Preparation method of benzimidazole derivative

Abstract

The invention relates to a preparation method of a benzimidazole derivative. In particular, the methods described herein include the step of converting a compound of formula D-1a to a compound of formula E-1a. The method is simple to operate and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing a benzimidazole derivative. Background Art

[0002] P2X receptors are a family of cation-permeable, ligand-gated ion channels. Seven individual genes have been identified, including P2X1 to P2X7. The P2X3 receptor possesses four ATP-binding sites on a single subunit. Studies have shown that P2X3 receptors are highly expressed in small and medium-diameter neurons specifically involved in nociceptive information, and are also involved in the transmission of some non-nociceptive sensations.

[0003] (S)-1-(4-(1-((4-acetylmorpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3-chloro-5-fluorophenyl)pyrrolidin-2-one (Compound AA), reported in WO2022033567, is a P2X3 receptor activity antagonist that has entered clinical development.

[0004]

[0005] WO2022033567 discloses a method for preparing the target product by using tert-butyl (2R)-2-(hydroxymethyl)morpholine-4-carboxylate as the starting material through nearly 6 steps of reaction (see Example 1).

[0006]

[0007] The total process yield is about 4.2%, which is not ideal and has room for improvement. At the same time, the overall process cost is high, making it difficult to apply to industrialization. Summary of the Invention

[0008] The present disclosure provides a method for preparing a compound of formula I or a salt thereof, comprising the steps of reacting a compound of formula A or a salt thereof with a compound of formula B or a salt thereof to form a compound of formula I or a salt thereof.

[0009]

[0010] Among them, R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting groups;

[0011] R 2 Selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted by one or more radicals selected from halogen, hydroxy, cyano, C1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0012] R 3 Selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0013] R 4 Selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0014] m is selected from 0, 1, 2, 3 or 4;

[0015] n is selected from 0, 1, 2, 3 or 4;

[0016] o is selected from 0, 1, 2, 3 or 4.

[0017] In some embodiments, the compound represented by Formula A or a salt thereof is reacted with the compound represented by Formula B or a salt thereof in the presence of a reducing agent, and the reducing agent is selected from sodium dithionite.

[0018] In some embodiments, the solvent used for the reaction of the compound represented by Formula A or its salt with the compound represented by Formula B or its salt is selected from protic polar solvents, and the protic polar solvents include but are not limited to ethanol.

[0019] In some embodiments, the molar ratio of the compound represented by Formula A or its salt to the reducing agent is 1:1 to 1:5, including 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4.0, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5.0 or any value between two numbers.

[0020] In some embodiments, the molar ratio of the compound represented by Formula B or its salt to the compound represented by Formula A or its salt is 1:1 to 1:2, including 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0 or any value between two numbers.

[0021] In some embodiments, the reaction temperature of the compound represented by formula B or its salt with the compound represented by formula A or its salt is selected from 60 to 100°C, including 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C or any value between two numbers.

[0022] In some embodiments, the reaction temperature of the compound represented by formula B or its salt and the compound represented by formula A or its salt is selected from 75 to 85°C, for example, 80°C.

[0023] Furthermore, in some embodiments, the method for preparing a compound of formula I or a salt thereof further comprises the step of converting a compound of formula B-1 or a salt thereof into a compound of formula B or a salt thereof.

[0024] where R 4 , o as defined above.

[0025] In some embodiments, the method for preparing a compound of formula I or a salt thereof comprises reacting a compound of formula B-1 or a salt thereof under thionyl chloride conditions to form a compound of formula B-2 or a salt thereof, and then reacting the compound of formula B-2 or a salt thereof under oxidizing conditions to form a compound of formula B or a salt thereof.

[0026] In some embodiments, the oxidizing agent includes but is not limited to N-methylmorpholine-N-oxide.

[0027] In some embodiments, the molar ratio of compound B-2 or a salt thereof to N-methylmorpholine-N-oxide is 1:1 to 1:2, including but not limited to 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0 or any value between two numbers.

[0028] In some embodiments, the reaction temperature of compound B-2 or its salt under N-methylmorpholine-N-oxide conditions is controlled at 30 to 60° C. In some embodiments, the reaction temperature of compound B-2 or its salt under N-methylmorpholine-N-oxide conditions is controlled at 40 to 60° C. In some embodiments, the reaction temperature of compound B-2 or its salt under N-methylmorpholine-N-oxide conditions is controlled at 55° C.

[0029] In some embodiments, the solvent for the reaction of compound B-2 or a salt thereof under N-methylmorpholine-N-oxide conditions is selected from, but not limited to, acetonitrile.

[0030] In other embodiments, the compound represented by formula B-1 or a salt thereof is reacted under thionyl chloride / triformaldehyde conditions to form the compound represented by formula B-2 or a salt thereof.

[0031] In some embodiments, the reaction temperature of the compound represented by formula B-1 or its salt under dichloroxyl / triformaldehyde conditions is selected from 15 to 30°C, including but not limited to 15°C, 20°C, 25°C, 30°C or any value between two numbers.

[0032] In some embodiments, the method for preparing a compound of formula I or a salt thereof further comprises the step of reacting a compound of formula B-0 or a salt thereof with pyrrolidone to form a compound of formula B-1 or a salt thereof.

[0033] where R 4 , o as defined above.

[0034] In some embodiments, the compound represented by formula B-0 or a salt thereof is reacted with pyrrolidone in the presence of a metal catalyst. In some embodiments, the metal catalyst is selected from at least one of palladium and copper. In some embodiments, the metal catalyst is selected from a copper catalyst, including but not limited to cuprous iodide.

[0035] In some embodiments, the compound represented by formula B-0 or a salt thereof is reacted with pyrrolidone in the presence of cuprous iodide.

[0036] Furthermore, the reaction of the compound represented by formula B-0 or its salt with pyrrolidone also includes a base (2), and the base (2) is selected from but not limited to K2CO3, K3PO4, LiOMe, NaOEt, NaOPr, NaOiPr, LiOtBu, NaOtBu or KOtBu.

[0037] On the other hand, the reaction of the compound represented by formula B-0 or its salt with pyrrolidone also contains a catalyst ligand, which is selected from but not limited to 1,2-ethylenediamine, N,N'-dimethylethylenediamine, trans-1,2-cyclohexanediamine, trans-N,N'-dimethyl-1,2-cyclohexanediamine or trans-N,N'-diethyl-1,2-cyclohexanediamine.

[0038] In some embodiments, the compound represented by formula B-0 or a salt thereof is reacted with pyrrolidone in the presence of cuprous iodide / potassium carbonate.

[0039] In some embodiments, the reaction temperature of the compound represented by formula B-0 or its salt with pyrrolidone is selected from 80 to 120°C, including but not limited to 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C or any value therebetween. In some embodiments, the reaction temperature of the compound represented by formula B-0 or its salt with pyrrolidone is selected from 85 to 100°C, for example, 90°C.

[0040] In some embodiments, the solvent used for the reaction of the compound represented by formula B-0 or its salt with pyrrolidone is selected from at least one of tetrahydrofuran, dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, toluene, and acetonitrile.

