WO2025209508A1 - Method for preparing zavegepant intermediate and derivative thereof - Google Patents

Abstract

The present invention relates to the field of drug synthesis, and specifically relates to a method for preparing a Zavegepant intermediate and a derivative thereof. Specifically, the method comprises reacting a compound of formula II with a compound of formula III to obtain a compound of formula I, reacting the compound of formula I with isoamyl nitrite to obtain compound V, and removing a protecting group from the compound of formula V to obtain a compound of formula VI or a salt thereof. On the basis of the preparation method provided by the present invention, the raw materials are readily available, the production cost is relatively low, there are fewer synthesis steps, and the operation is simpler and more convenient.

Description

Preparation method of zavidipam intermediate and its derivatives

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefits of Chinese Patent Application No. 2024103986162 filed with the National Intellectual Property Administration of China, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to the field of drug synthesis, and in particular to a method for preparing a zavidipam intermediate and derivatives thereof.

Background Art

Zavigipan is a calcitonin gene-related peptide (CGRP) receptor antagonist developed by Pfizer Inc. and approved for marketing by the U.S. Food and Drug Administration (FDA) on March 9, 2023. For the acute treatment of migraine with or without aura in adults.

The chemical name of zavidipam is (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide, and its specific structure is shown in Formula 1:

The compound of formula VI-1-A is an important intermediate in the synthesis of zavirigopam. Although its synthesis method has been reported in documents such as Org.Process Res.Dev.2012,16,1953-1966 and CN102834388, there is still an urgent need to develop a simpler preparation method.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a method for preparing a compound of formula I, which is characterized by comprising the following steps: reacting a compound of formula II with a compound of formula III in a solvent in the presence of a catalyst and a ligand to obtain a compound of formula I,

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group.

In a second aspect, the present invention also provides a method for preparing a compound of formula II, characterized in that: a compound of formula IV and zinc powder react in a solvent under the action of an initiator to obtain a compound of formula II,

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, and PG is an amino protecting group.

In a third aspect, the present invention further provides a method for preparing the compound of formula I, characterized by comprising the following steps:

(1A) The compound of formula IV reacts with zinc powder in a solvent under the action of an initiator to obtain the compound of formula II;

(1) The compound of formula II and the compound of formula III are reacted in a solvent in the presence of a catalyst and a ligand to obtain the compound of formula I.

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group.

In a fourth aspect, the present invention further provides a method for preparing a compound of formula VI or a salt thereof, characterized by comprising the following steps:

(1) The compound of formula II and the compound of formula III react in a solvent in the presence of a catalyst and a ligand to obtain the compound of formula I;

(2) reacting the compound of formula I with isoamyl nitrite in a solvent in the presence of a buffer system to obtain compound V;

(3) removing the protecting group from the compound of formula V to obtain the compound of formula VI or its salt,

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group.

In a fifth aspect, the present invention further provides a method for preparing a compound of formula VI or a salt thereof, characterized by comprising the following steps:

(1A) The compound of formula IV reacts with zinc powder in a solvent under the action of an initiator to obtain the compound of formula II;

(1) The compound of formula II and the compound of formula III react in a solvent in the presence of a catalyst and a ligand to obtain the compound of formula I;

(2) reacting the compound of formula I with isoamyl nitrite in a solvent in the presence of a buffer system to obtain compound V;

(3) removing the protecting group from the compound of formula V to obtain the compound of formula VI or its salt,

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group.

In a sixth aspect, the present invention further provides a compound of formula I, characterized in that it has the following structure:

Wherein, R ⁰ is C1-C4 alkyl; PG is tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl.

In a seventh aspect, the present invention further provides a compound of formula V, characterized in that it has the following structure:

Wherein, R ⁰ is C1-C4 alkyl; PG is 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl.

Summary of the Invention

In a first aspect, the present invention provides a method for preparing a compound of formula I, which comprises: reacting a compound of formula II with a compound of formula III in a solvent in the presence of a catalyst and a ligand to obtain a compound of formula I,

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group.

In some embodiments of the present invention, the compound of formula II has a structure as shown in formula II-A, and the compound of formula I has a structure as shown in formula I-A,

In some embodiments of the present invention, the R ⁰ is methyl, ethyl, n-propyl or isopropyl; in some typical embodiments of the present invention, the R ⁰ is methyl or ethyl; in some more typical embodiments of the present invention, the R ⁰ is methyl.

In some embodiments of the present invention, R ¹ is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ¹ is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ¹ is bromine or iodine; in some more typical embodiments of the present invention, R ¹ is iodine.

In some embodiments of the present invention, R ² is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ² is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ² is bromine or iodine; in some more typical embodiments of the present invention, R ² is iodine.

In some embodiments of the present invention, the PG is tert-butyloxycarbonyl, 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl, benzyloxycarbonyl or tert-butyloxycarbonyl; in some typical embodiments of the present invention, the PG is tert-butyloxycarbonyl, p-methoxybenzyl or benzyl; in some more typical embodiments of the present invention, the PG is tert-butyloxycarbonyl.

In some embodiments of the present invention, the catalyst is tris(dibenzylideneacetone)dipalladium or palladium acetate; in some typical embodiments of the present invention, the catalyst is palladium acetate.

In some embodiments of the present invention, the ligand is triphenylphosphine, tricyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2',6'-diisopropyloxy-1,1'-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; in some typical embodiments of the present invention, the ligand is triphenylphosphine , tricyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthene, 2-bisdicyclohexylphosphine-2',6'-dimethoxybiphenyl or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; in some more typical embodiments of the present invention, the ligand is tricyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthene or 2-bisdicyclohexylphosphine-2',6'-dimethoxybiphenyl; in some more typical embodiments of the present invention, the ligand is 2-bisdicyclohexylphosphine-2',6'-dimethoxybiphenyl.

In some embodiments of the present invention, the catalyst and the ligand are the same substance, which are tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, 1,1-bis(diphenylphosphine)dibrominated iron palladium dichloride or dichlorobis(tricyclohexylphosphine)palladium.

In some embodiments of the present invention, the catalyst is palladium acetate, and the ligand is 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-1,1'-biphenyl or 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; in some typical embodiments of the present invention, the catalyst is palladium acetate, and the ligand is 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; in some more typical embodiments of the present invention, the catalyst is palladium acetate, and the ligand is 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl.

