A process for the preparation of a btk inhibitor intermediate

Abstract

The application relates to a preparation method of a BTK inhibitor intermediate. In particular, the application relates to a preparation method of a compound as shown in formula (A'K), which comprises the following steps: a step of preparing a compound as shown in formula (IIK) from a compound as shown in formula (IIIK), and a step of preparing a compound as shown in formula (A'K) from a compound as shown in formula (IIK). The method has high yield and mild reaction conditions, and is suitable for industrial production.

Description

[0001] This application claims priority to Chinese Patent Application No. 2021105596779, filed May 21, 2021, and Chinese Patent Application No. 2022100351464, filed January 13, 2022. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the pharmaceutical field and relates to a method for preparing a BTK inhibitor intermediate. Background Technology

[0003] Immune cells are generally classified into two categories: T cells and B cells. The primary function of B cells is to secrete various antibodies to help the body defend against various invading foreign substances. Bruton's tyrosine protein kinase (BTK) is a member of the tyrosine protein kinase subfamily, belonging to the Tec family of kinases. It is mainly expressed in B cells and distributed in the lymphatic, hematopoietic, and blood systems. The B cell receptor (BCR) plays a crucial regulatory role in the proliferation and survival of various lymphomas, including chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) subtypes, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). Furthermore, the role of B cells in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and other immune diseases has been clinically confirmed. Bruton's tyrosine protein kinase (BTK) is a key protein kinase in the BCR signaling pathway. It regulates the maturation and differentiation of normal B cells and is closely related to various B-cell lymphopathic disorders. Therefore, the targeted small molecule inhibitor BTK may provide benefits for the treatment of B-cell malignancies and autoimmune diseases.

[0004] WO2016007185A1 relates to a compound of formula (I), namely (R)-4-amino-1-(1-(but-2-ynyl)pyrrolidine-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one. This compound is a novel BTK kinase inhibitor with improvements in kinase selectivity, clinical efficacy or indications, and safety. Its structure is shown below:

[0005]

[0006] WO2016007185A1 also discloses the compound shown in formula (A), which is an important intermediate for the preparation of the compound of formula (I). The yield and purity of the compound shown in formula (A) directly affect the product quality of subsequent compounds.

[0007] Summary of the Invention

[0008] The purpose of this disclosure is to provide a new method for preparing BTK inhibitor intermediates.

[0009] This disclosure also provides a method for preparing a compound of formula (A'K), comprising the steps of preparing a compound of formula (IIK) from a compound of formula (IIIK) and preparing a compound of formula (A'K) from a compound of formula (IIK).

[0010] in:

[0011] R1 is selected from a hydrogen atom or a carboxyl protecting group, preferably a carboxyl protecting group, and more preferably C. 1-6 alkyl;

[0012] R2 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl;

[0013] R3 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl;

[0014] R w Selected from halogens, C 1-6 Alkyl, C 1-6 Alkyloxy, 3- to 8-membered cycloalkyloxy, 3- to 8-membered heterocyclic alkyloxy, 6- to 10-membered aryloxy and 5- to 10-membered heteroaryloxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 8-membered cycloalkyloxy, 3- to 8-membered heterocyclic alkyloxy, 6- to 10-membered aryloxy and 5- to 10-membered heteroaryloxy are optionally selected from halogens, C 1-6 Alkyl and C 1-6 One or more substituents in the alkoxy group are substituted;

[0015] n is selected from 0, 1, 2, 3, 4, and 5.

[0016] In some embodiments, this disclosure provides a method for preparing a compound of formula (A'G), comprising the steps of preparing a compound of formula (IIG) from a compound of formula (IIIG) and preparing a compound of formula (A'G) from a compound of formula (IIG).

[0017]

[0018] in:

[0019] R1 is selected from a hydrogen atom or a carboxyl protecting group, preferably a carboxyl protecting group, and more preferably C. 1-6 alkyl;

[0020] R2 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl;

[0021] R3 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl;

[0022] R w Selected from halogens, C 1-6 Alkyl, C 1-6 Alkyloxy, 3- to 8-membered cycloalkyloxy, 3- to 8-membered heterocyclic alkyloxy, 6- to 10-membered aryloxy and 5- to 10-membered heteroaryloxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 8-membered cycloalkyloxy, 3- to 8-membered heterocyclic alkyloxy, 6- to 10-membered aryloxy and 5- to 10-membered heteroaryloxy are optionally selected from halogens, C 1-6 Alkyl and C 1-6 One or more substituents in the alkoxy group are substituted.