[0041] On the other hand, the method for preparing a compound of formula I or a salt thereof disclosed herein comprises the steps of reacting a compound of formula A-8 or a salt thereof with a compound of formula A-9 or a salt thereof in the presence of a base (1) to form a compound of formula A.

[0042] where R 1 、R 2 、R 3 , n, m are as defined above.

[0043] In some embodiments, the base (1) is selected from, but not limited to, potassium carbonate or sodium carbonate.

[0044] In some embodiments, the compound of Formula A-8 reacts with the compound of Formula A-9 under potassium carbonate conditions to form the compound of Formula Aa or a salt thereof. For relevant reaction conditions or procedures, see WO2022033567, and the relevant content is incorporated herein.

[0045] In some embodiments, the reaction temperature of the compound represented by Formula A-8 with the compound represented by Formula A-9 under potassium carbonate conditions is selected from 80 to 120°C, including but not limited to 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, or any number therebetween. In some embodiments, the reaction temperature of the compound represented by Formula A-8 with the compound represented by Formula A-9 under potassium carbonate conditions is selected from 90 to 120°C, for example, 110°C.

[0046] In some embodiments, R 2 Selected from halogen, oxo, nitro, cyano.

[0047] In some embodiments, R 2 Selected from halogen C 1-6 Alkyl or C 1-6Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

[0048] In some embodiments, R 2 Selected from C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0049] In some embodiments, R 2 Selected from halogen or C 1-6 Alkyl groups such as fluoro, chloro, methyl or ethyl.

[0050] In some embodiments, m in the compound of Formula I or a salt thereof is selected from 0.

[0051] In some embodiments, R 4 Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0052] In some embodiments, R 4 Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, for example fluoro, chloro, methyl or methoxy.

[0053] In some embodiments, R 3 Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0054] In some embodiments, R 3 Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, for example fluoro, chloro, methyl or methoxy.

[0055] In some embodiments, R 1 Selected from C 1-6 Alkyl groups, such as methyl or ethyl.

[0056] In some embodiments, R 1 Selected from C 1-6 Alkyl C(O)- or amino protecting groups (eg, -Boc or benzyl).

[0057] In some embodiments, R 1 Selected from C 1-6 Alkyl C(O)-, for example CH3C(O)- or C2H5C(O)-.

[0058] In some embodiments, R 1 Selected from C 1-6 Alkyl C(O)- or amino protecting group (eg, -Boc or benzyl); R 3 Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, such as fluoro, chloro, methyl or methoxy; R 4 Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, such as fluorine, chlorine, methyl or methoxy; n is 1 or 2; m is 0; o is 1 or 2.

[0059] Some embodiments provide that the compound represented by Formula I is a compound represented by Formula Ia,

[0060] The preparation method comprises the steps of reacting a compound represented by formula Aa or a salt thereof with a compound Ba or a salt thereof to form a compound represented by formula Ia or a salt thereof.

[0061] in,

[0062] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting groups.

[0063] In some embodiments, the aforementioned method further comprises the step of converting compound Ba-1 or its salt into a compound represented by formula Ba or its salt.

[0064]

[0065] In other embodiments, the aforementioned method comprises the steps of reacting compound Ba-1 or a salt thereof under thionyl chloride conditions to form compound Ba-2 or a salt thereof, and then reacting compound Ba-2 or a salt thereof under oxidizing conditions to form compound Ba or a salt thereof, wherein the oxidizing agent is N-methylmorpholine-N-oxide.

[0066]

[0067] In some embodiments, compound Ba-1 reacts with triformaldehyde under thionyl chloride conditions to form compound Ba-2. In some embodiments, the molar ratio of compound Ba-1 to thionyl chloride is 1:1 to 1:4, including but not limited to 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:3.0 or any value between two numbers. In some embodiments, the molar ratio of compound Ba-1 to thionyl chloride is 1:2.

[0068] In some embodiments, the molar ratio of compound Ba-1 to trioxymethylene is 1:1 to 1:3, including but not limited to 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0, or any value therebetween. In some embodiments, the molar ratio of compound Ba-1 to trioxymethylene is 1:1.5.

[0069] In some embodiments, the reaction temperature of compound Ba-1 with triformaldehyde under thionyl chloride conditions is controlled at 10-30°C, for example, 20°C.

[0070] In some embodiments, the solvent for the reaction of compound Ba-1 with triformaldehyde under thionyl chloride conditions is concentrated sulfuric acid.

[0071] In some embodiments, compound Ba-2 or a salt thereof is reacted under N-methylmorpholine-N-oxide conditions to form compound Ba or a salt thereof.

[0072] In some embodiments, the molar ratio of compound Ba-2 or a salt thereof to N-methylmorpholine-N-oxide is 1:1 to 1:2, including but not limited to 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0 or any value between two numbers.

[0073] In some embodiments, the reaction temperature of compound Ba-2 or its salt under N-methylmorpholine-N-oxide conditions is controlled at 30 to 60° C. In some embodiments, the reaction temperature of compound Ba-2 or its salt under N-methylmorpholine-N-oxide conditions is controlled at 40 to 60° C. In some embodiments, the reaction temperature of compound Ba-2 or its salt under N-methylmorpholine-N-oxide conditions is controlled at 55° C.

[0074] In some embodiments, the solvent for the reaction of compound Ba-2 or a salt thereof under N-methylmorpholine-N-oxide conditions is selected from, but not limited to, acetonitrile.

[0075] In other embodiments, the method for preparing the compound represented by Formula Ia or a salt thereof further comprises the step of reacting compound Ba-0 with pyrrolidone to form compound Ba-1.

[0076]

[0077] In some embodiments, the compound represented by formula Ba-0 or a salt thereof is reacted with pyrrolidone in the presence of cuprous iodide.

[0078] In some embodiments, the compound represented by formula Ba-0 or a salt thereof is reacted with pyrrolidone in the presence of cuprous iodide / potassium carbonate.

[0079] On the other hand, the reaction of the compound represented by formula Ba-0 or its salt with pyrrolidone also contains a catalyst ligand, which is selected from but not limited to 1,2-ethylenediamine, N,N'-dimethylethylenediamine, trans-1,2-cyclohexanediamine, trans-N,N'-dimethyl-1,2-cyclohexanediamine or trans-N,N'-diethyl-1,2-cyclohexanediamine.

[0080] On the other hand, the method for preparing the compound represented by formula Ia or a salt thereof comprises the steps of reacting the compound represented by formula Aa-8 or a salt thereof with compound Aa-9 or a salt thereof in the presence of a base (1) to form the compound represented by formula Aa,

[0081] Among them, R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting groups.

[0082] In some embodiments, the base (1) is selected from, but not limited to, potassium carbonate or sodium carbonate.

[0083] In some embodiments, the compound represented by formula Aa-8 reacts with compound Aa-9 under potassium carbonate conditions to form a compound represented by formula Aa or a salt thereof. For relevant reaction conditions or procedures, see WO2022033567, and the relevant content is incorporated herein.

