A process for the preparation of a chlorinated compound

Abstract

Disclosed is a method for preparing a chlorinated compound, and specifically disclosed is a method for preparing a compound of formula (I).

Description

[0001] The present invention claims the following priority:

[0002] CN202010528778.5, application date: June 11, 2020. Technical Field

[0003] The present invention relates to a method for preparing a chlorinated compound, and in particular to a method for preparing a compound of formula (I). Background Art

[0004] In recent years, with changes in people's lifestyles, the incidence of hyperuricemia and gout has been increasing year by year. In Europe and the United States, epidemiological studies indicate that gouty arthritis affects 1-2% of the total population and is the most common type of arthritis in adult men. Bloomberg estimates that there will be 17.7 million gout patients in 2021. In China, a survey revealed that 25.3% of people aged 20 to 74 have elevated blood uric acid levels, and 0.36% suffer from gout. Currently, clinical treatment options primarily include: 1) drugs that inhibit uric acid production, such as the xanthine oxidase inhibitors allopurinol and febuxostat; 2) drugs that promote uricosuric acid excretion, such as probenecid and benzbromarone; and 3) anti-inflammatory drugs, such as colchicine. These drugs all have limitations, with poor efficacy, significant side effects, and high costs being key bottlenecks to their clinical application. Reports indicate that 40%-70% of patients fail to achieve the desired therapeutic target (<6 mg / dL) after standard treatment.

[0005] URAT1 is an important renal anion transporter located on the brush border membrane of renal tubular epithelial cells. It specifically transports uric acid from the renal tubules to the epithelial cells and is the primary driver of uric acid reabsorption in the renal tubules. Therefore, if the urate transporter URAT1 can be significantly inhibited, it will increase uric acid excretion in the body, thereby lowering blood uric acid levels and reducing the likelihood of gout attacks.

[0006] In December 2015, the US FDA approved AstraZeneca's first targeted URAT1 inhibitor, lesinurad, as shown below. The 200 mg / day dose was approved for combination with a xanthine oxidase inhibitor (XOI) (such as febuxostat) for the treatment of hyperuricemia and gouty arthritis. However, the additive effect of the combination was not significant compared with the XOI alone. Furthermore, the 400 mg / day dose of lesinurad was not approved due to a significant increase in toxicities (including a higher incidence of kidney-related adverse events, particularly nephrolithiasis) observed at the higher dose, despite the significant additive effect observed with the combination. Therefore, the FDA required a boxed warning to be added to the lesinurad label to alert healthcare professionals to the risk of acute renal failure with lesinurad, particularly when used without an XOI. The risk of renal failure is even higher with use of lesinurad at doses exceeding the approved dosage. Furthermore, the FDA required AstraZeneca to continue its renal and cardiovascular safety studies after the launch of lesinurad. For long-term medication for metabolic diseases, drug safety is particularly important. Therefore, the development of a safe uric acid-lowering drug has become a strong demand in this field.

[0007]

[0008] AstraZeneca's disclosed new drug application report detailed the results of in vitro metabolite identification experiments for the compound lesinurad in liver microsomes and hepatocytes from various animal species. The data showed that the two major metabolites, M3 and M4, were significantly detected in monkey and human hepatocytes, but were not detected in dog and rat hepatocytes, as shown in Table-a below.

[0009] Table-a

[0010]

[0011] At the same time, AstraZeneca also reported the main metabolites and metabolic pathways of Lesinurad after administration in various species of animals. Among them, the dihydroxy metabolite M4 was specifically detected in human metabolites:

[0012]

[0013] This is consistent with the clinical data of lesinurad in humans. Experimental data show that M3 and M4 are the main metabolites found in human clinical practice, as shown in Table-b below.

[0014] Table-b

[0015]

[0016] The production pathway of the M4 metabolite has been identified as the result of the combined action of cytochrome CYP2C9 and the primate epoxide hydrolase mEH. This mEH metabolic pathway is unique to primates, explaining why M4 was not observed in rats and dogs.

[0017] Summary of the Invention

[0018] The present invention provides a method for preparing a compound of formula (I).

[0019]

[0020] It is characterized by comprising the following steps:

[0021]

[0022] in,

[0023] n is selected from 0, 1 and 2

[0024] Reagent A is selected from CS2;

[0025] Base B is selected from TEA, DBU, DIPEA and

[0026] Solvent C is selected from a single solvent or a mixed solvent. The single solvent is selected from n-heptane, DMF, acetone and methyl tert-butyl ether. The mixed solvent is selected from a mixed solvent of acetone and methyl tert-butyl ether.

[0027] In some embodiments of the present invention, the preparation method, wherein,

[0028] Reagent A is selected from CS2;

[0029] Base B is selected from

[0030] Solvent C is selected from a single solvent or a mixed solvent. The single solvent is selected from methyl tert-butyl ether, and the mixed solvent is selected from a mixed solvent of acetone and methyl tert-butyl ether.

