Process for preparing pyridine-N-oxide compounds

Abstract

The present invention discloses a method for preparing a pyridine-N-oxide compound. Specifically, the present invention discloses a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt or hydrate thereof. The feature is that a compound represented by formula (I-5) or a pharmaceutically acceptable salt thereof is contacted 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. This method is simple in operation, high in yield, and suitable for industrial large-scale production. TIFF2025518207000084.tif49117

Description

Technical Field

[0001] This application claims the following priorities. 1) CN202210629774.5, June 2, 2022, 2) CN202310570708.X, May 19, 2023.

[0002] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a method for preparing a pyridine-N-oxide compound and its crystal form.

Background Art

[0003] Pain is one of the most common symptoms clinically and is the fifth vital sign following respiration, pulse, blood pressure, and body temperature, significantly affecting the quality of patients' lives. According to statistics, the global analgesic market in 2018 was approximately $36 billion, but it is expected to reach $56 billion in 2023. Among them, for acute moderate to severe pain, it mainly relies on opioid drugs, accounting for around two-thirds of the analgesic market share and will steadily increase in the future at a compound growth rate of 2.5% per year. However, the number of patients with chronic pain mainly including neuropathic pain and arthritis pain is increasing year by year, and the market is expected to show a compound growth rate of around 18% per year, which is the main driving force for the sustainable growth of the global pain market in the next decade.

[0004] Recent research findings have gradually revealed that sodium ion channel subtype 1.8 (NaV1.8) plays an important role in the generation and transmission of pain. NaV1.8 is a voltage-dependent sodium ion channel that is mainly expressed in afferent neurons including sensory neurons, and by controlling the entry and exit of sodium ions into and out of cells, it plays an important role in maintaining the excitability of nociceptive sensory neurons, releasing and sustaining action potentials, and regulating pain sensitivity. Patients with activating mutations in NaV1.8 exhibit episodic pain due to small fiber neuropathy (damage to Aδ fibers and unmyelinated C fibers mainly responsible for pain transmission). Diseases such as chronic inflammation and diabetes can cause an increase in the expression or a change in the properties of NaV1.8, thereby activating or damaging nociceptive sensory neurons and causing various types of pain. NaV1.8 knockout mice are insensitive to pain.

[0005] In Patent Document 1 (publication date: March 12, 2021), a novel NaV1.8 inhibitor is disclosed, and its general formula is TIFF2025518207000002.tif4552, and at the same time, the compound TIFF2025518207000003.tif4236 is also disclosed.

[0006] In the patent application documents of Patent Document 2 (filing date: March 11, 2022), crystalline forms A and B of compound 7X are disclosed.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Summary of the Invention

[0008] The inventors have found that the synthesis route of compound 7X in Patent Document 1 is as follows. [Chemical formula]

[0009] Among them, the second step in the whole route has a low yield, and in the third step, m-CPBA is used as an oxidant, so there are many impurities, which is not suitable for quality control with the final compound as a raw drug and is not suitable for industrial mass production.

[0010] Based on this, the inventors have developed a new synthesis method, which has a higher yield, lower cost, simpler operation, higher product purity, meets the quality standards of raw drugs, and is suitable for industrial mass production than the methods in the prior art.

[0011] In the first aspect of the present invention, a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt or hydrate thereof is presented. According to an embodiment of the present invention, the above method includes 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 to obtain a compound represented by formula (I) or a pharmaceutically acceptable salt or hydrate thereof. [Chemical formula] T 1 is selected from N or C(R 7 ), T 2 is selected from N or C(R 8 ), T 3 is selected from N or C(R 9 ), T 4 is selected from N or C(R 10 ), R 1 、R 2 、R 8 、R 9 are each independently H, halogen, OH, NH 2 、CN、SF 5 、C 1-6 alkyl group, C1-6 An alkoxy group, C 1-6 An alkylamino group, vinyl group-C 1-6 An alkyl group-, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, C 3-6 A cycloalkyl group-C 1-6 An alkyl group-, a 3- to 6-membered heterocycloalkyl group-C 1-6 An alkyl group-, a 3- to 6-membered heterocycloalkyl group-C 1-6 An alkyl group-O-, a phenyl group-C 1-3 An alkyl group-, C 3-6 A cycloalkyl group-C 1-3 An alkyl group-O-, a 3- to 6-membered heterocycloalkyl group-C 1-3 An alkyl group-O-, a phenyl group-C 1-3 An alkyl group-O-, a phenyl group-C 1-3 An alkyl group-NH-, a 5- to 6-membered heteroaryl group-C 1-3 An alkyl group-, a 5- to 6-membered heteroaryl group-C 1-3 An alkyl group-O- and a 5- to 6-membered heteroaryl group-C 1-3 Selected from an alkyl group-NH-, and said C 1-6 An alkyl group, C 1-6 An alkoxy group, C 1-6 An alkylamino group, vinyl group-C 1-6 An alkyl group-, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, C 3-6 A cycloalkyl group-C 1-6 An alkyl group-, a 3- to 6-membered heterocycloalkyl group-C 1-6 An alkyl group-, a 3- to 6-membered heterocycloalkyl group-C 1-6 An alkyl group-O-, a phenyl group-C 1-3 An alkyl group-, C 3-6 A cycloalkyl group-C 1-3 An alkyl group-O-, a 3- to 6-membered heterocycloalkyl group-C 1-3 An alkyl group-O-, a phenyl group-C 1-3 An alkyl group-O-, a phenyl group-C 1-3 An alkyl group-NH-, a 5- to 6-membered heteroaryl group-C 1-3 An alkyl group-, a 5- to 6-membered heteroaryl group-C 1-3Alkyl group -O- or 5- to 6-membered heteroaryl group -C 1-3 The alkyl group -NH- is optionally substituted with 1, 2 or 3 R's, R 3 、R 4 、R 5 、R 6 、R 10 each independently is H, halogen, OH, NH 2 、SF 5 、CN, C 1-6 alkyl group, C 1-6 alkylamino group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 cycloalkyl group -C 1-6 alkyl group - and 3- to 6-membered heterocycloalkyl group -C 1-6 alkyl group - and are selected from, said C 1-6 alkyl group, C 1-6 alkylamino group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 cycloalkyl group -C 1-6 alkyl group - or 3- to 6-membered heterocycloalkyl group -C 1-6 The alkyl group - is optionally substituted with 1, 2 or 3 R's, R 7 is H, F, Cl, Br, I, C 1-6 alkyl group, C 1-6 alkoxy group and C 1-6 alkylamino and is selected from, said C 1-6 alkyl group, C 1-6 alkoxy group or C 1-6 alkylamino group is optionally substituted with 1, 2 or 3 R's, L 2 is selected from O, S, NH and CH 2 wherein said CH 2 is optionally substituted with 1 or 2 R's, NH is optionally substituted with R, R 13a and R 13b are each independently selected from H, halogen, and C 1-6 alkyl group, and the C 1-6 alkyl group is optionally substituted with 1, 2, or 3 R's, R's are each independently selected from H, D, halogen, OH, NH 2 , CN, TIFF2025518207000006.tif2022C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, and C 1-6 alkylamino group, and the C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, or C 1-6 alkylamino group is optionally substituted with 1, 2, or 3 R's, R's are selected from F, Cl, Br, I, OH, NH 2 , and CH 3 , The above 3- to 6-membered heterocycloalkyl group or 5- to 6-membered heteroaryl group contains 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 -, and N.

[0012] In some forms of the present invention, the above R's are selected from H, D, F, Cl, Br, I, OH, NH 2 , TIFF2025518207000007.tif2022Me, CF 3 , CHF 2 , CH 2 F, TIFF2025518207000008.tif1658, and the other variables are as defined in the present invention.

[0013] In some forms of the present invention, the above R 1 , R 2 , R 8 , R9 is, independently of each other, H, halogen, OH, NH 2 , CN, SF 5 , C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, vinyl group - C 1-3 alkyl group -, C 3-6 cycloalkyl group, 3 - to 6 - membered heterocycloalkyl group, C 3-6 cycloalkyl group - C 1-3 alkyl group -, 3 - to 6 - membered heterocycloalkyl group - C 1-3 alkyl group -, 3 - to 6 - membered heterocycloalkyl group - C 1-3 alkyl group - O -, phenyl group - C 1-3 alkyl group -, phenyl group - C 1-3 alkyl group - O -, phenyl group - C 1-3 alkyl group - NH -, pyridyl group - C 1-3 alkyl group -, pyrimidinyl group - C 1-3 alkyl group -, thiophene group - C 1-3 alkyl group -, thiazolyl group - C 1-3 alkyl group -, pyridyl group - C 1-3 - alkyl group -, imidazolyl group - C 1-3 alkyl group -, pyridyl group - C 1-3 alkyl group - O -, pyrimidinyl group - C 1-3 alkyl group - O -, thiophene group - C 1-3 alkyl group - O -, thiazolyl group - C 1-3 alkyl group - O -, pyrazolyl group - C 1-3 alkyl group - O -, imidazolyl group - C 1-3 alkyl group - O -, pyridyl group - C 1-3 alkyl group - NH -, pyrimidinyl group - C 1-3 alkyl group - NH -, thiophene group - C 1-3 alkyl group - NH -, thiazolyl group - C 1-3 alkyl group - NH -, pyrazolyl group - C 1-3 alkyl group - NH - and imidazolyl group - C 1-3 selected from alkyl group - NH -, and the C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3Alkylamino group, vinyl group-C 1-3 Alkyl group-, C 3-6 Cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 Cycloalkyl group-C 1-3 Alkyl group-, 3- to 6-membered heterocycloalkyl group-C 1-3 Alkyl group-, 3- to 6-membered heterocycloalkyl group-C 1-3 Alkyl group-O-, phenyl group-C 1-3 Alkyl group-, phenyl group-C 1-3 Alkyl group-O-, phenyl group-C 1-3 Alkyl group-NH-, pyridyl group-C 1-3 Alkyl group-, pyrimidinyl group-C 1-3 Alkyl group-, thiophene group-C 1-3 Alkyl group-, thiazolyl group-C 1-3 Alkyl group-, pyrazolyl group-C 1-3 Alkyl group-, imidazolyl group-C 1-3 Alkyl group-, pyridyl group-C 1-3 Alkyl group-O-, pyrimidinyl group-C 1-3 Alkyl group-O-, thiophene group-C 1-3 Alkyl group-O-, thiazolyl group-C 1-3 Alkyl group-O-, pyrazolyl group-C 1-3 Alkyl group-O-, imidazolyl group-C 1-3 Alkyl group-O-, pyridyl group-C 1-3 Alkyl group-NH-, pyrimidinyl group-C 1-3 Alkyl group-NH-, thiophene group-C 1-3 Alkyl group-NH-, thiazolyl group-C 1-3 Alkyl group-NH-, pyrazolyl group-C 1-3 Alkyl group-NH- or imidazolyl group-C 1-3 The alkyl group-NH- is optionally substituted with 1, 2 or 3 R's, and the other variables are as defined in the present invention.