[0023] In some embodiments, the compound of formula (IIIK) is reacted with the compound of formula (III-1) in the presence of a base reagent to prepare the compound of formula (IIK), where formula (III-1) is... X is a halogen.

[0024] In some embodiments, the compound of formula (IIIG) is reacted with the compound of formula (III-1) in the presence of a base reagent to prepare the compound of formula (IIG), where formula (III-1) is... X is a halogen.

[0025] In some embodiments, the compound of formula (IIIK) is reacted with the compound of formula (III-1) in the presence of a base reagent to prepare the compound of formula (IIK), where formula (III-1) is... X is a halogen, and the alkaline reagent is selected from common reagents such as lithium diisopropylamino (LDA), butyllithium, and isopropyl magnesium chloride.

[0026] In some embodiments, the compound of formula (IIIG) is reacted with the compound of formula (III-1) in the presence of a base reagent to prepare the compound of formula (IIG), where formula (III-1) is... X is a halogen, and the alkaline reagent is selected from common reagents such as lithium diisopropylamino (LDA), butyllithium, and isopropyl magnesium chloride.

[0027] In some implementations, X is chlorine.

[0028] In some embodiments, the base reagent is lithium diisopropylamino. This disclosure also provides a method for preparing a compound of formula (A'), comprising the steps of preparing a compound of formula (II) from a compound of formula (III), and preparing a compound of formula (A') from a compound of formula (II).

[0029]

[0030] R1 is selected from hydrogen atoms or carboxyl protecting groups, preferably carboxyl protecting groups, and more preferably C. 1-6 alkyl;

[0031] R2 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl;

[0032] R3 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl.

[0033] In some embodiments, the compound shown in formula (III) and the compound shown in formula (III-1) are used to prepare the compound shown in formula (II) in the presence of a base reagent, where X is a halogen, preferably chlorine, and the base reagent is preferably a common type of reagent such as lithium diisopropylamino (LDA), butyllithium, or isopropyl magnesium chloride, with lithium diisopropylamino being more preferred.

[0034]

[0035] In some embodiments, the molar ratio of the compound represented by formula (III) to the lithium reagent is 1:0.1 to 1:10, preferably 1:1 to 1:5, and more preferably 1:1 to 1:3.

[0036] In some embodiments, the molar ratio of the compound represented by formula (III) to the compound represented by formula (III-1) is 1:0.1 to 1:10, preferably 1:1 to 1:5, and more preferably 1:1 to 1:3.

[0037] In some embodiments, the reaction temperature is -100 to -30°C, preferably -85 to -65°C.

[0038] In some embodiments, R3 is an amino protecting group, and the method further includes

[0039]

[0040] Where: R1, R w And n is as defined in equation (IIK).

[0041] In some embodiments, R3 is an amino protecting group, and the method further includes

[0042]

[0043] Where: R1 and R w As defined in formula (IIG).

[0044] In some implementations, where R w It is a halogen or phenyloxy group, wherein the phenyl group is optionally selected from halogens, C 1-6 Alkyl and C 1-6 One or more substituents in the alkoxy group are substituted.

[0045] In some embodiments, a method for preparing A'G is provided, comprising:

[0046]

[0047] R w It is a halogen;

[0048] R1 is selected from a hydrogen atom or a carboxyl protecting group, preferably a carboxyl protecting group, and more preferably C. 1-6 alkyl;

[0049] R2 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl;

[0050] R3 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl.

[0051] In some embodiments, a method for preparing A'G is provided, comprising:

[0052]

[0053] Where R w It is bromine;

[0054] R1 is selected from a hydrogen atom or a carboxyl protecting group, preferably a carboxyl protecting group, and more preferably C. 1-6 alkyl;

[0055] R2 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl;

[0056] R3 is selected from hydrogen atoms or amino protecting groups, preferably amino protecting groups, and more preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl.

[0057] In some implementations, where R w The phenyl group is a phenyloxy group, wherein the phenyl group is optionally selected from halogens, C 1-6 Alkyl and C 1-6 One or more substituents in the alkoxy group are substituted.

[0058] In some embodiments, R3 is an amino protecting group, and the method further includes

[0059]

[0060] R1 is defined in equation (II).

[0061] The amino protecting group can be removed using methods commonly used in the field, such as using appropriate deprotection reagents depending on the different amino protecting groups.