[0031] In some embodiments of the present invention, the preparation method, wherein,

[0032] Reagent A is selected from CS2;

[0033] Base B is selected from

[0034] Solvent C is selected from a mixed solvent of acetone and methyl tert-butyl ether.

[0035] In some embodiments of the present invention, the preparation method, wherein the molar ratio of reagent A to compound 1-2 is 1 to 6:1, the molar ratio of base B to compound 1-2 is 2 to 5:1, and the volume ratio of the mixed solvent methyl tert-butyl ether and acetone in solvent C is 15 to 25:1.

[0036] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the temperature of the reaction system is controlled in the range of 0 to 45°C.

[0037] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the temperature of the reaction system is controlled in the range of 30 to 35°C.

[0038] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the reaction time is controlled to be 16 to 60 hours.

[0039] In some embodiments of the present invention, the preparation method comprises the following steps:

[0040]

[0041] in,

[0042] Reagent D is selected from hydrazine hydrate;

[0043] Solvent E is selected from EtOH, isopropanol, toluene, MTBE, THF and DMF;

[0044] Reagent F is selected from DMF-DMA;

[0045] Solvent G is selected from MTBE, EtOAc, n-heptane, THF, isopropanol and DMF.

[0046] In some embodiments of the present invention, the preparation method, wherein,

[0047] Reagent D is selected from hydrazine hydrate;

[0048] Solvent E is selected from EtOH and isopropanol;

[0049] Reagent F is selected from DMF-DMA;

[0050] Solvent G is selected from isopropyl alcohol.

[0051] In some embodiments of the present invention, in the preparation method, the molar ratio of reagent D to compound 1-3A is 3 to 15:1, and the molar ratio of reagent F to compound 1-4 is 1 to 3:1.

[0052] In some embodiments of the present invention, the preparation method comprises the following steps:

[0053]

[0054] in,

[0055] n is selected from 0, 1 and 2;

[0056] Reagent A, base B and solvent C are defined as above;

[0057] Reagent D, solvent E, reagent F and solvent G are as defined above.

[0058] In some embodiments of the present invention, the preparation method comprises the following steps:

[0059]

[0060] in,

[0061] n is selected from 0, 1 and 2;

[0062] Reagent A, base B and solvent C are defined as above;

[0063] Reagent D, solvent E, reagent F and solvent G are defined as above;

[0064] The base H is selected from basic compounds;

[0065] Reagent I is selected from NCS;

[0066] Solvent J is selected from EtOAc, DCM, PE, THF, MTBE and CH3CN;

[0067] Reagent K is selected from

[0068] The acid binding agent L is selected from K2CO3, NaHCO3, K3PO4 and NaOAc;

[0069] Solvent M is selected from EtOAc, DCM, DMF, THF and CH3CN;

[0070] Reagent N is selected from NBS and dibromohydantoin;

[0071] Catalyst O is selected from thiocarbonyldiimidazole;

[0072] Solvent P is selected from THF, CH3CN and EtOAc;

[0073] Reagent Q is selected from a base;

[0074] The solvent R is selected from a mixed solvent, and the mixed solvent is selected from a mixed solvent of tetrahydrofuran and water, a mixed solvent of methanol and water, and a mixed solvent of methanol, tetrahydrofuran and water.

[0075] In some embodiments of the present invention, the preparation method, wherein,

[0076] Reagent A, base B and solvent C are defined as above;

[0077] Reagent D, solvent E, reagent F and solvent G are defined as above;

[0078] The base H is selected from NaOH;

[0079] Reagent I is selected from NCS;

[0080] Solvent J is selected from EtOAc;

[0081] Reagent K is selected from

[0082] The acid binding agent L is selected from NaOAc;

[0083] Solvent M is selected from EtOAc;

[0084] Reagent N is selected from NBS;

[0085] Catalyst O is selected from thiocarbonyldiimidazole;

[0086] Solvent P is selected from EtOAc;

[0087] Reagent Q is selected from lithium hydroxide monohydrate, lithium hydroxide, sodium hydroxide and potassium hydroxide;

[0088] The solvent R is selected from a mixed solvent of tetrahydrofuran and pure water, wherein the volume ratio of tetrahydrofuran to pure water in the mixed solvent is 0.25 to 4:1.

[0089] The present invention provides a method for preparing a compound of formula (I).

[0090]

[0091] It is characterized by comprising the following steps:

[0092]

[0093] in,

[0094] Reagent A is selected from CS2;

[0095] Base B is selected from TEA, DBU, DIPEA and

[0096] Solvent C is selected from a single solvent and a mixed solvent. The single solvent is selected from n-heptane, DMF, acetone and methyl tert-butyl ether. The mixed solvent is selected from a mixed solvent of acetone and methyl tert-butyl ether.

[0097] In some embodiments of the present invention, the preparation method, wherein,

[0098] Reagent A is selected from CS2;

[0099] Base B is selected from

[0100] Solvent C is selected from a single solvent and a mixed solvent. The single solvent is selected from methyl tert-butyl ether, and the mixed solvent is selected from a mixed solvent of acetone and methyl tert-butyl ether. Other variables are as defined in the present invention.