In some embodiments of the present invention, the solvent is one or a mixed solvent of two or more selected from N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N-methylpyrrolidone or N,N-dimethylacetamide; in some typical embodiments of the present invention, the solvent is one or a mixed solvent of two or more selected from N,N-dimethylformamide, 2-methyltetrahydrofuran, N-methylpyrrolidone or N,N-dimethylacetamide; in some more typical embodiments of the present invention, the solvent is one or a mixed solvent of two or more selected from N,N-dimethylformamide, N-methylpyrrolidone or N,N-dimethylacetamide; in some more typical embodiments of the present invention, the solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

In some embodiments of the present invention, the molar ratio of the compound III to the compound of formula II is 1:0.8, 1:1.0, 1:1.2, 1:1.29, 1:1.3, 1:1.35, 1:1.4, 1:1.5, 1:2.0 or a range between any two of the above ratios; in some typical embodiments of the present invention, the molar ratio of the compound III to the compound of formula II is 1:0.8-2.0; in some more typical embodiments of the present invention, the molar ratio of the compound III to the compound of formula II is 1:1.0-1.5; in some more typical embodiments of the present invention, The molar ratio of the compound III to the compound of formula II is 1:1.2-1.5; in some extremely typical embodiments of the present invention, the molar ratio of the compound III to the compound of formula II is 1:1.2-1.4; in some most typical embodiments of the present invention, the molar ratio of the compound III to the compound of formula II is 1:1.29-1.3; in some most typical embodiments of the present invention, the molar ratio of the compound III to the compound of formula II is 1:1.3-1.4; in some most typical embodiments of the present invention, the molar ratio of the compound III to the compound of formula II is 1:1.35-1.5.

In some embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.0001, 1:0.0005, 1:0.005, 1:0.009, 1:0.01, 1:0.011, 1:0.014, 1:0.015, 1:0.05, 1:0.1, 1:0.2 or a range between any two of the above ratios; in some typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.0001 to 0.2; in some more typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.0005 to 0.1; in some more typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.0005 to 0.1; in some more typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.0005 to 0.1. In some typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.005-0.05; in some very typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.005-0.015; in some most typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.009-0.011; in some most typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.01-1:0.014; in some most typical embodiments of the present invention, the molar ratio of the compound of formula III to the catalyst is 1:0.011-0.015.

In some embodiments of the present invention, the ligand and the catalyst are different substances, the catalyst is calculated as palladium, and the molar ratio of the catalyst to the ligand is 1:0.8-4; in some typical embodiments of the present invention, the ligand and the catalyst are different substances, the catalyst is calculated as palladium, and the molar ratio of the catalyst to the ligand is 1:1-4; in some more typical embodiments of the present invention, the ligand and the catalyst are different substances, the catalyst is calculated as palladium, and the molar ratio of the catalyst to the ligand is 1:0.8-2; in some more typical embodiments of the present invention, the ligand and the catalyst are different substances, the catalyst is calculated as palladium, and the molar ratio of the catalyst to the ligand is 1:1-2; in some extremely typical embodiments of the present invention, the ligand and the catalyst are different substances, the catalyst is calculated as palladium, and the molar ratio of the catalyst to the ligand is 1:0.9-1.1; in some most typical embodiments of the present invention, the ligand and the catalyst are different substances, the catalyst is calculated as palladium, and the molar ratio of the catalyst to the ligand is 1:1.

In some embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula III (mL:g) is 1:0.01 to 0.3; in some typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula III (mL:g) is 1:0.03 to 0.2; in some more typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula III (mL:g) is 1:0.05 to 0.2; in some more typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula III (mL:g) is 1:0.08 to 0.15; in some extremely typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula III (mL:g) is 1:0.1 to 0.15; in some most typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula III (mL:g) is 1:0.09 to 0.11; in some most typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula III (mL:g) is 1:0.1 to 0.12.

In some embodiments of the present invention, the reaction temperature of the preparation method is 0°C to 100°C; in some typical embodiments of the present invention, the reaction temperature of the preparation method is 0°C to 80°C; in some more typical embodiments of the present invention, the reaction temperature of the preparation method is 25°C to 60°C; in some more typical embodiments of the present invention, the reaction temperature of the preparation method is 45°C to 60°C.

In some embodiments of the present invention, the reaction time of the preparation method is 1h, 1.8h, 2h, 2.2h, 4h, 10h, 18h or a range between any two of the above values; in some typical embodiments of the present invention, the reaction time of the preparation method is 1h~18h; in some more typical embodiments of the present invention, the reaction time of the preparation method is 1h~10h; in some more typical embodiments of the present invention, the reaction time of the preparation method is 1h~4h; in some most typical embodiments of the present invention, the reaction time of the preparation method is 1.8~2.2h; in some most typical embodiments of the present invention, the reaction time of the preparation method is 1h~2h.

In a second aspect, the present invention also provides a method for preparing a compound of formula II, characterized in that: a compound of formula IV and zinc powder react in a solvent under the action of an initiator to obtain a compound of formula II,

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, and PG is an amino protecting group.

In some embodiments of the present invention, the compound of formula IV has a structural formula as shown in formula IV-A, and the compound of formula II has a structural formula as shown in formula II-A,

In some embodiments of the present invention, the R ⁰ is methyl, ethyl, n-propyl or isopropyl; in some typical embodiments of the present invention, the R ⁰ is methyl or ethyl; in some more typical embodiments of the present invention, the R ⁰ is methyl.

In some embodiments of the present invention, R ¹ is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ¹ is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ¹ is bromine or iodine; in some more typical embodiments of the present invention, R ¹ is iodine.

In some embodiments of the present invention, the PG is tert-butyloxycarbonyl, 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl, benzyloxycarbonyl or tert-butyloxycarbonyl; in some typical embodiments of the present invention, the PG is tert-butyloxycarbonyl, p-methoxybenzyl or benzyl; in some more typical embodiments of the present invention, the PG is tert-butyloxycarbonyl.

In some embodiments of the present invention, the initiator is one or a mixture of two or more of dibromoethane, trimethylsilyl chloride, and elemental iodine.

