Preparation method of obrutinib and intermediate compound of obrutinib

Abstract

The invention relates to a preparation method of obrutinib and an intermediate compound of the obrutinib. Specifically, the invention relates to a preparation method of 6-(1-acryloyl piperidine-4-yl)-2-(phenoxy phenyl) pyridine-3-formamide and an intermediate compound of 6-(1-acryloyl piperidine-4-yl)-2-(phenoxy phenyl) pyridine-3-formamide. The method provided by the invention has the characteristics of simple route, cheap and easily available raw materials, mild conditions, high product yield and the like, can greatly reduce the production cost, is environment-friendly, and is easy for industrial large-scale production.

Description

Technical Field

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

[0002] Obtunib, i.e. 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 and can be used to treat cancer, inflammation and autoimmune diseases (see WO2015 / 048662).

[0003]

[0004] There are some reports on the preparation method of obeticholic acid. WO2015 / 048662 discloses a small batch preparation method of compound V, which requires multiple palladium-catalyzed Suzuki coupling reactions to connect the piperidine group and the phenoxyphenyl group to the pyridine group, respectively, to construct the compound of formula (V).

[0005] WO2020 / 173407 also discloses a method for preparing compound V in large quantities by a palladium-catalyzed coupling reaction, and its synthetic route is as follows:

[0006]

[0007] However, the above synthesis route not only requires the repeated use of expensive and environmentally unfriendly Pd catalysts, but also requires Pd-catalyzed pressurized hydrogenation reactions, which are hazardous chemical processes with high requirements for equipment. At the same time, the reaction route is long and the reaction steps are complicated, resulting in high production costs and the generation of more industrial wastes, so further improvements are needed.

[0008] Chinese patent application CN113563305 also reports a synthesis method, which not only requires two condensation reactions, but also needs to undergo Pd-catalyzed hydrogenation reduction to convert the nitro group carried in the molecule into an amino group, and then self-cyclization and isomerization to obtain the intermediate I of obeticholic acid. This method still requires the use of an expensive and environmentally unfriendly Pd catalyst, and the reaction steps are complicated. At the same time, the self-cyclization reaction may produce different by-products at different temperatures, affecting the purity of the product.

[0009]

[0010]

[0011] Therefore, there is still a need in the art for a synthesis method of obeticholic acid that is simple to operate, has cheap raw materials, and is suitable for industrial mass production.

[0012] In order to overcome the shortcomings and deficiencies of the prior art, the present invention provides a new method for synthesizing obeticholic acid. The method has the characteristics of convenient operation, cheap and readily available raw materials, high product yield, high intermediate purity, etc., which can not only reduce the overall production cost to about 10% of the existing method, but also avoid the use of heavy metals such as Pd, is environmentally friendly, and is easy to carry out industrial-scale production. Summary of the invention

[0013] definition

[0014] In the present invention, the following terms have the following meanings:

[0015] 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, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-hexyl.

[0016] 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. The alkenyl group can have 2-8, such as 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 vinyl, propenyl, allyl, butenyl, pentenyl, etc.

[0017] 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, isopentyl, neopentyl), hexoxy (including n-hexyl, isohexyl), etc. Representative examples of alkenyloxy include, but are not limited to, allyloxy.

[0018] The term "carbonyl" alone or in combination with other groups refers to the group -C(=O)-.

[0019] The term "halogen" refers to fluorine, chlorine, bromine, iodine.

[0020] 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.

[0021] The term "cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having a specified number of ring atoms. A cycloalkyl group may have 3 to 12 carbon atoms (i.e., C3-C 12 Cycloalkyl) such as 3 to 10, 3 to 8, 3 to 7, 3 to 6, or 5 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0022] 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 a 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, for example phenyl, naphthyl or fluorenyl.

[0023] 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, for example benzyl.