[0101] In some embodiments of the present invention, the preparation method, wherein,

[0102] Reagent A is selected from CS2;

[0103] Base B is selected from

[0104] Solvent C is selected from a mixed solvent of acetone and methyl tert-butyl ether, and other variables are as defined in the present invention.

[0105] In some embodiments of the present invention, the preparation method, wherein the molar ratio of reagent A to compound 1-2 is 1 to 6:1, the molar ratio of base B to compound 1-2 is 2 to 5:1, the volume ratio of the mixed solvent methyl tert-butyl ether and acetone in solvent C is 15 to 25:1, and other variables are as defined in the present invention.

[0106] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the temperature of the reaction system is controlled in the range of 0 to 45° C., and other variables are as defined in the present invention.

[0107] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the temperature of the reaction system is controlled in the range of 30-35° C., and other variables are as defined in the present invention.

[0108] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the reaction time is controlled to be 16 to 60 hours, and other variables are as defined in the present invention.

[0109] In some embodiments of the present invention, the preparation method comprises the following steps:

[0110]

[0111] in,

[0112] Reagent D is selected from hydrazine hydrate;

[0113] Solvent E is selected from EtOH, isopropanol, toluene, MTBE, THF and DMF;

[0114] Reagent F is selected from DMF-DMA;

[0115] Solvent G is selected from MTBE, EtOAc, n-heptane, THF, isopropanol and DMF, and other variables are as defined in the present invention.

[0116] In some embodiments of the present invention, the preparation method, wherein,

[0117] Reagent D is selected from hydrazine hydrate;

[0118] Solvent E is selected from EtOH and isopropanol;

[0119] Reagent F is selected from DMF-DMA;

[0120] Solvent G is selected from isopropyl alcohol, and other variables are as defined in the present invention.

[0121] In some embodiments of the present invention, the preparation method, wherein the molar ratio of reagent D to compound 1-3A is 3 to 15:1, the molar ratio of reagent F to compound 1-4 is 1 to 3:1, and other variables are as defined in the present invention.

[0122] In some embodiments of the present invention, the preparation method comprises the following steps:

[0123]

[0124] in,

[0125] Reagent A, base B and solvent C are as defined in the present invention;

[0126] Reagent D, solvent E, reagent F and solvent G are as defined herein, and other variables are as defined herein.

[0127] In some embodiments of the present invention, the preparation method comprises the following steps:

[0128]

[0129] in,

[0130] Reagent A, base B and solvent C are as defined in the present invention;

[0131] Reagent D, solvent E, reagent F and solvent G are as defined in the present invention;

[0132] The base H is selected from basic compounds;

[0133] Reagent I is selected from NCS;

[0134] Solvent J is selected from EtOAc, DCM, PE, THF, MTBE and CH3CN;

[0135] Reagent K is selected from

[0136] The acid binding agent L is selected from K2CO3, NaHCO3, K3PO4 and NaOAc;

[0137] Solvent M is selected from EtOAc, DCM, DMF, THF and CH3CN;

[0138] Reagent N is selected from NBS and dibromohydantoin;

[0139] Catalyst O is selected from thiocarbonyldiimidazole;

[0140] Solvent P is selected from THF, CH3CN and EtOAc;

[0141] Solvent Q is selected from a base;

[0142] The solvent R is selected from a mixed solvent selected from a mixed solvent of tetrahydrofuran and water, a mixed solvent of methanol and water, and a mixed solvent of methanol, tetrahydrofuran and water, and other variables are as defined in the present invention.

[0143] In some embodiments of the present invention, the preparation method, wherein,

[0144] Reagent A, base B and solvent C are as defined in the present invention;

[0145] Reagent D, solvent E, reagent F and solvent G are as defined in the present invention;

[0146] The base H is selected from NaOH;

[0147] Reagent I is selected from NCS;

[0148] Solvent J is selected from EtOAc;

[0149] Reagent K is selected from

[0150] The acid binding agent L is selected from NaOAc;

[0151] Solvent M is selected from EtOAc;

[0152] Reagent N is selected from NBS;

[0153] Catalyst O is selected from thiocarbonyldiimidazole;

[0154] Solvent P is selected from EtOAc;

[0155] Solvent Q is selected from lithium hydroxide monohydrate;

[0156] The solvent R is selected from a mixed solvent of tetrahydrofuran and pure water, and other variables are as defined in the present invention.

[0157] The present invention provides a method for preparing a compound of formula (I).

[0158]

[0159] It is characterized by comprising the following steps:

[0160]

[0161] in,

[0162] Reagent A is selected from CS2;

[0163] Base B is selected from

[0164] Solvent C is selected from a single solvent or a mixed solvent. The single solvent is selected from n-heptane, DMF, acetone and methyl tert-butyl ether. The mixed solvent is selected from a mixed solvent of acetone and methyl tert-butyl ether.