[0062] In some embodiments, the compound shown in formula (II) is prepared from the compound shown in formula (II-1) under the presence of a base to form the compound shown in formula (A'), where R4 is a leaving group.

[0063]

[0064] R1 and R2 are defined as in equation A'.

[0065] In some embodiments, the molar ratio of the compound represented by formula (II) to the base is 1:0.1 to 1:10, preferably 1:1.5 to 1:5.

[0066] In some embodiments, the alkali is selected from alkali metal carbonates, bicarbonates, or hydroxides, preferably sodium carbonate, potassium carbonate, or cesium carbonate.

[0067] In some embodiments, the molar ratio of the compound represented by formula (II) to the compound represented by formula (II-1) is 1:0.1 to 1:10, preferably 1:1 to 1:5, and more preferably 1:1 to 1:3.

[0068] In some embodiments, the reaction temperature is -100 to -30°C, preferably -85 to -65°C.

[0069] In some embodiments, the method further includes

[0070]

[0071] Among them, R6 is selected from C 1-6 alkyl.

[0072] In some embodiments, R3 is an amino protecting group, and the method further includes

[0073]

[0074] The solvent used in the reaction described in this disclosure can be a conventional solvent, such as one or more of dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, dioxane, toluene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol, and water, preferably one or more of tetrahydrofuran, ethyl acetate, dioxane, toluene, dimethyl sulfoxide, diethyl ether, isopropyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, and isopropanol.

[0075] In some embodiments, the compound represented by formula (A') is selected from...

[0076] Preferred This disclosure also provides a method for preparing the compound shown in formula (A'G-1), including...

[0077]

[0078] This disclosure also provides a method for preparing the compound shown in formula (A), including...

[0079]

[0080] Wherein, R3' is an amino protecting group, and R6' is a C-protecting group. 1-6 alkyl.

[0081] In some embodiments, the compound represented by formula (A) is selected from...

[0082]

[0083] This disclosure also provides a method for preparing the compound shown in formula (I), including the method described in this disclosure for preparing the compound shown in formula (A') or the compound shown in formula (A).

[0084] Alternatively, the compound shown in formula (I) can be prepared using the compound shown in formula (A') or the compound shown in formula (A) as reactants by methods disclosed in the prior art, such as those disclosed in CN106573001A, WO2020038405, WO2019196915, etc., which are incorporated herein by reference in their entirety.

[0085] Optional solutions include, for example:

[0086]

[0087] This disclosure also provides compounds of formula (III-K1),

[0088]

[0089] Among them, R w Selected from Or halogen, preferred Or bromine,

[0090] R3 is selected from hydrogen atoms or amino protecting groups, preferably hydrogen atoms, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl.

[0091] This disclosure also provides compounds of formula (II'-K1),

[0092]

[0093] Among them, R w Selected from Or halogen, preferred Or bromine,

[0094] R1 is selected from a hydrogen atom or a carboxyl protecting group, preferably a carboxyl protecting group, and more preferably C. 1-6 alkyl;

[0095] R3 is selected from amino protecting groups, preferably tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl.

[0096] This disclosure also provides compounds of formula (II-K1),

[0097]

[0098] Among them, R w Selected from Or halogen, preferred Or bromine,

[0099] R1 is selected from a hydrogen atom or a carboxyl protecting group, preferably a carboxyl protecting group, and more preferably C. 1-6 alkyl.

[0100] The "alkyl" referred to in this disclosure is preferably a C1-C6 alkyl.

[0101] The "alkenyl" as described in this disclosure is preferably a C2-C6 alkenyl.

[0102] The "alkynyl group" described in this disclosure is preferably a C2-C6 alkynyl group.

[0103] The "alkylene" described in this disclosure is preferably a C1-C6 alkylene.

[0104] The "sub-alkenyl" described in this disclosure is preferably a C2-C6 sub-alkenyl.

[0105] The "sub-chain alkynyl" described in this disclosure is preferably a C2-C6 sub-chain alkynyl.

[0106] The "alkoxy group" described in this disclosure is preferably a C1-C6 alkoxy group.

[0107] The "alkyl thioether group" described in this disclosure is preferably a C1-C6 alkyl thioether group.

[0108] The "cycloalkyl" in this disclosure is preferably 3 to 12-membered, and more preferably 3 to 6-membered cycloalkyl.

