A method for preparing chiral oxazine compounds

Abstract

A method for preparing a chiral oxazine compound, specifically a method for preparing a compound of formula (I) and its intermediates. #imgabs0#

Description

[0001] This application claims priority to Chinese patent application No. 202110053483.1, filed January 15, 2021. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a method for preparing a chiral oxazine compound, and in particular to a method for preparing a compound of formula (I) and an intermediate thereof of formula (II). Background Art

[0003] Hepatitis B, or HBV for short, is a disease caused by infection with the hepatitis B virus (HBV). HBV is a hepatotropic virus that primarily resides in and damages liver cells, causing inflammation, necrosis, and fibrosis. Hepatitis B can be classified as acute or chronic. Acute HBV in adults is generally self-resolved through the body's own immune system. However, chronic hepatitis B (CHB) has become a significant challenge to global healthcare and a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). An estimated 2 billion people worldwide are infected with chronic HBV, over 350 million have developed HBV, and nearly 600,000 people die annually from complications of CHB. my country is a high-incidence area for HBV, with a high cumulative number of patients and severe consequences. According to data, there are about 93 million people infected with hepatitis B virus in my country, and about 20 million of them are diagnosed with chronic hepatitis B. Among them, 10%-20% may develop into cirrhosis and 1%-5% may develop into liver cancer.

[0004] The key to a functional cure for hepatitis B is clearance of HBsAg (hepatitis B virus surface antigen) and the production of surface antibodies. HBsAg quantification is a crucial biomarker. HBsAg reduction and seroconversion, currently the endpoint of treatment, are rarely observed in chronically infected patients.

[0005] Patent WO2018214875 discovered a surface antigen inhibitor that can effectively reduce HBsAg. Currently approved anti-HBV drugs are mainly immunomodulators (interferon-α and pegylated interferon-α-2α) and antiviral drugs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir, clavulanate, etc.). Among them, antiviral drugs belong to the nucleotide class of drugs, whose mechanism of action is to inhibit the synthesis of HBV DNA and cannot directly reduce HBsAg levels. Like extended treatment, nucleotide drugs show HBsAg clearance rates similar to natural observations (Janssen et al. Lancet (2005), 365, 123-129; Marcellin et al. N. Engl. J. Med. (2004), 351, 1206-1217; Buster et al. Hepatology (2007), 46, 388-394). Existing clinical therapies are not effective in reducing HBsAg. Therefore, the development of small molecule oral inhibitors that can effectively reduce HBsAg is urgently needed for clinical use. Summary of the Invention

[0006] The present invention provides a method for preparing a compound of formula (I),

[0007]

[0008] It is characterized by comprising the following steps:

[0009]

[0010] in,

[0011] T is selected from CH and N;

[0012] R1 is selected from H, OH, CN, NH2, C 1～5 Alkyl, C 1～5 Heteroalkyl, C 2～5 Alkynyl, C 3～6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1～5 Alkyl, C 1～5 Heteroalkyl, C 2～5 Alkynyl, C 3～6 Cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

[0013] R2 is selected from H, F, Cl, Br, I, C 1～3 Alkyl and C 1～3 heteroalkyl, the C 1～3 Alkyl and C 1～3 Heteroalkyl is optionally substituted with 1, 2, or 3 R;

[0014] R3 is selected from H, F, Cl, Br, I, CN, -C(=O)-OC 1～3 Alkyl, -C(=O)-NH-C 1～3 Alkyl, -C(=O)-N(C 1～3 Alkyl)2;

[0015] m is selected from 0, 1, 2, 3, 4 and 5;

[0016] A is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 R;

[0017] R is selected from H, F, Cl, Br, I, OH, CN, NH2, =O, CH3, CH3CH2, CH3O, CF3, CHF2, CH2F;

[0018] The C 1～5 Heteroalkyl, 3-6 membered heterocycloalkyl, C 1～3 The heteroalkyl and 5- to 6-membered heteroaryl groups each independently contain 1, 2 or 3 heteroatoms or heteroatom groups each independently selected from N, -O-, =O, -S-, -NH-, -(C=O)-, -(S=O)- and -(S=O)2-.

[0019] In some embodiments of the present invention, the method for preparing the compound of formula (I) further comprises the following steps:

[0020]

[0021] wherein R1, R2 and m are as defined in the present invention.