In some embodiments of the present invention, the solvent is N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N-methylpyrrolidone or N,N-dimethylacetamide; in some typical embodiments of the present invention, the solvent is N,N-dimethylformamide, 2-methyltetrahydrofuran, N-methylpyrrolidone or N,N-dimethylacetamide; in some more typical embodiments of the present invention, the solvent is N,N-dimethylformamide, N-methylpyrrolidone or N,N-dimethylacetamide; in some more typical embodiments of the present invention, the solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

In some embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula IV (mL: g) is 1: 0.02, 1: 0.06, 1: 0.1, 1: 0.12, 1: 0.18, 1: 0.2, 1: 0.24, 1: 0.26, 1: 0.29, 1: 0.35, 1: 0.4, 1: 0.6 or a range between any two of the above ratios; in some typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula IV (mL: g) is 1: 0.02 to 0.6; in some more typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula IV (mL: g) is 1: 0.06 to 0.4; in some more typical embodiments of the present invention, In the present invention, the volume mass ratio of the solvent to the compound of formula IV (mL:g) is 1:0.1 to 0.4; in some extremely typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula IV (mL:g) is 1:0.12 to 0.35; in some most typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula IV (mL:g) is 1:0.24 to 0.35; in some most typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula IV (mL:g) is 1:0.18 to 0.26; in some most typical embodiments of the present invention, the volume mass ratio of the solvent to the compound of formula IV (mL:g) is 1:0.2 to 0.29.

In some embodiments of the present invention, the molar ratio of the compound of formula IV to zinc powder is 1:1.2, 1:1.5, 1:2, 1:3, 1:3.3, 1:4, 1:5, 1:6 or a range between any two of the above ratios; in some typical embodiments of the present invention, the molar ratio of the compound of formula IV to zinc powder is 1:1.2-6; in some more typical embodiments of the present invention, the molar ratio of the compound of formula IV to zinc powder is 1:2-5; in some more typical embodiments of the present invention, the molar ratio of the compound of formula IV to zinc powder is 1:1.2-4; in some more typical embodiments of the present invention, the molar ratio of the compound of formula IV to zinc powder is 1:1.2-3.3; in some more typical embodiments of the present invention, the molar ratio of the compound of formula IV to zinc powder is 1:3-4; in some more typical embodiments of the present invention, the molar ratio of the compound of formula IV to zinc powder is 1:1.2-1.8.

In some embodiments of the present invention, the molar ratio of the zinc powder to the total amount of initiator is 1:0.02-0.2; in some typical embodiments of the present invention, the molar ratio of the zinc powder to the total amount of initiator is 1:0.02-0.15; in some more typical embodiments of the present invention, the molar ratio of the zinc powder to the total amount of initiator is 1:0.02-0.1; in some more typical embodiments of the present invention, the molar ratio of the zinc powder to the total amount of initiator is 1:0.02-0.08; in some most typical embodiments of the present invention, the molar ratio of the zinc powder to the total amount of initiator is 1:0.03-0.07.

In some embodiments of the present invention, the initiator is dibromoethane and trimethylchlorosilane, wherein the molar ratio of zinc powder to dibromoethane is 1:0.001-0.1; in some typical embodiments of the present invention, the initiator is dibromoethane and trimethylchlorosilane, wherein the molar ratio of zinc powder to dibromoethane is 1:0.01-0.05; in some more typical embodiments of the present invention, the initiator is dibromoethane and trimethylchlorosilane, wherein the molar ratio of zinc powder to dibromoethane is 1:0.02-0.05; in some more typical embodiments of the present invention, the initiator is dibromoethane and trimethylchlorosilane, wherein the molar ratio of zinc powder to dibromoethane is 1:0.03-0.04.

In some embodiments of the present invention, the initiator is dibromoethane and trimethylchlorosilane, wherein the molar ratio of zinc powder to trimethylchlorosilane is 1:0.001~0.1; in some typical embodiments of the present invention, the initiator is dibromoethane and trimethylchlorosilane, wherein the molar ratio of zinc powder to trimethylchlorosilane is 1:0.01~0.05; in some more typical embodiments of the present invention, the initiator is dibromoethane and trimethylchlorosilane, wherein the molar ratio of zinc powder to trimethylchlorosilane is 1:0.015~0.05; in some more typical embodiments of the present invention, the initiator is dibromoethane and trimethylchlorosilane, wherein the molar ratio of zinc powder to trimethylchlorosilane is 1:0.018~0.021.

In some embodiments of the present invention, the activation temperature of the dibromoethane is 50°C to 120°C. In some typical embodiments of the present invention, the activation temperature of the dibromoethane is 70°C to 100°C.

In some embodiments of the present invention, the activation time of the dibromoethane is 0.25h~4h; in some typical embodiments of the present invention, the activation temperature of the dibromoethane is 0.25h~2h; in some more typical embodiments of the present invention, the activation temperature of the dibromoethane is 0.25h~1h.

In some embodiments of the present invention, the initiator is trimethylchlorosilane, and the molar ratio of zinc powder to trimethylchlorosilane is 1:0.02-0.2; in some typical embodiments of the present invention, the initiator is trimethylchlorosilane, and the molar ratio of zinc powder to trimethylchlorosilane is 1:0.02-0.15; in some more typical embodiments of the present invention, the initiator is trimethylchlorosilane, and the molar ratio of zinc powder to trimethylchlorosilane is 1:0.02-0.1; in some more typical embodiments of the present invention, the initiator is trimethylchlorosilane, and the molar ratio of zinc powder to trimethylchlorosilane is 1:0.02-0.05; in some most typical embodiments of the present invention, the initiator is trimethylchlorosilane, and the molar ratio of zinc powder to trimethylchlorosilane is 1:0.03-0.05.

In some embodiments of the present invention, the reaction temperature of the preparation method is 0°C to 120°C; in some typical embodiments of the present invention, the reaction temperature of the preparation method is 15°C to 90°C; in some more typical embodiments of the present invention, the reaction temperature of the preparation method is 20°C to 60°C; in some more typical embodiments of the present invention, the reaction temperature of the preparation method is 20°C to 40°C; in some most typical embodiments of the present invention, the reaction temperature of the preparation method is 20°C to 35°C.

In some embodiments of the present invention, the reaction time of the preparation method is 0.5h~8h, and the reaction time includes the feeding time; in some typical embodiments of the present invention, the reaction time of the preparation method is 0.5h~4h, and the reaction time includes the feeding time; in some more typical embodiments of the present invention, the reaction time of the preparation method is 1h~3h, and the reaction time includes the feeding time; in some more typical embodiments of the present invention, the reaction time of the preparation method is 1.8~2.2h, and the reaction time includes the feeding time.