[0165] In some embodiments of the present invention, the preparation method, wherein,

[0166] Reagent A is selected from CS2;

[0167] Base B is selected from

[0168] Solvent C is selected from a mixed solvent of acetone and methyl tert-butyl ether, and other variables are as defined in the present invention.

[0169] In some embodiments of the present invention, the preparation method, wherein the molar ratio of reagent A to compound 1-2 is 1 to 6:1, the molar ratio of base B to compound 1-2 is 2 to 5:1, the volume ratio of the mixed solvent methyl tert-butyl ether and acetone in solvent C is 15 to 25:1, and other variables are as defined in the present invention.

[0170] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the temperature of the reaction system is controlled in the range of 0 to 45° C., and other variables are as defined in the present invention.

[0171] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the temperature of the reaction system is controlled in the range of 30-35° C., and other variables are as defined in the present invention.

[0172] In some embodiments of the present invention, in the preparation method, in the step of preparing compound 1-3A, the reaction time is controlled to be 16 to 60 hours, and other variables are as defined in the present invention.

[0173] In some embodiments of the present invention, the preparation method comprises the following steps:

[0174]

[0175] wherein,

[0176] Reagent D is selected from hydrazine hydrate;

[0177] Solvent E is selected from EtOH, isopropanol, toluene, MTBE, THF, and DMF;

[0178] Reagent F is selected from DMF-DMA;

[0179] Solvent G is selected from MTBE, EtOAc, n-heptane, THF, isopropanol, and DMF, and other variables are as defined herein.

[0180] In some embodiments of the application, the process for preparing, wherein,

[0181] Reagent D is selected from hydrazine hydrate;

[0182] Solvent E is selected from EtOH and isopropanol;

[0183] Reagent F is selected from DMF-DMA;

[0184] Solvent G is selected from isopropanol, and other variables are as defined herein.

[0185] In some embodiments of the application, the process for preparing, wherein the molar ratio of reagent D to compound 1-3A is 3 to 15: 1, and the molar ratio of reagent F to compound 1-4 is 1 to 3: 1, and other variables are as defined herein.

[0186] In some embodiments of the application, the process for preparing, comprising the steps of:

[0187]

[0188] wherein,

[0189] Base B is selected from

[0190] Reagent A and solvent C are as defined herein;

[0191] Reagent D, solvent E, reagent F, and solvent G are as defined herein, and other variables are as defined herein.

[0192] In some embodiments of the application, the process for preparing, comprising the steps of:

[0193]

[0194] wherein,

[0195] Base B is selected from

[0196] Reagent A and solvent C are as defined herein;

[0197] Reagent D, solvent E, reagent F and solvent G are as defined in the present application;

[0198] Base H is selected from basic compounds;

[0199] Reagent I is selected from NCS;

[0200] Solvent J is selected from EtOAc, DCM, PE, THF, MTBE and CH3CN;

[0201] Reagent K is selected from

[0202] Acid L is selected from K2CO3, NaHCO3, K3PO4 and NaOAc;

[0203] Solvent M is selected from EtOAc, DCM, DMF, THF and CH3CN;

[0204] Reagent N is selected from NBS and dibromohydantoin;

[0205] Catalyst O is selected from thiocarbonyldiimidazole;

[0206] Solvent P is selected from THF, CH3CN and EtOAc;

[0207] Reagent Q is selected from bases;

[0208] Solvent R is selected from mixed solvents selected from mixed solvents of tetrahydrofuran and water, mixed solvents of methanol and water and mixed solvents of methanol and tetrahydrofuran and water, other variables are as defined in the present application.

[0209] In some aspects of the present application, the process for preparing, wherein,

[0210] Reagent A, base B and solvent C are as defined in the present application;

[0211] Reagent D, solvent E, reagent F and solvent G are as defined in the present application;

[0212] Base H is selected from NaOH;

[0213] Reagent I is selected from NCS;

[0214] Solvent J is selected from EtOAc;

[0215] Reagent K is selected from

[0216] Acid L is selected from NaOAc;

[0217] Solvent M is selected from EtOAc;

[0218] Reagent N is selected from NBS;

[0219] Catalyst O is selected from thiocarbonyldiimidazole;

[0220] Solvent P is selected from EtOAc;

[0221] Reagent Q is selected from lithium hydroxide monohydrate, lithium hydroxide, sodium hydroxide and potassium hydroxide;

[0222] The solvent R is selected from a mixed solvent of tetrahydrofuran and pure water, wherein the volume ratio of tetrahydrofuran to pure water in the mixed solvent is 0.25 to 4:1, and other variables are as defined in the present invention.

[0223] Technical Effects

[0224] The process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the following beneficial effects: the raw materials are cheap and readily available, and the disadvantages of being difficult to separate and purify and not easy to industrialize are overcome.

[0225] Specifically:

[0226] 1) The raw materials of the method for preparing the compound of formula (I) of the present invention are conventional or common reagents, which are easily available on the market and inexpensive, thus avoiding the use of highly toxic reagents;

[0227] 2) The reaction conditions during the preparation of the compound are mild, easy to control, and the post-processing is simple. The solid product is directly precipitated and can be obtained by simple recrystallization with high purity and high yield, which is easy to industrialize.