[0109] The "fused cycloalkyl" described in this disclosure is preferably a 6- to 14-membered fused cycloalkyl, more preferably a 7- to 10-membered fused cycloalkyl.

[0110] The "heterocyclic group" described in this disclosure is preferably a 3- to 12-membered heterocyclic group, and more preferably a 3- to 6-membered heterocyclic group.

[0111] The "fused heterocyclic group" described in this disclosure is preferably a 6- to 14-membered fused heterocyclic group, more preferably a 7- to 10-membered fused heterocyclic group.

[0112] The "aryl" in this disclosure is preferably 6 to 14 methyl groups, and more preferably 6 to 10 methyl groups.

[0113] The "heteroaryl" as described in this disclosure is preferably 5 to 12 quinones, and more preferably 5 to 10 quinones.

[0114] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0115] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0116] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0117] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0118] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Carbocyclic" refers to the ring system within the cycloalkyl group.

[0119] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m The heteroatom (where m is an integer from 0 to 2) excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl or pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. "Heterocyclic" refers to the ring system within the heterocyclic group.

[0120] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. "Aromatic ring" refers to the ring system within the aryl group. Non-limiting examples of aryl groups include:

[0121]

[0122] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group, preferably phenyl.

[0123] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, such as imidazolyl, furanyl, thiophenel, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. "Heteroaryl ring" refers to the ring system within the heteroaryl group. Non-limiting examples of heteroaryl groups include:

[0124]

[0125] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0126] The term "cycloalkyloxy" refers to -O-cycloalkyl, as defined above;

[0127] The term "heterocyclic oxy group" refers to an -O-heterocyclic group as defined above;

[0128] The term "aryloxy group" refers to -O-aryl, as defined above;

[0129] The term "heteroaryloxy" refers to -O-heteroaryl, which is as defined above;

[0130] "Carboxyl protecting group" is a suitable group known in the art for carboxyl protection, see reference ("Protective Groups in Organic Synthesis", 5). Th The carboxyl protecting group in Ed.TWGreene & P.GMWuts, as an example, can be a substituted or unsubstituted C. 1-10 Straight-chain or branched alkyl, substituted or unsubstituted C 2-10Straight-chain or branched alkenyl or alkynyl, substituted or unsubstituted C 3-8 Cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 Alkyl or aryl) 3-silyl, etc.

[0131] "Amino protecting group" is a suitable group known in the art for amino protection, see reference ("Protective Groups in Organic Synthesis", 5). Th The amino protecting group in Ed.TW Greene & P. ​​GMWuts, preferably, is a (C 1-10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C 6-10 Aryloxy)carbonyl, such as Boc or Cbz; can also be substituted or unsubstituted alkyl, such as triphenylmethyl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).

[0132] The term "leaving group" refers to an atom or functional group that detaches from a larger molecule during a chemical reaction. Representative leaving groups include halogens, substituted sulfonyloxy groups, phosphoryloxy groups, amino groups, and (R... j )3N-, cyano, R j S-etc., where R j It is independently selected from hydrogen atoms or C1 to C6 alkyl groups.

[0133] The substituted sulfonyloxy group can be C1-C6 alkylsulfonyloxy, perfluorinated C1-C6 alkylsulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, etc.

[0134] Specific examples of C1-C6 alkylsulfonyloxy groups include C1-C6 straight-chain or branched alkylsulfonyloxy groups, such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, tert-butylsulfonyloxy, n-pentylsulfonyloxy, and n-hexylsulfonyloxy.

[0135] Specific examples of perfluoroC1–C6 alkylsulfonyloxy groups include C1–C6 straight-chain or branched perfluoroalkylsulfonyloxy groups, such as trifluoromethylsulfonyloxy, 1,1,2,2,2-pentafluoro-1-ethylsulfonyloxy, 1,1,2,2,3,3,3-heptafluoro-1-propylsulfonyloxy, and 1,1,2,2,3,3,4,4,4-nonafluoro-1-butylsulfonyloxy.

[0136] Examples of arylsulfonyloxy groups include phenylsulfonyloxy and naphthylsulfonyloxy groups, which optionally have 1 to 3 substituents on the benzene ring, selected from the group consisting of a C1-C6 straight-chain or branched alkyl group, a C1-C6 straight-chain or branched alkyl group, a nitro group, and a halogen atom. Specific examples of phenylsulfonyloxy groups optionally having substituents include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-tolylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and so on. Specific examples of naphthylsulfonyloxy groups include α-naphthylsulfonyloxy, β-naphthylsulfonyloxy, and so on.