[0022] In some embodiments of the present invention, the method for preparing the compound of formula (I) further comprises the following steps:

[0023]

[0024] wherein R1, R2, m and A are as defined in the present invention.

[0025] In some embodiments of the present invention, the preparation method of the compound of formula (I) above, wherein R1 is selected from H, OH, CN, NH2, CH3, CH3CH2, CH3CH2CH2, CH3CH2CH2CH2, CH3O, CH3CH2O, CH3S, CH3S(=O), CH3S(=O)2, CH3SCH2, CH3CH2S, CH3NH, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, 2-pyrrolidonyl and 3-pyrrolidonyl, the CH3, CH3CH2, CH3CH2CH2, CH3CH2CH2CH2, CH3O, CH3CH2O, CH3S, CH3S(=O), CH3S(=O)2, CH3SCH2, CH3CH2S, CH3NH, Pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, 2-pyrrolidonyl and 3-pyrrolidonyl are optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0026] In some embodiments of the present invention, the preparation method of the compound of formula (I) above, wherein R1 is selected from H, OH, CN, NH2, CH3, CH3CH2, CH3CH2CH2, CH3CH2CH2CH2, CH3O, CH3CH2O, CH3S, CH3S(=O), CH3S(=O)2, CH3SCH2, CH3CH2S, CH3NH, The CH3, CH3CH2, CH3CH2CH2, CH3CH2CH2CH2, CH3O, CH3CH2O, CH3S, CH3S(=O), CH3S(=O)2, CH3SCH2, CH3CH2S, CH3NH, It is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0027] In some embodiments of the present invention, the above R1 is selected from H, OH, CH3, CHF2, CH3O, Other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, the preparation method of the compound of formula (I) above, wherein R2 is selected from H, F, Cl, Br, CH3, CH3CH2, CH3O, CH3CH2O and The CH3, CH3CH2, CH3O, CH3CH2O and It is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0029] In some embodiments of the present invention, the method for preparing the compound of formula (I) above, wherein R2 is selected from Cl and CH3O, and the other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the preparation method of the compound of formula (I) above, wherein A is selected from phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, and the phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl are optionally substituted with 1, 2 or 3 R, and other variables are as defined herein.

[0031] In some embodiments of the present invention, the preparation method of the compound of formula (I) above, wherein A is selected from described It is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0032] In some embodiments of the present invention, the preparation method of the compound of formula (I) above, wherein A is selected from Other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the preparation method of the compound of formula (I) above, wherein A is selected from Other variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the preparation method of the compound of formula (I) above, wherein R3 is selected from -C(=O)-N(CH3)2, -C(=O)-O-CH3, Cl and CN, and the other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, the preparation method of the compound of formula (I) is as follows:

[0036]

[0037] wherein T, A and R3 are as defined in the present invention.

[0038] In some embodiments of the present invention, the preparation method of the compound of formula (I) is as follows:

[0039]

[0040]

[0041]

[0042]

[0043]

[0044] The present invention also provides a compound of formula (II)

[0045]

[0046] in,

[0047] T and A are as defined in the present invention,

[0048] R3 is selected from -C(=O)-N(CH3)2, -C(=O)-O-CH3, Cl and CN.

[0049] In some embodiments of the present invention, the compound of formula (II) is selected from

[0050] The present invention also provides a method for preparing the compound of formula (II), comprising the following steps:

[0051]

[0052] wherein T, R3 and A are as defined in the present invention.

[0053] The present invention also provides a method for preparing the compound of formula (I), comprising the following steps:

[0054]

[0055] in,

[0056] M, R1, R2, R3, T and A are as defined herein.

[0057] Some other technical solutions of the present invention are obtained by arbitrarily combining the above variables.

[0058] Technical Effects

[0059] The preparation methods of such compounds disclosed in the prior art are not chiral synthesis methods and require chiral separation to obtain a single configuration, which results in low yields and high costs.

[0060] The present invention adopts a chiral induction synthesis strategy, which can obtain the target product with a single configuration without chiral resolution. The process route of the present invention has the following advantages:

[0061] 1) The raw materials are readily available and inexpensive, are commonly used reagents, have stable physical and chemical properties, and are easy to operate.

[0062] 2) The entire route is simple and easy to operate, requiring only simple extraction, washing, filtration and other methods, and no column chromatography purification is required throughout the process.

[0063] 3) Oxidation and hydrolysis are added continuously without separation, which is simple to operate and improves product yield.

