optionally, the basic conditions are provided by N,N-diisopropylethylamine; Optionally, the molar ratio of the compound represented by formula (I-5) to the N,N-diisopropylethylamine is 1:(1.0-5.0), optionally 1:(2.5-3.0); Optionally, the contacting is carried out in a solvent of N,N-dimethylformamide, acetonitrile or dichloromethane; Optionally, the contacting is carried out in the presence of N,N-dimethylformamide as the solvent.

4. The method according to claim 2, characterized in that The compound represented by formula (I-5-A) is obtained by a substitution reaction between the compound represented by formula (I-2) and the compound represented by formula (I-3). Among them, Rx is selected from C 1-6 alkyl; Optionally, the compound represented by formula (I-2) or its optical isomer is selected from Optionally, the compound represented by formula (I-3) or its optical isomer is selected from Optionally, the substitution reaction is carried out in the presence of a base; Optionally, the base is selected from Cs2CO3, K2CO3 and K3PO4; Optionally, the base is Cs2CO3; Optionally, the molar ratio of the compound represented by formula (I-2) to the Cs2CO3 is 1:(1.3-1.5); Optionally, the substitution reaction is carried out in a solvent of N,N-dimethylformamide or tetrahydrofuran; Optionally, the molar ratio of the compound represented by formula (I-2) to the compound represented by formula (I-3) is 1:(1.10-1.25), optionally 1:1.

15.

5. The method according to claim 4, characterized in that The compound represented by formula (I-2) is obtained by esterification reaction of the compound represented by formula (I-1). Optionally, the compound represented by formula (I-1) or its optical isomers are selected from Optionally, the esterification reaction is carried out in the presence of SOCl2; Optionally, the molar ratio of the compound represented by formula (I-1) to the SOCl2 is 1:(1.0-2.0), optionally 1:(1.2-1.5); Optionally, the esterification reaction is carried out under the condition that the solvent is ethanol; Optionally, the ratio of the compound represented by formula (I-1) to the ethanol is 1:(1672-2090); Optionally, the esterification reaction further comprises post-treatment; Optionally, the post-treatment is performed by adding aqueous sodium bicarbonate solution.

6. An intermediate compound or a pharmaceutically acceptable salt thereof, characterized in that: The structure is shown in compound 5.

7. Use of the compound represented by Compound 5 or a pharmaceutically acceptable salt thereof in the preparation of the compound represented by Compound 7X or an optical isomer thereof.

8. A method for preparing compound 1, characterized in that The method comprises subjecting the compound represented by formula (X-1) to a chlorination reaction to obtain compound 1, wherein the chlorination reaction is carried out in a solvent selected from one or more of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid or ethanesulfonic acid.

9. The method according to claim 8, characterized in that The chlorination reaction is carried out under the condition of a chlorination reagent; Optionally, the chlorination agent is selected from dichlorodimethylhydantoin and N-chlorosuccinimide; Optionally, the molar ratio of the compound represented by formula (X-1) to dichlorodimethylhydantoin is 1:(0.5-0.7); Optionally, the molar ratio of the compound represented by formula (X-1) to N-chlorosuccinimide is 1:(1.1-1.6); Optionally, the chlorination reaction is carried out at a temperature of 55 to 60°C.

10. A method for preparing compound 6, characterized in that: The method comprises subjecting the compound represented by formula (Y-2) to oxidation reaction and deprotection reaction to obtain compound 6, 11. The method according to claim 10, characterized in that The compound represented by formula (Y-2) is obtained by subjecting the compound represented by formula (Y-1) to an acylation reaction.

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