Method for preparing orelabrutinib, and intermediate compound thereof

Abstract

A method for preparing orelabrutinib, and an intermediate compound thereof. Specifically, the present invention relates to a method for preparing 6-(1-acryloylpiperidin-4-yl)-2-(phenoxyphenyl)pyridine-3-carboxamide, and an intermediate compound thereof. The preparation method has the characteristics of a simple route, inexpensive and easily available raw materials, mild conditions, a high product yield, etc., can greatly reduce the production cost, is environmentally friendly, and is easily applicable to industrial large-scale production.

Description

Preparation method of orelabrutinib and intermediate compound thereof Technical Field

[0001] The present invention relates to the field of organic compound synthesis, and in particular to a preparation method of obeticholic acid (6-(1-acryloylpiperidin-4-yl)-2-(phenoxyphenyl)pyridine-3-carboxamide) and an intermediate compound thereof. Background Art

[0002] Obtunib, 6-(1-acryloylpiperidin-4-yl)-2-(phenoxyphenyl)pyridine-3-carboxamide of formula (V), is a Bruton's tyrosine kinase (BTK) inhibitor developed by Innovent Biologics for the treatment of cancer, inflammation, and autoimmune diseases (see WO2015 / 048662).

[0003] There are currently some reports on the preparation of orelabrutinib. WO2015 / 048662 discloses a small-batch preparation method for compound V, which requires multiple palladium-catalyzed Suzuki coupling reactions to connect piperidine and phenoxyphenyl groups to the pyridine group, thereby constructing the compound of formula (V).

[0004] WO2020 / 173407 also discloses a method for preparing compound V in large quantities through a palladium-catalyzed coupling reaction, and its synthetic route is as follows:

[0005] However, the above synthesis route not only requires the repeated use of expensive and environmentally unfriendly Pd catalysts, but also requires a Pd-catalyzed pressurized hydrogenation reaction, which is a hazardous chemical process with high equipment requirements. At the same time, the reaction route is long and the reaction steps are complex, resulting in high production costs and the generation of more industrial waste, so further improvements are needed.

[0006] Chinese patent application CN113563305 also reports a synthesis method that requires not only two condensation reactions but also a Pd-catalyzed hydrogenation reduction to convert the nitro group carried within the molecule to an amino group, followed by self-cyclization and isomerization to obtain the intermediate I of orelabrutinib. This method still requires the use of the expensive and environmentally unfriendly Pd catalyst, and the reaction steps are complex. Furthermore, the self-cyclization reaction may produce different byproducts at different temperatures, affecting product purity.

[0007] Therefore, there is still a need in the art for a synthesis method of orelabrutinib that is simple to operate, uses cheap raw materials, and is suitable for industrial mass production.

[0008] To overcome the shortcomings and deficiencies of existing technologies, the present invention provides a novel method for synthesizing orelabrutinib. This method features convenient operation, readily available and inexpensive raw materials, high product yield, and high intermediate purity. It not only reduces overall production costs to approximately 10% of existing methods, but also avoids the use of heavy metals such as Pd, is environmentally friendly, and is amenable to industrial-scale production.

[0009] Summary of the Invention

[0010] definition

[0011] In the present invention, the following terms have the following meanings:

[0012] The term "alkyl" alone or in combination with other groups means a linear or branched monovalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. "C1-C6 alkyl" means a branched or linear alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-hexyl.

[0013] The term "alkenyl," alone or in combination with other groups, refers to a straight or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and containing at least one double bond. An alkenyl group may have 2 to 8, for example, 2 to 6, 2 to 5, 2 to 4, or 2 to 3, carbon atoms. For example, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, propenyl, allyl, butenyl, pentenyl, and the like.

[0014] The term "alkoxy" or "alkenyloxy" alone or in combination with other groups refers to a group R x -O-, where R x is an alkyl or alkenyl group as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, isobutoxy, tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, neopentoxy), hexoxy (including n-hexoxy, isohexoxy), and the like. Representative examples of alkenyloxy include, but are not limited to, allyloxy.

[0015] The term "carbonyl," alone or in combination with other groups, refers to the group -C(=O)-.

[0016] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0017] The term "haloalkyl" refers to an alkyl group as described above substituted by one or more halogens, preferably a halogenated C1-C6 alkyl group, such as trifluoromethyl.

[0018] The term "cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having the specified number of ring atoms. A cycloalkyl group may have 3 to 12 carbon atoms (i.e., C3-C 12 The cycloalkyl group may be a cycloalkyl group having 3 to 10, 3 to 8, 3 to 7, 3 to 6, or 5 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0019] The term "aryl" refers to a monovalent aromatic hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom in an aromatic ring system. Specifically, aryl refers to a monocyclic or fused polycyclic aromatic ring structure having the specified number of ring atoms. For example, aryl includes groups containing 6 to 14, such as 6 to 10, preferably 6, ring atoms. Examples of aryl groups include C 6-14 Aryl or C 6-10 Aryl, such as phenyl, naphthyl or fluorenyl.

[0020] The term "aralkyl" refers to an alkyl group as described above substituted with an aryl group as described above, for example, C6-C 10 Aryl-C 1-6 Alkyl groups, such as benzyl.

[0021] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S and the specified number of ring atoms, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Specifically, the aromatic ring structure may have 5 to 10 ring members. The heteroaryl group may be, for example, a 5-6 membered monocyclic ring, or a fused bicyclic structure formed by condensing two 6-membered rings, condensing two 5-membered rings, condensing a 6-membered ring and a 5-membered ring, or condensing a 5-membered ring and a 4-membered ring. The heteroaryl ring will typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2 heteroatoms, for example, a single heteroatom independently selected from O, N, and S, wherein N and S may be in an oxidized state such as N-oxide, S=O, or S(O)2. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom, at least one ring sulfur atom, or at least one ring oxygen atom. For example, the heteroaryl group can be a fused ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, such as benzofuran, benzothiophene, indole, benzimidazole, indazole, benzotriazole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, imidazo[4,5-b]pyridine, pyridine, imidazo[4,5-c]pyridine, pyrazolo[4,3-d]pyridine, pyrazolo[4,3-c]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[3,4-b]pyridine, isoindole, purine, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridazine, pyrrolo[1,2-b]pyrimidine , imidazo[1,2-c]pyrimidine, 5H-pyrrolo[3,2-b]pyrazine, 1H-pyrazolo[4,3-b]pyrazine, 1H-pyrazolo[3,4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 1,5-naphthyridine, 2,

[0015] The heteroaryl group may be a 5-6 membered heteroaryl group comprising 1 or 2 heteroatoms independently selected from N, O or S. Examples of suitable 5-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl; examples of suitable 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.The atom in a heteroaryl group that is attached to the rest of the compound can be a carbon atom or a heteroatom, as long as it is chemically feasible.