[0014] In some embodiments of the present invention, the above R 1 , R 2 , R 8 , R 9are each independently H, F, Cl, Br, I, OH, NH 2 , CN, SF 5 , Me, CF 3 , CHF 2 , CH 2 F, CF 3 CF 2 , OCF 3 , HOCH 2 CH 2 O, CH 3 NHCH 2 CH 2 , (CH 3 ) 2 NCH 2 CH 2 O selected from TIFF2025518207000009.tif36164, and the other variables are as defined in the present invention.

[0015] In some forms of the present invention, the above structural unit

Chemical formula

Chemical formula

[0016] In some forms of the present invention, the above R 3 , R 4 , R 5 , R 6 , R 10 are each independently H, halogen, OH, NH 2 , SF 5 , CN, C 1-3 alkyl group, C 1-3 alkylamino group, C 1-3 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 3-6 cycloalkyl group-C 1-3An alkyl group- and a 3- to 6-membered heterocycloalkyl group C 1-3 Selected from an alkyl group-, said C 1-3 Alkyl group, C 1-3 Alkylamino group, C 1-3 Alkoxy group, C 3-6 Cycloalkyl group, -O-C 3-6 Cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 Cycloalkyl group-C 1-3 An alkyl group- or a 3- to 6-membered heterocycloalkyl group-C 1-3 The alkyl group- is optionally substituted with 1, 2 or 3 R's, and the other variables are as defined in the present invention.

[0017] In some forms of the present invention, the above R 3 , R 4 , R 5 , R 6 , R 10 are each independently H, F, Cl, Br, I, OH, NH 2 , SF 5 , Me, CF 3 , CHF 2 , CH 2 F, CN, CH(F 2 )CH 3 , CD 3 , OCD 3 , Selected from TIFF2025518207000013.tif27164, and the other variables are as defined in the present invention.

[0018] In some forms of the present invention, the above structural unit

Chemical formula

Chemical formula

[0019] In some forms of the present invention, the above R 13a , R13b is independently selected from H, F, Cl, Br, I and Me, and the other variables are as defined in the present invention.

[0020] In some forms of the present invention, the compound represented by the above formula (I) or its optical isomer is

Chemical formula

[0021] In some forms of the present invention, the compound represented by the above formula (I) is

Chemical formula

[0022] In some forms of the present invention, the compound represented by the above formula (I) is

Chemical formula

[0023] In some forms of the present invention, the compound represented by the above formula (I) is

Chemical formula

[0024] In some forms of the present invention, the compound represented by the above formula (I-5) is

Chemical formula

[0025] In some forms of the present invention, the compound represented by the above formula (I-5) is [Chemical formula] selected from, and other variables are as defined in the present invention.

[0026] In some forms of the present invention, the compound represented by the above formula (I-6) is [Chemical formula] selected from, and other variables are as defined in the present invention.

[0027] In some forms of the present invention, the compound represented by the above formula (I-6) is [Chemical formula] selected from, and other variables are as defined in the present invention.

[0028] In some forms of the present invention, the above contact is carried out under the conditions of a condensing agent, and other variables are as defined in the present invention.

[0029] In some forms of the present invention, the above condensing agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate ester, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole, and N,N'-carbonyldiimidazolyl, and other variables are as defined in the present invention. The inventors have discovered that the condensation effect is good under the conditions of these condensing agents.

[0030] In some embodiments of the present invention, the condensing agent is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate ester, and the other variables are as defined in the present invention. The inventors have found that under the conditions of these condensing agents, the condensation effect is even better.

[0031] In some embodiments of the present invention, the condensing agent is one of chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate or N-methylimidazolyl, and the other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, the condensing agent is a mixture of chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate and N-methylimidazolyl, and the other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-5) to the 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate ester is 1:(1.0 - 2.0), and the other variables are as defined in the present invention. The inventors have found that the condensation effect is good at these ratios.

[0034] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-5) to the 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate ester is 1:(1.2 - 1.5), and the other variables are as defined in the present invention. The inventors have found that the condensation effect is even better at these ratios.

[0035] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-5) to the chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate is 1:(1.0 - 2.0), and the other variables are as defined in the present invention.

[0036] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-5) to the chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate is 1:(1.1 to 1.2), and the other variables are as defined in the present invention.

[0037] In some embodiments of the present invention, the molar ratio of the N-methylimidazolyl to the chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate is 1:(1.2 to 2.0), and the other variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the molar ratio of the above N-methylimidazolyl to the chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate is 1:(1.4 to 1.6), and the other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the above contact is carried out under alkaline conditions, and the other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above alkaline conditions are provided by N,N-diisopropylethylamine, and the other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-5) to the N,N-diisopropylethylamine is 1:(1.0 to 5.0), and the other variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-5) to the N,N-diisopropylethylamine is 1:(2.5 to 3.0), and the other variables are as defined in the present invention.

[0043] In some embodiments of the present invention, the above contact is carried out under the conditions of the solvent N,N-dimethylformamide, acetonitrile or dichloromethane, and the other variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above contact is carried out under the condition that the solvent is N,N-dimethylformamide, and the other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the compound represented by the above formula (I-5-A) is obtained by carrying out a substitution reaction between the compound represented by formula (I-2) and the compound represented by formula (I-3)

Chemical formula

[0046] In some embodiments of the present invention, the compound represented by the above formula (I-2) or its optical isomer is

Chemical formula

[0047] In some embodiments of the present invention, the compound represented by the above formula (I-3) or its optical isomer is

Chemical formula

[0048] In some embodiments of the present invention, the above substitution reaction is carried out in the presence of an alkali, and the other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, the above alkali is Cs 2 CO 3 、K 2 CO3 and K 3 PO 4 selected from, and other variables are as defined in the present invention. The inventors have discovered that when the above alkali is employed, the yield is high.

[0050] In some forms of the present invention, the above alkali is Cs 2 CO 3 and other variables are as defined in the present invention. The inventors have discovered that when Cs 2 CO 3 is employed, the yield is even higher.

[0051] In some forms of the present invention, the molar ratio of the compound represented by the above formula (I-2) to the Cs 2 CO 3 is 1:(1.3 - 1.5), and other variables are as defined in the present invention.

[0052] In some forms of the present invention, the above substitution reaction is carried out under the condition that the solvent is N,N-dimethylformamide or tetrahydrofuran, and other variables are as defined in the present invention.

[0053] In some forms of the present invention, the molar ratio of the compound represented by the above formula (I-2) to the compound represented by the above formula (I-3) is 1:(1.10 - 1.25), and other variables are as defined in the present invention.

[0054] In some forms of the present invention, the molar ratio of the compound represented by the above formula (I-2) to the compound represented by the above formula (I-3) is 1:1.15, and other variables are as defined in the present invention.

[0055] In some forms of the present invention, the compound represented by the above formula (I-2) is obtained by carrying out an esterification reaction on the compound represented by formula (I-1)

Chemical formula

[0056] In some embodiments of the present invention, the compound represented by the above formula (I-1) or its optical isomer is

Chemical formula

[0057] In some embodiments of the present invention, the above esterification reaction is carried out under the condition that SOCl 2 is present, and the other variables are as defined in the present invention.

[0058] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-1) to the SOCl 2 is 1:(1.0 - 2.0), and the other variables are as defined in the present invention.

[0059] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (I-1) to the SOCl 2 is 1:(1.2 - 1.5), and the other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, the above esterification reaction is carried out under the condition that the solvent is ethanol, and the other variables are as defined in the present invention.

[0061] 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 here the ratio refers to the molar volume ratio (mol:mL), and the other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, the above esterification reaction further includes post-treatment, and the other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, the post-treatment is carried out by adding an aqueous solution of sodium hydrogen carbonate, and the other variables are as defined in the present invention.