[0064] Therefore, the preparation method of the present invention has obvious advantages: the raw materials are cheap and easily available, the reaction conditions are mild and controllable, the intermediates and the final product are easy to separate and purify, and the reaction scale is very suitable for industrialization.

[0065] Definition and Description

[0066] 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.

[0067] 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.

[0068] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0069] 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.

[0070] 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.

[0071] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0072] 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

[0073] 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).

[0074]

[0075]

[0076] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0077] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0078] 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%.

[0079] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0080] 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.

[0081] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0082] The term "substituted" refers to any one or more hydrogen atoms on a particular atom being replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced.

[0083] The term "optionally substituted" means that the group may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any based on chemical feasibility.

[0084] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0 to 2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0085] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond, and -C0alkyl-A means that the structure is actually -A.

[0086] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0087] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0088] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0089] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0090] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0091] When a substituent's bond can cross-link to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g. It means that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0092] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0093] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0094] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members. For example, a "5- to 7-membered ring" refers to a "ring" having 5 to 7 atoms arranged around it.

[0095] Unless otherwise specified, the term “C 1～5 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 5 carbon atoms.1～5 Alkyl groups include C 1～4 、C 1～3 、C 1～2 、C 2～5 、C 2～4 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1～5 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), and the like.

[0096] Unless otherwise specified, the term “C 1～3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1～3 Alkyl groups include C 1～2 and C 2～3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1～3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0097] Unless otherwise specified, “C 2～5 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 5 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2～5 Alkynyl groups include C 2～4 、C 2～3 , C5, C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2～6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0098] Unless otherwise specified, “C 3～6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3～6 Cycloalkyl groups include C 3～5 、C 4～5 and C 5～6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3～6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0099] Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., C(=O), NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings. In addition, with respect to the "3- to 6-membered heterocycloalkyl", heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3- to 6-membered heterocycloalkyl includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyls, etc. Examples of 3- to 6-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0100] Unless otherwise specified, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" of the present invention can be used interchangeably. The term "5- to 6-membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO and S(O)p, where p is 1 or 2). The 5- to 6-membered heteroaryl can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5- and 6-membered heteroaryl groups. Examples of the 5- to 6-membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl), and the like. and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0101] The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 In other embodiments, the heteroalkyl group is C 1～5 In other embodiments, the heteroalkyl group is C 1～3Heteroalkyl. The heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are customary expressions and refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-S-CH-CH, -CH-CH, -S(=O)-CH, -CH-CH-S(=O)-CH, and -CH. Up to two heteroatoms may be consecutive, for example, -CH-NH-OCH.

[0102] The solvents used in the present invention are commercially available. The present invention uses the following abbreviations:

[0103] DMF-DMA N,N-Dimethylformamide dimethyl acetal DCM dichloromethane THF Tetrahydrofuran PMB p-Methoxybenzyl, a protecting group DMF N,N-Dimethylformamide TFA Trifluoroacetic acid DCM dichloromethane PIFA [Bis(trifluoroacetyloxy)iodo]benzene DMSO Dimethyl sulfoxide EtOH ethanol MeOH Methanol <![CDATA[SOCl2]]> Thionyl chloride DIPEA Diisopropylethylamine <![CDATA[SiO2]]> 100-200 mesh silica gel powder, for column chromatography SFC Supercritical fluid chromatography p-HPLC Preparative HPLC for compound purification

[0104] Compounds are named according to the conventional nomenclature in the art or using The software named the commercially available compounds using the supplier's catalog name. DETAILED DESCRIPTION

[0105] 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.

[0106] Preparation of intermediate 1-1:

[0107]

[0108] In a 50L reactor under nitrogen, add 2.8L of dichloromethane at 23°C. Cool to 0-5°C, add 899mL of thionyl chloride, start stirring, and slowly add 1458mL of methyl isonicotinate dropwise at 2-3°C. After the addition is complete, the temperature rises to 4-5°C. Then, slowly add thiophene-2-carboxaldehyde dropwise, maintaining the internal temperature at 0-5°C. After the addition is complete, slowly raise the temperature to 25-35°C. Continue stirring and react for 19 hours to form intermediate 1-1, which is used directly in the next reaction.