[0022] The term "heterocyclyl" refers to a non-aromatic saturated ring structure comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S and a specified number of ring atoms, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. A heterocyclyl group may have 3 to 12 ring members (which may be referred to as a 3-12 membered heterocycloalkyl group), for example, 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 8 ring members, 4 to 7 ring members, 4 to 6 ring members, 5 to 6 ring members. A heterocyclyl group typically contains up to 4 (e.g., 1, 2, 3, or 4) heteroatoms. Examples of suitable heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g., 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl, and 3-tetrahydrothiophenyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl (e.g., morpholino), thiomorpholinyl, dioxanyl, piperazinyl or azepanyl, diazepanyl such as 1,4-diazacycloheptyl, 3,6-diaza-bicyclo[3.1.1]heptyl or 3-aza-bicyclo[3.2.1]octyl. The atom in the heterocyclic group that is attached to the rest of the compound can be a carbon atom or a heteroatom, as long as it is chemically feasible.

[0023] The term "heterocyclyl" also includes "heterocyclyl" as defined above that contains at least one (e.g., 1, 2, or 3) double bonds, such as pyrrolinyl (e.g., 1-pyrrolinyl, 2-pyrrolidinyl, 3-pyrrolinyl, 4-pyrrolinyl, or 5-pyrrolinyl), dihydrofuranyl (e.g., 1-dihydrofuranyl, 2-dihydrofuranyl, 3-dihydrofuranyl, 4-dihydrofuranyl, or 5-dihydrofuranyl), dihydrothiophenyl (e.g., 1-dihydrothiophenyl, 2-dihydrothiophenyl, 3-dihydrothiophenyl, or 4-dihydrothiophenyl), tetrahydropyridinyl (e.g., 1-, 2-, 3-, 4-, 5-, or 6-tetrahydropyridinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), or tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl).

[0024] The term "acyl" refers to a group R y -C(=O)-, where R y is an alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl group as defined above.

[0025] The term "substituted or unsubstituted" means that the group may be unsubstituted or substituted with one or more (eg, 1, 2, 3, 4, or 5 or more) substituents, wherein the substituents may be the same or different.

[0026] "Substituted or unsubstituted C 1-6 Alkyl", "substituted or unsubstituted C3-C8 cycloalkyl", "substituted or unsubstituted C6-C 10 Aryl", "substituted or unsubstituted C5-C 10 Heteroaryl", "substituted or unsubstituted 3-12 membered heterocyclic group", "substituted or unsubstituted C3-C8 cycloalkyl-C 1-6 Alkyl", "substituted or unsubstituted C6-C 10 Aryl-C 1-6 Alkyl", "substituted or unsubstituted C5-C 10 Heteroaryl-C 1-6 Alkyl", or "substituted or unsubstituted 3-12 membered heterocyclic-C 1-6 "Alkyl" refers to the alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl as described above, respectively, which are optionally substituted by alkyl, alkoxy, halogen, haloalkyl, nitro, cyano, hydroxy and / or amino groups as described above. Examples thereof include, but are not limited to, 2-hydroxy-ethyl, 2-amino-ethyl, 3-hydroxypropyl, 4-hydroxy-butyl, methylcyclohexyl, 2-methylphenyl, 4-methylphenyl, 4-propylbenzyl, 4-methylbenzyl, 3-chloro-propyl, 4-chloro-benzyl, 4-nitro-benzyl, and the like.

[0027] The term "C1-C4 alcohol" refers to an alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.

[0028] The term "about" when used in conjunction with a numerical value is intended to encompass all values ​​within the range having a lower limit that is 10% less than the stated numerical value and an upper limit that is 10% greater than the stated numerical value.

[0029] Implementation Plan

[0030] The present invention aims to provide a novel method for preparing a compound of formula (V). This method has the advantages of a simple route, readily available and inexpensive raw materials, mild conditions, high product yield, and high intermediate purity. It can significantly reduce production costs, is environmentally friendly, and is easy to industrialize.

[0031] In a first aspect, the present invention provides a method for preparing a compound of formula (III-3),

[0032] The method includes:

[0033] (a) reacting a compound of formula (I) or a compound of formula (II) with ammonia or an ammonium salt in the presence of an acid to give a compound of formula (III-3);

[0034] in

[0035] R is -CN, -C(O)NH2, -C(O)N(R 1 )2 or -C(O)OR 2 ,

[0036] R 3 -NH2, -N(R 1 )2OR-OR 2 ,

[0037] PG is an amino protecting group, such as acyl, alkyl, aralkyl, alkoxycarbonyl or aralkyloxycarbonyl, such as benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, preferably tert-butoxycarbonyl;

[0038] R' is independently substituted or unsubstituted C 1-6 Alkyl, or R′ and the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group;

[0039] R 1 are each independently H or an amino protecting group, such as acyl, alkyl, aralkyl, alkoxycarbonyl or aralkyloxycarbonyl, such as benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, preferably tert-butyloxycarbonyl; provided that the two R 1 are not simultaneously hydrogen; and

[0040] R 2 are each independently substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C3-C8 cycloalkyl-C 1-6 Alkyl, substituted or unsubstituted C6-C 10 Aryl-C 1-6 Alkyl, substituted or unsubstituted C5-C 10 Heteroaryl-C 1-6 Alkyl, or substituted or unsubstituted 3-12 membered heterocyclic group-C 1- 6-alkyl;

[0041] or

[0042] (b) reacting the compound of formula (VI) or the compound of formula (VII) with ammonia or an ammonium salt in the presence of an acid to give a compound of formula (III-3);

[0043] Among them, R 1 、R 2 、R 3 , PG and R′ are as defined above.