[0137] Examples of aralkylsulfonyloxy groups include: C1-C6 straight-chain or branched alkylsulfonyloxy groups substituted with a phenyl group (which optionally has 1 to 3 substituents selected from C1-C6 straight-chain or branched alkyl groups, C1-C6 straight-chain or branched alkyl groups, nitro groups, and halogen atoms on the benzene ring); and C1-C6 straight-chain or branched alkylsulfonyloxy groups substituted with a naphthyl group. Specific examples of phenyl-substituted alkylsulfonyloxy groups include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methylbenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, etc. Specific examples of naphthyl-substituted alkylsulfonyloxy groups include α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy, etc.

[0138] "Optional" or "optionally" means that the event or circumstance described below may, but does not have to, occur. This description includes situations in which the event or circumstance may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may, but does not have to, be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0139] In the chemical structure of the compounds described in this disclosure, the bonds... The configuration is not specified, meaning that if configurational isomerism exists in the chemical structure, the bond... It can be Or simultaneously include Two configurations. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations. Detailed Implementation

[0140] The following detailed explanation of this disclosure will be provided with specific examples to enable those skilled in the art to have a more comprehensive understanding of this disclosure. The specific examples are only used to illustrate the technical solutions of this disclosure and do not limit this disclosure in any way.

[0141] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0142] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0143] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated three times.

[0144] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0145] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0146] Example 1

[0147]

[0148] Step 1: Synthesis of Compound 1

[0149] 25g of 2,6-difluorophenol was added to 250ml of DMF, along with 79g of potassium carbonate and 28.6g of p-fluorobenzaldehyde. The mixture was heated to 110℃ and stirred until complete. Ice water was added, and the mixture was filtered. The filter cake was washed with purified water, dried, and then slurried with ethyl acetate and n-hexane to obtain 38g of compound 1, with a yield of 85% and an HPLC purity of 98.7%.

[0150] 1 HNMR (400MHz, DMSO-d6): δ9.93 (s, 1H), 7.95 (d, 2H, J = 8.8Hz), 7.45-7.37 (m, 3H), 7.15 (d, 2H, J = 8.8Hz),

[0151] Step 2: Synthesis of Compound 2

[0152] Compound 1 (20 g) was dissolved in 200 ml of ethanol, and 1.32 g of ammonium acetate and 10.14 g of ethyl cyanoacetate were added. The mixture was heated to 60 °C and stirred until the reaction was complete. After cooling to room temperature, water was slowly added, and the mixture was filtered. The filter cake was washed with a mixed solvent of ethanol and purified water (EtOH:H2O = 1:2), and dried to obtain 28.7 g of compound 2, with a yield of 100% and an HPLC purity of 98.4%.

[0153] 1 HNMR (400MHz, DMSO-d6): δ8.374 (s, 1H), 8.14 (d, 2H, J = 8.8Hz), 7.46-7.34 (m, 3H), 7.19 (d, 2H, J = 8.8Hz), 4.32 (q, 2H, J = 7.2Hz), 1.310 (t, 3H, J = 7.2Hz)

[0154] Step 3: Synthesis of Compound 3

[0155] 28.7 g of compound 2 was dissolved in 200 mL of ethanol, and 35.6 g (20%) of sodium ethoxide solution was added under ice bath conditions. 18.7 g of compound 2-1 was added to the reaction system, and the mixture was stirred until complete. The mixture was washed with ammonium chloride solution, and ethyl acetate was added to separate the layers. The organic phase was washed with saturated brine, dried, and concentrated to obtain the crude product. The crude product was recrystallized from DCM:PE = 1:6 to give 23.3 g of compound 3, yield 91%, HPLC purity: 99.19%.

[0156] 1 HNMR (400MHz, DMSOd6): δ11.91 (s, 1H), 7.70 (d, 1H, J = 2.0Hz), 7.69 (d, 2H, J = 8.4Hz), 7.61-7.30 (m, 3H), 7.26 (d, 1H, J = 2.0Hz), 7.13 (d, 2H, J = 8.4Hz)

[0157] Step 4: Synthesis of Compound 4

[0158] 23.2 g of compound 3 was dissolved in 230 mL of dichloromethane, and 2 eq of triethylamine and 0.1 eq of DMAP were added. The mixture was cooled to 0 °C, and 1.1 eq of benzenesulfonyl chloride was added dropwise. The mixture was stirred at this temperature until the reaction was complete. The product was washed successively with purified water, dilute hydrochloric acid, sodium bicarbonate, and brine. After drying with anhydrous sodium sulfate, the product was filtered and concentrated to obtain the crude product. The crude product was slurried with PE:EA at a ratio of 10:1 and dried to obtain 30.6 g of compound 4, with a yield of 90% and an HPLC purity of 99.80%.