[0024] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure including 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. 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 fused two 6-membered rings, fused two 5-membered rings, fused 6-membered rings and 5-membered rings, or fused 5-membered rings and 4-membered rings. The heteroaryl ring will typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, for example, a single heteroatom independently selected from O, N, and S, wherein N and S may be in an oxidation 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, pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrimido[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine and pyrimido[4,5-d]pyrimidine. For example, the heteroaryl group can be a 5-6 membered heteroaryl group containing 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 the 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.

[0025] The term "heterocyclyl" refers to a non-aromatic saturated ring structure including 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 a monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. The heterocyclyl may have 3 to 12 ring members (which may be referred to as a 3-12 membered heterocycloalkyl), such as 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. The heterocyclyl 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.

[0026] The term "heterocyclyl" also includes "heterocyclyl" as defined above containing 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).

[0027] The term "acyl" refers to the group R y -C(=O)-, where R y is an alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl group as defined above.

[0028] 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.

[0029] "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, which are optionally substituted by alkyl, alkoxy, halogen, haloalkyl, nitro, cyano, hydroxyl and / or amino as described above. Their examples 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.

[0030] 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.

[0031] The term "about" when used in conjunction with a numerical value means encompassing all values ​​within the range having a lower limit that is 10% less than the specified numerical value and an upper limit that is 10% greater than the specified numerical value.

[0032] Implementation

[0033] The purpose of the present invention is to provide a novel method for preparing a compound of formula (V). The method has the characteristics of simple route, cheap and readily available raw materials, mild conditions, high product yield, high intermediate purity, etc., can greatly reduce production costs, is environmentally friendly, and is easy to carry out industrial production.

[0034] In a first aspect, the present invention provides a method for preparing a compound of formula (III-3),

[0035]

[0036] The method includes:

[0037] (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);

[0038]

[0039] in

[0040] R is -CN, -C(O)NH2, -C(O)N(R 1 )2 or -C(O)OR 2 ,

[0041] R 3 -NH2, -N(R 1 )2OR 2 ,

[0042] 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;

[0043] 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;

[0044] 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

[0045] 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;

[0046] or

[0047] (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),

[0048]

[0049] Among them, R 1 , R 2 , R 3 , PG and R′ are as defined above.

[0050] In one embodiment, the present invention provides a method for preparing a compound of formula (III),

[0051]

[0052] The method includes:

[0053] (A) firstly performs the cyclization reaction of step (a) as described above, and then:

[0054] (A1) When R is -CN or -C(O)NH2, the cyclization reaction directly yields a compound of formula (III), wherein R 3 The compound of formula (III-3) is -NH2,

[0055]

[0056] (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),

[0057]

[0058] or

[0059] (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;

[0060]

[0061] Among them, R 1 , R 2 , R 3, PG and R′ are as defined above; or

[0062] (B) firstly carrying out the cyclization reaction of step (b) as described above, and then:

[0063] (B1) When R is -CN or -C(O)NH2, the cyclization reaction directly yields a compound of formula (III), wherein R 3 The compound of formula (III-3) is -NH2,

[0064]

[0065] (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),

[0066]

[0067]

[0068] (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;

[0069]

[0070] Among them, R 1 , R 2 , R 3 , PG and R′ are as defined above.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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 usually 10 to 24 hours.

[0078] 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, and the like.

[0079] 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.

[0080] In a preferred embodiment, for R is -C(O)N(R 1 The deprotection method of the amino protecting group described in )2 is well known to those skilled in the art, for example, see Protective Groups in Organic Synthesis, Green and Wuts, 1999, ISBN:9780471160199.

[0081] In a second aspect, the present invention provides a method for preparing a compound of formula (V), the method comprising:

[0082] Step 1: Carry out step (A) or (B) as described above to obtain a compound of formula (III),

[0083] Step 2: Deprotect the compound of formula (III) to obtain a compound of formula (IV),

[0084]

[0085] and

[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]

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

[0089] In another embodiment, the present invention provides a method for preparing a compound of formula (V), the method comprising:

[0090] Step 1: Carry out step (A) or (B) as described above to obtain a compound of formula (III"),

[0091] Step 2: Remove PG and R from the compound of formula (III”) 1 Group, to obtain a compound of formula (IV),

[0092]

[0093] and

[0094] 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),

[0095]

[0096] Alternatively, after step 1, the reactions of steps 2', 3' and 4' are carried out,

[0097] Step 2': Deprotect the compound of formula (III") to obtain a compound of formula (IV'),

[0098]

[0099] 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'),

[0100]

[0101] Step 4': Remove the R 1 To obtain a compound of formula (V),

[0102]

[0103] Among them, R 1 , R 2 , PG and R′ are as defined above.