[0044] In one embodiment, the present invention provides a method for preparing a compound of formula (III),

[0045] The method includes:

[0046] (A) firstly performs the cyclization reaction of step (a) as described above, and then:

[0047] (A1) When R is -CN or -C(O)NH2, the cyclization reaction directly yields a compound of formula (III), wherein R 3 is a compound of formula (III-3) wherein -NH2,

[0048] (A2) When R is -C(O)OR 2 When the ester intermediate III' is obtained after the cyclization reaction, it can be reacted with an amidating agent to undergo urethane exchange to obtain the compound of formula (III), or the ester intermediate III' is first hydrolyzed to an acid in an alkaline solution and then condensed with ammonia or an ammonium salt to obtain the compound of formula (III).

[0049] or

[0050] (A3) When R is -C(O)N(R 1 )2, after the cyclization reaction, compound III" is converted into a compound of formula (III) by a deprotection reaction,

[0051] Among them, R 1 、R 2 、R 3 , PG and R′ are as defined above; or

[0052] (B) firstly carrying out the cyclization reaction of step (b) as described above, and then:

[0053] (B1) When R is -CN or -C(O)NH2, the cyclization reaction directly yields a compound of formula (III), wherein R 3 is a compound of formula (III-3) wherein -NH2,

[0054] (B2) When R is -C(O)OR 2 When the ester intermediate III' is obtained after the cyclization reaction, it can be reacted with an amidating agent to undergo urethane exchange to obtain the compound of formula (III), or the ester intermediate III' is first hydrolyzed to an acid in an alkaline solution and then condensed with ammonia or an ammonium salt to obtain the compound of formula (III).

[0055] (B3) When R is -C(O)N(R 1 )2, after the cyclization reaction, compound III" is converted into a compound of formula (III) by a deprotection reaction,

[0056] Among them, R 1 、R 2 、R 3 , PG and R′ are as defined above.

[0057] In a preferred embodiment, the ammonium salt includes ammonium salts formed with inorganic acids or organic acids, such as ammonium formate, ammonium acetate, ammonium oxalate, ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium methanesulfonate, ammonium trifluoroacetate, and the like.

[0058] In a preferred embodiment, the acid includes organic acids and inorganic acids, such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, oxalic acid, p-toluenesulfonic acid, and the like.

[0059] In a preferred embodiment, compound I, compound II, ammonia or an ammonium salt and an acid are reacted in a single organic solvent or a mixed solvent to form compound III.

[0060] In another preferred embodiment, compound VI, compound VII, ammonia or an ammonium salt and an acid are reacted in a single organic solvent or a mixed solvent to form compound III.

[0061] The reaction solvent is selected from common organic solvents, such as methanol, ethanol, trifluoroethanol, n-propanol, isopropanol, hexafluoroisopropanol, n-butanol, acetonitrile, tetrahydrofuran, toluene, or a mixed solvent of any two or more thereof.

[0062] The reaction temperature is 40 to 120°C, preferably 60 to 90°C, for example 60 to 75°C, or 75 to 90°C, more preferably 75°C.

[0063] The molar ratio of ammonium salt / acid is 0.80 / 1.00 to 1.20 / 0.80, preferably 0.95 / 1.00, 1.00 / 1.05, 1.00 / 1.15, more preferably 1.00 / 1.05 or 1.00 / 1.15. The reaction time is generally 10 to 24 hours.

[0064] In a preferred embodiment, for R is -C(O)OR 2 The amidating agent includes ammonia or ammonium salts, such as ammonium chloride, ammonium formate, ammonium acetate, ammonium oxalate, ammonium sulfate, ammonium nitrate, ammonium methanesulfonate, ammonium trifluoroacetate, etc.

[0065] In a preferred embodiment, for R is -C(O)OR 2 The alkaline solution includes a hydroxide, carbonate, bicarbonate or alcoholate solution of an alkali metal or alkaline earth metal, such as a hydroxide, carbonate, alcoholate of lithium, sodium, potassium or calcium, such as sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

[0066] In a preferred embodiment, for R is -C(O)N(R 1 ) 2 when the amino protecting group deprotection method is well known to those skilled in the art, for example, see Protective Groups in Organic Synthesis, Green and Wuts, 1999, ISBN: 9780471160199.

[0067] In a second aspect, the present invention provides a method for preparing a compound of formula (V), the method comprising:

[0068] Step 1: Carry out step (A) or (B) as described above to obtain a compound of formula (III),

[0069] Step 2: Deprotect the compound of formula (III) to obtain the compound of formula (IV),

[0070] and

[0071] Step 3: reacting the compound of formula (IV) with acryloyl chloride, or reacting with 3-chloropropionyl chloride and then eliminating HCl under alkaline conditions to obtain a compound of formula (V).

[0072] Among them, R 1 、R 2 , PG and R′ are as defined above.

[0073] In another embodiment, the present invention provides a method for preparing a compound of formula (V), comprising:

[0074] Step 1: Carry out step (A) or (B) as described above to obtain a compound of formula (III"),

[0075] Step 2: Remove PG and R from the compound of formula (III) 1 Group, to obtain a compound of formula (IV),

[0076] and

[0077] Step 3: reacting the compound of formula (IV) with acryloyl chloride, or reacting with 3-chloropropionyl chloride and then eliminating HCl under alkaline conditions to obtain a compound of formula (V).

[0078] Alternatively, after step 1, the reactions of steps 2', 3' and 4' are carried out,

[0079] Step 2': Deprotect the compound of formula (III") to obtain the compound of formula (IV'),

[0080] Step 3': reacting the compound of formula (IV') with acryloyl chloride, or reacting with 3-chloropropionyl chloride and then eliminating HCl under alkaline conditions to obtain a compound of formula (V').