[0084] On the other hand, some embodiments provide that the compound represented by Formula I is a compound represented by Formula I-1,

[0085] The preparation method comprises the steps of reacting a compound represented by formula A or a salt thereof with a compound represented by formula B or a salt thereof to form a compound represented by formula I-1 or a salt thereof,

[0086]

[0087] In some embodiments, the aforementioned preparation method further comprises the step of isomer resolution.

[0088] In some embodiments, the method for preparing a compound of formula I-1 or a salt thereof comprises the step of reacting a compound of formula A-1 or a salt thereof with a compound of formula B or a salt thereof to form a compound of formula I-1 or a salt thereof,

[0089]

[0090] On the other hand, the method for preparing the compound represented by formula I-1 or a salt thereof further comprises the step of reacting the compound represented by formula A-8 or a salt thereof with the compound represented by formula A-9 or a salt thereof in the presence of a base (1) to form the compound represented by formula A-1,

[0091] Among them, R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting groups.

[0092] In some embodiments, the method for preparing the compound of formula I-1 or a salt thereof further comprises the step of reacting the compound of formula A-8a or a salt thereof with the compound of formula A-9 or a salt thereof in the presence of a base (1) to form the compound of formula A-1.

[0093]

[0094] In some embodiments, the compound represented by formula Ia is a compound represented by formula Ia-1

[0095] The preparation method comprises the steps of reacting a compound represented by formula Aa or a salt thereof with a compound Ba or a salt thereof to form a compound represented by formula Ia-1 or a salt thereof.

[0096] in,

[0097] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting groups.

[0098] In some embodiments, the aforementioned preparation method further comprises the step of isomer resolution.

[0099] In other embodiments, the method for preparing the compound of formula Ia-1 or its salt comprises the steps of reacting the compound of formula Aa-a or its salt with compound Ba or its salt to form the compound of formula Ia-1 or its salt.

[0100]

[0101] In some embodiments, R 1 Selected from C 1-6 Alkyl C(O)-, for example CH3C(O)- or C2H5C(O)-.

[0102] In some embodiments, the compound represented by Formula Ia is Compound Ia-1a,

[0103] The preparation method comprises the steps of reacting compound Aa1 or a salt thereof with compound Ba or a salt thereof to form compound Ia-1 or a salt thereof,

[0104]

[0105] In some embodiments, R 1 is selected from amino protecting groups such as -Boc or benzyl.

[0106] In some embodiments, the compound represented by Formula Ia is Compound Ia-3a

[0107] The preparation method comprises the steps of reacting compound Aa3 or a salt thereof with compound Ba or a salt thereof to form compound Ia-3a or a salt thereof,

[0108]

[0109] In other embodiments, the method for preparing the compound represented by Formula Ia or a salt thereof comprises the following steps:

[0110] a) Compound Ba-0 reacts with pyrrolidone in the presence of a metal catalyst to form compound Ba-1,

[0111] b) Compound Ba-1 reacts with trioxymethylene and thionyl chloride to form compound Ba-2,

[0112] c) Compound Ba-2 reacts with N-methylmorpholine-N-oxide to form compound Ba,

[0113] d) the compound represented by formula Aa and compound Ba form the compound represented by formula Ia in the presence of a reducing agent,

[0114]

[0115] In other embodiments, the method for preparing the compound represented by Formula Ia-1a or a salt thereof comprises the following steps:

[0116] a) Compound Ba-0 reacts with pyrrolidone in the presence of a metal catalyst to form compound Ba-1,

[0117] b) Compound Ba-1 reacts with trioxymethylene and thionyl chloride to form compound Ba-2,

[0118] c) Compound Ba-2 reacts with N-methylmorpholine-N-oxide to form compound Ba,

[0119] d) the compound represented by formula Aa1 and compound Ba are reacted in the presence of a reducing agent to form a compound represented by formula Ia-1a,

[0120]

[0121] In some embodiments, the compound represented by Formula Ia is Compound AA,

[0122] The preparation method comprises the steps of reacting compound Aa1 or its salt with compound Ba or its salt to form compound AA or its salt.

[0123]

[0124] In some embodiments, the aforementioned preparation method further comprises the step of isomer resolution.

[0125] In some embodiments, the method for preparing compound AA or a salt thereof comprises the step of reacting compound Aa1-a or a salt thereof with compound Ba or a salt thereof to form compound AA or a salt thereof,

[0126]

[0127] In some embodiments, the compound represented by Formula Ia is Compound BB,

[0128] The preparation method comprises the steps of reacting compound Aa3 or its salt with compound Ba or its salt to form compound BB.

[0129]

[0130] In some embodiments, the aforementioned preparation method further comprises the step of isomer resolution.

[0131] In some embodiments, a method for preparing compound BB or a salt thereof comprises the step of reacting compound Aa3-a or a salt thereof with compound Ba or a salt thereof to form compound BB,

[0132]

[0133] The present disclosure also provides a method for preparing compound AA or a pharmaceutically acceptable salt thereof, the method comprising the steps of the aforementioned method,

[0134]

[0135] When R 1 When an amino protecting group (such as -Boc or benzyl) is selected, the method for preparing compound AA or a pharmaceutically acceptable salt thereof includes the step of removing the protecting group.

[0136] In some embodiments, the method for preparing Compound AA or a pharmaceutically acceptable salt thereof comprises the step of reacting Compound Ia-3 or a salt thereof under acidic conditions to form Compound Ca or a salt thereof, wherein the acid includes but is not limited to trifluoroacetic acid,

[0137]

[0138] In some embodiments, the method for preparing Compound AA or a pharmaceutically acceptable salt thereof comprises the steps of reacting Compound Ia-3 or a salt thereof under acidic conditions to form Compound Ca or a salt thereof, and then reacting Compound Ca or a salt thereof with acetic anhydride to form Compound Ia-1 or a salt thereof.

[0139]

[0140] In some embodiments, the aforementioned preparation method further comprises the step of isomer resolution.

[0141] In some embodiments, the method for preparing Compound AA or a pharmaceutically acceptable salt thereof comprises the step of reacting Compound Ia-3a or a salt thereof under acidic conditions to form Compound Ca-a or a salt thereof, wherein the acid includes but is not limited to trifluoroacetic acid,

[0142]

[0143] In some embodiments, the method for preparing Compound AA or a pharmaceutically acceptable salt thereof comprises the steps of reacting Compound Ia-3a or a salt thereof under acidic conditions to form Compound Ca-a or a salt thereof, and then reacting Compound Ca-a or a salt thereof with acetic anhydride to form Compound AA or a salt thereof.

[0144]

[0145] In other embodiments, the method for preparing compound AA or a salt thereof comprises the following steps:

[0146] a) Compound Ba-0 reacts with pyrrolidone in the presence of a metal catalyst to form compound Ba-1,

[0147] b) Compound Ba-1 reacts with trioxymethylene and thionyl chloride to form compound Ba-2,

[0148] c) Compound Ba-2 reacts with N-methylmorpholine-N-oxide to form compound Ba,

[0149] d) the compound represented by formula Aa1-a reacts with compound Ba in the presence of a reducing agent to form compound AA,

[0150]

[0151] The present disclosure also provides a method for preparing a compound of formula B or a salt thereof, which comprises the steps of converting compound B-1 or a salt thereof into a compound of formula B or a salt thereof.