[0228] Therefore, the present invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediates.

[0229] Definition and Description

[0230] 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.

[0231] 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.

[0232] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0233] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0234] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0235] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0236] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0237] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound. For example, the following formula (A) represents that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of a mixture of two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of a mixture of two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of a mixture of two isomers of formula (C-1) and formula (C-2).

[0238]

[0239]

[0240] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0241] 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 the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0242] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0243] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0244] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0245] The solvents used in the present invention are commercially available. The present invention uses the following abbreviations:

[0246] DMF-DMA N,N-Dimethylformamide dimethyl acetal DCM dichloromethane THF Tetrahydrofuran DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide EtOH ethanol TEA triethanolamine DBU 1,8-diazabicycloundec-7-ene <![CDATA[CS2]]> Carbon disulfide DIPEA N,N-Diisopropylethylamine MTBE Methyl tert-butyl ether EtOAc Ethyl acetate <![CDATA[CH3CN]]> Acetonitrile <![CDATA[K2CO3]]> potassium carbonate

[0247] <![CDATA[NaHCO3]]> Sodium bicarbonate <![CDATA[K3PO4]]> potassium phosphate NCS N-chlorosuccinimide PE Petroleum ether NaOAc Sodium acetate NBS N-Bromosuccinimide

[0248] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0249] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the content of the present invention.

[0250] Example 1: Preparation of compound of formula (I)

[0251]

[0252] Step 1: Synthesis of compound 1-2

[0253] Compound 1-1 (1.0 kg, 4.55 mol, 1 eq) was added to 5.0 L of water, adjusted to pH 10 with a 2 M aqueous NaOH solution, and extracted with 5.0 L of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with 2.0 L of ethyl acetate. The mother liquors were combined and concentrated under reduced pressure to obtain the free form of 1-1. This free form of 1-1 was dissolved in ethyl acetate (5.0 L) at an external temperature of 25-30°C, and then N-chlorosuccinimide (668.32 g, 5.01 mol, 1.1 eq) was added in portions. After the addition, the internal temperature was raised to 40-45°C. The resulting reaction solution was stirred for 12 hours. As the reaction proceeded, the internal temperature slowly dropped to 25-30°C. The reaction solution was filtered through diatomaceous earth and the mother liquor was collected. To this mother liquor, 7.0 L of a 10% aqueous sodium bisulfite solution was added, and the mixture was stirred for 15 minutes. The layers were separated, and the organic phase was washed twice with 7.0 L of a 10% aqueous sodium bisulfite solution each time. The resulting organic phase was then washed once with water (7.0 L) and once with a saturated aqueous sodium chloride solution (7.0 L), dried over anhydrous sodium sulfate (1 kg), filtered, and the filtrate was concentrated under reduced pressure to provide compound 1-2 (896.36 g, yield: 90.47%). 1 H NMR (400MHz, CDCl3) δ: 8.41-8.35 (m, 1H), 7.85-7.80 (m, 1H), 7.57-7.52 (m, 2H), 7.19 (d , J=0.8Hz, 1H), 4.43 (s, 2H), 2.26-2.17 (m, 1H), 1.07-0.97 (m, 2H), 0.74-0.67 (m, 2H); MS m / z: 217.9[M+H] + .

[0254] Step 2: Synthesis of Compounds 1-3

[0255] Compound 1-2 (650.00 g, 2.98 mol, 1 eq) was dissolved in a mixed solvent of methyl tert-butyl ether and acetone (6.5 L, v:v = 95:5) at 25-30°C. Carbon disulfide (1134.49 g, 14.9 mol, 5 eq) and triethylenediamine (1002.79 g, 8.94 mol, 3 eq) were then added sequentially with stirring. The resulting reaction solution was stirred at 30-35°C for 48 hours. After the reaction was completed, stirring was continued and the reaction solution was programmed to cool to 0°C (controlling the cooling rate at 5°C per hour). The suspension was filtered, and the filter cake was washed twice with a mixed solvent of methyl tert-butyl ether and acetone (methyl tert-butyl ether:acetone = 95:5, v:v), 100 mL each time. The filter cake was vacuum dried to obtain a light yellow solid, Compound 1-3 (1345.68 g, 90.51% yield). 1 H NMR (400MHz, DMSO-d6) δ: 9.86 (br s, 1H), 8.37-8.31 (m, 1H), 7.93-7.85 (m, 1H), 7.59-7.51 (m, 2H), 7.20 (s, 1H), 3.82 (br s, 24H), 2.45-2.35 (m, 1H), 1.11-1.01 (m, 2H), 0.80-0.71 (m, 2H).