[0081] Step 4': remove R from the compound of formula (V') 1 To obtain a compound of formula (V),

[0082] Among them, R 1 、R 2 , PG and R′ are as defined above.

[0083] In another embodiment, the present invention provides a method for preparing a compound of formula (V), comprising:

[0084] Step 1": Carry out step (A) or (B) as described above to obtain a compound of formula (III'),

[0085] Step 2": Remove the PG group from the compound of formula (III') to obtain a compound of formula (IV"),

[0086] Step 3": reacting the compound of formula (IV) with acryloyl chloride, or reacting with 3-chloropropionyl chloride and then eliminating HCl under alkaline conditions to obtain a compound of formula (V).

[0087] Step 4": Reverse the -OR2 The group is amidated and converted into a compound of formula (V),

[0088] Among them, R 1 、R 2 , PG and R′ are as defined above.

[0089] In a preferred embodiment, the above-OR 2 The amidating agent used for the amidation of the group includes ammonia or an ammonium salt such as ammonium chloride, ammonium formate, ammonium acetate, ammonium oxalate, ammonium sulfate, ammonium nitrate, ammonium methanesulfonate, ammonium trifluoroacetate and the like.

[0090] In a particularly preferred embodiment, the present invention relates to a process for preparing the compound of formula (V):

[0091] Among them, R 1 、R 2 , PG and R' are as defined above, and

[0092] The reaction conditions of the first, second and third steps are as defined above for the corresponding reactions.

[0093] In a preferred embodiment, when PG is tert-butyloxycarbonyl, compound III is deprotected in a hydrochloric acid solution to obtain the hydrochloride of compound IV.

[0094] In another preferred embodiment, when PG is a benzyl or benzyloxycarbonyl protecting group, compound III is deprotected by hydrogenation with a palladium catalyst to obtain compound IV;

[0095] In another preferred embodiment, compound IV or its hydrochloride is reacted with acryloyl chloride or 3-chloropropionyl chloride under alkaline conditions to obtain 6-(1-acryloylpiperidin-4-yl)-2-(phenoxyphenyl)pyridine-3-carboxamide (compound V).

[0096] In a more preferred embodiment, in the second step, when PG is Boc, hydrochloric acid gas or an organic solution containing hydrochloric acid (e.g., a solution of hydrochloric acid in ethyl acetate or a C1-C4 alcohol such as ethanol) is added to an organic solution of compound III (e.g., a solution of compound III in a C1-C4 alcohol such as ethanol or dichloromethane), or the organic solution of compound III is added to an organic solution of hydrochloric acid to carry out a de-Boc reaction to obtain the hydrochloride salt of compound IV.

[0097] In another more preferred embodiment, in the second step, when PG is Boc, hydrochloric acid gas, hydrochloric acid or an organic solution containing hydrochloric acid (for example, a solution of hydrochloric acid in ethyl acetate or a C1-C4 alcohol such as ethanol) is added to an organic solution of compound III (for example, a solution of compound III in a C1-C4 alcohol such as ethanol, acetone or dichloromethane), or the organic solution of compound III is added to an organic solution of hydrochloric acid to carry out a de-Boc reaction to obtain the hydrochloride salt of compound IV.

[0098] In another more preferred embodiment, in the second step, when PG is benzyl or benzyloxycarbonyl, deprotection is performed using a palladium catalyst under hydrogen to produce compound IV. Palladium catalysts include palladium-carbon, palladium hydroxide-carbon, palladium chloride, triphenylphosphine palladium chloride, palladium acetate, and the like. After compound IV is produced, hydrochloric acid solution can be added to VI to produce the hydrochloride salt of compound IV.

[0099] In another more preferred embodiment, in the third step, compound IV or its hydrochloride, acryloyl chloride, and a base are reacted in a single or mixed solvent (pH 8 to 14) at low temperature (0 to 8°C) to produce compound V. The solvent can be an organic solvent (e.g., THF or dichloromethane), or a mixture of an organic solvent and water. The base can be an inorganic salt such as a bicarbonate, carbonate, phosphate, or hydroxide. The reaction time is generally 1 to 5 hours or 1 to 3 hours.

[0100] Alternatively, in another more preferred embodiment, in the third step, compound IV or its hydrochloride is first reacted with 3-chloropropionyl chloride in a moderately alkaline solution (pH 10 to 12, such as a carbonate solution or a phosphate solution) to form an intermediate, and then a strong alkaline solution (e.g., DBU or a hydroxide solution) is added to increase the pH to 14 to form compound V. The solvent may be an organic solvent containing or not containing water (e.g., THF or dichloromethane). DETAILED DESCRIPTION

[0101] Example:

[0102] Examples 1-3 are shown in Scheme 1.

[0103] Solution 1

[0104] Example 1. Preparation of Compound III

[0105] Compound Ia (8.00 g, 33.7 mmol), Compound II (10.52 g, 37.2 mmol), ammonium acetate (10.40 g, 135 mmol), ethanol (120 mL, 15 v / v), and acetonitrile (120 mL, 15 v / v) were added to a reaction vessel in sequence. Mechanical stirring was initiated, and methanesulfonic acid (13.28 g, 138 mmol) was added. The mixture was heated to 80°C and maintained for approximately 24 h. The temperature was then lowered to 30°C and concentrated under reduced pressure until virtually no fractions were collected. Pure water (50.0 g, 6.25 w / w), toluene (100 mL, 12.5 v / v) and dichloromethane (50 mL, 12.5 v / v) were added to extract and separate the liquids. The organic phase was washed with 5% sodium chloride aqueous solution (50.0 g, 6.25 w / w). The organic phase was separated and n-heptane (100 mL, 12.5 v / v) was added. The mixture was heated to 70 ° C. and concentrated and crystallized at normal pressure. The temperature was then slowly lowered to 10 ° C. over 4.0 h, and kept at 10 ° C. for 2.0 h before filtration. The filter cake was dried under reduced pressure to obtain compound III (10.00 g, yield 62.5%, purity 98.9%).