[0109] Example 1: Preparation of compound (1)

[0110]

[0111] Step 1: Synthesis of compound 2

[0112] Under nitrogen, a 200-L reactor was charged with 17 kg of compound 1, 37 kg of potassium phosphate, 85 L of acetonitrile, and 32 kg of 1-bromo-3-methoxypropane (1.5 eq.). The atmosphere was replaced with nitrogen once, and the internal temperature was raised to 80-85°C and stirred for 20 h. The mixture was then cooled to room temperature (25°C) and filtered. The filter cake was rinsed with 20 L of acetonitrile. The filtrate was concentrated under reduced pressure, with the external temperature below 50°C. 40 L of toluene was added, and the mixture was stirred for 1 h. Then, 50 kg of 10% aqueous sodium hydroxide solution was added, stirred for 1 h, and the layers separated. The aqueous phase was adjusted to pH 4-5 with concentrated hydrochloric acid and extracted with ethyl acetate (85 L). The organic phase was concentrated under reduced pressure to obtain compound 2 (22.7 kg, purity: 99.4%, yield: 90.0%) as a brown oil.

[0113] Step 2: Synthesis of compound 3

[0114] Under nitrogen protection, compound 2 (22.7 kg) and 228 L of dichloromethane were added to a 500 L reactor, cooled to -10 ° C, and 21 kg of sulfonyl chloride was added dropwise at -10 ~ 5 ° C. The mixture was stirred for 1 h at -10 ~ 5 ° C. After the reaction was completed, the reaction solution was pumped into 90 L of water, stirred for 30 min, and separated. The organic phase was washed with saturated sodium bicarbonate (50 L), allowed to stand and separated, and concentrated to dryness under reduced pressure. DMF 110 L, p-methoxybenzyl chloride 16.8 kg, and potassium carbonate 9 kg were added to the concentrated dry matter, and the temperature was raised to 40 ° C. and stirred for 2 h. The reaction was completed. The mixture was cooled to room temperature, 50 L of water was added, and the mixture was stirred. 110 L of ethyl acetate was added, and the mixture was stirred for 30 min. The mixture was allowed to stand for separation. The organic phase was washed with 60 L of water, and the mixture was concentrated under reduced pressure with the temperature controlled below 50°C. 70 L of isopropanol was added, and the mixture was heated at 60°C to dissolve the mixture. The mixture was cooled to 0-10°C for crystallization, and the mixture was filtered and dried to obtain compound 3 (25.1 kg, purity: 98.7%, yield: 63.8%).

[0115] Step 3: Synthesis of compound 4

[0116] Compound 3 (25.1 kg), R-tert-butylsulfenamide (10 kg), potassium phosphate (17.6 kg), and toluene (125 L) were added to a 200 L reactor and heated to 60°C under nitrogen for 20 h. After cooling to room temperature (25-30°C), 50 L of water was added and stirred for 30 min. The mixture was allowed to stand for 1 h. The layers were separated and the organic phase was dried over anhydrous sodium sulfate (5 kg). The mixture was filtered and the filtrate was concentrated to dryness. 50 L of n-heptane was added and the temperature was lowered by 10-20°C. The mixture was slurried for 2 h, filtered, and dried to obtain compound 4 (29.1 kg, purity: 98.5%, yield: 90%).

[0117] Step 4: Synthesis of compound 5

[0118] Under nitrogen, 2-Me-THF (11.25 L) and NaHMDS (2M THF, 12.937 L) were added to a 50 L reactor at 25-34°C. Stirring was initiated and the reactor was cooled to -45°C using dry ice ethyl acetate as an external bath. Methyl acetate (2.058 L) was added dropwise to the reactor under nitrogen, maintaining the internal temperature between -45°C and -48°C during the addition. After completion, stirring was continued at -40°C to -48°C for 0.5 hour. A solution of compound 4 (3000 g) in 2-Me-THF (5.62 L) was added dropwise to the reactor at -48°C. After completion, the internal temperature was raised to -40°C, and the reaction was continued at -40°C to -49°C for 0.5 hour. Hydrochloric acid (4 M, 11.53 L) was added dropwise to the reactor at -20°C to -15°C, controlling the addition rate. After completion, the pH was 7-8. The reaction mixture was transferred to a 50L separatory vessel and allowed to stand for separation. The aqueous phase was discarded, and the organic phase was washed once with saturated brine (3.6L), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. This reaction was repeated in two batches, yielding a total of compound 5 (7900g, 92.45% purity).