[0064] In another aspect of the present invention, the present invention further provides an intermediate compound or a pharmaceutically acceptable salt thereof. According to the examples of the present invention, the structure of the intermediate compound is Compound 5

Chemical formula

[0065] In another aspect of the present invention, the present invention further provides the use of the compound shown in Compound 5 or a pharmaceutically acceptable salt thereof in the preparation of the compound shown in Compound 7X or an optical isomer thereof.

[0066] In another aspect of the present invention, the present invention further

Chemical formula

[0067] In another aspect of the present invention, the present invention further

Chemical formula

[0068] In another aspect of the present invention, the present invention further

Chemical formula

[0069] In another aspect of the present invention, the present invention presents a method for preparing Compound 1. According to an embodiment of the present invention, the method includes subjecting the compound represented by formula (X-1) to a chlorination reaction to obtain Compound 1, and the chlorination reaction is carried out under the condition that the solvent is one or more of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid or ethanesulfonic acid.

Chemical formula

[0070] In another aspect of the present invention, the present invention presents a method for preparing Compound 1. According to an embodiment of the present invention, the method includes subjecting the compound represented by formula (X-1) to a chlorination reaction to obtain Compound 1, and the chlorination reaction is carried out under the condition that the solvent is concentrated sulfuric acid.

Chemical formula

[0071] The inventors have found that the conventional method for preparing Compound 1 in the prior art uses a Friedel-Crafts alkylation reaction, in which highly toxic carbon tetrachloride is used, and the reaction and post-treatment processes are relatively complex and the yield is low. However, the method of the present invention is easy to operate, does not use highly toxic reagents, and has a high yield. Moreover, the inventors have found 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.

[0072] In some forms of the present invention, the above chlorination reaction is carried out under the condition of a chlorination reagent, and other variables are as defined in the present invention.

[0073] In some forms of the present invention, the above chlorination reagent is selected from dichlorodimethylhydantoin and N-chlorosuccinimide, and other variables are as defined in the present invention.

[0074] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (X-1) to dichlorodimethylhydantoin is 1:(0.5 - 0.7), and the other variables are as defined in the present invention. The inventors have found that at the above ratio, the yield of the chlorination reaction is relatively high.

[0075] In some embodiments of the present invention, the molar ratio of the compound represented by the above formula (X-1) to N-chlorosuccinimide is 1:(1.1 - 1.6), and the other variables are as defined in the present invention. The inventors have found that at the above ratio, the yield of the chlorination reaction is higher.

[0076] In some embodiments of the present invention, the above chlorination reaction is carried out under the condition that the temperature is 55 - 60°C, and the other variables are as defined in the present invention. The inventors have found that within this temperature range, the yield is higher.

[0077] In another aspect of the present invention, the present invention further presents a method for preparing Compound 6. According to the examples of the present invention, the method includes performing an oxidation reaction and a deprotection reaction on the compound represented by the formula (Y-2) to obtain Compound 6.

Chemical formula

[0078] The inventors have found that the conventional method for preparing Compound 6 uses nicotinic acid N-oxide as a starting material, forms a -Boc protected amino group with DPPA and t-butanol, and obtains the target product by de-Boc protection. In this method, DPPA, which has a relatively high cost, is used, and there are too many impurities generated during the reaction process. Or the compound represented by the formula (Y-2) is directly used with MCPBA to directly oxidize pyridine, but it has been found that this method is very likely to generate a polymerization product of a two-molecule product and has a low yield. The method presented in the present invention is easy to operate, has inexpensive raw materials, is easy to post-treat, and is suitable for large-scale industrial production.

[0079] In some embodiments of the present invention, the compound represented by the above formula (Y-2) is obtained by acylating the compound represented by the formula (Y-1), TIFF2025518207000040.tif2221 and the other variables are as defined in the present invention. Definitions and Explanations

[0080] Unless otherwise explained, the following terms and phrases used in the text have the following meanings. If a particular term or phrase does not have a specific definition, it should not be considered uncertain or unclear, but should be understood in its general meaning. When a trade name appears in the text, it means referring to the corresponding product or its active ingredient.

[0081] The term "contact" should be understood in a broad sense and can be any means by which at least two reactants can undergo a chemical reaction, for example, mixing the two reactants under appropriate conditions. Based on the requirements, the reactants that need to be contacted can be mixed under stirring, where the type of stirring is not particularly limited and can be, for example, mechanical stirring, i.e., stirring by the action of mechanical force.

[0082] 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, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, and all these mixtures are within the scope of the present invention. Substituents such as alkyl groups may contain another asymmetric carbon. All these isomers and their mixtures are included within the scope of the present invention.

[0083] Certain compounds of the present invention may exist. Unless otherwise stated, the terms "tautomer" or "tautomeric form" refer to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (e.g., in solution), the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversions carried out by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions carried out by recombination of some bonding electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxy-3-penten-2-one.

[0084] The compounds of the present invention contain atoms of unnatural abundance on one or more atoms constituting the compound. For example, tritium ( 3 H), iodine-125 ([[]] 125 I) or C-14 ([[]] 14 C), etc. can be labeled using radioactive isotopes. Also, for example, hydrogen can be replaced with deuterium to form a deuterated drug, and the bond composed of deuterium and carbon is stronger than the bond composed of ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has the advantages of reduced toxic side effects, increased drug stability, enhanced therapeutic effect, and extended biological half-life of the drug. All conversions of the isotope composition of the compounds of the present invention, whether radioactive or not, are all included within the scope of the present invention. "Optionally" or "optionally" means that the events or situations described below may occur, but do not necessarily have to occur, and the description includes the situations where the events or situations described therein occur and the situations where the events or situations do not occur.

[0085] If any variable (e.g., R) appears one or more times in the composition or structure of a compound, the definitions in each situation are all independent. Thus, for example, when one group is substituted with 0 to 2 Rs, said group can optionally be substituted with up to 2 Rs, and each R in each situation has independent options. Also, combinations of substituents and / or their variants are only permitted in situations where such combinations produce stable compounds. For example, It can be selected from TIFF2025518207000041.tif17131, etc.

[0086] "Room temperature" in the present invention refers to a temperature ranging from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature ranging from about 20°C to about 30°C, and in some other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0087] "Under room temperature or heating conditions" in the present invention refers to the reaction being carried out at a certain temperature, and said certain temperature is any specific temperature reached by room temperature or heating. For example, when it is stated that the reaction for preparing the compound of formula (III) with the compound of formula (IV) described in the present invention is carried out under room temperature or heating conditions, it indicates that the reaction is carried out under certain temperature conditions, and said certain temperature is any specific temperature reached by room temperature or heating. For example, when the reaction is carried out at room temperature (e.g., 20°C to 30°C) or under heating to 30°C to 65°C, the reaction is carried out at 20°C to 65°C.

[0088] In the context of the present invention, all numbers disclosed herein are approximate values. Each number may vary by, for example, 1%, 2%, 5%, 7%, 8% or 10%. Whenever one number with an N value is disclosed, all numbers with values of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% are explicitly disclosed, where "+ / -" refers to addition or subtraction. Whenever one lower limit, DL, and one upper limit, DU, within a numerical range are disclosed, any numerical value within the disclosed range is explicitly disclosed.

[0089] In all of the above reaction steps of the present invention, after the reaction has proceeded to a certain degree where the consumption of the raw material generally exceeds 70%, 80%, 90%, 95%, or it is detected that the reaction raw material has been completely consumed, post-treatment is carried out by cooling, collecting, extracting, filtering, separating, purifying, or a combination thereof. The degree of the reaction can be detected by conventional methods, such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), etc. Conventional methods, such as collecting the crude product after evaporation under reduced pressure or normal distillation of the reaction solution and directly introducing it into the next reaction, or directly filtering the obtained crude product and directly introducing it into the next reaction, are adopted to perform post-treatment on the reaction solution. Or, after standing, pour off the supernatant to obtain the crude product and directly introduce it into the next reaction, or appropriate organic solvents or a combination thereof can be selected to perform purification steps such as extraction, distillation, crystallization, column chromatography, washing, and pulverization.

[0090] Regardless of whether the numerical values of the present invention are modified by the term "substantially", it should be understood that the numerical values are modified using "substantially", and the term "substantially" is used to modify numerical values with a plus or minus 10% difference. In some embodiments, "substantially" is used to modify numerical values with a plus or minus 5% difference. In some embodiments, "substantially" is used to modify numerical values with a plus or minus 3% or 2% or 1% difference. The error range of the numerical value modified by "substantially" is determined by the actual or reasonable error range of the modified numerical value.

[0091] In the reaction process of each step of the present invention, the reaction raw materials or other reagents can be added to the reaction system by a dropping method. Each of the above dropping processes and the reactions of each step are all carried out under certain temperature conditions, and any temperature applied to each dropping process or each reaction process is included in the present invention. Also, many similar modifications, equivalent substitutions, or temperatures and temperature ranges equivalent to those described in the present invention in this field are all regarded as being within the scope included in the present invention. In the present invention, the preferred temperature or temperature range for each dropping process and the preferred reaction temperature for each reaction are presented.

[0092] There are no special restrictions on the solvents used in each reaction step of the present invention. As long as the solvents can dissolve the starting materials to a certain extent and do not inhibit the reaction, they are all included in the present invention. Also, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different ratios of solvent combinations equivalent to those described in the present invention in this field are all regarded as being within the scope encompassed by the present invention. In the present invention, the preferred solvents used in each reaction step are presented.