[0106] 1 H NMR (400MHz, DMSO-d6) δppm 1.41 (s, 9H), 1.55-1.73 (m, 2H), 1.86 (br d, J = 10.76Hz, 2H), 2.74-3.07 (m, 3H), 4.08 (br d,J=11.49Hz,2H),6.99-7.12(m,4H),7.14-7.23(m,1H),7.29(d,J=7.82Hz,1H),7.40-7.46(m,2H),7.48(s,1H),7.69-7.76(m,3H),7.85(s,1 H).

[0107] The preparation method of compound Ia refers to J.Am.Chem.Soc.2011,133(4),774-776, and 4-phenoxybenzoic acid SM1 (purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.) is used as raw material to prepare the compound through two steps of chemical reaction.

[0108] The preparation method of compound II refers to Org.Lett.2023,25(25),4688-4693, using 1-tert-butyloxycarbonyl-4-acetylpiperidine (VII) (purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.) as raw material, and the compound was prepared by one step chemical reaction.

[0109] Example 2. Preparation of the hydrochloride salt of compound IV

[0110] Compound III (8.00 g, 16.9 mmol) and dichloromethane (40 mL, 5 v / v) were added to the reactor, mechanical stirring was started, and a clear solution was obtained, which was transferred to a dropping bottle. An ethanolic solution of hydrochloric acid (40 mL, 30 wt%, 5 v / v) and anhydrous ethanol (40 mL, 5 v / v) were added to the reactor, the temperature was lowered to 0°C, and the solution in the dropping bottle was added dropwise to the reactor over about 1 hour. The reaction was heated to 30°C and kept warm for about 12 hours. The reactor was concentrated under reduced pressure until almost no fraction was collected, and methanol (60 mL, 7.5 v / v) and ethyl acetate (60 mL, 7.5 v / v) were added in sequence and crystallized at 10°C. After incubation at 10°C for 2.0 h, the mixture was filtered and the filter cake was dried under reduced pressure to obtain the hydrochloride salt of compound IV (6.92 g, yield 94%, purity 99.1%).

[0111] 1 H NMR (400MHz, DMSO-d6) δppm 1.98-2.15(m,4H),2.93-3.07(m,2H),3.12(tt,J=10.21,5.07Hz,1H),3.35(br d,J=12.47Hz,2H),7.00-7.13(m,4H),7.14-7.26(m,1H),7.33(d,J=8.07Hz,1H),7.38-7.49(m,2H),7.54(br s,1H),7.66-7.78(m,2H),7.84(d,J=7.83Hz,1H),7.92(br s,1H),8.99(br d,J=10.03Hz,1H),9.35(br d, J = 10.51 Hz, 1H).

[0112] Example 2'. Preparation of the hydrochloride salt of compound IV

[0113] Compound III (8.00 g, 16.9 mmol) and acetone (80 mL, 10 v / v) were added to a reaction vessel and stirred. Concentrated hydrochloric acid (9.20 g, 36-38 wt%, 1.15 w / w) was added to the vessel and the reaction was maintained at 20-30°C for approximately 8 hours. Acetone (80 mL, 10 v / v) was added and the mixture was stirred at 25°C for 2 hours. Filter the mixture, rinse the filter cake with acetone (32 mL, 4 v / v), and dry it to obtain the hydrochloride salt of Compound IV (6.92 g, 94% yield, 99.8% purity).

[0114] 1H NMR (400MHz, DMSO-d6) δppm 1.98-2.15(m,4H),2.93-3.07(m,2H),3.12(tt,J=10.21,5.07Hz,1H),3.35(br d,J=12.47Hz,2H),7.00-7.13(m,4H),7.14-7.26(m,1H),7.33(d,J=8.07Hz,1H),7.38-7.49(m,2H),7.54(br s,1H),7.66-7.78(m,2H),7.84(d,J=7.83Hz,1H),7.92(br s,1H),8.99(br d,J=10.03Hz,1H),9.35(br d, J = 10.51 Hz, 1H).

[0115] Example 3. Preparation of Compound V

[0116] Add the hydrochloride of compound IV (4.00 g, 9.76 mmol), tetrahydrofuran (64 mL, 16 v / v) and pure water (64 mL, 16 v / v) to the reactor. Start mechanical stirring and add sodium bicarbonate (4.76 g, 56.7 mmol) in batches. Cool to 0 ° C, add pre-prepared 3-chloropropionyl chloride (2.88 g, 22.7 mmol) to the reactor, add dropwise, and keep at 0 ° C for about 2 hours. Warm to 15 ° C, add pure water (50 mL, 12.5 v / v), and crystallize at 20 ° C. Keep at 20 ° C for 2.0 hours, filter, transfer the filter cake to the reactor, add dichloromethane (64 mL, 16 v / v) and DBU (3.71 g, 24.4 mmol), and heat to reflux for 6 hours. The mixture was cooled to 20°C, 1N hydrochloric acid was added to adjust the pH to 7, and the phases were separated. The organic phase was concentrated to dryness and dissolved in tetrahydrofuran (64 mL, 16 v / v). The mixture was cooled to 20°C and pure water (100 mL, 25 v / v) was added dropwise to crystallize. The mixture was kept at 20°C for 2.0 h, then filtered and the filter cake was dried under reduced pressure to obtain compound V (3.55 g, 85% yield, 99.8% purity).