[0152] where R 4 Selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 The moiety is substituted by cycloalkyl or 3- to 6-membered heterocycloalkyl, and o is selected from 0, 1, 2, 3 or 4.

[0153] In some embodiments, the method for preparing a compound of formula B or a salt thereof comprises reacting a compound of formula B-1 or a salt thereof under conditions of thionyl chloride and triformaldehyde to form a compound of formula B-2 or a salt thereof, and then reacting the compound of formula B-2 or a salt thereof under conditions of an oxidant to form a compound of formula B or a salt thereof.

[0154]

[0155] In some embodiments, the oxidizing agent is selected from N-methylmorpholine-N-oxide.

[0156] The present disclosure also provides a method for preparing compound Ba or its salt, which comprises the steps of converting compound Ba-1 or its salt into a compound represented by formula Ba or its salt.

[0157]

[0158] In some embodiments, the method for preparing compound Ba or a salt thereof comprises the steps of reacting compound Ba-1 or a salt thereof under thionyl chloride conditions to form compound Ba-2 or a salt thereof, and then reacting compound Ba-2 or a salt thereof under oxidizing agent conditions to form compound Ba or a salt thereof, wherein the oxidizing agent is selected from N-methylmorpholine-N-oxide,

[0159]

[0160] In some embodiments, the method for preparing compound Ba or a salt thereof further comprises the step of reacting compound Ba-0 with pyrrolidone to form compound Ba-1.

[0161]

[0162] In some embodiments, the compound represented by formula Ba-0 or a salt thereof is reacted with pyrrolidone in the presence of cuprous iodide.

[0163] In some embodiments, the compound represented by formula Ba-0 or a salt thereof is reacted with pyrrolidone in the presence of cuprous iodide / potassium carbonate.

[0164] In some embodiments, the reaction temperature of the compound represented by formula Ba-0 or its salt with pyrrolidone is selected from 80 to 120°C, including but not limited to 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, or any value therebetween. In some embodiments, the reaction temperature of the compound represented by formula Ba-0 or its salt with pyrrolidone is selected from 85 to 100°C, for example, 90°C.

[0165] On the other hand, the present disclosure also provides compound Ba or its salt

[0166]

[0167] On the other hand, the present disclosure also provides a method for preparing the compound represented by formula Aa or its salt

[0168] The method comprises the steps of reacting compound Aa-2 or a salt thereof with a compound represented by formula Aa-3 or a salt thereof to form a compound represented by formula Aa-5 or a salt thereof.

[0169] where R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting group; P 1 is selected from amino protecting groups, such as benzyl.

[0170] In some embodiments, the method for preparing a compound represented by formula Aa or a salt thereof comprises reacting compound Aa-2 or a salt thereof with a compound represented by formula Aa-3 or a salt thereof to form a compound represented by formula Aa-4 or a salt thereof, and reacting the compound represented by formula Aa-4 or a salt thereof under phosphine reagent / azo reagent conditions to form a compound represented by formula Aa-5 or a salt thereof.

[0171] Among them, P 1 is selected from amino protecting groups, such as benzyl.

[0172] In some embodiments, the reaction temperature of compound Aa-2 or a salt thereof with the compound represented by formula Aa-3 or a salt thereof is selected from 90 to 120°C, including but not limited to 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, or any value between two numbers. In some embodiments, the reaction temperature of compound Aa-2 or a salt thereof with the compound represented by formula Aa-3 or a salt thereof is selected from 100 to 120°C.

[0173] In some embodiments, the solvent used for the reaction of compound Aa-2 or a salt thereof with the compound represented by formula Aa-3 or a salt thereof is selected from but not limited to toluene.

[0174] In some embodiments, the phosphine reagent is selected from at least one of PPh3, nBu3P, Ph2PMe, and P(Me)3; the azo reagent is selected from at least one of DMAD, DEAD, DIAD, TMAD, ADDP, DBAD, TIPA, and DHTD.

[0175] In some embodiments, the phosphine reagent / azo reagent is selected from, but not limited to, PPh3 / DIAD and PPh3 / DEAD. The reaction of the compound represented by Formula Aa-4 or its salt is a Mitsunobu reaction. The Mitsunobu operation can be referred to in "Strategic Applications of Named Reactions in Organic Synthesis" by László Kürti et al., and the relevant content is incorporated herein.

[0176] In some embodiments, the reaction temperature of the compound represented by formula Aa-4 or its salt is selected from 0 to 20°C, including but not limited to 0°C, 5°C, 10°C, 15°C, 20°C, or any value between two numbers. In some embodiments, the reaction temperature of the compound represented by formula Aa-4 or its salt is selected from 0 to 10°C.

[0177] In some embodiments, the solvent used in the reaction of the compound represented by formula Aa-4 or its salt is selected from but not limited to toluene.

[0178] In other embodiments, compound Aa-2 or a salt thereof is reacted with a compound represented by formula Aa-3 or a salt thereof in a one-pot reaction to form a compound represented by formula Aa-5 or a salt thereof.

[0179] In some embodiments, the method for preparing the compound represented by formula Aa or a salt thereof further comprises the steps of deprotecting the compound represented by formula Aa-5 or a salt thereof to form compound Aa-6 or a salt thereof, and converting compound Aa-6 into the compound represented by formula Aa-7 or a salt thereof.

[0180] where R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting group; P 1 is selected from amino protecting groups, such as benzyl.

[0181] In some embodiments, compound Aa-5 or a salt thereof is deprotected under 1-chloroethyl chloroformate or 2,2,2-trichloroethyl chloroformate conditions to form compound Aa-6 or a salt thereof.

[0182] In some embodiments, the reaction solvent for compound Aa-5 or a salt thereof under the conditions of 1-chloroethyl chloroformate or 2,2,2-trichloroethyl chloroformate is selected from but not limited to dichloromethane.

[0183] In other embodiments, the reaction of compound Aa-5 or a salt thereof with 1-chloroethyl chloroformate or 2,2,2-trichloroethyl chloroformate is carried out in the presence of a base (3), wherein the base (3) is selected from but not limited to N,N-diisopropylethylamine.

[0184] In some embodiments, compound Aa-5 or a salt thereof is deprotected under catalytic hydrogenation conditions to form compound Aa-6 or a salt thereof, wherein the catalytic hydrogenation conditions are selected from Pd / C. In some embodiments, the reaction solvent for compound Aa-5 or a salt thereof under catalytic hydrogenation conditions is selected from methanol or ethanol.

[0185] In some embodiments, the method for preparing the compound of formula Aa or a salt thereof further comprises removing the phthaloyl group (Pht) from the compound of formula Aa-7 or a salt thereof to form the compound of formula Aa-8 or a salt thereof,

[0186]

[0187] In some embodiments, the conditions for removing phthaloyl (Pht) include, but are not limited to, methylamine ethanol solution, methylamine aqueous solution, ethanolamine, sodium borohydride, and hydrazine hydrate.