[0104] In another embodiment, the present invention provides a method for preparing a compound of formula (V), the method comprising:

[0105] Step 1": Carry out step (A) or (B) as described above to obtain a compound of formula (III'),

[0106] Step 2": Remove the PG group from the compound of formula (III') to obtain a compound of formula (IV"),

[0107]

[0108] 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"),

[0109]

[0110] Step 4": Reverse the -OR 2 The group is amidated to convert into a compound of formula (V),

[0111]

[0112] Among them, R 1 , R 2 , PG and R′ are as defined above.

[0113] 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.

[0114] In a particularly preferred embodiment, the present invention relates to a process for preparing the following compound of formula (V):

[0115]

[0116] Among them, R 1 , R 2 , PG and R′ are as defined above, and

[0117] The reaction conditions of the first step, the second step and the third step are as defined above for the corresponding reactions.

[0118] 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.

[0119] 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;

[0120] 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).

[0121] In a more preferred embodiment, in the second step, when PG is Boc, hydrochloric acid gas 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 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 of compound IV.

[0122] In another more preferred embodiment, in the second step, when PG is benzyl or benzyloxycarbonyl, deprotection is carried out using a palladium catalyst under hydrogen to obtain compound IV. Palladium catalysts include palladium carbon, palladium hydroxide carbon, palladium chloride, triphenylphosphine palladium chloride, palladium acetate, etc. After compound IV is generated, hydrochloric acid solution can be added to VI to generate the hydrochloride of compound IV.

[0123] In another more preferred embodiment, in the third step, compound IV or its hydrochloride, acryloyl chloride and 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 bicarbonate, carbonate, phosphate, hydroxide, etc. The reaction time is generally 1 to 5 hours or 1 to 3 hours.

[0124] 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 water or water (e.g., THF or dichloromethane). DETAILED DESCRIPTION

[0125] Example:

[0126] Examples 1-3 are shown in Scheme 1.

[0127]

[0128] Example 1. Preparation of Compound III

[0129] 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 the reaction kettle in sequence, mechanical stirring was started, and methanesulfonic acid (13.28 g, 138 mmol) was added. The mixture was heated to 80°C and kept for about 24 hours, then cooled to 30°C and concentrated under reduced pressure until almost no fraction was 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 for concentration and crystallization at normal pressure, and then slowly cooled to 10 ° C over 4.0 h. The mixture was kept at 10 ° C for 2.0 h and then filtered. The filter cake was dried under reduced pressure to obtain compound III (10.00 g, yield 62.5%, purity 98.9%).

[0130] 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=7.82 Hz,1H),7.40-7.46(m,2H),7.48(s,1H),7.69-7.76(m,3H),7.85(s,1H).

[0131] 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 a raw material to prepare the compound through two steps of chemical reaction.

[0132] The preparation method of compound II refers to Org. Lett. 2023, 25 (25), 4688-4693, using 1-tert-butoxycarbonyl-4-acetylpiperidine (VII) (purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.) as raw material, and the compound is prepared by one step chemical reaction.

[0133] Example 2. Preparation of the hydrochloride salt of compound IV

[0134] Compound III (8.00 g, 16.9 mmol) and dichloromethane (40 mL, 5 v / v) were added to the reactor, mechanical stirring was turned on, a clear solution was obtained, and the solution was transferred to a dropping bottle. An ethanol 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, the solution in the dropping bottle was dripped into the reactor within about 1 hour, and the reaction was heated to 30 ° C for about 12 hours. The reactor was concentrated under reduced pressure until almost no fraction was collected, 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 filtration at 10 ° C for 2.0 h, the filter cake was dried under reduced pressure to obtain the hydrochloride of compound IV (6.92 g, yield 94%, purity 99.1%).