[0159] 1HNMR (400MHz, DMSOd6): δ8.50 (s, 1H), 8.15 (dd, 2H, J = 6.8Hz, 3.2Hz), 7.93 (d, 1 H,J=3.2Hz),7.75(m,1H),7.65-7.62(m,4H),7.42(m,3H),7.04(d,2H,J=8.8Hz)

[0160] Step 5: Synthesis of Compound 5

[0161] Add 220 mL of tetrahydrofuran to the reaction flask, cool to -70 °C, add 1.5 eq of LDA (2 M in THF) dropwise to the reaction flask, slowly add 50 mL of a tetrahydrofuran solution of compound 3 (22 g), maintain -70 °C and stir for 1 h, then slowly add 2.0 eq of ethyl chloroformate to the reaction flask, maintain -70 °C and stir for 1 h, allow to rise naturally to room temperature, stir until the reaction is complete, quench with ammonium chloride, extract with ethyl acetate, wash with brine, dry, concentrate to obtain crude product, slurry the crude product with PE:EA = 10:1 to obtain 23.2 g of compound 5, yield 90.6%, HPLC purity: 98.97%.

[0162] 1 HNMR (400MHz, DMSOd6): δ8.32(s,1H),8.20(d,2H,J=8.8Hz),7.85(m,1H),7.77-7.72(m,4 H),7.44-7.33(m,3H),7.15(d,2H,J=8.8Hz),4.34(q,1H,J=7.2Hz),1.27(t,3H,J=7.2Hz)

[0163] Step 6: Synthesis of Compound 6

[0164] 23g of compound 5 was dissolved in 200mL of tetrahydrofuran, and 1.1 eq of TBAF was added. The mixture was heated to 70℃ and stirred until the reaction was complete. The mixture was washed with purified water, extracted with ethyl acetate, and the organic phase was washed with sodium bicarbonate, dilute hydrochloric acid, and sodium chloride. The organic phase was dried, filtered, and concentrated to obtain the crude product. The crude product was slurried with PE:EA at a ratio of 10:1 to obtain 15.0g of compound 6, with a yield of 90% and an HPLC purity of 99.32%.

[0165] 1H NMR (400MHz, DMSOd6): δ13.01(s,1H),7.70(2H,dd,J=7.8Hz,3.2Hz),7.65(1H,s),7.54- 7.32(m,3H),7.05(2H,dd,J=7.8Hz,3.2Hz),4.35(q,1H,J=7.2Hz),1.34(t,3H,J=7.2Hz)

[0166] Step 7: Synthesis of compound A1

[0167] 10 g of compound 6 was dissolved in 100 mL of DMF. 1.5 eq of compound 6-1 and 3 eq of cesium carbonate were added. Under nitrogen protection, the mixture was heated to 80 °C and stirred until complete. Water and ethyl acetate were added to separate the layers. The organic phase was washed with ammonium chloride and brine. After separation, the organic phase was dried and concentrated to obtain the crude product. The crude product was dissolved in 2V of anhydrous ethanol by heating. Insoluble matter was filtered off, and the mixture was cooled to room temperature. Seed crystals were added, and the mixture was stirred overnight to induce crystallization, yielding 11.6 g of high-purity compound A1 (80% yield, HPLC purity: 99.94%).

[0168] 1 H NMR (400MHz, DMSOd6): δ7.72-7.62(m,3H),7.42-7.31(m,3H),7.06(d,1H,J=7.2Hz)5.62 (m,1H),4.37(q,1H,J=7.2Hz),3.79(m,1H),3.50(m,1H),3.42(m,1H),2.51-2.36(m,1H)

[0169] 1.40-1.33 (m, 12H)

[0170] Example 2

[0171]

[0172] Step 1: Synthesis of compound (II'G-1)

[0173] 40 g of compound (IIIG-1) was dissolved in 900 mL of tetrahydrofuran, cooled to -80 °C, and 77 mL of 2 M LDA solution was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 h. Then, 22.4 g of ethyl chloroformate was added dropwise, and the reaction was carried out at low temperature for 2 h before being slowly raised to room temperature. The reaction was monitored by TLC until it was complete.