[0093] The products of each reaction step of the present invention can be purified by recrystallization under appropriate conditions. There are no particular restrictions on the recrystallization solvent to be used, 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. Also, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different ratios of solvent combinations equivalent to those described in the present invention in this field are all considered to be within the scope encompassed by the present invention. Among them, the solvent may be alcohols, ethers, alkanes, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, acetic acid, water, DMF, or combinations thereof. For example, water, acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, DMF, tetrahydrofuran, ether, isopropyl ether, dioxane, methyl-t-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 combinations thereof.

[0094] There are no special restrictions on the water content in the solvent of the present invention, that is, the water content in the solvent does not affect the occurrence of the reaction of the present invention. Solvents containing a certain amount of water that can be used in the present invention to a certain degree are all regarded as the solvent of the present invention. For example, the water content in the solvent is generally 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, if the water content of the solvent is within a certain range, it is more advantageous for the progress of the reaction. For example, in the step of using ethanol as the reaction solvent, it is more advantageous for the progress of the reaction to use anhydrous ethanol. In some embodiments, if the water content of the solvent exceeds a certain range, it may affect the progress of the reaction (for example, affect the yield of the reaction), but it does not affect the occurrence of the reaction.

[0095] The intermediate compounds related to the present invention can be prepared by various synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combination with other chemical synthesis methods, and the equivalent substitution methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. However, all of them must be regarded as being included in the protection scope of the present invention.

[0096] The solvent used in the present invention can be procured on the market.

[0097] A short horizontal bar ("-") that is not between two characters or symbols represents the bonding point of the substituent. For example, C 1-6 The alkylcarbonyl group - refers to a C alkyl group bonded to the rest of the molecule through the carbonyl group. However, when the bonding site of the substituent is obvious to those skilled in the art, such as a halogen substituent, the "-" may be omitted. 1-6 When the bonding site of the substituent is obvious to those skilled in the art, such as a halogen substituent, the "-" may be omitted.

[0098] A dashed line for the valence bond of the group If there is TIFF2025518207000042.tif1017, for example In TIFF2025518207000043.tif1422, the wavy line represents the bonding point between the group and the other part of the molecule.

[0099] As used herein, the term "hydrogen" refers to the group -H.

[0100] As used herein, the term "deuterium" refers to the group -D.

[0101] As used herein, the term "hydroxyl group" refers to the group -OH.

[0102] As used herein, the term "halogenation" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0103] As used herein, the term "cyano group" refers to the group -CN.

[0104] Unless otherwise specified, C n-n+m or C n -C n+m includes any specific situation of n to n + m carbons. For example, C 1-12 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 and also includes any range within n to n + m. For example, C 1-12 is 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 9-12including etc., for the same reason, n to n + m members represent 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. Also, any range within 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, a 6 - 10 membered ring, etc.

[0105] Unless otherwise specified, the number of atoms in the ring is usually defined as the number of members of the ring. For example, a "3 - 6 membered ring" refers to a "ring" in which 3 to 6 atoms are arranged to surround.

[0106] Unless otherwise specified, the term "C 1-6 alkyl group" is used to represent a saturated hydrocarbon group consisting of 1 to 6 straight - chain or branched - chain carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups etc., and they can be monovalent (e.g., CH 3 ), divalent (-CH 2 -) or polyvalent TIFF2025518207000044.tif1635. Examples of C 1-6 alkyl groups include TIFF2025518207000045.tif16164 etc., but are not limited thereto.

[0107] Unless otherwise specified, the term "C 1-3 alkyl group" is used to represent a saturated hydrocarbon group consisting of 1 to 3 straight - chain or branched - chain carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups etc., and they can be monovalent (e.g., CH 3 ), divalent (-CH 2 -) or polyvalent TIFF2025518207000046.tif may be 1136. C 1-3 Examples of the alkyl group include TIFF2025518207000047.tif 12106 and the like, but are not limited thereto.

[0108] Unless otherwise specified, the term "C 1-6 alkoxy group" represents an alkyl group containing 1 to 6 carbon atoms bonded to the other part of the molecule through one oxygen atom. The C 1-6 alkoxy group is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups and the like. C 1-6 Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group (including an n-propoxy group and an isopropoxy group), a butoxy group (including an n-butoxy group, an isobutoxy group, an s-butoxy group and a t-butoxy group), a pentyloxy group (including an n-pentyloxy group, an isopentyloxy group, a neopentyloxy group), a hexyloxy group and the like, but are not limited thereto.

[0109] Unless otherwise specified, the term "C 1-3 alkoxy group" represents an alkyl group containing 1 to 3 carbon atoms bonded to the other part of the molecule through one oxygen atom. The C 1-3 alkoxy group is C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. C 1-3 Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group (including an n-propoxy group and an isopropoxy group) and the like, but are not limited thereto.

[0110] Unless otherwise specified, the term "C 1-6"Alkylamino group" represents an alkyl group containing 1 to 6 carbon atoms bonded to the other part of the molecule through an amino group. The said C 1-6 alkylamino group is C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 、C 5 、C 4 、C 3 and C 2 alkylamino groups and the like. C 1-6 Examples of the alkylamino group include -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-N(CH 2 CH 3 )(CH 2 CH 3 )、-NHCH 2 CH 2 CH 3 、-NHCH 2 (CH 3 ) 2 、-NHCH 2 CH 2 CH 2 CH 3 and the like, but are not limited thereto.

[0111] Unless otherwise specified, the term "C 1-3 alkylamino group" represents an alkyl group containing 1 to 3 carbon atoms bonded to the other part of the molecule through an amino group. The said C 1-3 alkylamino group is C 1-2 、C 3 and C 2 alkylamino groups and the like. C 1-3 Examples of the alkylamino group include -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH2 CH 3 、 -NHCH 2 CH 2 CH 3 、 -NHCH 2 (CH 3 ) 2 and the like are included, but not limited thereto.

[0112] Unless otherwise specified, the term "C 1-6 alkylthio group" represents an alkyl group containing 1 to 6 carbon atoms bonded to the other part of the molecule through a sulfur atom. The C 1-6 alkylthio group includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 、C 5 、C 4 、C 3 and C 2 alkylthio groups and the like. Examples of the C 1-6 alkylthio group include -SCH 3 、 -SCH 2 CH 3 、 -SCH 2 CH 2 CH 3 、 -SCH 2 (CH 3 ) 2 and the like are included, but not limited thereto.

[0113] Unless otherwise specified, the term "C 1-3 alkylthio group" represents an alkyl group containing 1 to 3 carbon atoms bonded to the other part of the molecule through a sulfur atom. The C 1-3 alkylthio group includes C 1-3 、C 1-2 and C 3 alkylthio groups and the like. Examples of the C 1-3 alkylthio group include -SCH 3 、 -SCH 2 CH 3 、 -SCH 2 CH 2 CH 3 、 -SCH 2 (CH3 ) 2 including, but not limited to, etc.

[0114] Unless otherwise specified, "C 3-6 cycloalkyl group" represents a cyclic saturated hydrocarbon group consisting of 3 to 6 carbon atoms, which is monocyclic and bicyclic, and the C 3-6 cycloalkyl group is C 3-5 , C 4-5 and C 5-6 cycloalkyl groups, etc., and they may be monovalent, divalent or polyvalent. Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.

[0115] Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl group" or its combination with other terms represents a cyclic saturated group consisting of 3 to 6 ring atoms, and 1, 2, 3 or 4 of its ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, among which the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) pwhere p is 1 or 2). It includes monocyclic and bicyclic systems, among which the bicyclic systems include spiro rings, bicyclic rings and bridged rings. Also, for the "3- to 6-membered heterocycloalkyl group", the heteroatom can occupy the bonding position between the heterocycloalkyl group and the other part of the molecule. The 3- to 6-membered heterocycloalkyl group includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc. Examples of the 3- to 6-membered heterocycloalkyl group include azetidinyl group, oxetanyl group, thietanyl group, pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, tetrahydrothienyl group (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl group (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl group, piperidinyl group (including 1-piperidinyl group, 2-piperidinyl group and 3-piperidinyl group, etc.), piperazinyl group (including 1-piperazinyl group and 2-piperazinyl group, etc.), morpholino group (including 3-morpholino group and 4-morpholino group, etc.), dioxanyl group, dithian group, isoxazolinyl group, isothiazolidinyl group, 1,2-oxazinyl group, 1,2-thiazinyl group, hexahydropyridazinyl group, homopiperazinyl group or homopiperidinyl group, etc., but not limited thereto.

[0116] Unless otherwise specified, the term "3- to 6-membered ring" or its combination with other terms represents a saturated monocyclic group or an unsaturated monocyclic group composed of 3 to 6 cyclic atoms respectively, which can include a pure carbon ring and can also include a ring with heteroatoms. Among them, 3 to 6 refers to the number of atoms forming the ring. Examples of the "3- to 6-membered ring" include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetanyl group, thietanyl group, cyclopentanone group, cyclohexanone group, etc., but not limited thereto.