[0119] Step 5: Synthesis of compound 6

[0120] Compound 5 (3.95 kg) was dissolved in 8 L of DCM. DMF-DMA (3.59 L) was added at 25°C to 31°C and stirred within this temperature range for 18.5 h. The reaction mixtures were combined and concentrated. This reaction was repeated in two parallel batches. A total of compound 6 (9100 g, 75.82% purity) was obtained.

[0121] Step 6: Synthesis of compound 7

[0122] The crude product of compound 6 (5700g) was dissolved in 20.37L methanol, and the temperature was lowered to 5°C to 10°C. 8.92L of aqueous hydrochloric acid solution (2M) was slowly added to the reactor, and the internal temperature was controlled at 20°C-25°C during the dropwise addition. After the dropwise addition was completed, the reaction was continued for 17 hours. Two pots were added in parallel for this reaction, and the amount of material added to the other pot was 3400g. The two pots of reaction liquid were combined, filtered, and dried. The dried crude product was transferred to a 50L reactor, 23.5L of ethanol was added, and the temperature was raised to 60°C and continued to stir for 2 hours, and then naturally cooled to room temperature (20°C-25°C). Compound 7 (4300g, purity 99.11%) was obtained by filtration and drying. 1H NMR (400 MHz, deuterated dimethyl sulfoxide) δ 9.1-9.2 (d, 1H, J = 8.0 Hz), 8.25 (d, 1H, J = 4.0 Hz), 7.41 (d, 2H, J = 8.0 Hz), 7.21 (s, 1H), 6.9-7.0 (d, 3H, J = 8.0 Hz), 5.1-5.2 (m, 2H), 5.0-5.1 (m, 1H), 4.15 (t, 2H, J = 8.0 Hz), 3.76 (s, 3H), 3.57 (s, 3H), 3.42-3.50 (m, 4H), 2.51-2.54 (m, 2H), 1.92-1.99 (m, 2H).

[0123] Step 7: Synthesis of compound 8

[0124] In a 50L reactor, 8.5L of dichloromethane, 4250.00g of compound 7, and m-phenylenedimethyl ether (1187mL) were added in sequence, stirred evenly, and the internal temperature was 25°C. Cooled in an ice-water bath, TFA (3220mL) was added dropwise while maintaining the temperature at 10°C to 18°C, and the reaction was completed. The temperature was raised to 35°C to 40°C and stirred for 20 hours, and the crude product was filtered. The crude product was transferred to a 50L reactor, 20L of ethyl acetate was added, heated to 60°C and stirred for 2 hours, then cooled to 25°C and stirred for 17 hours. The stirred solution was centrifuged and the filter cake was washed with ethyl acetate (1.5L). The filter cake was vacuum dried to obtain compound 8 (2803.50g, yield 87.40%). 1H NMR (400 MHz, deuterated dimethyl sulfoxide) δ 10.19 (s, 1H), 9.13 (d, 1H, J = 8.0 Hz), 8.23 (d, 1H, J = 4.0 Hz), 7.12 (s, 1H), 6.62 (s, 1H), 4.9-5.0 (m, 1H), 4.01 (t, 2H, J = 8.0 Hz), 3.57 (s, 3H), 3.48 (t, 2H, J = 8.0 Hz), 3.37 (s, 3H), 3.24 (s, 3H), 2.5-2.6 (m, 2H), 1.96 (m, 2H).