[0117] Example 3'. Preparation of Compound V

[0118] Add the hydrochloride of compound IV (equivalent to 8.00 g, 21.45 mmol of free base), tetrahydrofuran (128 mL, 16 v / v) and pure water (117 mL, 14.6 v / v) to the reactor. Start mechanical stirring and add sodium bicarbonate (9.52 g, 113.30 mmol) in batches. Cool to 2 ° C, add pre-prepared acryloyl chloride (4.08 g, 42.45 mmol) to the reactor, add dropwise, and keep the reaction at 2 ° C for about 2 hours. Heat to 20 ° C, add pure water (93 mL, 11.6 v / v) dropwise, and crystallize at 20 ° C. After incubation at 20°C for 2.0 h, the mixture was filtered and the filter cake was transferred to a reactor. Tetrahydrofuran (112 mL, 14 v / v) and butylated hydroxytoluene (BHT, CAS No. 128-37-0) (72 mg, 0.01% w / w) were added. The temperature was maintained at 20°C and stirred for 1 h. Purified water (231 mL, 28.9 v / v) was added dropwise and crystallized at 20°C. The mixture was incubated at 20°C for 2.0 h, filtered, and dried at 25°C to obtain a dry product. The dry product was added to a reactor, ethanol (56 mL, 7 v / v) and BHT (72 mg, 0.005% w / w) were added, and the temperature was raised to 73°C. The temperature was then gradually decreased to 5°C to allow crystallization. The mixture was incubated at 5°C for 2.0 h, filtered, and the filter cake was dried under reduced pressure to obtain Compound V (7.34 g, 80% yield, 99.9% purity).

[0119] Examples 4-5 are shown in Scheme 2.

[0120] Option 2

[0121] Example 4. Preparation of Compound Ic

[0122] To a reaction kettle, add 4-phenoxybenzoic acid SM1 (4.0 g, 18.7 mmol), toluene (40 mL, 10 v / v), thionyl chloride (2.7 g, 22.7 mmol), and N,N-dimethylformamide (5 wt %, 20 mg) and stir at 60°C for 4 h. Cool to room temperature, concentrate under reduced pressure to remove the toluene, add toluene (30 mL, 7.5 v / v) and distill once, then add dichloromethane (30 mL, 7.5 v / v) to dissolve the concentrated acid chloride. To a separate reaction kettle, add cycloisopropyl malonate (2.7 g, 18.7 mmol), 4-dimethylaminopyridine (2.8 g, 22.9 mmol), and dichloromethane (30 mL, 7.5 v / v). Cool to 0°C, and add the acid chloride solution prepared above dropwise. After the addition is complete, warm to room temperature and stir for 16 h. The reaction was quenched by adding 2N hydrochloric acid solution (60 mL, 15 v / v), stirred for 10 minutes, separated, and the aqueous phase was extracted with dichloromethane (50 mL, 12.5 v / v). The organic phases were combined, washed sequentially with 2N hydrochloric acid solution (40 mL, 10 v / v) and pure water (50 mL, 12.5 v / v), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 5.53 g of intermediate compound Ib.

[0123] MS (ESI) m / z: 271.1 (M+H + )

[0124] To the reaction vessel were added 5.10 g of the intermediate compound Ib, methanol (15 mL, 7.5 v / v), and 7N ammonia in methanol (25 mL, 10 v / v), and stirred at 40°C for 23 h. The mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified to afford compound Ic (2.7 g, 56% yield).

[0125] MS (ESI) m / z: 256.2 (M+H + )

[0126] 1 H NMR (400MHz, DMSO-d6) δppm 3.32(s,2H),3.81(s,1H),7.01-7.17(m,4H),7.18-7.31(m,1H),7.40-7.51(m,2H),7.57(br s,0.6H),7.68-7.75(m,0.4H),7.95-8.03(m,1H).

[0127] Example 5. Preparation of Compound III

[0128] To a reaction vessel were added compound Ic (0.50 g, 2.0 mmol), compound II (0.61 g, 2.2 mmol), ammonium acetate (0.60 g, 7.9 mmol), trifluoroethanol (15 mL, 30 v / v), and acetic acid (0.11 g, 1.8 mmol), and the mixture was heated to 80°C and stirred for 22 h. The mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified to afford compound III (0.6 g, 65% yield).

[0129] Examples 6-8 are shown in Scheme 3.

[0130] Option 3

[0131] Example 6. Preparation of Compound Ib

[0132] To reactor A, add potassium monomethyl malonate (17.5 g, 112 mmol), magnesium chloride (10.7 g, 112 mmol), and tetrahydrofuran (120 mL, 16 v / v). The mixture was heated to 65°C for reaction. To reactor B, add 4-phenoxybenzoic acid SM1 (8.0 g, 37 mmol) and tetrahydrofuran (80 mL, 10 v / v). N,N'-carbonyldiimidazole (7.3 g, 45 mmol) was added portionwise and stirred at 40°C. After 3 h of reaction, the contents of reactor A were cooled to 20°C. Reaction solution B was added dropwise to reaction solution A over 30 minutes and stirred at room temperature for 16 hours. The reaction was quenched by the addition of 2N hydrochloric acid solution (80 mL, 10 v / v), and extracted with ethyl acetate (100 mL, 12.5 v / v). The organic phase was washed with 5 wt % sodium bicarbonate solution (80 mL, 10 v / v) and concentrated to dryness under reduced pressure to obtain a crude product of compound Ib (9.9 g, yield 97.1%), which was used for the next reaction.

[0133] MS (ESI) m / z: 271.1 (M+H + )

[0134] Example 7. Preparation of Compound VIII

[0135] Compound Ib (5.7 g, 21 mmol), Compound II (6.57 g, 23.3 mmol), ammonium acetate (6.5 g, 84 mmol), trifluoroethanol (30 mL, 5 v / v), and acetic acid (1.2 g, 20 mmol) were added to a reaction vessel and heated to 80°C with stirring for 22 h. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Ethyl acetate (100 mL, 18 v / v) and purified water (40 mL, 7 v / v) were added to the residue, stirred for 15 minutes, and separated. The organic phase was washed with purified water (40 mL, 7 v / v) and concentrated to dryness under reduced pressure to obtain the crude product. Methanol (50 mL, 9 v / v) was added, the mixture was heated to 60°C with stirring for 20 minutes, then slowly cooled to 15°C and stirred for 1 h. The mixture was filtered, and the filter cake was rinsed with methanol (15 mL, 3 v / v). The wet product was dried under vacuum to obtain Compound VIII (8.6 g, 84% yield, 98.6% purity).