[0188] In some embodiments, the compound represented by formula Aa-7 or a salt thereof is reacted under hydrazine hydrate conditions to form the compound represented by formula Aa-8 or a salt thereof.

[0189] Furthermore, the method for preparing the compound represented by formula Aa or a salt thereof further comprises the step of reacting the compound represented by formula Aa-8 or a salt thereof with compound Aa-9 to form the compound represented by formula Aa or a salt thereof.

[0190]

[0191] In some embodiments, the compound of formula Aa-8 reacts with compound Aa-9 under alkaline conditions (1) to form a compound of formula Aa or a salt thereof, wherein (1) is selected from, but not limited to, potassium carbonate or sodium carbonate. For relevant reaction conditions or procedures, see WO2022033567, and the relevant content is incorporated herein.

[0192] In some embodiments, the compound represented by formula Aa-7 or its salt is 1 It is benzyl.

[0193] In some embodiments, R 1 It is acetyl (Ac).

[0194] In other embodiments, the compound represented by formula Aa or its salt is compound Aa-a or its salt

[0195]

[0196] In other embodiments, the compound represented by formula Aa or its salt is compound Aa1 or its salt

[0197]

[0198] In other embodiments, the compound represented by formula Aa or its salt is compound Aa1-a or its salt

[0199]

[0200] In other embodiments, the compound represented by formula Aa or its salt is compound Aa3 or its salt

[0201]

[0202] In other embodiments, the compound represented by formula Aa or its salt is compound Aa3-a or its salt

[0203]

[0204] In other embodiments, the method for preparing the compound represented by formula Aa or a salt thereof comprises the following reaction steps:

[0205] 1) Compound Aa-2 or a salt thereof reacts with a compound represented by formula Aa-3 or a salt thereof to form a compound represented by formula Aa-4 or a salt thereof, and 2) the compound represented by formula Aa-4 or a salt thereof reacts under phosphine reagent / azo reagent conditions to form a compound represented by formula Aa-5 or a salt thereof,

[0206]

[0207] In other embodiments, compound Aa-2 or a salt thereof is reacted with a compound represented by formula Aa-3 or a salt thereof in a one-pot reaction to form a compound represented by formula Aa-5 or a salt thereof.

[0208] In other embodiments, the method for preparing the compound represented by formula Aa1-a or a salt thereof comprises the following reaction steps:

[0209] 1) Compound Aa1-2a or a salt thereof reacts with Compound Aa1-3 or a salt thereof to form Compound Aa1-4a or a salt thereof, and 2) Compound Aa1-4a or a salt thereof reacts under phosphine reagent / azo reagent conditions to form Compound Aa1-5a or a salt thereof,

[0210]

[0211] In other embodiments, Compound Aa-2a or a salt thereof is reacted with Compound Aa1-3 or a salt thereof in a "one-pot" process to form Compound Aa1-5a or a salt thereof.

[0212] In other embodiments, the method for preparing the compound represented by formula Aa or a salt thereof comprises the following reaction steps:

[0213] 1) Compound Aa-2 or a salt thereof reacts with a compound represented by formula Aa-3 or a salt thereof to form a compound represented by formula Aa-4 or a salt thereof,

[0214] 2) the compound represented by formula Aa-4 or its salt reacts under phosphine reagent / azo reagent conditions to form the compound represented by formula Aa-5 or its salt,

[0215] 3) deprotecting the compound represented by formula Aa-5 or its salt to form compound Aa-6 or its salt,

[0216] 4) converting compound Aa-6 or a salt thereof into a compound represented by formula Aa-7 or a salt thereof, and removing the phthaloyl group (Pht) from the compound represented by formula Aa-7 or a salt thereof to form a compound represented by formula Aa-8 or a salt thereof,

[0217] 5) the compound represented by formula Aa-8 or its salt reacts with compound Aa-9 to form the compound represented by formula Aa or its salt,

[0218]

[0219] In other embodiments, the method for preparing the compound represented by formula Aa-a or a salt thereof comprises the following reaction steps:

[0220] 1) Compound Aa-2a or a salt thereof reacts with a compound represented by formula Aa-3 or a salt thereof to form a compound represented by formula Aa-4a or a salt thereof,

[0221] 2) the compound represented by formula Aa-4a or its salt reacts under phosphine reagent / azo reagent conditions to form the compound represented by formula Aa-5a or its salt,

[0222] 3) deprotecting the compound represented by formula Aa-5a or its salt to form compound Aa-6a or its salt,

[0223] 4) converting compound Aa-6a or a salt thereof into a compound represented by formula Aa-7a or a salt thereof, and removing the phthaloyl group (Pht) from the compound represented by formula Aa-7a or a salt thereof to form a compound represented by formula Aa-8a or a salt thereof,

[0224] 5) the compound represented by formula Aa-8a or its salt reacts with compound Aa-9 to form the compound represented by formula Aa-a or its salt,

[0225]

[0226] In other embodiments, the method for preparing the compound represented by formula Aa1-a or a salt thereof comprises the following reaction steps:

[0227] 1) Compound Aa1-2a or a salt thereof reacts with Compound Aa1-3 or a salt thereof to form Compound Aa1-4a or a salt thereof,

[0228] 2) Compound Aa1-4a or a salt thereof reacts under phosphine reagent / azo reagent conditions to form compound Aa1-5a or a salt thereof,

[0229] 3) Compound Aa1-5a or its salt is deprotected to form compound Aa-6a or its salt,

[0230] 4) Compound Aa-6a or its salt is converted into compound Aa1-7a or its salt

[0231] 5) removing the phthaloyl group (Pht) from compound Aa1-7a or a salt thereof to form compound Aa1-8a or a salt thereof,

[0232] 6) Compound Aa1-8a or a salt thereof reacts with compound Aa-9 to form compound Aa1-a or a salt thereof,

[0233]

[0234] In other embodiments, in step 2), compound Aa1-4a or a salt thereof is reacted under PPh3 / DIAD or PPh3 / DEAD conditions to form compound Aa1-5a or a salt thereof.

[0235] In some embodiments, in step 3), compound Aa1-5a or a salt thereof is deprotected under catalytic hydrogenation conditions to form compound Aa-6a or a salt thereof, and the catalytic hydrogenation conditions are selected from Pd / C.

[0236] In other embodiments, in step 3), compound Aa1-5a or a salt thereof is deprotected under the conditions of 1-chloroethyl chloroformate or 2,2,2-trichloroethyl chloroformate to form compound Aa-6a or a salt thereof.

[0237] In some embodiments, in step 4), compound Aa1-6a or a salt thereof is reacted with acetic anhydride to form compound Aa1-7a or a salt thereof.

[0238] In some embodiments, in step 5), compound Aa1-7a or a salt thereof is subjected to hydrazine hydrate conditions to remove the phthaloyl group (Pht) to form compound Aa1-8a or a salt thereof.