[0125] Step 8: Synthesis of compound 9

[0126] 25.2L of dichloromethane was added to the reaction solution of intermediate 1-1, cooled to 20°C, and then 2773.50g of compound 8 was added. After that, 4582mL of diisopropylethylamine was slowly added dropwise to the reaction solution, and the internal temperature was maintained at 22-28°C during the addition. After the dropwise addition, the reaction was continued at 22-28°C for 1 hour. The reaction solution was cooled to 0-5°C, 14.0L of ice water was added to the reactor, stirred, and extracted, and the organic phase was washed with 14.0L of ice water. The organic phase was collected and concentrated under reduced pressure. The dark brown concentrated residue was transferred to a 25L bucket, 10.5L of ethanol and 3.5L of aqueous hydrochloric acid solution (2M) were added, stirred for 1.5 hours, and a large amount of solid was precipitated. The filter cake was washed with 2.0L of ethanol and a light yellow filter cake was collected. The mixture was transferred to a 30 L reactor, and 10.0 L of acetone and 2.0 L of water were added. Stirring was started, and the temperature was slowly raised to 60°C and stirred for 6 hours. Heating was stopped, and the mixture was allowed to cool naturally to room temperature and continued to stir for 10 hours. The mixture was filtered under reduced pressure, and the filter cake was washed with 2.0 L of ethanol to obtain a light yellow solid. The filter cake was vacuum dried to obtain compound 9 (1560.00 g, 44.8% yield). 1H NMR (400 MHz, deuterated chloroform) δ 7.90 (s, 1H), 7.60 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.19 (d, 1H, J = 4.0 Hz), 7.13 (s, 1H), 6.62 (s, 1H), 6.26 (s, 1H), 5.11 (dd, 1H, J = 8.0, 12.0 Hz), 4.07 (t, 2H, J = 8.0 Hz), 3.67 (s, 3H), 3.56 (t, 2H, J = 8.0 Hz), 3.33 (s, 3H), 2.88 (dd, 1H, J = 4.0, 16.0 Hz), 2.67 (t, 1H, J = 16.0 Hz), 2.07 (m, 2H).

[0127] Step 9: Synthesis of compound (1)

[0128] In a dry 50L reactor, add 15.0L of methanol and start stirring. Add compound 9 (1500.00g) to the reactor. Cool to 18°C and slowly add 3160.00g of cesium carbonate. A small amount of heat will be released, and the internal temperature will rise to 25°C. Then slowly add 3160.00g of PIFA. The internal temperature is controlled at 20-25°C. Stir evenly, raise the temperature to 40°C, and react for 1 hour. Stop the reaction. Cool to 20-25°C and add 4M sodium hydroxide solution (prepared by dissolving 256.00g of sodium hydroxide solid in 1.6L of water) dropwise. After completion of the dropwise addition, react at room temperature for 20.5 hours. Add 10.5L of 2M hydrochloric acid dropwise to the reactor. Exotherm is released and the temperature is controlled at 20-25°C. After completion of the dropwise addition, the pH is 2-3. Continue stirring for 15 minutes, filter under reduced pressure, and wash the filter cake with water (5L). The filter cake was added to the kettle, and methanol / water (1:1, 15 L) was added to the kettle and stirred at room temperature for 1 hour. The filter cake was collected by filtration under reduced pressure and dried under vacuum to obtain a crude product of compound (1) (1505.73 g).

[0129] In a 30 L reactor, add 7.5 L of dimethyl sulfoxide and the above crude product, and heat to 78°C to 85°C while stirring to dissolve. Stop heating and allow the mixture to cool naturally to 30°C to 35°C. Solids will precipitate, which is filtered under reduced pressure. The mother liquor is added to 37.5 L of methanol with stirring, resulting in the precipitation of a large amount of white solids. Filter under reduced pressure, rinse the filter cake with 1.5 L of methanol, and collect the filter cake. The filter cake is dried under vacuum to obtain compound (1) (892.41 g, purity 99.47%, yield 61.6%). 1 H NMR (400 MHz, deuterated chloroform) δ 15.6 (s, 1H), 8.54 (s, 1H), 7.69 (s, 1H), 7.41 (d, 1H, J = 4.0 Hz), 7.16 (s, 1H), 6.9-7.1 (m, 3H), 6.68 (s, 1H), 4.15 (t, 2H, J = 8.0 Hz), 3.57 (t, 2H, J = 8.0 Hz), 3.34 (s, 3H), 2.11 (m, 2H).

[0130] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A method for preparing a compound of formula (I), It is characterized by: The following steps are included: in, T is selected from CH and N; R1 is selected from H, OH, CN, NH2, C 1～5 Alkyl, C 1～5 Heteroalkyl, C 2～5 Alkynyl, C 3～6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1～5 Alkyl, C 1～5 Heteroalkyl, C 2～5 Alkynyl, C 3～6 Cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; R2 is selected from H, F, Cl, Br, I, C 1～3 Alkyl and C 1～3 heteroalkyl, the C 1～3 Alkyl and C 1～3 Heteroalkyl is optionally substituted with 1, 2, or 3 R; R3 is selected from H, F, Cl, Br, I, CN, -C(=O)-OC 1～3 Alkyl, -C(=O)-NH-C 1～3 Alkyl, -C(=O)-N(C 1～3 Alkyl)2; m is selected from 0, 1, 2, 3, 4 and 5; A is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 R; R is selected from H, F, Cl, Br, I, OH, CN, NH2, =O, CH3, CH3CH2, CH3O, CF3, CHF2, CH2F; The C 1～5 Heteroalkyl, 3-6 membered heterocycloalkyl, C 1～3 The heteroalkyl and 5- to 6-membered heteroaryl groups each independently contain 1, 2 or 3 heteroatoms or heteroatom groups each independently selected from N, -O-, =O, -S-, -NH-, -(C=O)-, -(S=O)- and -(S=O)2-.