[0117] Unless otherwise specified, the terms "5- to 6-membered heteroaryl ring" and "5- to 6-membered heteroaryl group" of the present invention can be used interchangeably. The term "5- to 6-membered heteroaryl group" represents a monocyclic group having a conjugated π-electron system composed of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms. Among them, the nitrogen atom is optionally quaternized ammonium, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p where p is 1 or 2). The 5- to 6-membered heteroaryl group can be bonded to the rest of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5- to 6-membered heteroaryl group include a pyrrolyl group (including an N-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, etc.), a pyrazolyl group (including a 2-pyrazolyl group, a 3-pyrazolyl group, etc.), an imidazolyl group (including an N-imidazolyl group, a 2-imidazolyl group, a 4-imidazolyl group, and a 5-imidazolyl group, etc.), an oxazolyl group (including a 2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, etc.), a triazolyl group (including a 1H-1,2,3-triazolyl group, a 2H-1,2,3-triazolyl group, a 1H-1,2,4-triazolyl group, and a 4H-1,2,4-triazolyl group, etc.), a tetrazolyl group, an isoxazolyl group (including a 3-isoxazolyl group, a 4-isoxazolyl group, and a 5-isoxazolyl group, etc.), a thiazolyl group (including a 2-thiazolyl group, a 4-thiazolyl group, and a 5-thiazolyl, etc.), a furyl group (including a 2-furyl group, a 3-furyl group, etc.), a thiophene group (including a 2-thiophene group and a 3-thiophene group, etc.), a pyridyl group (including a 2-pyridyl group, a 3-pyridyl group, and a 4-pyridyl group, etc.), a pyrazinyl group, or a pyrimidinyl group (including a 2-pyrimidinyl group and a 4-pyrimidinyl group, etc.), but are not limited thereto.

[0118] Correspondingly, the term "heteroaryl ring" as used herein refers to the ring of the heteroaryl group defined above.

[0119] As used herein, an "aryl group" or an "aromatic group" follows Huckel's rule, wherein the number of π electrons is equal to 4n + 2, where n is zero or any positive integer up to a maximum of 6.

[0120] The term "carbonyl group" as used herein refers to the group -C(O)- and can also be represented as -CO-.

[0121] The term "amino group" as used herein refers to the group -NH 2 -.

[0122] The term "optional" as used herein means that the events described hereinafter may or may not occur, and the description includes the situations where the events occur and the situations where the events do not occur. For example, an "optionally substituted alkyl group" refers to both an unsubstituted alkyl group and a substituted alkyl group, where the alkyl group is as defined herein. One of ordinary skill in the art should understand that for any group containing one or more substituents, the group does not include spatially unrealistic, chemically incorrect, synthetically infeasible, and / or inherently unstable substitution modes.

[0123] As used herein, the terms "substituted" or "substituted with" in reference to a given atom or group means that one or more hydrogen atoms on the given atom or group are replaced, for example, by one or more substituents selected from a defined group of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxygen (i.e., =O), two hydrogen atoms on a single atom are replaced by oxygen. Such combinations are only permitted when the combination of substituents and / or variables results in a chemically correct and stable compound. By a chemically correct and stable compound is meant a compound that is sufficiently stable to be separable from a reaction mixture, whose chemical structure can be determined, and which can subsequently be formulated into a preparation having at least substantial utility. For example, in situations where the substituents are not explicitly enumerated, the terms "substituted" or "substituting" as used herein in reference to a given atom or group mean that one or more hydrogen atoms on the given atom or group are independently replaced by one or more, for example, 1, 2, 3, or 4 substituents, said substituents being independently deuterium (D), halogen, OH, mercapto group, cyano group, -CD 3 , alkyl group (preferably C 1-6 alkyl group), alkoxy group (preferably C 1-6 alkoxy group), haloalkyl group (preferably haloC 1-6 alkyl group), haloalkoxy group (preferably haloC 1-6 alkoxy group), -C(O)NR a R b and -N(R a )C(O)R b and -C(O)OC 1-4 alkyl group, wherein R a and R b are each independently selected from hydrogen, C 1-4 alkyl group, haloC 1-4 alkyl group), carboxy group (COOH), cycloalkyl group (preferably 3- to 8-membered cycloalkyl group), heterocyclic group (preferably 3- to 8-membered heterocyclic group), aryl group, heteroaryl group, aryl group C 1-6 alkyl group, heteroaryl group C 1-6 alkyl group, OC1-6 Alkylphenyl group, -C 1-6 Alkyl group OH (preferably -C 1-4 Alkyl group OH), -C 1-6 Alkyl group SH, -C 1-6 Alkyl group O-C 1-2 、C 1-6 Alkyl group NH 2 (preferably C 1-3 Alkyl group NH 2 )、N(C 1-6 Alkyl group) 2 (preferably N(C 1-3 Alkyl group) 2 )、NH(C 1-6 Alkyl group)(preferably NH(C 1-3 Alkyl group))、N(C 1-6 Alkyl group)(C 1-6 Alkylphenyl group)、NH(C 1-6 Alkylphenyl group)、nitro group、C(O)OC 1-6 Alkyl group (preferably C(O)OC 1-3 Alkyl group)、NHC(O)(C 1-6 Alkyl group)、NHC(O)(phenyl group)、N(C 1-6 Alkyl group)C(O)(C 1-6 Alkyl group)、N(C 1-6 Alkyl group)C(O)(phenyl group)、C(O)C 1-6 Alkyl group、C(O)heteroaryl group (preferably C(O)-5-7 membered heteroaryl group)、C(O)C 1-6 Alkylphenyl group、C(O)C 1-6 Haloalkyl group、OC(O)C 1-6 Alkyl group (preferably OC(O)C 1-3 Alkyl group)、alkyl group sulfonyl group (e.g. -S(O) 2 -C 1-6 Alkyl group)、alkyl sulfinyl group (-S(O)-C 1-6 Alkyl group)、-S(O) 2 -phenyl group、-S(O) 2 -C 1-6 Haloalkyl group、-S(O) 2 NH 2 、S(O) 2 NH(C 1-6(alkyl group), S(O) 2 NH(phenyl group), -NHS(O) 2 (C 1-6 (alkyl group), -NHS(O) 2 (phenyl group) and NHS(O) 2 (C 1-6 selected from (haloalkyl group), wherein said alkyl group, cycloalkyl group, phenyl group, aryl group, heterocyclo group and heteroaryl group are each optionally one or more substituents selected from the following substituents: halogen, -OH, -NH 2 , cycloalkyl group, 3- to 8-membered heterocyclo group, C 1-4 alkyl group, C 1-4 haloalkyl group-, -OC 1-4 alkyl group, -C 1-4 alkyl group OH, -C 1-4 alkyl group O-C 1-4 alkyl group, OC 1-4 haloalkyl group, cyano group, nitro group, -C(O)-OH, C(O)OC 1-6 alkyl group, -CON(C 1-6 alkyl group) 2 , -CONH(C 1-6 alkyl group), CONH 2 , NHC(O)(C 1-6 alkyl group), NH(C 1-6 alkyl group)C(O)(C 1-6 alkyl group), -SO 2 (C 1-6 (alkyl group), -SO 2 (phenyl group), -SO 2 (C 1-6 (haloalkyl group), -SO 2 NH 2 , SO 2 NH(C 1-6 alkyl group), SO 2 NH(phenyl group), -NHSO 2 (C 1-6 (alkyl group), -NHSO 2 (phenyl group) and NHSO 2 (C 1-6It is further substituted by a haloalkyl group). When one atom or group is substituted by a plurality of substituents, the substituents may be the same or different.

[0124] When any variable (e.g., R) appears one or more times in the composition or structure of a compound, the definitions in each situation are all independent. Thus, for example, when one group is substituted by 0 to 2 R's, the said group can optionally be substituted by up to 2 R's at most, and R in each situation has independent options. Also, combinations of substituents and / or their variants are permitted only in situations where such combinations produce stable compounds.

[0125] The following abbreviations are adopted in the present invention.

[0126] SOCl 2 is dichlorosulfoxide, Cs 2 CO 3 is cesium carbonate, NaHCO 3 is sodium hydrogen carbonate, K 2 CO 3 is potassium carbonate, K 3 PO 4 is potassium phosphate, DMF is dimethylformamide, THF is tetrahydrofuran, T3P is 1-propylphosphonic anhydride, HATU is 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate ester, EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt is 1-hydroxybenzotriazole, CDI is N,N'-carbonyldiimidazolyl, DCM is dichloromethane, DIPEA is N,N-diisopropylethylamine, DCDMH is dichlorodimethylhydantoin, NCS is N-chlorosuccinimide, MTBE is methyl t-butyl ether, TCFH is chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, NMI represents N-methylimidazolyl.

[0127] The volume nV used in the present invention generally refers to the n-fold product, which is the weight ratio of the solvent volume to the compound used, with the unit of mL / g. For example, the volume 8V of ethanol used in Table 3 means that the volume of ethanol is 8-fold product, that is, the volume of ethanol (mL / ) is 8 times the weight (g) of Compound 1.

[0128] Compounds are named according to the general naming principles in this field or using ChemDraw (registered trademark) software. For commercially available compounds, the names in the suppliers' catalogs are adopted.

Embodiments for Carrying Out the Invention

[0129] Hereinafter, the present application will be described in detail through examples, which does not mean that there are any adverse limitations to the present application. The present application has already been described in detail in the text, and specific embodiments thereof have also been disclosed therein. Therefore, it is obvious to those skilled in the art to make various changes and improvements to the specific embodiments of the present application without departing from the gist and scope of the present application.

[0130] The raw materials used in the present invention are all commercially available unless otherwise specified.