In some embodiments of the present invention, the compound of formula IV is mixed with a solvent to form a solution, and then the solution is added dropwise.

In a third aspect, the present invention further provides a method for preparing a compound of formula I, characterized in that it comprises the following steps:

(1A) The compound of formula IV reacts with zinc powder in a solvent under the action of an initiator to obtain the compound of formula II;

(1) The compound of formula II and the compound of formula III are reacted in a solvent in the presence of a catalyst and a ligand to obtain the compound of formula I.

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group.

In some embodiments of the present invention, the compound of formula IV has a structural formula as shown in formula IV-A, the compound of formula II has a structural formula as shown in formula II-A, and the compound of formula I has a structural formula as shown in formula I-A,

In some embodiments of the present invention, the R ⁰ is methyl, ethyl, n-propyl or isopropyl; in some typical embodiments of the present invention, the R ⁰ is methyl or ethyl; in some more typical embodiments of the present invention, the R ⁰ is methyl.

In some embodiments of the present invention, R ¹ is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ¹ is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ¹ is bromine or iodine; in some more typical embodiments of the present invention, R ¹ is iodine.

In some embodiments of the present invention, R ² is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ² is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ² is bromine or iodine; in some more typical embodiments of the present invention, R ² is iodine.

In some embodiments of the present invention, the PG is tert-butyloxycarbonyl, 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl, benzyloxycarbonyl or tert-butyloxycarbonyl; in some typical embodiments of the present invention, the PG is tert-butyloxycarbonyl, p-methoxybenzyl or benzyl; in some more typical embodiments of the present invention, the PG is tert-butyloxycarbonyl.

In some embodiments of the present invention, the reaction conditions of step (1A) and/or step (1) are as described above; in some typical embodiments of the present invention, the solvent of step (1A) and step (1) is the same solvent.

In a fourth aspect, the present invention further provides a method for preparing a compound of formula VI or a salt thereof, characterized by comprising the following steps:

(1) The compound of formula II and the compound of formula III react in a solvent in the presence of a catalyst and a ligand to obtain the compound of formula I;

(2) reacting the compound of formula I with isoamyl nitrite in a solvent in the presence of a buffer system to obtain compound V;

(3) removing the protecting group from the compound of formula V to obtain the compound of formula VI or its salt,

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group.

In some embodiments of the present invention, the compound II has a structural formula as shown in Formula II-A, the compound I has a structural formula as shown in Formula I-A, the compound V has a structural formula as shown in Formula V-A, and the compound VI has a structural formula as shown in Formula VI-A.

In some embodiments of the present invention, the compound of formula VI or its salt is a compound of formula VI or its hydrochloride; in some typical embodiments of the present invention, the compound of formula VI or its salt is a compound of formula VI or its dihydrochloride; in some more typical embodiments of the present invention, the compound of formula VI or its salt is the dihydrochloride of compound VI.

In some embodiments of the present invention, the R ⁰ is methyl, ethyl, n-propyl or isopropyl; in some typical embodiments of the present invention, the R ⁰ is methyl or ethyl; in some more typical embodiments of the present invention, the R ⁰ is methyl.

In some embodiments of the present invention, R ¹ is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ¹ is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ¹ is bromine or iodine; in some more typical embodiments of the present invention, R ¹ is iodine.

In some embodiments of the present invention, R ² is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ² is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ² is bromine or iodine; in some more typical embodiments of the present invention, R ² is iodine.

In some embodiments of the present invention, the PG is tert-butyloxycarbonyl, 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl, benzyloxycarbonyl or tert-butyloxycarbonyl; in some typical embodiments of the present invention, the PG is tert-butyloxycarbonyl, p-methoxybenzyl or benzyl; in some more typical embodiments of the present invention, the PG is tert-butyloxycarbonyl.

In some embodiments of the present invention, the reaction conditions of step (1) are as described above.

In some embodiments of the present invention, the buffer system in step (2) is composed of an acid and a salt having a corresponding acid radical ion, and the acid is acetic acid, formic acid, phosphoric acid or potassium dihydrogen phosphate; in some typical embodiments of the present invention, the buffer system in step (2) is composed of an acid and a salt having a corresponding acid radical ion, and the acid is acetic acid, phosphoric acid or potassium dihydrogen phosphate; in some more typical embodiments of the present invention, the buffer system in step (2) is composed of an acid and a salt having a corresponding acid radical ion, and the acid is acetic acid or potassium dihydrogen phosphate; in some more typical embodiments of the present invention, the buffer system in step (2) is composed of an acid and a salt having a corresponding acid radical ion, and the acid is acetic acid.

In some typical embodiments of the present invention, the buffer system in step (2) is a combination of acetic acid and potassium acetate, a combination of formic acid and sodium formate, a combination of phosphoric acid and sodium phosphate, or potassium dihydrogen phosphate; in some typical embodiments of the present invention, the buffer system in step (2) is a combination of acetic acid and potassium acetate, a combination of phosphoric acid and sodium phosphate, or potassium dihydrogen phosphate; in some more typical embodiments of the present invention, the buffer system in step (2) is a combination of acetic acid and potassium acetate or a combination of phosphoric acid and sodium phosphate; in some more typical embodiments of the present invention, the buffer system in step (2) is a combination of acetic acid and potassium acetate.

In some embodiments of the present invention, the solvent in step (2) is one or a mixed solvent of two or more of ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene, dioxane or methyl tert-butyl ether; in some typical embodiments of the present invention, the solvent in step (2) is ethyl acetate, isopropyl acetate, toluene, tetrahydrofuran or methyl tert-butyl ether; in some more typical embodiments of the present invention, the solvent in step (2) is ethyl acetate, isopropyl acetate or toluene; in some more typical embodiments of the present invention, the solvent in step (2) is ethyl acetate or toluene.

In some embodiments of the present invention, the solvent in step (2) is different from the solvent in step (1A) and/or step (1).

In some embodiments of the present invention, in step (2), the salt is calculated as monovalent acid ions, and the molar ratio of the compound of formula I to the salt is 1:1-4; in some typical embodiments of the present invention, in step (2), the salt is calculated as monovalent acid ions, and the molar ratio of the compound of formula I to the salt is 1:1.5-2; in some more typical embodiments of the present invention, in step (2), the salt is calculated as monovalent acid ions, and the molar ratio of the compound of formula I to the salt is 1:1.2-1.3; in some more typical embodiments of the present invention, in step (2), the salt is calculated as monovalent acid ions, and the molar ratio of the compound of formula I to the salt is 1:1.25.