[0239] In some embodiments, in step 6), compound Aa1-8a or a salt thereof is reacted with compound Aa-9 under base (1) to form compound Aa1-a or a salt thereof, wherein the base (1) is selected from but not limited to potassium carbonate or sodium carbonate.

[0240] In some embodiments, Compound Aa1-8a exists in the form of a salt. In some embodiments, Compound Aa1-8a exists in the form of an oxalate. Compared to an oil, Compound Aa1-8a oxalate has better stability and process advantages.

[0241] In other embodiments, compound Aa1-8a can also form salts with other acids, including but not limited to succinic acid, fumaric acid, tartaric acid, D-dibenzoyltartaric acid, and p-toluenesulfonic acid.

[0242] The present disclosure also provides compound Aa1-8a oxalate

[0243] In other embodiments, the method for preparing compound AA or a salt thereof comprises the following steps:

[0244] 1) Compound Aa1-2a or a salt thereof reacts with Compound Aa1-3 or a salt thereof to form Compound Aa1-4a or a salt thereof,

[0245] 2) Compound Aa1-4a or a salt thereof reacts under phosphine reagent / azo reagent conditions to form compound Aa1-5a or a salt thereof,

[0246] 3) Compound Aa1-5a or its salt is deprotected to form compound Aa-6a or its salt,

[0247] 4) converting compound Aa-6a or a salt thereof into compound Aa1-7a or a salt thereof,

[0248] 5) removing the phthaloyl group (Pht) from compound Aa1-7a or a salt thereof to form compound Aa1-8a or a salt thereof,

[0249] 6) Compound Aa1-8a or a salt thereof reacts with compound Aa-9 to form compound Aa1-a or a salt thereof,

[0250] 7) The compound represented by formula Aa1-a reacts with compound Ba in the presence of a reducing agent to form compound AA,

[0251]

[0252] Furthermore, the preparation method disclosed herein further comprises at least one of the steps of extraction, washing, drying, filtration, and concentration.

[0253] The terms "to form" and "to convert" do not necessarily imply a single-step conversion reaction between two substrates; they may be a single-step or multi-step reaction between two substrates. If an intermediate contains a protecting group, the intermediate is subjected to a one-step removal of the protecting group and then reacted with the corresponding substrate to obtain the corresponding target product.

[0254] The "one-pot method" means that in one reaction system, two or more reactions are completed continuously by controlling the addition of materials and the reaction time of each step, without any processing of intermediates.

[0255] The numerical values in this disclosure are instrumental measurements and are subject to a certain degree of error. Generally speaking, within a reasonable error range of plus or minus 10%. The context in which the numerical value is used must be considered. For example, the particle size of an active ingredient, where the error after measurement does not exceed plus or minus 10%, may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0256] The pharmaceutically acceptable salts of the compounds described herein or their salts may be selected from inorganic or organic salts, including "acid" addition salts and "base" addition salts. For example, salts formed by acid-base reactions with basic groups (amino groups), wherein the acid comprises an organic acid or an inorganic acid.

[0257] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations. For example include

[0258] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0259] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted.

[0260] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups can be optionally substituted or unsubstituted.

[0261] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 6 carbon atoms, such as 4 or 5 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls. Cycloalkyls can be substituted or unsubstituted.

[0262] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 6 ring atoms, such as 4 ring atoms or 5 ring atoms, wherein one or more ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Non-limiting examples of "heterocycloalkyl" include: Heterocycloalkyl groups may be optionally substituted or unsubstituted.

[0263] "Hydroxy" refers to an -OH group.

[0264] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0265] "Amino" refers to -NH2.

[0266] "Cyano" refers to -CN.

[0267] "Nitro" refers to -NO2.

[0268] "Oxo" refers to =0.

[0269] The "amino protecting group" disclosed herein is a group known in the art that can be used to protect an amino group, such as the hydroxy protecting group in the literature (Protective Groups in Organic Synthesis, 5th Ed. TW Greene & P.GMWuts). Examples include, but are not limited to, tert-butyloxycarbonyl (BOC).

[0270] When the functional groups disclosed herein are substituted, the substituents are preferably one or more of the following groups, such as halogen, hydroxyl, cyano, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl. DETAILED DESCRIPTION

[0271] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0272] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0273] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectroscopy (MS). NMR shifts (δ) are given in units of 10-6 (ppm).

[0274] NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the solvent was deuterated chloroform (CDCl3).

[0275] MS was determined using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive / negative ion mode with a mass scan range of 120-1300.

[0276] HPLC column: YMC-Pack ODS-A (3 μm, 4.6 mm x 150 mm)

[0277] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0278] Example 1 Preparation of 2-chloro-6-fluoro-4-(2-oxopyrrolidin-1-yl)benzaldehyde (Compound 1)

[0279]

[0280] Step 1:

[0281] At room temperature, compound 1a (52.36 g, 0.25 mol, purchased from Shanghai Bid) and toluene (500 mL) were added to a 1L three-necked flask and stirred evenly. Then, compound 1b (27.66 g, 0.325 mol, purchased from Anaiji Chemical), N, N'-dimethylethylenediamine (4.41 g, 0.05 mol), cuprous iodide (4.76 g, 0.025 mol) and potassium carbonate (69.11 g, 0.5 mol) were added, nitrogen was replaced three times, and stirred at 90 ° C for 16 hours. Cool to room temperature, filter, wash the filtrate three times with deionized water, and concentrate the organic solvent under reduced pressure. N-heptane was added to the concentrate to precipitate the solid, slurry for one hour, filter, and the filter cake was dried under reduced pressure to obtain 45.25 g of compound 1c as an off-white solid with a yield of 84.73%.

[0282] MS (ESI): m / z 213.9 [M+1] + .

[0283] 1 H NMR (400MHz, DMSO-d6): δ7.66(s,1H),7.56-7.59(m,1H),7.17-7.19(m,1H),3.81-3.85(t,2H),2.51-2.55(t,2H),2.04-2.07(m,2H).

[0284] Step 2:

[0285] Under N2 protection, concentrated sulfuric acid (128 mL) was added to a 500 mL three-necked flask, cooled in an ice-salt bath, and thionyl chloride (22 mL, 0.3 mol) was added dropwise. After the addition was complete, the mixture was stirred for 10 minutes. Trioxymethylene (20.27 g, 0.225 mol) was added portionwise, followed by compound 1c (32.05 g, 0.15 mol). The mixture was slowly warmed to room temperature and stirred for 19 hours. The reaction solution was slowly poured into ice water, whereupon a large amount of solid precipitated. The solid was filtered, and the filter cake was air-dried to constant weight to obtain 35.03 g of compound 1d, with a yield of 89.03%.

[0286] MS (ESI): m / z 261.9 [M+1] + .

[0287] 1H NMR (400MHz, DMSO-d6): δ7.75-7.76(m,1H),7.64-7.68(dd,1H),4.81(s,2H),3.82-3.86(t,2H),2.51-2.56(t,2H),2.04-2.08(m,2H).