[0131] Example 1

Chemical Formula

[0132] 2) Crystallization: The temperature in the reaction kettle is lowered to 15 - 25 °C, and a pre - prepared 10% potassium phosphate (60.0 kg, 10.1X) aqueous solution is dropped in, the pH is adjusted to 6 - 8, and stirred for 3 - 6 hours.

[0133] 3) Centrifugation 1: The substances in the reaction kettle are centrifuged by a centrifuge, and the filter cake is washed with process water (46.5 kg, 7.8X).

[0134] 4) Pulping: The wet product (7.0 kg, 1.2X) and process water (61.2 kg, 10.3X) are put into the reaction kettle R1 and stirred at 15 - 25 °C for 3 - 6 hours.

[0135] 5) Centrifugation 2: The substances in the reaction kettle are centrifuged by a centrifuge, and the filter cake is washed with process water (42.8 kg, 7.2X) to obtain the wet product. The next operation is carried out after the wet product passes the inspection.

[0136] 6) Drying: The wet product is transferred to a vacuum dryer, the temperature in the dryer is controlled at 30 - 40 °C, and dried under reduced pressure for 24 - 30 hours. Samples are inspected until the moisture content is qualified (KF ≤ 0.3%). If it is unqualified, the drying time is extended until the moisture content is qualified. In this lot, 6.1 kg of white solid is obtained, and the yield is 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). HPLC conditions Instrument: High-performance liquid chromatograph (ultraviolet detector) Agilent 1260 Column: Waters Xbridge C18 / 4.6×150 mm, 3.5 μm Mobile phase: Mobile phase A, 0.05% aqueous formic acid solution; Mobile phase B, 0.05% formic acid acetonitrile solution Flow rate: 1.0 ml / min Measurement time: 28 minutes Analysis temperature: 35 °C Detection wavelength: 222 nm / 248 nm Retention time: Compound 1: 10.013 minutes; Compound 2: 16.029 minutes

[0137]

Table 1

[0138] Steps 2, 3 1) Reaction 1: Under the protection of micro nitrogen, compound 2 (6.0 kg, 1.00X) and tetrahydrofuran (44.0 kg, 7.33X) are put into the reaction kettle and stirring is started. Compound 3 (5.1 kg, 0.85X) and cesium carbonate (10.7 kg, 1.78X) are added. The temperature is lowered to 55 - 65 °C and stirred for 16 - 24 hours to react. Then the temperature is lowered to 15 - 25 °C, samples are taken and inspected by in-process control. If the in-process control is qualified (the purity ratio of compound 2 / (compound 2 + compound 4 + compound 5) ≤ 4.0%), proceed to the next operation. If not, extend the reaction time until the in-process control is qualified.

[0139] 2) Reaction 2: Under the protection of micro nitrogen, the prepared lithium hydroxide aqueous solution (35.8 kg, 6.0X) is put into the reaction kettle R1, the temperature is controlled at 55 - 65 °C, and stirred for 8 - 16 hours for reaction. The temperature is lowered to 15 - 25 °C, samples are taken and inspected by in-process control. If the in-process control is qualified (the purity ratio of compound 4 / (compound 4 + compound 5) ≤ 1.0%), proceed to the next operation. If it is unqualified, extend the reaction time until the in-process control is qualified.

[0140] 3) Oxidation: Under the protection of nitrogen, the temperature is controlled at 0 - 25 °C, and 35% hydrochloric acid (12 kg, 2.0X) is slowly dropped into the reaction kettle R1.

[0141] 4) Extraction: Methyl t-butyl ether (21.5 kg, 3.6X) is added to the reaction kettle. The temperature of the reaction kettle is adjusted to 15 - 25 °C, stirred for 0.5 - 2 hours, left standing for 0.5 - 2 hours, the layers are separated, and the aqueous phase is transferred to a steel-plastic composite container.

[0142] 5) Washing: The prepared 10% sodium chloride aqueous solution (35.35 kg, 5.9X) is put into the reaction kettle, the temperature of the reaction kettle is adjusted to 15 - 25 °C, stirred for 0.5 - 2 hours, left standing for 0.5 - 2 hours, the layers are separated, and the aqueous phase is transferred to a steel-plastic composite container.

[0143] 6) Concentration: Control the internal temperature ≤ 40 °C, reduce the pressure of the solution in the reaction kettle to concentrate it to 12 - 18 L (2 - 3X), and add anhydrous ethanol (25.0 kg, 4.2X). Control the internal temperature ≤ 40 °C, reduce the pressure of the solution in the reaction kettle to concentrate it to 12 - 18 L (2 - 3X), and add anhydrous ethanol (104.0 kg, 17.3X). Control the internal temperature ≤ 40 °C, reduce the pressure of the solution in the reaction kettle to concentrate it to 12 - 18 L (2 - 3X), and add anhydrous ethanol (31.5 kg, 5.3X) to the reaction kettle R1.

[0144] 7) Crystallization: Control the temperature of the reaction kettle at 50 - 60 °C, dropwise add process water (78.0 kg, 13.0X), and keep it warm and stir for 1 - 3 hours. Lower the reaction temperature to 15 - 25 °C, control so that the temperature reduction time does not exceed 2 hours, and stir at 15 - 25 °C for 1 - 3 hours.

[0145] 8) Centrifugation: Transfer the substances in the reaction kettle to a centrifuge for centrifugation, add a prepared ethanol / process water = 1:1 (v / v) solution (26.1 kg, 4.3X) to wash the filter cake to obtain 8.60 kg of wet product. After the wet product passes the inspection, proceed to the operation of the next step.

[0146] 9) Drying: Transfer the wet product to a vacuum dryer, control the internal temperature at 40 - 50 °C and carry out vacuum drying for 18 hours or more until it becomes qualified (KF: 0.3% ≤ 0.3%, EtOH: 0.1% ≤ 0.2%). If it is unqualified, extend the drying time until the in - process control becomes qualified. A white solid compound 7 (8.18 kg) is obtained, and the yield is 85.4%. 1H NMR (400 MHz, DMSO - d6) δ 8.05 (s, 1H), 7.50 (s, 1H), 7.42 - 7.32 (m, 2H), 7.12 - 7.02 (m, 2H). ESI + , [M + H] + : 366.9746, [M + H] + : 368.9719 HPLC conditions Instrument: High - performance liquid chromatograph (ultraviolet detector) Agilent 1260 Column: Waters Xbridge C18 / 4.6×150 mm, 3.5 μm Mobile phase: Mobile phase A, 0.05% aqueous formic acid solution, Mobile phase B, 0.05% formic acid acetonitrile solution Flow rate: 1.0 ml / min Measurement time: 28 minutes Analysis temperature: 35 °C Detection wavelength: 222 nm / 248 nm Retention time: Compound 2: 16.029 minutes, Compound 3: 10.712 minutes, Compound 4: 18.792 minutes, Compound 5: 16.232 minutes.

[0147] Step 4 1) Reaction: Under nitrogen protection, add DCM (56.5 kg, 6.93X) and intermediate compound 5 (8.15 kg, 1.0X) to a dry reaction kettle and start stirring. Add starting material compound 6 (3.95 kg, 0.48X) and HATU (10.2 kg, 1.25X). Control the temperature at 20 - 30°C and dropwise add DIPEA (8.5 kg, 1.05X) into the reaction kettle. After the addition is complete, raise the temperature to 25 - 35°C and stir for 8 - 16 hours. Take samples and inspect by in - process control. If the in - process control is qualified (purity ratio of compound 5 / (compound 5 + compound 7) ≤ 1.0%), proceed to the next operation. If not, extend the reaction time until the in - process control is qualified.

[0148] 2) Washing 1: Lower the temperature to 15 - 25°C, add DCM (27.0 kg, 3.3X), and add the prepared 5% K 2 CO 3 aqueous solution (49.0 kg, 6.0X). Control the internal temperature at 15 - 25°C and 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.

[0149] 3) Washing 2: Add the prepared 7% NaHCO 3 aqueous solution (81.0 kg, 9.9X). Control the internal temperature at 15 - 25°C and 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% NaHCO 3 aqueous solution (83.0 kg, 10.2X). Control the internal temperature at 15 - 25°C and 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.

[0150] 4) Washing 3: Process water (80.0 kg, 9.8X) is added to the organic phase and put into the reaction kettle R1. The internal temperature is controlled at 15 - 25 °C and stirred for 0.5 - 2 hours, then left standing for 0.5 - 2 hours to separate the layers. The aqueous phase is separated and the organic phase is retained. Process water (80.8 kg, 9.9X) is put into the reaction kettle R1, the internal temperature is controlled at 15 - 25 °C, stirred for 0.5 - 2 hours, left standing for 0.5 - 2 hours to separate the layers, the aqueous phase is separated and the organic phase is retained.

[0151] 5) Concentration: The organic phase is transferred to the reaction kettle, the internal temperature is controlled at ≤ 35 °C, and vacuum concentrated to 16 - 24 L (2.0 - 3.0X). Acetonitrile (97.0 kg, 11.9X) is added to the reaction kettle R1, the internal temperature is controlled at ≤ 40 °C, and the solvent is continuously vacuum concentrated. Vacuum concentrate to 73 - 81 L (9.0 - 10.0X), add acetonitrile (32.8 kg, 4.0X) to the reaction kettle R1, control the internal temperature at ≤ 40 °C, and continue to vacuum concentrate the solvent to 73 - 81 L (9.0 - 10.0X). Stop the concentration.