[0136] MS (ESI) m / z: 489.3 (M+H + )

[0137] 1 H NMR (400MHz, DMSO-d6) δppm 1.41 (s, 9H), 1.53-1.71 (m, 2H), 1.88 (br d, J=11.00Hz, 2H), 2.85 (br s,1H),2.97(tt,J=11.74,3.55Hz,1H),3.31(s,1H),3.68(s,3H),4.07(br d,J=12.47Hz,2H),7.02-7.12(m,4H),7.15-7.23(m,1H),7.38(d,J=8.07Hz,1H),7.40-7.47(m,2H),7.49-7.57(m,2H),8.05(d,J=8.07Hz,1H).

[0138] Example 8. Preparation of Compound III

[0139] Compound VIII (2.6 g, 5.3 mmol) and a 7 M methanolic ammonia solution (20 mL, 8 v / v) were added to an autoclave, heated to 70°C, and stirred for 8 h. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Ethyl acetate (40 mL, 15 v / v) and purified water (20 mL, 7.5 v / v) were added to the residue, stirred for 15 minutes, and the layers separated. The organic phase was concentrated under reduced pressure to dryness, and the crude product was purified to obtain Compound III (2.0 g, 80% yield, 97.2% purity).

[0140] Examples 9-10 are shown in Scheme 4.

[0141] Option 4

[0142] Example 9. Preparation of Compound VI-a

[0143] Compound Ia (2.0 g, 8.4 mmol), 1,4-dioxane (20 mL, 10 v / v), and N,N-dimethylformamide dimethyl acetal (1.6 g, 13.4 mmol) were added to a reaction vessel and heated to 100°C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (6 mL, 3 v / v) was added to the residue and stirred at room temperature for 15 minutes. The mixture was filtered, and the filter cake was rinsed with n-hexane (5 mL, 2.5 v / v) and dried under vacuum to yield compound VI-a (1.4 g, 56.1% yield).

[0144] Example 10. Preparation of Compound III

[0145] Compound VI-a (3.0 g, 10 mmol), compound VII (2.6 g, 11 mmol), potassium tert-butoxide (2.3 g, 20 mmol), and tetrahydrofuran (30 mL, 10 v / v) were added to a reaction flask and stirred at room temperature for 1 h. Acetic acid was added dropwise to adjust the pH to approximately 7, followed by the addition of acetic acid (30 mL, 10 v / v) and ammonium acetate (3.2 g, 41 mmol). The mixture was heated to 100°C and stirred for 12 h. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. Ethyl acetate (50 mL, 17 v / v) and purified water (30 mL, 10 v / v) were added to the residue, stirred for 15 minutes, and the layers separated. The organic phase was washed with purified water (30 mL, 10 v / v) and concentrated to dryness under reduced pressure to obtain the crude product, which was then purified to obtain compound III (1.2 g, 26% yield, 87.5% purity).

[0146] Example 11 is shown in Scheme 5.

[0147] Option 5

[0148] Compound Ib (1.0 g, 3.7 mmol), 1,4-dioxane (20 mL, 20 v / v), and N,N-dimethylformamide dimethyl acetal (0.5 g, 4.2 mmol) were added to a reaction vessel and heated to 100°C for 2 h. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure to obtain crude compound VI-c (0.64 g).

[0149] Compound VI-c (2.5 g, 7.7 mmol), compound VII (1.9 g, 8.4 mmol), potassium tert-butoxide (1.7 g, 15 mmol), and tetrahydrofuran (25 mL, 10 v / v) were added to a reaction vessel and stirred at room temperature for 1 h. Acetic acid was added dropwise to adjust the pH to approximately 7, followed by the addition of acetic acid (20 mL, 8 v / v) and ammonium acetate (2.4 g, 31 mmol). The temperature was raised to 100°C and stirred for 13 h. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. Ethyl acetate (50 mL, 20 v / v) and pure water (30 mL, 12 v / v) were added to the residue and stirred for 15 minutes. The organic phase was separated, washed with pure water (30 mL, 12 v / v), and concentrated to dryness under reduced pressure to obtain the crude product, which was purified to afford compound VIII (2.6 g, 68% yield, 98.1% purity).

Claims

1. A method for preparing a compound of formula (III-3), The method includes: (a) subjecting the compound of formula (I) and the compound of formula (II) to a cyclization reaction with ammonia or an ammonium salt in the presence of an acid to obtain a compound of formula (III-3); in R is -CN, -C(O)NH2, -C(O)N(R 1 )2 or -C(O)OR 2 , R 3 -NH2, -N(R 1 )2OR 2 , PG is an amino protecting group, such as acyl, alkyl, aralkyl, alkoxycarbonyl or aralkyloxycarbonyl, such as benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, preferably tert-butoxycarbonyl; R' is independently substituted or unsubstituted C 1-6 Alkyl, or R′ and the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group; R 1 are each independently H or an amino protecting group, such as acyl, alkyl, aralkyl, alkoxycarbonyl or aralkyloxycarbonyl, such as benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, preferably tert-butyloxycarbonyl; provided that the two R attached to the same N atom 1 are not simultaneously hydrogen; and R 2 are each independently substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 heteroaryl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C3-C8 cycloalkyl-C 1-6 Alkyl, substituted or unsubstituted C6-C 10 Aryl-C 1- 6 alkyl, substituted or unsubstituted C5-C 10 Heteroaryl-C 1-6 Alkyl, or substituted or unsubstituted 3-12 membered heterocyclic group-C 1-6 alkyl; or (b) subjecting the compound of formula (VI) and the compound of formula (VII) to a cyclization reaction with ammonia or an ammonium salt in the presence of an acid to obtain a compound of formula (III-3), Among them, R 1 , R 2 , R 3 , PG and R′ are as defined above.