[0135] 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).

[0136] Example 3. Preparation of Compound V

[0137] 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. Turn on the mechanical stirring and add sodium bicarbonate (4.76 g, 56.7 mmol) in batches. Cool down to 0 ° C, add the pre-configured 3-chloropropionyl chloride (2.88 g, 22.7 mmol) to the reactor, add dropwise, and keep warm at 0 ° C for about 2 hours. Warm up to 15 ° C, add pure water (50 mL, 12.5 v / v), and crystallize at 20 ° C. Keep warm at 20 ° C for 2.0 h and 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 h. The temperature was lowered to 20°C, 1N hydrochloric acid was added to adjust the pH to 7, the phases were separated, the organic phase was concentrated to dryness, tetrahydrofuran (64 mL, 16 v / v) was added to dissolve. The temperature was lowered to 20°C, pure water (100 mL, 25 v / v) was added dropwise to crystallize. After keeping warm at 20°C for 2.0 h, the mixture was filtered, and the filter cake was dried under reduced pressure to obtain compound V (3.55 g, yield 85%, purity 99.8%).

[0138] Examples 4-5 are shown in Scheme 2.

[0139]

[0140] Example 4. Preparation of Compound Ic

[0141] 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) to the reaction kettle and stir at 60 ° C for 4 h. Cool to room temperature, concentrate under reduced pressure to remove toluene, add toluene (30 mL, 7.5 v / v) and steam once, then add dichloromethane (30 mL, 7.5 v / v) to dissolve the acyl chloride concentrate. 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) to another reaction kettle, cool to 0 ° C, add the above prepared acyl chloride solution dropwise, warm to room temperature after the addition is complete, and stir for 16 h. 2N hydrochloric acid solution (60 mL, 15 v / v) was added to quench the reaction, 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 with 2N hydrochloric acid solution (40 mL, 10 v / v) and pure water (50 mL, 12.5 v / v) in sequence, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 5.53 g of intermediate compound Ib.

[0142] MS (ESI) m / z: 271.1 (M+H + )

[0143] 5.10 g of the intermediate compound Ib, methanol (15 mL, 7.5 v / v) and 7N ammonia methanol solution (25 mL, 10 v / v) were added to the reaction kettle and stirred at 40°C for 23 h. The mixture was concentrated to dryness under reduced pressure to obtain a crude product, which was purified to obtain compound Ic (2.7 g, yield 56%).

[0144] MS (ESI) m / z: 256.2 (M+H + )

[0145] 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).

[0146] Example 5. Preparation of Compound III

[0147] 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) were added to the reaction kettle, and the temperature was raised to 80°C and stirred for 22 h. The mixture was concentrated to dryness under reduced pressure to obtain a crude product, which was purified to obtain compound III (0.6 g, yield 65%).

[0148] Examples 6-8 are shown in Scheme 3.

[0149]

[0150] Example 6. Preparation of Compound Ib

[0151] Add potassium monomethyl malonate (17.5 g, 112 mmol), magnesium chloride (10.7 g, 112 mmol) and tetrahydrofuran (120 mL, 16 v / v) to reactor A, and heat to 65 ° C for reaction. Add 4-phenoxybenzoic acid SM1 (8.0 g, 37 mmol) and tetrahydrofuran (80 mL, 10 v / v) to reactor B, add N, N'-carbonyl diimidazole (7.3 g, 45 mmol) in batches, and stir at 40 ° C. After 3 hours of reaction, cool the material in reactor A to 20 ° C, add reaction solution B dropwise to reaction solution A within 30 minutes, and stir at room temperature for 16 hours. Add 2N hydrochloric acid solution (80 mL, 10 v / v) to quench the reaction, and add ethyl acetate (100 mL, 12.5 v / v) for extraction. 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.