[0152] 6) Crystallization: Raise the reaction temperature to 50 - 60 °C, and drop process water (135.2 kg, 16.6X) into the reaction kettle. Slowly lower the temperature to 40 - 50 °C, stir at 40 - 50 °C for 2 - 4 hours, lower the internal temperature to 0 - 10 °C, and stir for 6 - 8 hours.

[0153] 7) Centrifugation: Transfer the substances in the reaction kettle to the centrifuge for centrifugation, add process water (17.5 kg, 2.1X) to wash the filter cake, and after inspecting the sample to be qualified (IM - A ≤ 0.15%), proceed to the next operation. If unqualified, repeat the crystallization operation.

[0154] 8) Drying: Transfer the filter cake to the vacuum dryer and vacuum dry at 35 - 45 °C for 18 - 24 hours until the moisture content is qualified (KF ≤ 5.0%). Compound 7 (9.68 kg) is obtained with a yield of 91.4%. The moisture content inspection of Compound 7 shows that the molar ratio of the compound to water is 1:1, and TGA shows that the weight loss at 50 - 150 °C is 3.5%. Converting the water molecular weight to the molar ratio is close to 1:1. ESI+ , [M+H] + : 459.0019, [M+H] + : 461.0090 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 8.00 (ddd, J = 6.3, 1.8, 1.0 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.41 - 7.34 (m, 3H), 7.20 - 7.15 (m, 2H). HPLC conditions Instrument: High Performance Liquid Chromatograph (UV detector) Agilent 1260 Column: Waters Xbridge C18 / 4.6×150 mm, 3.5 μm Mobile phase: Mobile phase A, 0.05% aqueous formic acid solution; Mobile phase B, 0.05% formic acid acetonitrile solution Flow rate: 1.0 ml / min Measurement time: 28 minutes Analysis temperature: 35 °C Detection wavelength: 222 nm / 248 nm Retention time: Compound 5: 16.232 minutes, Compound 6: 1.729 minutes, Compound 7: 13.976 minutes.

[0155] Example 2 Step 1: At room temperature, add anhydrous ethanol (464 mL, 8.0 v / w) and Compound 1 (58.0 g, 278 mmol) to a reaction flask, stir to dissolve. Lower the temperature to 30 - 40 °C, and dropwise add SOCl 2 (39.6 g, 333 mmol). After completion of the dropwise addition, heat to 55 - 60 °C and react for 4 - 8 hours. Take samples and perform in-process control until the reaction is qualified. Dropwise add 10% potassium phosphate solution to adjust the pH to 6 - 8, precipitate the product, filter, add water to the filter cake for washing to obtain a wet product, and dry at 30 - 40 °C to obtain Compound 2.

[0156] Steps 2 and 3: Place THF (130 mL, 8.0 v / w) in a three-necked flask at room temperature, start stirring, add Compound 2 (56.2 g, 237 mmol), Compound 3 (48.5 g, 272 mmol), Cs 2 CO 3 (100.4 g, 308 mmol), heat to 55 - 60 °C and react for 20 - 24 hours. Take samples and inspect by in-process control. After the in-process control is qualified, add water (280 mL), react lithium hydroxide hydrate (24.9 g, 593 mmol) at 55 - 60 °C for 2 - 4 hours. Take samples and inspect by in-process control. After the in-process control is qualified, lower the temperature to 20 - 30 °C, dropwise add concentrated hydrochloric acid (101 ml, 1.8 vol). After the addition is complete, add MTBE (130 mL), stir for 10 - 15 minutes, separate the layers, add 10% sodium chloride solution (280 mL, 5 vol) to the organic phase and wash. Concentrate the organic phase under reduced pressure to 2 - 3 volumes, add absolute ethanol (280 mL, 5V) and continue to concentrate to 2 - 3 volumes, then add absolute ethanol to about 10 volumes. Control the temperature at 20 - 30 °C, dropwise add water (504 mL, 9V) to precipitate a solid, filter to obtain a wet product, and dry at 40 - 50 °C to obtain Compound 5.

[0157] Synthesis in Step 4: Place DCM (200 ml) and Compound 5 (40.0 g, 109 mmol) in a three-necked flask at room temperature, start stirring, and add HATU (53.8 g, 144 mmol) and Compound 6 (19.1 g, 131 mmol). Dropwise add DIPEA (42.2 g, 327 mmol) at 30 - 35 °C. After completion of the dropwise addition, react at 30 - 35 °C for 16 hours. After the sample passes the in-process control, lower the temperature of the reaction system to 25 - 35 °C, add DCM (100 ml), add 5% aqueous potassium carbonate solution (240 ml, 6V) for washing, let it stand to separate the layers, add 7% aqueous sodium hydrogen carbonate solution (400 ml, 10V) to the organic phase for washing twice, and further add water (400 ml, 10V) for washing twice. Concentrate the organic phase under reduced pressure to the remaining 3.0 - 3.5V, add acetonitrile (480 ml, 12V), and continue to concentrate and replace the solvent twice, concentrate to the remaining 10V, raise the temperature of the reaction system to 50 - 60 °C to dissolve, dropwise add water (560 ml, 14V), after completion of the dropwise addition, keep warm at 50 - 60 °C for 1 hour. Lower the temperature to 0 - 10 °C and stir for 2 hours. Filter to obtain the wet product, and dry it under reduced pressure at 45 - 50 °C to obtain Compound 7.

[0158] Example 3

Chemical formula

[0159] Example 4

Chemical formula

[0160] Synthesis of Compound Y-3: Place Y-2 (10 g, 52 mmol) and DCM (100 ml, 10V) into a reaction flask at room temperature and stir. Lower the temperature to 0 - 10 °C, add solid m-CPBA in several portions. After addition, return to room temperature (20 - 25 °C) and react overnight. After the sample passes in-process control, add 10% Na 2 SO 3 (20 ml, 2V) for one wash, and then add 10% Na 2 SO 3 (20 ml, 2V) for one wash. Separate the layers, add ethyl acetate (50 ml, 5V) to the aqueous phase for extraction. Concentrate and dry the organic phase, add ethyl acetate (100 ml, 10V), combine the ethyl acetate phases twice, and obtain the filtrate through a silica gel pad. Concentrate and dry the filtrate, add 1,4-dioxane (50 ml, 5V) to dissolve to obtain the Y-3 solution.

[0161] Synthesis of Compound 6: Place the Y-3 solution (52 mmol) into a reaction flask at room temperature, control the temperature at 10 - 20 °C, and dropwise add HCl / 1,4-dioxane solution (520 mmol, 10.0 eq.). After the addition is complete, return to room temperature and react for 3 - 4 hours. Take a sample and make it qualified by in-process control. A solid precipitates during the reaction process, filter to obtain the filter cake, put the filter cake into the reaction flask, add acetonitrile (50 ml, 5V), shake at room temperature for 1 - 2 hours, filter to obtain the wet product, and dry at 45 - 50 °C to obtain Compound 6.

[0162] Example 5 [Chemical Formula] Under nitrogen protection, CH 3 CN (62.2 kg) and Compound 5 (13.5 kg) are put into the dry reaction kettle R1, and stirring is started. Compound 6 (6.5 kg) and TCFH (15.5 kg) are added. The temperature is controlled at 0 - 10°C, and NMI (10.5 kg) is added dropwise into the reaction kettle. After the completion of the dropwise addition, the temperature is raised to 25 - 35°C and stirred for 2 - 4 hours. The sample is inspected by in-process control. After passing the in-process control, the next operation is carried out. The temperature is controlled at 25 - 35°C, and the prepared 3% K 3 PO 4 aqueous solution (138 kg) is added dropwise, and the internal temperature is controlled at 25 - 35°C and stirred for 2 - 4 hours. The substances in the reaction kettle are transferred to a centrifuge for centrifugation, and process water (37.1 kg) is added to wash the filter cake. The above wet product and process water (140 kg) are put into the reaction kettle R1 and stirred at 35 - 45°C for 2 - 4 hours. The substances in the reaction kettle are transferred to a centrifuge for centrifugation, and process water (211.7 kg) is added to wash the filter cake. The above wet product and process water (140 kg) are put into the reaction kettle R1 and stirred at 35 - 45°C for 2 - 4 hours. The substances in the reaction kettle are transferred to a centrifuge for centrifugation, and process water (185.4 kg) is added to wash the filter cake. The filter cake is transferred to a vacuum dryer and dried under reduced pressure at 35 - 45°C for 18 - 24 hours until the moisture content meets the standard (KF ≤ 5.0%). Compound 7 (15.7 kg) is obtained, and the yield is 85%.

[0163] Comparative Example 1 While keeping other conditions the same as those in Step 1 of Example 2, only the usage amount of SOCl 2 in Step 1 was changed. The results are as shown in Table 2.

[0164] [Table 2]

[0165] Comparative Example 2 While keeping other conditions the same as those in Step 1 of Example 2, only the dosage of the ethanol volume in Step 1 was changed. The results are as shown in Table 3.

[0166]

Table 3

[0167] Comparative Example 3 While keeping other conditions the same as those in Step 1 of Example 2, only the post-treatment operation in Step 1 was changed. The results are as shown in Table 4.

[0168]

Table 4

[0169] Comparative Example 4 While keeping other conditions the same as those in Step 2 of Example 2, only the selection of the alkali in Step 2 was changed. The results are as shown in Table 5.

[0170]

Table 5

[0171] Comparative Example 5 While keeping other conditions the same as those in Step 2 of Example 2, only the selection of the solvent in Step 2 was changed. The results are as shown in Table 6.