2. The method according to claim 1, which is used to prepare a compound of formula (III), The method includes: (A) firstly carrying out the cyclization reaction of step (a) as claimed in claim 1, and then: (A1) When R is -CN or -C(O)NH2, the cyclization reaction directly yields a compound of formula (III), wherein R 3 is a compound of formula (III-3) wherein -NH2, (A2) When R is -C(O)OR 2 When, after the cyclization reaction, the obtained ester intermediate III' can be reacted with an amidating agent to undergo aminoester exchange to obtain the compound of formula (III), or the ester intermediate III' is first hydrolyzed in an alkaline solution to form an acid, and then condensed with ammonia or an ammonium salt to obtain the compound of formula (III), or (A3) When R is -C(O)N(R 1 )2, after the cyclization reaction, compound III" is converted into a compound of formula (III) by a deprotection reaction; Among them, R 1 , R 2 , R 3 , PG and R′ as defined in claim 1; or (B) firstly carrying out the cyclization reaction of step (b) as claimed in claim 1, and then: (B1) When R is -CN or -C(O)NH2, the cyclization reaction directly yields a compound of formula (III), wherein R 3 is a compound of formula (III-3) wherein -NH2, (B2) When R is -C(O)OR 2 When, after the cyclization reaction, the obtained ester intermediate III' can be reacted with an amidating agent to undergo aminoester exchange to obtain the compound of formula (III), or the ester intermediate III' is first hydrolyzed in an alkaline solution to form an acid, and then condensed with ammonia or an ammonium salt to obtain the compound of formula (III), (B3) When R is -C(O)N(R 1 )2, after the cyclization reaction, compound III" is converted into a compound of formula (III) by a deprotection reaction; Among them, R 1 , R 2 , R 3 , PG and R′ are as defined in claim 1.

3. A method for preparing a compound of formula (V), the method comprising: Step 1: Carry out step (A) or (B) as claimed in claim 2 to obtain a compound of formula (III), Step 2: Deprotect the compound of formula (III) to obtain a compound of formula (IV), and Step 3: reacting the compound of formula (IV) with acryloyl chloride, or reacting with 3-chloropropionyl chloride and then eliminating HCl under alkaline conditions to obtain a compound of formula (V), Among them, R 1 , R 2 , PG and R′ are as defined in claim 1.

4. A method for preparing a compound of formula (V), the method comprising: Step 1: Carry out step (A) or (B) as claimed in claim 2 to obtain a compound of formula (III"), Step 2: Remove PG and R from the compound of formula (III”) 1 Group, to obtain a compound of formula (IV), Step 3: reacting the compound of formula (IV) with acryloyl chloride or 3-chloropropionyl chloride and then eliminating HCl under alkaline conditions to obtain a compound of formula (V), Alternatively, after step 1, the reactions of steps 2', 3' and 4' are carried out, Step 2': Deprotect the compound of formula (III") to obtain a compound of formula (IV'), Step 3': reacting the compound of formula (IV') with acryloyl chloride, or reacting with 3-chloropropionyl chloride and then eliminating HCl under alkaline conditions to obtain a compound of formula (V'), Step 4': Remove the R 1 To obtain a compound of formula (V), Among them, R 1 , R 2 , PG and R′ are as defined in claim 1.

5. A method for preparing a compound of formula (V), the method comprising: Step 1": Carry out step (A) or (B) as claimed in claim 2 to obtain a compound of formula (III'), Step 2": Remove the PG group from the compound of formula (III') to obtain a compound of formula (IV"), Step 3": reacting the compound of formula (IV") with acryloyl chloride, or reacting with 3-chloropropionyl chloride and then eliminating HCl under alkaline conditions to obtain a compound of formula (V"), Step 4": Reverse the -OR 2 The group is amidated to convert into a compound of formula (V), Among them, R 1 , R 2 , PG and R′ are as defined in claim 1.

6. A method for preparing a compound of formula (V), the method comprising the following steps: Among them, R 1 , R 2 , PG and R′ are as defined in claim 1, and The reaction conditions of the first step, the second step and the third step are defined as the corresponding reactions described in any one of claims 1 to 5.

7. The method according to any one of claims 1 to 6, wherein R is -CN, -C(O)NH2 or -C(O)OR 2 .

8. The method according to any one of claims 1 to 7, wherein PG is selected from tert-butyloxycarbonyl, benzyl or benzyloxycarbonyl.

9. The method according to any one of claims 1 to 8, wherein R' is independently substituted or unsubstituted C 1-6 alkyl.

10. The method according to any one of claims 1 to 9, wherein the ammonium salt in step (a) or (b) comprises an ammonium salt formed with an inorganic acid or an organic acid, such as ammonium formate, ammonium acetate, ammonium oxalate, ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium methanesulfonate, ammonium trifluoroacetate, etc.

11. The method according to any one of claims 1 to 10, wherein the acid described in step (a) or (b) comprises an organic acid and an inorganic acid, such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, oxalic acid, p-toluenesulfonic acid.

12. The method according to any one of claims 1 to 11, wherein the molar ratio of ammonium salt / acid in step (a) or (b) is 0.80 / 1.00 to 1.20 / 0.80, preferably 0.95 / 1.00, 1.00 / 1.05, 1.00 / 1.15, more preferably 1.00 / 1.05 or 1.00 / 1.

15.

13. The method according to any one of claims 1 to 12, wherein the -OR 2 The amidating agent used for the amidation of the group includes ammonia or an ammonium salt such as ammonium chloride, ammonium formate, ammonium acetate, ammonium oxalate, ammonium sulfate, ammonium nitrate, ammonium methanesulfonate or ammonium trifluoroacetate.

14. The method according to any one of claims 1 to 13, wherein the solvent for the reaction in step (a) or (b) is selected from methanol, ethanol, trifluoroethanol, n-propanol, isopropanol, hexafluoroisopropanol, n-butanol, acetonitrile, tetrahydrofuran, toluene, or a mixed solvent of any two or more thereof, preferably ethanol, more preferably a mixed solvent of ethanol and acetonitrile.

15. The method according to any one of claims 1 to 14, wherein the reaction temperature of the reaction in step (a) or (b) is 40 to 120°C, preferably 60 to 90°C, such as 60 to 75°C, or 75 to 90°C, more preferably 75°C.

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