In some embodiments of the present invention, in step (2), the molar ratio of the acid, calculated as hydrogen ions, to the compound of formula I is 1:1-4; in some typical embodiments of the present invention, in step (2), the molar ratio of the acid, calculated as hydrogen ions, to the compound of formula I is 1:1-2; in some more typical embodiments of the present invention, in step (2), the molar ratio of the acid, calculated as hydrogen ions, to the compound of formula I is 1:1.4-1.6; in some more typical embodiments of the present invention, in step (2), the molar ratio of the acid, calculated as hydrogen ions, to the compound of formula I is 1:1.5.

In some embodiments of the present invention, the molar ratio of the compound of formula I to isoamyl nitrite in step (2) is 1:1-2; in some typical embodiments of the present invention, the molar ratio of the compound of formula I to isoamyl nitrite in step (2) is 1:1.05-1.5; in some more typical embodiments of the present invention, the molar ratio of the compound of formula I to isoamyl nitrite in step (2) is 1:1.05-1.2.

In some embodiments of the present invention, the volume mass ratio (mL:g) of the solvent to the compound of formula I in step (2) is 1:0.03 to 0.3; in some typical embodiments of the present invention, the volume mass ratio (mL:g) of the solvent to the compound of formula I in step (2) is 1:0.03 to 0.2; in some more typical embodiments of the present invention, the volume mass ratio (mL:g) of the solvent to the compound of formula I in step (2) is 1:0.06 to 0.1.

In some embodiments of the present invention, the isoamyl nitrite in step (2) can be added dropwise, and the temperature during the addition includes but is not limited to 0°C to 50°C, 10°C to 30°C or 15°C to 25°C.

In some embodiments of the present invention, the reaction temperature after the dropwise addition of isoamyl nitrite in step (2) is 40°C, 50°C, 60°C, 70°C, 80°C or a range between any two of the above values; in some typical embodiments of the present invention, the reaction temperature after the dropwise addition of isoamyl nitrite in step (2) is 40°C to 80°C; in some more typical embodiments of the present invention, the reaction temperature after the dropwise addition of isoamyl nitrite in step (2) is 50°C to 80°C; in some more typical embodiments of the present invention, the reaction temperature after the dropwise addition of isoamyl nitrite in step (2) is 40°C to 70°C; in some more typical embodiments of the present invention, the reaction temperature after the dropwise addition of isoamyl nitrite in step (2) is 50°C to 70°C; in some most typical embodiments of the present invention, the reaction temperature after the dropwise addition of isoamyl nitrite in step (2) is 60°C to 70°C.

In some embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 60-70°C is 0.5h-16h; in some typical embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 60-70°C is 0.5h-8h; in some more typical embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 60-70°C is 1h-4h; in some more typical embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 60-70°C is 1.8h-2.2h.

In some embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 40-50°C is 0.5h-16h; in some typical embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 40-50°C is 5h-16h; in some more typical embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 40-46°C is 8h-16h; in some more typical embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 40-46°C is 10h-16h; in some most classic embodiments of the present invention, the reaction time after the isoamyl nitrite is added dropwise in step (2) and the temperature is raised to 40-46°C is 12h-16h.

In some embodiments of the present invention, step (3) removes the PG group in different ways according to the different structures of the PG group.

In some embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, and the reaction reagent is acetyl chloride, thionyl chloride, oxalyl chloride or methanolic hydrochloric acid solution; in some typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, and the reaction reagent is acetyl chloride, thionyl chloride or methanolic hydrochloric acid solution; in some more typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, and the reaction reagent is acetyl chloride or methanolic hydrochloric acid solution.

In some embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, 4 mol/L hydrochloric acid methanol solution or 30% hydrochloric acid methanol solution. In some typical embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, and the reaction reagent is 2 mol/L hydrochloric acid methanol solution.

In some embodiments of the present invention, when the PG group in step (3) is tert-butyloxycarbonyl and the reaction reagent is a 2 mol/L methanolic hydrochloric acid solution, the volume mass ratio (mL:g) of the reaction reagent to the compound of formula V is 1:0.02 to 0.3; in some typical embodiments of the present invention, when the PG group in step (3) is tert-butyloxycarbonyl and the reaction reagent is a 2 mol/L methanolic hydrochloric acid solution, the volume mass ratio (mL:g) of the reaction reagent to the compound of formula V is 1:0.05 to 0.3; in some more typical embodiments of the present invention, when the PG group in step (3) is tert-butyloxycarbonyl and the reaction reagent is a 2 mol/L methanolic hydrochloric acid solution, the volume mass ratio (mL:g) of the reaction reagent to the compound of formula V is 1:0.1 to 0.25.

In some embodiments of the present invention, in step (3), when the PG group is tert-butyloxycarbonyl and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, the reaction temperature is 0°C to 50°C; in some typical embodiments of the present invention, in step (3), when the PG group is tert-butyloxycarbonyl and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, the reaction temperature is 10°C to 40°C; in some more typical embodiments of the present invention, in step (3), when the PG group is tert-butyloxycarbonyl and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, the reaction temperature is 15°C to 25°C;

In some embodiments of the present invention, when the PG group in step (3) is tert-butoxycarbonyl and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, the reaction time is 0.5 h to 8 h; in some typical embodiments of the present invention, when the PG group in step (3) is tert-butoxycarbonyl and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, the reaction time is 1 h to 4 h; in some more typical embodiments of the present invention, when the PG group in step (3) is tert-butoxycarbonyl and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, the reaction time is 1.8 h to 2.2 h.

In some embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the molar ratio of the compound of formula V to acetyl chloride is 1:3 to 15; in some typical embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the molar ratio of the compound of formula V to acetyl chloride is 1:3 to 10; in some more typical embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the molar ratio of the compound of formula V to acetyl chloride is 1:3 to 8; in some typical embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the molar ratio of the compound of formula V to acetyl chloride is 1:3 to 8; In some more typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the molar ratio of the compound of formula V to acetyl chloride is 1:3-7; in some extremely typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the molar ratio of the compound of formula V to acetyl chloride is 1:4-6; in some most typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the molar ratio of the compound of formula V to acetyl chloride is 1:4.9-5.1.