[0172]

Table 6

[0173] Comparative Example 6 While keeping other conditions the same as those in Step 2 of Example 2, only the selection of cesium carbonate in Step 2 was changed. The results are as shown in Table 7.

[0174]

Table 7

[0175] Comparative Example 7 While keeping the other conditions the same as those in Step 2 of Example 2, only the amount of Compound 3 used in Step 2 was changed. The results are as shown in Table 7.

[0176]

Table 8

[0177] Comparative Example 8 While keeping the other conditions the same as those in Step 4 of Example 2, only the type of condensing agent used in Step 4 was changed. The results are as shown in Table 9.

[0178]

Table 9

[0179] Comparative Example 9 While keeping the other conditions the same as those in Step 4 of Example 2, only the type of solvent used in Step 4 was changed. The results are as shown in Table 10.

[0180]

Table 10

[0181] Comparative Example 10 While keeping the other conditions the same as those in Step 4 of Example 2, only the amount of HATU used in Step 4 was changed. The results are as shown in Table 11.

[0182]

Table 11

[0183] Comparative Example 11 While keeping the other conditions the same as those in Step 4 of Example 2, only the amount of DIPEA used in Step 4 was changed. The results are as shown in Table 12.

[0184]

Table 12

[0185] Comparative Example 12 While keeping the other conditions the same as those in Step 4 of Example 2, only the post-treatment conditions in Step 4 were changed. The results are as shown in Table 13.

[0186]

Table 13

[0187] Comparative Example 13 The results of screening the reaction conditions in Example 3 are as shown in Table 14.

[0188]

Table 14

[0189] In the description of this specification, references to terms such as "one embodiment", "several embodiments", "illustration", "specific illustration", or "several illustrations" mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or illustration are included in at least one embodiment or illustration of the present invention. In this specification, the above general expressions of terms do not necessarily refer to the same embodiment or illustration. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable form in any one or more embodiments or illustrations. Also, in situations where there is no contradiction, those skilled in the art can combine or combine the different embodiments or illustrations described in this specification and the features of different embodiments or illustrations.

[0190] As described above, the embodiments of the technical method of the present invention have been outlined. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention shall all be included in the protection scope 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, comprising 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 to obtain a compound represented by formula (I) or a pharmaceutically acceptable salt or hydrate thereof, T 1 is selected from N or C(R 7 ), T 2 is selected from N or C(R 8 ), T 3 is selected from N or C(R 9 ), T 4 is selected from N or C(R 10 ), R 1 、R 2 、R 8 、R 9 are each independently H, halogen, OH, NH 2 , CN, SF 5 , C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, vinyl group-C 1-6 alkyl group-, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 cycloalkyl group-C 1-6 alkyl group-, 3- to 6-membered heterocycloalkyl group-C 1-6 alkyl group-, 3- to 6-membered heterocycloalkyl group-C 1-6 alkyl group-O-, phenyl group-C 1-3 , C 3-6 cycloalkyl group-C 1-3 alkyl group-O-, 3- to 6-membered heterocycloalkyl group-C 1-3 alkyl group-O-, phenyl group-C 1-3 alkyl group-O-, phenyl group-C 1-3 alkyl group-NH-, 5- to 6-membered heteroaryl group-C 1-3 alkyl group-, 5- to 6-membered heteroaryl group-C 1-3 alkyl group-O- and 5- to 6-membered heteroaryl group-C 1-3 alkyl group-NH- and are selected from C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, vinyl group-C 1-6 alkyl group-, C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 heterocycloalkyl group-C 1-6 alkyl group-, 3- to 6-membered heterocycloalkyl group-C 1-6 -alkyl group-, 3- to 6-membered heterocycloalkyl group-C 1-6 alkyl group-O-, phenyl group-C 1-3 , C 3-6 cycloalkyl group-C 1-3 alkyl group-O-, 3- to 6-membered heterocycloalkyl group-C 1-3 alkyl group -O-, phenyl group -C 1-3 alkyl group -O-, phenyl group -C 1-3 alkyl group -NH-, 5- or 6-membered heteroaryl group -C 1-3 alkyl group -, 5- or 6-membered heteroaryl group -C 1-3 alkyl group -O- or 5- or 6-membered heteroaryl group -C 1-3 The alkyl group -NH- is optionally substituted with 1, 2 or 3 R's, R 3 、 R 4 、 R 5 、 R 6 、 R 10 are each independently H, halogen, OH, NH 2 、 SF 5 、 CN, C 1-6 alkyl group, C 1-6 alkylamino group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 cycloalkyl group-C 1-6 alkyl group- and 3- to 6-membered heterocycloalkyl group-C 1-6 alkyl group- are selected from, said C 1-6 alkyl group, C 1-6 alkylamino group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C 3-6 cycloalkyl group-C 1-6 alkyl group- or 3- to 6-membered heterocycloalkyl group-C 1-6 alkyl group- is optionally substituted with 1, 2 or 3 R's, R 7 is selected from H, F, Cl, Br, I, C 1-6 alkyl group, C 1-6 alkoxy group and C 1-6 alkylamino group, and the C 1-6 alkyl group, C 1-6 alkoxy group or C 1-6 alkylamino group is optionally substituted with 1, 2 or 3 R's, L 2 is selected from O, S, NH and CH 2 wherein said CH 2 is optionally substituted with one or two R's, and NH is optionally substituted with R R 13a 、R 13b are each independently selected from H, halogen and C 1-6 alkyl groups, and said C 1-6 alkyl group is optionally substituted with 1, 2 or 3 R's, R is, independently of one another, H, D, halogen, OH, NH 2 , CN, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group and C 1-6 alkylamino group, and the C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group or C 1-6 alkylamino group is optionally substituted with 1, 2 or 3 R's, R' is selected from F, Cl, Br, I, OH, NH 2 and CH 3 and The 3- to 6-membered heterocycloalkyl group or 5- to 6-membered heteroaryl group contains 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N, and is characterized by this. method.

2. The compound represented by the formula (I) is selected from, Optionally, the compound represented by the formula (I) is selected from, Optionally, the compound represented by the formula (I) is selected from, Optionally, the compound represented by the formula (I-5) is selected from, Optionally, the compound represented by the formula (I-5) is selected from, Optionally, the compound represented by the formula (I-6) is selected from, Optionally, the compound represented by the formula (I-6) is selected from, characterized in that, The method according to claim 1.

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

4. The compound represented by the formula (I-5-A) is obtained by carrying out a substitution reaction between the compound represented by the formula (I-2) and the compound represented by the formula (I-3), Among them, Rx is C 1-6 selected from an alkyl group, Optionally, the compound represented by the formula (I-2) or its optical isomer is selected from Optionally, the compound represented by the formula (I-3) or its optical isomer is selected from Optionally, the substitution reaction is carried out in the presence of an alkali, Optionally, the alkali is Cs 2 CO 3 、K 2 CO 3 and K 3 PO 4 selected from, Optionally, the alkali is Cs 2 CO 3 and Optionally, the molar ratio of the compound represented by the formula (I-2) to the Cs 2 CO 3 is 1:(1.3 to 1.5), Optionally, the substitution reaction is carried out under the condition that the solvent is N,N-dimethylformamide or tetrahydrofuran, Optionally, the molar ratio of the compound represented by the formula (I-2) to the compound represented by the formula (I-3) is 1:(1.10 to 1.25), and optionally 1:1.15, The method according to claim 2.

5. The compound represented by the formula (I-2) is obtained by carrying out an esterification reaction on the compound represented by the formula (I-1), Optionally, the compound represented by the formula (I-1) or its optical isomer is selected from Optionally, the esterification reaction is carried out in the presence of SOCl 2 and Optionally, the molar ratio of the compound represented by the formula (I-1) to the SOCl 2 is 1:(1.0 to 2.0), and optionally 1:(1.2 to 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 the formula (I-1) to the ethanol is 1:(1672 to 2090), Optionally, the esterification reaction further includes post-treatment, Optionally, the post-treatment is carried out by adding an aqueous sodium bicarbonate solution, The method according to claim 4.

6. The structure is Compound 5 【Chemical 1】 as shown, An intermediate compound or a pharmaceutically acceptable salt thereof.

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

8. A method for preparing Compound 1, comprising subjecting the compound shown in formula (X-1) to a chlorination reaction to obtain Compound 1, wherein the chlorination reaction is carried out under conditions where the solvent is one or more of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid or ethanesulfonic acid. 【Chemical 2】

9. The chlorination reaction is carried out under conditions of a chlorination reagent, Optionally, the chlorination reagent is selected from dichlorodimethylhydantoin and N-chlorosuccinimide, Optionally, the molar ratio of the compound shown in formula (X-1) to dichlorodimethylhydantoin is 1:(0.5-0.7), Optionally, the molar ratio of the compound shown in formula (X-1) to N-chlorosuccinimide is 1:(1.1-1.6), Optionally, the chlorination reaction is carried out under conditions where the temperature is 55-60 °C, The method according to Claim 8.

10. A method for preparing Compound 6, comprising subjecting the compound shown in formula (Y-2) to an oxidation reaction and a deprotection reaction to obtain Compound 6. 【Chemical Formula 3】

11. The method according to Claim 10, wherein the compound shown in formula (Y-2) is obtained by subjecting the compound shown in formula (Y-1) to an acylation reaction. 【Chemical 4】

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