[0152] MS (ESI) m / z: 271.1 (M+H + )

[0153] Example 7. Preparation of Compound VIII

[0154] 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 the reaction kettle, and the temperature was raised to 80 ° C and stirred for 22 h. The temperature was lowered to room temperature, and the solvent was removed by vacuum concentration. Ethyl acetate (100 mL, 18 v / v) and pure water (40 mL, 7 v / v) were added to the residue, stirred for 15 minutes, and separated. The organic phase was washed with pure water (40 mL, 7 v / v) and concentrated to dryness under reduced pressure to obtain a crude product. Methanol (50 mL, 9 v / v) was added, the temperature was raised to 60 ° C and stirred for 20 minutes, the temperature was slowly lowered to 15 ° C, and stirred for 1 h. Filter, the filter cake was rinsed with methanol (15 mL, 3 v / v), and the wet product was vacuum dried to obtain compound VIII (8.6 g, yield 84%, purity 98.6%).

[0155] MS (ESI) m / z: 489.3 (M+H) + )

[0156] 1H 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).

[0157] Example 8. Preparation of Compound III

[0158] Compound VIII (2.6 g, 5.3 mmol) and ammonia methanol solution (7M, 20 mL, 8 v / v) were added to the autoclave, and the temperature was raised to 70°C and stirred for 8 h. The temperature was lowered to room temperature, and the solvent was removed by vacuum concentration. Ethyl acetate (40 mL, 15 v / v) and pure water (20 mL, 7.5 v / v) were added to the residue, and the mixture was stirred for 15 minutes and separated. The organic phase was concentrated to dryness under reduced pressure, and the crude product was purified to obtain compound III (2.0 g, yield 80%, purity 97.2%).

[0159] Examples 9-10 are shown in Scheme 4.

[0160]

[0161] Example 9. Preparation of Compound VI-a

[0162] 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 the reaction kettle, and the temperature was raised to 100 °C for 2 h. The reaction solution 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 filter cake was filtered and rinsed with n-hexane (5 mL, 2.5 v / v), and vacuum dried to obtain compound VI-a (1.4 g, yield 56.1%).

[0163] Example 10. Preparation of Compound III

[0164] Add 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) to the reaction flask and stir at room temperature for 1 h. Add acetic acid dropwise to adjust the pH to about 7, then add acetic acid (30 mL, 10 v / v) and ammonium acetate (3.2 g, 41 mmol), heat to 100 ° C and stir for 12 h. Cool to room temperature, concentrate to dryness under reduced pressure, add ethyl acetate (50 mL, 17 v / v) and pure water (30 mL, 10 v / v) to the residue, stir for 15 minutes, and separate. The organic phase is washed with pure water (30 mL, 10 v / v), concentrated to dryness under reduced pressure to obtain a crude product, and then purified to obtain compound III (1.2 g, yield 26%, purity 87.5%).

[0165] Example 11 is shown in Scheme 5.

[0166]

[0167] 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 the reaction kettle, heated to 100 °C for 2 h, cooled to room temperature, and the reaction solution was concentrated to dryness under reduced pressure to obtain a crude compound VI-c (0.64 g).

[0168] Add 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) to the reaction kettle and stir at room temperature for 1 h. Add acetic acid dropwise to adjust the pH to about 7, then add acetic acid (20 mL, 8 v / v) and ammonium acetate (2.4 g, 31 mmol), heat to 100 ° C and stir for 13 h. Cool to room temperature, concentrate to dryness under reduced pressure, add ethyl acetate (50 mL, 20 v / v) and pure water (30 mL, 12 v / v) to the residue, and stir for 15 minutes. Separate the liquid, wash the organic phase with pure water (30 mL, 12 v / v), and concentrate to dryness under reduced pressure to obtain a crude product, which is purified to obtain compound VIII (2.6 g, yield 68%, purity 98.1%).

Claims

1. A method for preparing a compound of formula (III-3), The method includes: (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 undergo a cyclization reaction; Should, obtain the 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 each 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′ are 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), and 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": removing 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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