[0174] The reaction system was quenched with 20 mL of saturated ammonium chloride solution, extracted with 1 L of ethyl acetate, washed with water and sodium chloride solution, dried by rotary evaporation, and the crude product was slurried with PE / EA = 10 / 1 and dried under vacuum to obtain compound (II'G-1), 41.0 g of off-white solid, yield 86.4%.

[0175] Compound of formula (II'G-1): 1 HNMR (400MHz, CDCl3), 8.08 (m, 2H), 7.81 (s, 1H), 7.71 (m, 1H), 7.60 (m, 4H), 7.49 (m, 2H), 4.38 (q, J = 7.2Hz, 2H), 1.39 (t, J = 7.2Hz, 3H).

[0176] Step 2: Synthesis of compound (IIG-1)

[0177] 40 g of compound (II'G-1) was dissolved in 300 mL of tetrahydrofuran, and 95 mL of TBAF solution (1 M) was added dropwise. The mixture was heated to 70 °C and reacted for 2 h. The reaction was monitored by TLC until it was complete.

[0178] The reaction system was extracted with 300 mL of ethyl acetate, washed with water and sodium chloride solution, dried by rotary evaporation, and the crude product was pulped with PE / EA = 10 / 1 and dried under vacuum to obtain compound (IIG-1), 27.7 g of gray solid, yield 100%.

[0179] Compound of formula (III-1): 1 HNMR (400MHz, CDCl3), 8.77 (brs, 1H), 7.51 (m, 4H), 7.17 (s, 1H), 4.44 (q, J = 7.2Hz, 2H), 1.43 (t, J = 7.2Hz, 3H).

[0180] Step 3: Synthesis of compound (A'G-1)

[0181] 8 g of compound (IIG-1), 8.1 g of triphenylphosphine, and 5.8 g of (S)-1-N-tert-butoxycarbonyl-3-hydroxypyrrolidine were dissolved in 200 mL of tetrahydrofuran. The mixture was cooled to approximately 0 °C in an ice bath, and 5.4 g of DEAD was added dropwise while maintaining the temperature at 0-5 °C. The reaction was kept at a low temperature for 2 h. The reaction was monitored by TLC until it was complete.

[0182] The reaction system was quenched with 5 mL of water and then directly evaporated to dryness. The crude product was subjected to PE / Acetone = 5 / 1 column chromatography and concentrated to obtain the compound of formula (A'G-1), 11.2 g of white foamy solid, with a yield of 92%.

[0183] Compound of formula (II-1): 1HNMR(400MHz, DMSO-d6),7.79(m,1H),7.67(m,4H),5.62(m,1H),4.35(m 2H),3.79(m,1H),3.49(m,3H),3.38(m,2H),2.39(m,2H),1.38(m,12H).

[0184] Since this disclosure has been described in accordance with its specific implementation, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of this disclosure.

Claims

1. A method for preparing a compound as shown in formula (A'K), wherein the compound shown in formula (A'K) is the compound shown in formula (A'). ， The preparation method includes the steps of preparing compound (II') from compound (III) and compound (III-1) in the presence of a base reagent, preparing compound (II) from compound (II'), and preparing compound (A') from compound (II) and compound (II-1) in the presence of a base. in: R1 is selected from a carboxyl protecting group; R2 is selected from an amino protecting group; R3 is selected from an amino protecting group; R4 is a leaving group; X is a halogen; The compound shown in formula (III) and the compound shown in formula (III-1) are used to prepare the compound shown in formula (II') in the presence of a base reagent, wherein the base reagent is selected from diisopropylaminolithium, butyllithium and Grignard reagent.

2. The preparation method according to claim 1, wherein R1 is selected from C 1-6 alkyl.

3. The preparation method according to claim 1, wherein R2 is selected from tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl.

4. The preparation method according to claim 1, wherein R3 is selected from tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl.

5. The preparation method according to claim 1, wherein the compound shown in formula (III) and the compound shown in formula (III-1) are used to prepare the compound shown in formula (II') in the presence of a base reagent, wherein the base reagent is lithium diisopropylamino.

6. The preparation method according to claim 1, wherein X is chlorine.

7. The preparation method according to claim 5, wherein the molar ratio of the compound of formula (III) to the lithium reagent is 1:0.1 to 1:

10.