[0256] Step 3: Synthesis of Compounds 1-4

[0257] Compound 1-3 (530.0 g, 0.97 mol, 1 eq) and ethanol (3.5 L) were added to a reaction flask and stirred. Hydrazine hydrate (248.34 g, 4.86 mol, 5 eq) was then added dropwise at 20-23°C. After the addition was complete, the resulting mixture was stirred at 20-23°C for 18 hours, followed by the addition of hydrazine hydrate (12 mL). Stirring was continued at 20-23°C for 48 hours. The reaction mixture was filtered, and the filter cake was washed twice with 100 mL of ethanol each time. The filter cake was collected and dried in a vacuum oven at 35°C to yield compound 1-4 (271.82 g, yield: 90.05%). 1 H NMR (400MHz, DMSO-d6) δ: 9.22 (br s, 1H), 8.48-8.31 (m, 1H), 7.91-7.75 (m, 1H), 7.67-7.48 (m, 2H), 7.27 (s, 1H ), 2.80(s, 2H), 2.47-2.40(m, 1H), 1.12-1.08(m, 2H), 0.85-0.71(m, 2H); MS m / z: 291.9[M+H] + .

[0258] Step 4: Synthesis of Compounds 1-5

[0259] To the reaction flask were added 1-4 (260.0 g, 0.89 mol, 1 eq), isopropanol (1.3 L), and N,N-dimethylformamide dimethyl acetal (159.26, 1.34 mol, 1.5 eq), and the resulting mixture was stirred at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure to approximately 500 mL, cooled to room temperature, and the pH of the reaction solution was adjusted to 5-6 with dilute aqueous hydrochloric acid (1 M), and stirring was continued for 2 hours. The reaction solution was filtered, and the filter cake was washed with 200 mL of filtered mother liquor. The filter cake was collected and vacuum dried to obtain a light gray solid. The solid was stirred and slurried with 2.0 L of n-heptane, stirred at 20-25°C for 16 hours, and filtered. The filter cake was washed twice with n-heptane (200 mL). The filter cake was collected and dried under reduced pressure to obtain compound 1-5 (210.68 g, yield: 83.35%). 1 H NMR (400MHz, CD3OD) δ: 8.58 (d, J=8.0Hz, 1H), 8.37 (s, 1H), 7.73-7.67 (m, 1H), 7.67-7.62 (m, 1H), 7.48-7.45(m,1H),7.38-7.34(m,1H),2.59-2.49(m,1H),1.25-1.18(m,2H),0.96-0.84(m,2H);MS m / z: 301.9[M+H] + .

[0260] Step 5: Synthesis of Compounds 1-6

[0261] Compound 1-5 (330.02 g) and ethyl acetate (3.3 L) were added to a 5L three-necked flask in sequence and stirred evenly. Sodium acetate (179.68 g) was then added at one time and stirred evenly. Methyl bromoacetate (200.86 g) was added once again and stirred evenly. The resulting reaction solution was stirred and reacted at an external temperature of 60°C for 16 hours. The reaction solution was then filtered while hot (external temperature 60°C), the filter cake was washed twice with ethyl acetate (100 mL), and the filtrate was combined. Four batches (same mass) were fed in parallel using the same process, and the ethyl acetate filtrates filtered after the reaction were combined and combined in the following manner.

[0262] First wash: Add 14 L of pure water to the ethyl acetate filtrate, stir vigorously for 20 minutes, and allow to stand to separate. After separation, the aqueous phase is discharged, and a small amount of flocculent layer remains in the ethyl acetate phase.

[0263] Second washing: Add 14 L of pure water to the ethyl acetate phase, stir vigorously for 20 minutes, and then let it stand to separate. After separation, the aqueous phase is released, and a small amount of flocculent layer remains in the ethyl acetate phase.

[0264] Third washing: To the ethyl acetate phase, add pure water 14 L, stir vigorously for 20 minutes, and then separate the layers. The lower aqueous phase is removed. The organic phase containing a small amount of flocculent is filtered through diatomite, and the filtrate is combined with the remaining organic phase (about 14 L) and dried over anhydrous sodium sulfate 5 kg, filtered, and the filtrate is concentrated under reduced pressure to obtain a dark red oil. The oil is cooled to room temperature to obtain a dark red solid crude product 1-6 (1640.73 g, yield 87.11%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.94 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 7.84-7.66 (m, 2H), 7.52 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.16-4.05 (m, 2H), 3.63 (s, 3H), 2.66-2.56 (m, 1H), 1.23-1.11 (m, 2H), 1.01-0.83 (m, 2H); MS m / z: 374.0 [M+H] + .

[0265] Step 6: Synthesis of compound 1-7

[0266] Into a 5 L three-necked flask, add compound 1-6 (330.05 g) and ethyl acetate (3.3 L) successively. Stir the mixture at 40-45 °C until it is completely dissolved. Add thionyl diimidazole (15.73 g) under stirring, and continue to stir at 40-45 °C for 10 minutes. Add N-bromosuccinimide (157.10 g) portionwise under stirring, and continue to stir the reaction mixture at 40-45 °C for 1 hour. Finally, add N-bromosuccinimide (15.74 g) again, and continue to stir at 40-45 °C for 15 minutes. Cool the reaction mixture to room temperature, filter through diatomite, wash the filter cake with ethyl acetate (200 mL) twice, and combine the filtrates. Repeat the same procedure for five batches (same amount), and combine the ethyl acetate filtrates after the reaction is completed. Then, the combined filtrates are treated as follows.