In some embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the solvent is methanol, dioxane, ethyl acetate, dichloromethane or isopropyl acetate; in some typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the solvent is methanol, dioxane, ethyl acetate or dichloromethane; in some more typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the solvent is methanol or dioxane; in some more typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the solvent is methanol.

In some embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the mass volume ratio (kg:L) of the compound of formula V to the solvent is 1:3 to 15; in some typical embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the mass volume ratio (kg:L) of the compound of formula V to the solvent is 1:3 to 10; in some more typical embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the mass volume ratio (kg:L) of the compound of formula V to the solvent is 1:3 to 10. is acetyl chloride, and the mass volume ratio (kg:L) of the compound of formula V to the solvent is 1:3 to 8; in some more typical embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the mass volume ratio (kg:L) of the compound of formula V to the solvent is 1:4 to 6; in some most typical embodiments of the present invention, the PG group in step (3) is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the mass volume ratio (kg:L) of the compound of formula V to the solvent is 1:4.9 to 5.1.

In some embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the reaction time is 2h to 16h; in some typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the reaction time is 2h to 10h; in some more typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the reaction time is 2h to 7h; in some more typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the reaction time is 3h to 5h; in some most typical embodiments of the present invention, the PG group in step (3) is tert-butoxycarbonyl, the reaction reagent is acetyl chloride, and the reaction time is 3.9 to 4.1h.

In a fifth aspect, the present invention further provides a method for preparing a compound of formula VI or a salt thereof, characterized in that it comprises the following steps:

(1A) The compound of formula IV reacts with zinc powder in a solvent under the action of an initiator to obtain the compound of formula II;

(1) The compound of formula II and the compound of formula III react in a solvent in the presence of a catalyst and a ligand to obtain the compound of formula I;

(2) reacting the compound of formula I with isoamyl nitrite in a solvent in the presence of a buffer system to obtain compound V;

(3) removing the protecting group from the compound of formula V to obtain the compound of formula VI or its salt,

Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group.

In some embodiments of the present invention, the compound of formula IV has a structural formula as shown in formula IV-A, the compound of formula II has a structural formula as shown in formula II-A, the compound of formula I has a structural formula as shown in formula I-A, the compound of formula V has a structural formula as shown in formula V-A, and the compound of formula VI has a structural formula as shown in formula VI-A.

In some embodiments of the present invention, the compound of formula VI or its salt is a compound of formula VI or its hydrochloride; in some typical embodiments of the present invention, the compound of formula VI or its salt is a compound of formula VI or its dihydrochloride; in some more typical embodiments of the present invention, the compound of formula VI or its salt is the dihydrochloride of compound VI.

In some embodiments of the present invention, the R ⁰ is methyl, ethyl, n-propyl or isopropyl; in some typical embodiments of the present invention, the R ⁰ is methyl or ethyl; in some more typical embodiments of the present invention, the R ⁰ is methyl.

In some embodiments of the present invention, R ¹ is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ¹ is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ¹ is bromine or iodine; in some more typical embodiments of the present invention, R ¹ is iodine.

In some embodiments of the present invention, R ² is fluorine, chlorine, bromine or iodine; in some typical embodiments of the present invention, R ² is chlorine, bromine or iodine; in some more typical embodiments of the present invention, R ² is bromine or iodine; in some more typical embodiments of the present invention, R ² is iodine.

In some embodiments of the present invention, the PG is tert-butyloxycarbonyl, 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl, benzyloxycarbonyl or tert-butyloxycarbonyl; in some typical embodiments of the present invention, the PG is tert-butyloxycarbonyl, p-methoxybenzyl or benzyl; in some more typical embodiments of the present invention, the PG is tert-butyloxycarbonyl.

In some embodiments of the present invention, the reaction conditions of step (1A), step (1), step (2) and/or step (3) are as described above.

In a sixth aspect, the present invention further provides a compound of formula I, characterized in that it has the following structure:

Wherein, R ⁰ is C1-C4 alkyl, PG is tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl.

In some embodiments of the present invention, the R ⁰ is a methyl group or an ethyl group; in some more typical embodiments of the present invention, the R ⁰ is a methyl group; in some more typical embodiments of the present invention, the R ⁰ is an ethyl group.

In some typical embodiments of the present invention, the PG is tert-butyloxycarbonyl, p-methoxybenzyl or benzyl; in some more typical embodiments of the present invention, the PG is tert-butyloxycarbonyl; in some more typical embodiments of the present invention, the PG is 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or w-methoxycarbonyl; in some more typical embodiments of the present invention, the PG is p-methoxybenzyl or benzyl.

In some embodiments of the present invention, the compound of formula I has the structural formula shown in formula IA,

Wherein, R ⁰ is C1-C4 alkyl; PG is tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl.

In some embodiments of the present invention, said R ⁰ is methyl or ethyl; in some typical embodiments of the present invention, said R ⁰ is methyl; in some typical embodiments of the present invention, said R ⁰ is ethyl.

In some embodiments of the present invention, the PG is tert-butyloxycarbonyl, p-methoxybenzyl or benzyl; in some typical embodiments of the present invention, the PG is tert-butyloxycarbonyl; in some typical embodiments of the present invention, the PG is 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or w-methoxycarbonyl; in some more typical embodiments of the present invention, the PG is p-methoxybenzyl or benzyl.

In a seventh aspect, the present invention further provides a compound of formula V, characterized in that it has the following structure:

Wherein, R ⁰ is C1-C4 alkyl; PG is 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl.

In some embodiments of the present invention, said R ⁰ is methyl or ethyl; in some typical embodiments of the present invention, said R ⁰ is methyl.

In some embodiments of the present invention, the PG is p-methoxybenzyl or benzyl.

In some embodiments, the compound of formula V has the structural formula shown in formula V-A,

Wherein, R ⁰ is C1-C4 alkyl; PG is 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl.

In some embodiments of the present invention, said R ⁰ is methyl or ethyl; in some typical embodiments of the present invention, said R ⁰ is methyl.

In some embodiments of the present invention, the PG is p-methoxybenzyl or benzyl.

In some embodiments of the present invention, the present invention provides the use of the aforementioned compound of formula I-1-A or its preparation method in the preparation of zavigepam free base; in some embodiments of the present invention, the present invention provides the use of the aforementioned compound of formula I-1-A or its preparation method in the preparation of zavigepam hydrochloride; in some embodiments of the present invention, the present invention provides the use of the aforementioned compound of formula I-1-A or its preparation method in the preparation of zavigepam dihydrochloride. In some embodiments of the present invention, the compound of formula I-1-A is reacted with the compound of formula VI-1-A to produce zavigepam,

Zavigipan can be prepared from the compound of formula VI-1-A of the present invention with reference to the existing technology, and the existing technology includes but is not limited to Org.Process Res.Dev.2012,16,1953-1966 and CN102834388.