[0288] Step 3:

[0289] At room temperature, compound 1d (10.48 g, 0.04 mol) was added to acetonitrile (105 mL), stirred and dissolved, and N-methylmorpholine-N-oxide (7.06 g, 0.06 mol) and potassium phosphate (8.48 g, 0.04 mol) were added. The mixture was stirred at 55 ° C for 3 h, and the temperature was cooled to room temperature. Water (315 mL) was slowly added to the reaction solution, and a large amount of solid precipitated. The solid was filtered and the filter cake was air-dried to constant weight to obtain 7.88 g of compound 1 as an off-white solid with a yield of 81.79%.

[0290] MS (ESI): m / z 241.9 [M+1] + .

[0291] 1 H NMR (400MHz, DMSO-d6): δ10.22(s,1H),7.81-7.82(m,1H),7.67-7.71(dd,1H),3.86-3.90(t,2H),2.56-2.60(t,2H),2.04-2.11(m,2H).

[0292] Example 2 Preparation of (S)-1-(2-(((4-methyl-2-nitrophenyl)amino)methyl)morpholinyl)ethan-1-one (Compound 2)

[0293]

[0294]

[0295] Step 1:

[0296] At room temperature, compound 2a (50.0 g, 246 mmol, purchased from Shaoyuan Chemical), compound 2b (42.8 g, 283 mmol, purchased from Titan Technology) and toluene (250 mL) were added to a reaction flask, stirred and dissolved, stirred at 105-115 ° C for 10 hours, cooled to 0-10 ° C, triphenylphosphine (96.2 g, 367 mmol.), diisopropyl azodicarboxylate (59.6 g, 295 mmol) was added dropwise, stirred for 2 hours, n-propanol (85 mL) was added, stirred evenly, and concentrated to dryness under reduced pressure. Ethanol was added to the concentrate, slurried for 16 hours, filtered, and the filter cake was dried under reduced pressure to obtain 67.30 g of compound 2d as a white solid with a yield of 81.32%.

[0297] MS (ESI): m / z 337.1[M+1] + .

[0298] 1H NMR (400MHz, CDCl3): δ7.78 (dd, J=5.4, 3.1Hz, 2H), 7.64 (dd, J=5.4, 3.0Hz, 2H), 7.28-7 .13(m,5H),3.99-3.72(m,3H),3.58-3.33(m,4H),2.83-2.39(m,2H),2.22-1.84(m,2H).

[0299] Step 2:

[0300] At room temperature, compound 2d (65.0 g, 193.2 mmol), dichloromethane (390 mL), and N,N-diisopropylethylamine (5.0 g, 38.6 mmol) were added to a reaction flask and stirred to dissolve. The temperature was lowered to 5-15°C, and 1-chloroethyl chloroformate (33.2 g, 231.9 mmol) was added dropwise. After addition, the reaction mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to dryness. Methanol (390 mL) was added to the concentrate, and the mixture was stirred at 45°C for 1-2 hours. The reaction solution was concentrated under reduced pressure to dryness. Dichloromethane and petroleum ether were added to the concentrate, and the mixture was stirred for 16 hours. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain 54.0 g of compound 2e as a white solid in a yield of 98.84%.

[0301] MS (ESI): m / z 247.1[M+1] + .

[0302] 1H NMR (400MHz, CD3OD): δ8.08-7.55(m,4H),4.16-4.01(m,2H),3.96-3.72(m,3H),3.41(d,J=1 2.7Hz, 1H), 3.28-3.21 (m, 1H), 3.14 (td, J=12.4, 3.8Hz, 1H), 3.00 (dd, J=12.7, 11.3Hz, 1H).

[0303] Step 3:

[0304] At room temperature, compound 2e (52.0 g, 184 mmol), dichloromethane (1040 mL), and triethylamine (55.8 g, 552 mmol) were added to a reaction flask. The mixture was cooled in an ice-water bath and acetic anhydride (22.6 g, 221 mmol) was added dropwise. After completion of the addition, the mixture was stirred for 1-2 hours. A 25% aqueous solution of citric acid (176 g of citric acid and 520 mL of water) was added dropwise to the reaction solution and stirred thoroughly. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain 52.9 g of compound 2f as a white foamy solid in a yield of 99.72%.

[0305] MS (ESI): m / z 289.1[M+1] + .

[0306] 1H NMR (400MHz, CDCl3): δ7.87-7.75(m,2H),7.73-7.61(m,2H),4.39(d,J=13.3H z,0.5H),4.24(d,J=13.7Hz,0.5H),3.96-3.75(m,2H),3.75-3.57(m,2.5H),3. 57-3.32(m,1.5H),3.23(ddd,J=13.1,11.2,3.4Hz,0.5H),3.12-2.93(m,0.5H) ,2.83-2.70(m,0.5H),2.59(dd,J=13.3,10.0Hz,0.5H),2.03(d,J=6.6Hz,3H).

[0307] Step 4:

[0308] At room temperature, compound 2f (10.0 g, 34.69 mmol), anhydrous ethanol (105 mL), and 80% hydrazine hydrate (4.34 g, 69.37 mmol) were added to a reaction flask. Mechanical stirring was initiated and stirred at 80°C for 2 hours. The temperature was then cooled to 60°C, and methyl tert-butyl ether (110 mL) was added. The temperature was further cooled to room temperature, filtered, and the filter cake discarded. An ethanolic solution of oxalic acid was added dropwise to the filtrate to precipitate a large amount of solid. The filter cake was then filtered and dried under reduced pressure to obtain 8.15 g of compound 2g as a white solid, with a yield of 94.66%.

[0309] MS (ESI): m / z 159.2[M+1] + .

[0310] 1H NMR (400MHz, DMSO): δ4.27 (d, J = 13.1Hz, 0.5H), 4.15 (d, J = 13.4Hz, 0.5H), 3. 95-3.80(m,1.5H),3.78-3.29(m,2.5H),3.23-3.10(m,0.5H),3.02(dd,J=13. 2,3.4Hz,1H),2.92(dd,J=13.2,10.5Hz,0.5H),2.87-2.77(m,1H),2.69(td,J =13.3, 3.5Hz, 0.5H), 2.46 (dd, J = 13.2, 10.8Hz, 0.5H), 2.01 (d, J = 6.0Hz, 3H).

[0311] Step 5:

[0312] At room temperature, compound 2g (5.0g, 20.14mmol), 4-fluoro-3-nitrotoluene (3.13g, 20.14mmol, purchased from Leyan Reagent), potassium carbonate (6.96g, 50.36mmol) and N,N-dimethylacetamide (25mL) were added to a reaction flask and stirred at 110°C for 2.5 hours. The temperature was cooled to room temperature, water (75mL) was added, a solid precipitated, and the mixture was filtered. The filter cake was dissolved in dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to a small amount of solvent. Petroleum ether was added to precipitate a solid and stirred for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 5.15g of compound 2 as an orange solid with a yield of 87.17%.

[0313] MS (ESI): m / z 294.1[M+1] + .