2. The method for preparing the compound of formula (I) according to claim 1, wherein The following steps are also included: wherein R1, R2 and m are as defined in claim 1.

3. The method for preparing the compound of formula (I) according to claim 1 or 2, wherein R1 is selected from H, OH, CN, NH2, CH3, CH3CH2, CH3CH2CH2, CH3CH2CH2CH2, CH3O, CH3CH2O, CH3S, CH3S(=O), CH3S(=O)2, CH3SCH2, CH3CH2S, CH3NH, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, 2-pyrrolidonyl and 3-pyrrolidonyl, the CH3, CH3CH2, CH3CH2CH2, CH3CH2CH2CH2, CH3O, CH3CH2O, CH3S, CH3S(=O), CH3S(=O)2, CH3SCH2, CH3CH2S, CH3NH, Pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, 2-pyrrolidonyl, and 3-pyrrolidonyl are optionally substituted with 1, 2, or 3 R groups.

4. The method for preparing the compound of formula (I) according to claim 3, wherein R1 is selected from H, OH, CN, NH2, CH3, CH3CH2, CH3CH2CH2, CH3CH2CH2CH2, CH3O, CH3CH2O, CH3S, CH3S(=O), CH3S(=O)2, CH3SCH2, CH3CH2S, CH3NH, The CH3, CH3CH2, CH3CH2CH2, CH3CH2CH2CH2, CH3O, CH3CH2O, CH3S, CH3S(=O), CH3S(=O)2, CH3SCH2, CH3CH2S, CH3NH, Optionally substituted with 1, 2 or 3 R.

5. The method for preparing the compound of formula (I) according to claim 4, wherein R1 is selected from H, OH, CH3, CHF2, CH3O, 6. The method for preparing the compound of formula (I) according to claim 1 or 2, wherein R2 is selected from H, F, Cl, Br, CH3, CH3CH2, CH3O, CH3CH2O and The CH3, CH3CH2, CH3O, CH3CH2O and Optionally substituted with 1, 2 or 3 R.

7. The method for preparing the compound of formula (I) according to claim 6, wherein R2 is selected from Cl and CH3O.

8. A method for preparing a compound of formula (I) according to claim 1 or 2, wherein A is selected from phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, wherein the phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl groups are optionally substituted with 1, 2 or 3 R groups.

9. The method for preparing the compound of formula (I) according to claim 8, wherein A is selected from described Optionally substituted with 1, 2 or 3 R.

10. The method for preparing the compound of formula (I) according to claim 9, wherein A is selected from 11. The method for preparing the compound of formula (I) according to claim 10, wherein A is selected from 12. A method for preparing a compound of formula (I) according to claim 1 or 2, wherein: R3 is selected from -C(=O)-N(CH3)2, -C(=O)-O-CH3, Cl and CN.

13. The method for preparing the compound of formula (I) according to any one of claims 1 to 2 and 12, wherein: The compound of formula (II) is selected from wherein T, A and R3 are as defined in any one of claims 1 to 2 and 12.

14. A method for preparing a compound of formula (I) according to claim 1 or 2, wherein: The compound of formula (I) is selected from 15. Compound of formula (II) in, T and A are as defined in claim 1 or 2, and R3 is selected from -C(=O)-N(CH3)2 or -C(=O)-O-CH3.

16. The compound of formula (II) according to claim 15, selected from 17. A method for preparing a compound of formula (II), comprising the following steps: wherein T and A are as defined in claim 1 or 2, and R3 is selected from -C(=O)-N(CH3)2 or -C(=O)-O-CH3.

18. A method for preparing a compound of formula (I), comprising the following steps: in, m as defined in claim 1; R1 is as defined in any one of claims 1 to 5; R2 is as defined in any one of claims 1, 6 and 7; R3 as defined in claim 1 or 12; T as defined in claim 1; A is as defined in any one of claims 1, 8, 9, 10 and 11.

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