In the present invention, the purity of the target compound can be measured by the following method:

1. Chromatographic conditions

Table 1 Chromatographic conditions

2. Reagents

Trifluoroacetic acid: chromatographic grade

Acetonitrile: chromatographic grade

Water: Purified water

3. Solution Preparation

Diluent: water: acetonitrile = 60:40 (% V/V)

Blank solution: diluent

Test solution: Accurately weigh 25 mg of the test sample into a 25 mL volumetric flask, dissolve it in diluent and dilute to the mark, then mix thoroughly.

4. Steps

Inject 1 injection of blank solution and 1 injection of test solution respectively, and record the chromatographic process.

5. Calculation

Calculated according to the area normalization method

The present invention provides a method for preparing methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate and its derivatives, which utilizes readily available raw materials, is simple to operate, and produces products with high yield and high purity. The present invention also provides a method for preparing a high-purity compound of formula VI-1-A and its derivatives, which utilizes readily available raw materials, has low production costs, shortens the synthesis steps, and is simpler to operate.

Unless otherwise specified, the terms in this invention have the following meanings:

DCM is dichloromethane;

DMF is N,N-dimethylformamide;

EA is ethyl acetate;

Pd(OAc) ₂ is palladium acetate;

SPhos is 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl;

In the present invention, the reaction endpoint can be confirmed by silica gel thin layer chromatography or high performance liquid chromatography;

h is hours;

C1-C4 alkyl refers to methyl, ethyl, n-propyl or isopropyl, etc.;

Halogen refers to fluorine, chlorine, bromine or iodine;

The amino-protecting group includes tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimido, p-methoxybenzyl, benzyl, benzyloxycarbonyl, or t-methoxycarbonyl.

DETAILED DESCRIPTION

The present invention will be further described below by way of specific examples, but these examples are not intended to limit the scope of the present invention. Any modifications or variations readily accomplished by those skilled in the art without departing from the scope of the present invention are intended to fall within the scope of the present invention. The reagents, solvents, and raw materials used in the present invention were all commercially available chemically pure or analytically pure.

Example 1. Preparation of (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propionic acid methyl ester

1-A. Preparation of (S)-(2-((tert-Butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc (II) iodide

Add DMF (3.0 mL) and zinc powder (1.3 g) to the reaction flask. Add dibromoethane (0.14 g), heat to 90°C, stir for 0.5 h, cool to 25°C, and add trimethylsilyl chloride (43.4 mg). Add a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (2.14 g) in DMF (4.0 mL) dropwise. After the addition is complete, stir at 25°C for 0.5 h. Filter to remove the zinc powder to obtain a solution of (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide.

1-B. Preparation of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propionate

To the reaction flask, add DMF (2.0 mL), 4-bromo-2,6-dimethylaniline (1.0 g), SPhos (20.5 mg), and Pd(OAc) ₂ (11.2 mg). Add the solution from 1-A to the reaction flask, heat to 50°C, and react for 2 h. Add water (18 mL) to the reaction system, and extract twice with DCM (3.0 mL x 2). The organic phases are combined and concentrated. Column chromatography affords 1.2 g of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate, with a purity of 99.0%. ESI-MS m/z: 323 [M+H] ⁺ .

Example 2. Preparation of (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propionic acid methyl ester

2-A. Preparation of (S)-(2-((tert-Butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc (II) iodide

Add DMF (3.0 mL) and zinc powder (1.06 g) to the reaction flask. Add dibromoethane (0.11 g), heat to 90°C, stir for 0.5 h, cool to 25°C, and add trimethylsilyl chloride (35.2 mg). Add a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1.73 g) in DMF (4.0 mL) dropwise. After the addition is complete, stir at 25°C for 0.5 h. Filter to remove the zinc powder to obtain a solution of (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide.

2-B. Preparation of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propionate

To a reaction flask, add DMF (2.0 mL), 4-iodo-2,6-dimethylaniline (1.0 g), SPhos (16.62 mg), and Pd(OAc) ₂ (9.1 mg). Add the solution in 2-A to the reaction flask, heat to 50°C, and react for 2 h. Add water (18 mL) to the reaction system, and extract twice with DCM (3.0 mL x 2). Combine the organic phases and concentrate. Column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) yields 1.18 g of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate, with a purity of 99.6%.

Example 3. Preparation of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-1H-indazol-5-yl)propanoate

Add EA (7.5 mL) and methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (0.5 g) to the reaction flask. Add potassium acetate (0.19 g) and acetic acid (0.14 g). Add isoamyl nitrite (0.2 g) dropwise at 20°C ± 5°C. After the addition is complete, raise the temperature to 65°C ± 5°C and stir for 2 h. Cool the mixture to 20°C ± 5°C, add water (2.5 mL) and potassium carbonate (0.31 g), stir for 0.5 h, and separate the layers. Add water (2.5 mL) to the organic phase, stir for 0.5 h, and separate the layers. Concentrate the organic phase to dryness, add toluene (2.5 mL) and n-heptane (4.0 mL), stir at 20°C ± 5°C for 2 h, filter, and collect the filter cake. The filter cake was dried at 45°C±5°C to obtain 0.44 g of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-1H-indazol-5-yl)propanoate with a purity of 99.0%. ESI-MS m/z: 334 [M+H] ⁺ .

Example 4. Preparation of (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propionic acid methyl ester dihydrochloride

To the reaction flask, add 2 mol/L methanolic hydrochloric acid solution (2.0 mL) and methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-1H-indazol-5-yl)propanoate (0.4 g). Stir at 20°C ± 5°C for 2 h, filter, and collect the filter cake. Dry the filter cake at 45°C ± 5°C to obtain 0.34 g of methyl (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate dihydrochloride with a purity of 99.5%. ESI-MS m/z: 234 [M+H] ⁺ .