[0314] 1H NMR (400MHz, DMSO): δ8.11(d,J=7.0Hz,1H),7.88(s,1H),7.48-7.30(m,1H),7.05(dd,J=8.7,6. 6Hz,1H),4.31(d,J=13.1Hz,0.5H),4.14(d,J=13.4Hz,0.5H),4.03-3.76(m,1.5H),3.82-3.62( m,1H),3.60-3.44(m,2H),3.44-3.34(m,1.5H),3.24-3.10(m,0.5H),3.00(dd,J=13.2,10.3Hz, 0.5H), 2.77-2.61 (m, 0.5H), 2.56-2.51 (m, 0.5H), 2.23 (d, J = 2.1Hz, 3H), 2.01 (d, J = 4.7Hz, 3H).

[0315] Example 3 Preparation of (S)-1-(4-(1-((4-acetylmorpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3-chloro-5-fluorophenyl)pyrrol-2-one (Compound 3)

[0316]

[0317] Step 1:

[0318] At room temperature, compound 2 (10 g, 34.09 mmol) and ethanol (200 mL) were added to a reaction flask, stirring was started, and compound 1 (8.3 g, 34.43 mmol), sodium dithionite (22.7 g, 130.38 mmol) and deionized water (20 mL) were added in sequence. The argon atmosphere was replaced three times and stirred at 80 ° C for 18 hours. Cooled to room temperature, filtered, and the filtrate was concentrated to dryness. Ethyl acetate (200 mL) was added to the concentrate to dissolve, washed with 2.5% brine, separated, and the organic phase was concentrated to dryness to obtain a crude product. The crude product was recrystallized twice from a mixed solvent of isopropanol and methyl tert-butyl ether to obtain 10.7 g of compound 3 as a white solid with a yield of 64.72%.

[0319] MS (ESI): m / z 485.0 [M+1] + .

[0320] 1H NMR(400MHz,DMSO-d6):δ7.88-7.89(m,1H),7.78-7.81(m,1H),7.68(m,0.5H),7.60-7.62(d,0.5H),7.49(s,1H),7.14-7.18(t,1H),3.89-4.34(m,6H),3.53-3.61(m,2H),3.42-3.43(m,0.5H),3.24(m,0.5H),3.21-3.22(m,0.5H),2.97-3.07(m,0.5H),2.73-2.76(m,0.5H),2.57-2.60(t,2H),2.44-2.50(d,3H),2.22-2.27(m,0.5H),2.06-2.13(m,2H),1.93-1.96(m,3H)。

Claims

1. A method for preparing a compound of formula I or a salt thereof, comprising the steps of reacting a compound of formula A or a salt thereof with a compound of formula B or a salt thereof to form a compound of formula I or a salt thereof in, R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting groups; R 2 Selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group; R 3 Selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group; R 4 Selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2, 3 or 4; o is selected from 0, 1, 2, 3 or 4.

2. The method according to claim 1, wherein the compound represented by formula A or a salt thereof reacts with the compound represented by formula B or a salt thereof in the presence of a reducing agent, and the reducing agent is selected from sodium dithionite.

3. The method according to claim 1 or 2, wherein the solvent used for the reaction of the compound represented by formula A or its salt with the compound represented by formula B or its salt is selected from protic polar solvents, preferably ethanol.

4. The method according to any one of claims 1 to 3, further comprising the step of converting the compound represented by formula B-1 or its salt into the compound represented by formula B or its salt where R 4 , o As defined in claim 1.

5. The method according to claim 4, wherein the compound of formula B-1 or its salt is reacted under thionyl chloride conditions to form the compound of formula B-2 or its salt, and then the compound of formula B-2 or its salt is reacted under oxidizing conditions to form the compound of formula B or its salt, wherein the oxidizing agent is preferably N-methylmorpholine-N-oxide. where R 4 , o As defined in claim 1.

6. The method according to any one of claims 1 to 5, further comprising the step of reacting the compound represented by formula A-8 or a salt thereof with the compound represented by formula A-9 or a salt thereof in the presence of a base (1) to form a compound represented by formula A. where R 1 、R 2 、R 3 , n, m as defined in claim 1.

7. The method according to any one of claims 1 to 6, wherein the compound represented by formula I is a compound represented by formula Ia, The method comprises the steps of reacting a compound represented by formula Aa or a salt thereof with a compound Ba or a salt thereof to form a compound represented by formula Ia or a salt thereof in, R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting groups.

8. The method according to claim 7, further comprising the step of converting compound Ba-1 or its salt into a compound represented by formula Ba or its salt Preferably, the method comprises the steps of reacting compound Ba-1 or a salt thereof under thionyl chloride conditions to form compound Ba-2 or a salt thereof, and then reacting compound Ba-2 or a salt thereof under oxidizing agent conditions to form compound Ba or a salt thereof, wherein the oxidizing agent is preferably N-methylmorpholine-N-oxide.

9. The method according to claim 7 or 8, which comprises the step of reacting the compound represented by formula Aa-8 or a salt thereof with compound Aa-9 or a salt thereof in the presence of a base (1) to form the compound represented by formula Aa, wherein the base (1) is preferably sodium carbonate or potassium carbonate. where R 1 As defined in claim 1.

10. Compound Ba or a salt thereof, which is 11. A method for preparing compound Ba or a salt thereof, comprising the steps of converting compound Ba-1 or a salt thereof into a compound represented by formula Ba or a salt thereof Preferably, the method comprises the steps of reacting compound Ba-1 or a salt thereof under thionyl chloride conditions to form compound Ba-2 or a salt thereof, and then reacting compound Ba-2 or a salt thereof under oxidizing agent conditions to form compound Ba or a salt thereof, wherein the oxidizing agent is selected from N-methylmorpholine-N-oxide, 12. A method for preparing a compound represented by formula Aa or a salt thereof, The method comprises the steps of reacting compound Aa-2 or a salt thereof with a compound represented by formula Aa-3 or a salt thereof to form a compound represented by formula Aa-5 or a salt thereof. Among them, P 1 is selected from amino protecting groups, such as benzyl.

13. The method according to claim 12, further comprising the step of deprotecting the compound represented by formula Aa-5 or a salt thereof to form compound Aa-6 or a salt thereof, and reacting compound Aa-6 to form a compound represented by formula Aa-7 or a salt thereof. where R 1 Selected from C 1-6 Alkyl, C 1-6 Alkyl C(O)- or amino protecting group; P 1 is selected from amino protecting groups, such as benzyl.

14. The method according to claim 12 or 13, comprising: The compound Aa-2 or a salt thereof reacts with the compound represented by formula Aa-3 or a salt thereof to form the compound represented by formula Aa-4 or a salt thereof, the compound represented by formula Aa-4 or a salt thereof reacts under phosphine reagent / azo reagent conditions to form the compound represented by formula Aa-5 or a salt thereof, the compound represented by formula Aa-5 or a salt thereof is deprotected to form the compound Aa-6 or a salt thereof, and the compound Aa-6 is converted into the compound represented by formula Aa-7 or a salt thereof.

15. A method for preparing compound AA or a pharmaceutically acceptable salt thereof, comprising the steps of the method according to any one of claims 1 to 9 and 11 to 14.

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