[0267] First washing: To the ethyl acetate filtrate, add pure water 17.2 L, stir vigorously for 20 minutes, and then separate the layers. The aqueous phase is removed, and a small amount of flocculent layer remains in the ethyl acetate phase.

[0268] Second washing: To the ethyl acetate phase, add 10% sodium bisulfite solution 17.2 L, stir vigorously for 20 minutes, and then separate the layers. The aqueous phase is removed, and a small amount of flocculent layer remains in the ethyl acetate phase.

[0269] Third washing: Add 17.2 L of 10% sodium bisulfite solution to the ethyl acetate phase, stir vigorously for 20 minutes, and allow to stand to separate. After separation, the aqueous phase is discharged, leaving a small amount of flocculent layer in the ethyl acetate phase.

[0270] Fourth wash: Add 17.2 L of pure water to the ethyl acetate filtrate, stir vigorously for 20 minutes, and allow to stand to separate. After separation, the aqueous phase is discharged, leaving a small amount of flocculent layer in the ethyl acetate phase.

[0271] Fifth wash: Add 17.2 L of pure water to the ethyl acetate filtrate, stir vigorously for 20 minutes, and allow to separate. After separation, the lower aqueous phase was discharged. The lower organic phase, which contained a small amount of flocculent material, was filtered through diatomaceous earth and combined with the remaining organic phase (approximately 17 L total), and dried over 8 kg of anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield a dark red crude solid (1562.17 g).

[0272] The dark red solid was added to methyl tert-butyl ether (5.5 L) and stirred at an external temperature of 80°C until it became clear. Then, n-heptane (3.5 L) was added to the methyl tert-butyl ether solution. After stirring at an external temperature of 60°C for 16 hours, a large amount of solid precipitated from the solution. n-heptane (2.0 L) was added and stirring continued at an external temperature of 60°C for 2 hours. The mixed solution was then programmed to cool to an external temperature of 40°C (5°C per hour). Stirring was stopped and the mixture was filtered. The filter cake was thoroughly washed with n-heptane (1.5 L). The filter cake was collected and dried under vacuum at 40°C for 2 hours to obtain a light yellow solid (1107.09 g).

[0273] The above-mentioned light yellow solid (1100.01 g) was added to isopropanol (5.5 L), heated to an external temperature of 110°C, and refluxed to obtain a clear solution. The isopropanol solution was programmed to cool to an external temperature of 95°C (5°C per hour) and stirred at this temperature for 16 hours, during which a small amount of off-white solid precipitated. The temperature was further programmed to cool to an external temperature of 60°C (5°C per hour) and stirred at this temperature for 60 hours, during which a large amount of solid precipitated. The mixture was filtered while hot and the filter cake was thoroughly washed with isopropanol (500 mL). The filter cake was collected and dried under vacuum at 40°C for 16 hours to obtain 1-7 (962.69 g, 52.27% yield) as a light yellow solid. 1 H NMR (400MHz, CD3OD) δ: 8.63 (d, J=8.3Hz, 1H), 7.82-7.65 (m, 2H), 7.51 (s, 1H), 7.29-7.20 (m, 1H) ), 4.16-3.94(m, 2H), 3.72(s, 3H), 2.64-2.49(m, 1H), 1.30-1.20(m, 2H), 0.99-0.85(m, 2H); MS m / z: 453.7[M+H+2] +.

[0274] Step 7: Synthesis of compound of formula (I)

[0275] Compound 1-7 (330.12 g) was added to a 5L three-necked flask, followed by a mixed solution of anhydrous tetrahydrofuran (1650 mL) and pure water (1650 mL), and stirred evenly. Lithium hydroxide monohydrate (183.91 g) was then added all at once, and the resulting reaction solution was stirred at an external temperature of 30°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature (20°C). Three batches of the same process were added in parallel, and the reaction solutions were combined and processed as follows.