8. The preparation method according to claim 7, wherein the molar ratio of the compound represented by formula (III) to the lithium reagent is 1:1 to 1:

5.

9. The preparation method according to claim 8, wherein the molar ratio of the compound represented by formula (III) to the lithium reagent is 1:1 to 1:

3.

10. The preparation method according to claim 1, wherein the molar ratio of the compound of formula (III) to the compound of formula (III-1) is 1:0.1 to 1:

10.

11. The preparation method according to claim 10, wherein the molar ratio of the compound shown in formula (III) to the compound shown in formula (III-1) is 1:1 to 1:

5.

12. The preparation method according to claim 11, wherein the molar ratio of the compound shown in formula (III) to the compound shown in formula (III-1) is 1:1 to 1:

3.

13. The preparation method according to claim 1, wherein the compound shown in formula (II) and the compound shown in formula (II-1) are used to prepare the compound shown in formula (A') under the presence of a base, wherein the molar ratio of the compound shown in formula (II) to the base is 1:0.1 to 1:

10.

14. The preparation method according to claim 13, wherein the compound shown in formula (II) and the compound shown in formula (II-1) are used to prepare the compound shown in formula (A') under the presence of a base, wherein the molar ratio of the compound shown in formula (II) to the base is 1:1.5 to 1:

5.

15. The preparation method according to claim 1, wherein the compound shown in formula (II) and the compound shown in formula (II-1) are prepared in the presence of a base to form the compound shown in formula (A'), wherein the base is selected from alkali metal carbonates, bicarbonates or hydroxides.

16. The preparation method according to claim 15, wherein the compound shown in formula (II) and the compound shown in formula (II-1) are prepared in the presence of a base to form the compound shown in formula (A'), wherein the base is selected from sodium carbonate, potassium carbonate or cesium carbonate.

17. The preparation method according to claim 1, wherein the molar ratio of the compound shown in formula (II) to the compound shown in formula (II-1) is 1:0.1 to 1:

10.

18. The preparation method according to claim 17, wherein the molar ratio of the compound shown in formula (II) to the compound shown in formula (II-1) is 1:1 to 1:

5.

19. The preparation method according to claim 18, wherein the molar ratio of the compound shown in formula (II) to the compound shown in formula (II-1) is 1:1 to 1:

3.

20. The preparation method according to claim 1, wherein R3 is an amino protecting group, and the method further comprises: ， Where: R6 is selected from C 1-6 alkyl.

21. The preparation method according to claim 1, wherein the compound represented by formula (A') is selected from... 。 22. The preparation method according to claim 1, wherein the compound represented by formula (A') is selected from... 。 23. A method for preparing the compound shown in formula (A'G-1), comprising: 。 24. A method for preparing the compound shown in formula (A), comprising: ； Wherein, R3' is an amino protecting group, and R6' is a C-protecting group. 1-6 alkyl.

25. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the method for preparing a compound of formula (A'K) according to any one of claims 1-22, the method for preparing a compound of formula (A'G-1) according to claim 23, or the method for preparing a compound of formula (A) according to claim 24. 。 26. The preparation method according to claim 25, further comprising: 。 27. The compound shown in formula (III-K1), ； in, R w Selected from ; R3 is selected from a hydrogen atom or an amino protecting group.

28. The compound according to claim 27, wherein R3 is selected from hydrogen atom, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzenesulfonyl.

29. The compound shown in formula (III-K1), ； in, R w Selected from halogens; R3 is selected from an amino protecting group.

30. The compound according to claim 29, wherein R3 is selected from tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl, and benzenesulfonyl.

31. The compound according to claim 29, wherein, R w 'Selected from bromine.' 32. The compound shown in formula (II'-K1), ； in, R w Selected from Or halogen; R1 is selected from a hydrogen atom or a carboxyl protecting group; R3 is selected from an amino protecting group.

33. The compound according to claim 32, wherein, R w Selected from Or bromine.

34. The compound according to claim 32, wherein, R1 is selected from C 1-6 alkyl.

35. The compound according to claim 32, wherein, R3 is selected from tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl, and benzenesulfonyl.

36. The compound shown in formula (II-K1), ； in, R w Selected from Or halogen; R1 is selected from hydrogen atoms or carboxyl protecting groups.

37. The compound according to claim 36, wherein, R w Selected from Or bromine.

38. The compound according to claim 36, wherein, R1 is selected from C 1-6 alkyl.

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