[0276] The combined reaction mixture was concentrated under reduced pressure (<40°C) to remove tetrahydrofuran, and the aqueous phase was cooled to 0°C. Aqueous hydrobromic acid (40%) was added dropwise at 0°C with stirring until the mixture reached a pH of 3, resulting in the precipitation of a large amount of solid. The mixture was stirred for 16 hours at an external temperature of 20°C, and the pH was retested to 3. The mixture was filtered, and the filter cake was thoroughly washed with pure water (500 mL). The filter cake was collected and dried under vacuum at 40°C for 6 hours to obtain 895.65 g of crude compound of formula (I). A 10-L three-necked flask was charged with crude compound of formula (I) (890.12 g), followed by a mixture of ethanol (2225 mL) and pure water (2225 mL), and stirred at an external temperature of 40°C for 48 hours. The mixture was then cooled gradually to an external temperature of 20°C (5°C / hour). The mixture was filtered, and the filter cake was thoroughly washed with a mixture of ethanol and pure water (450 mL, V:V = 1:1). The filter cake was collected and dried under vacuum at 40° C. for 16 hours to obtain the compound of formula (I) (692.16 g, yield 77.78%). 1 H NMR (400MHz, DMSO-d6) δ: 13.02 (s, 1H), 8.61 (d, J = 8.4Hz, 1H), 7.83-7.69 (m, 2H), 7.56 (d, J = 8.0Hz, 1H) , 7.19 (d, J=8.4Hz, 1H), 4.12-3.96 (m, 2H), 2.69-2.57 (m, 1H), 1.24-1.13 (m, 2H), 1.03-0.91 (m, 2H); MS m / z: 439.9[M+H+2] + .

Claims

1. A method for preparing a compound of formula (I), It is characterized by: The following steps are included: in, n is selected from 0, 1 and 2 Reagent A is selected from CS2; Base B is selected from TEA, DBU, DIPEA and Solvent C is selected from a mixed solvent of acetone and methyl tert-butyl ether.

2. The preparation method according to claim 1, wherein Reagent A is selected from CS2; Base B is selected from 3. The preparation method according to any one of claims 1 to 2, wherein The molar ratio of reagent A to compound 1-2 is 1-6:1, the molar ratio of base B to compound 1-2 is 2-5:1, and the volume ratio of the mixed solvent of solvent C, methyl tert-butyl ether and acetone, is 15-25:

1.

4. The preparation method according to any one of claims 1 to 2, wherein In the step of preparing compound 1-3A, the temperature of the reaction system is controlled in the range of 0 to 45°C.

5. The preparation method according to claim 4, wherein In the step of preparing compound 1-3A, the temperature of the reaction system is controlled in the range of 30-35°C.

6. The preparation method according to any one of claims 1 to 2, wherein In the step of preparing compound 1-3A, the reaction time is controlled to be 16 to 60 hours.

7. The preparation method according to any one of claims 1 to 2, comprising the steps of: in, Reagent D is selected from hydrazine hydrate; Solvent E is selected from EtOH, isopropanol, toluene, MTBE, THF and DMF; Reagent F is selected from DMF-DMA; Solvent G is selected from MTBE, EtOAc, n-heptane, THF, isopropanol and DMF.

8. The preparation method according to claim 7, wherein Reagent D is selected from hydrazine hydrate; Solvent E is selected from EtOH and isopropanol; Reagent F is selected from DMF-DMA; Solvent G is selected from isopropyl alcohol.

9. The preparation method according to claim 8, wherein The molar ratio of reagent D to compound 1-3A is 3 to 15:1, and the molar ratio of reagent F to compound 1-4 is 1 to 3:

1.

10. The preparation method according to any one of claims 1 to 2 and 8, comprising the following steps: in, n is selected from 0, 1 and 2; Reagent A, base B and solvent C are as defined in any one of claims 1 to 2; Reagent D, solvent E, reagent F and solvent G are as defined in claim 8.

11. The preparation method according to claim 10, comprising the steps of: in, n is selected from 0, 1 and 2; Reagent A, base B and solvent C are as defined in claim 10; Reagent D, solvent E, reagent F and solvent G are as defined in claim 10; The base H is selected from basic compounds; Reagent I is selected from NCS; Solvent J is selected from EtOAc, DCM, PE, THF, MTBE and CH3CN; Reagent K is selected from The acid binding agent L is selected from K2CO3, NaHCO3, K3PO4 and NaOAc; Solvent M is selected from EtOAc, DCM, DMF, THF and CH3CN; Reagent N is selected from NBS and dibromohydantoin; Catalyst O is selected from thiocarbonyldiimidazole; Solvent P is selected from THF, CH3CN and EtOAc; Reagent Q is selected from a base; The solvent R is selected from a mixed solvent, and the mixed solvent is selected from a mixed solvent of tetrahydrofuran and water, a mixed solvent of methanol and water, and a mixed solvent of methanol, tetrahydrofuran and water.

12. The preparation method according to any one of claims 1, 8 and 11, wherein Reagent A, base B and solvent C are as defined in claim 1; Reagent D, solvent E, reagent F and solvent G are as defined in claim 8; The base H is selected from NaOH; Reagent I is selected from NCS; Solvent J is selected from EtOAc; Reagent K is selected from The acid binding agent L is selected from NaOAc; Solvent M is selected from EtOAc; Reagent N is selected from NBS; Catalyst O is selected from thiocarbonyldiimidazole; Solvent P is selected from EtOAc; Reagent Q is selected from lithium hydroxide monohydrate, lithium hydroxide, sodium hydroxide and potassium hydroxide; The solvent R is selected from a mixed solvent of tetrahydrofuran and pure water, and the volume ratio of tetrahydrofuran to pure water in the mixed solvent is 0.25 to 4:1.

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