Example 5. Preparation of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate

5-A. Preparation of (S)-(2-((tert-Butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc (II) iodide

Add DMF (4.1 L) and zinc powder (0.82 kg) to the reaction kettle under nitrogen protection. Control the temperature at 30°C ± 3°C and add trimethylsilyl chloride (55 g) dropwise. Stir for 30 min. Control the temperature at 30°C ± 3°C and add a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (0.275 kg) in DMF (0.55 L) dropwise. Control the temperature at 35°C ± 3°C and add a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (2.475 kg) in DMF (4.95 L) dropwise. After the addition is complete, stir at 35°C ± 3°C for 30 min. Cool to 12°C ± 3°C and stop stirring to obtain a solution of (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc (II) iodide.

5-B. Preparation of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate

Add DMF (4.1 L), 4-iodo-2,6-dimethylaniline (1.31 kg), SPhos (31.2 g), and Pd(OAc) ₂ (17 g) to the reactor under nitrogen. Cool to 2°C ± 3°C and add 10/11 of the solution in 5-A (by weight) dropwise to the reactor. Heat to 50°C ± 3°C and stir at this temperature for 1 to 2 hours. After the reaction is complete, cool to 25°C ± 3°C. Keep the temperature at ≤ 40°C, add water (15 kg) dropwise, add seed crystals (5 g, prepared by the preparation method described in Example 2-B), and stir at this temperature for 30 minutes. Keep the temperature at ≤ 40°C, add water (5.6 kg) dropwise, cool to 20°C ± 3°C, stir at this temperature for 2 hours, and filter. Add the filter cake, EA (25 L), and activated carbon (0.55 kg) to the reactor, heat to 40°C, stir for 4 hours, and filter. Add the filtrate and a solution of cysteine (1.4 kg) in water (12.6 kg) to the reactor, heat to 40°C, and stir for 24 hours. Let stand for 30 minutes, filter, and let the filtrate stand for 30 minutes before separating the liquids. Add water (5.5 kg) to the organic phase, stir for 30 minutes, let stand for 30 minutes, and separate the liquids. The temperature was controlled at ≤45°C, and the product was distilled under reduced pressure until the fraction was very slow or no fraction was obtained. Then, n-heptane (8.25 L) was added. The temperature was controlled at ≤45°C, and the product was distilled under reduced pressure until the fraction was very slow or no fraction was obtained. Then, n-heptane (8.25 L) was added. The temperature was controlled at ≤45°C, and the product was distilled under reduced pressure until the fraction was very slow or no fraction was obtained. Then, n-heptane (8.25 L) was added. The product was heated to 63°C±2°C, stirred at this temperature for 15 minutes, cooled uniformly to 3°C±2°C, stirred at this temperature for 2 hours, and filtered. The product was controlled at ≤50°C, and dried under reduced pressure to obtain 1.57 kg of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate with a purity of 96.5%.

Example 6. Preparation of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-1H-indazol-5-yl)propanoate

Add EA (15 L) and methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.5 kg) to a reactor under nitrogen. Add potassium acetate (0.57 kg), acetic acid (0.42 kg), and isoamyl nitrite (0.57 kg). Raise the temperature to 43°C ± 3°C and stir at this temperature for 12 to 16 hours. Cool to 25°C ± 3°C and add the reaction mixture dropwise to an alkaline solution of sodium sulfite (prepared by mixing 0.12 kg sodium sulfite, 1.02 kg potassium bicarbonate, and 7.5 L water). Stir for 15 minutes and filter. Stir the filtrate for 15 minutes and separate the layers. Add water (7.5 L) and sodium chloride (1.5 kg) to the organic phase, stir for 15 minutes, and separate the layers. Concentrate the organic phase under reduced pressure to yield 1.74 kg of an oil.

Example 7. Preparation of (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propionic acid methyl ester dihydrochloride

Add the oily substance in Example 6 and methanol (8.6 L) to the reactor and protect with nitrogen. Cool to 10±3°C and add acetyl chloride (2.05 kg) dropwise. Heat to 40±3°C and stir at this temperature for 4 hours. Cool to 25±3°C and add methyl tert-butyl ether (8.6 L) dropwise. Cool to 0±3°C and stir at this temperature for 2 hours and filter. Add the filter cake and methanol (8.6 L) to the reactor and protect with nitrogen. Cool to 10±3°C and add acetyl chloride (2.05 kg) dropwise. Heat to 63±2°C and stir for 30 minutes. Cool to 25±3°C and add methyl tert-butyl ether (8.6 L) dropwise. Cool to 0±3°C and stir at this temperature for 2 hours and filter. The residue was dried under reduced pressure to obtain 0.85 kg of methyl (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate dihydrochloride with a purity of 99.2%.

Claims (18)

A method for preparing a compound of formula I, characterized by comprising: reacting a compound of formula II with a compound of formula III in a solvent in the presence of a catalyst and a ligand to obtain a compound of formula I,
Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group. The preparation method according to claim 1, wherein the compound of formula II has a structure as shown in formula II-A, and the compound of formula I has a structure as shown in formula I-A,
Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, and PG is an amino protecting group. The preparation method according to any one of claims 1-2, wherein The R ⁰ is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl, more preferably methyl; Said R ¹ is fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine, more preferably bromine or iodine, and more preferably iodine; Said R ² is fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine, more preferably bromine or iodine, and more preferably iodine; The PG is tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimide, p-methoxybenzyl, benzyl, benzyloxycarbonyl or t-methoxycarbonyl, preferably tert-butyloxycarbonyl, p-methoxybenzyl or benzyl, more preferably tert-butyloxycarbonyl. The preparation method according to any one of claims 1 to 3, wherein The catalyst is tris(dibenzylideneacetone)dipalladium or palladium acetate, preferably palladium acetate; The ligand is triphenylphosphine, tricyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2',6'-diisopropyloxy-1,1'-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, preferably triphenylphosphine. Phenylphosphine, tricyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, preferably tricyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene or 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, more preferably 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; The catalyst and the ligand are the same substance, which are tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, 1,1-bis(diphenylphosphine)dibrominated iron palladium dichloride or dichlorobis(tricyclohexylphosphine)palladium; The solvent is one or a mixed solvent of two or more selected from N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N-methylpyrrolidone or N,N-dimethylacetamide, preferably a mixed solvent of one or more selected from N,N-dimethylformamide, 2-methyltetrahydrofuran, N-methylpyrrolidone or N,N-dimethylacetamide, more preferably a mixed solvent of one or more selected from N,N-dimethylformamide, N-methylpyrrolidone or N,N-dimethylacetamide, and more preferably N,N-dimethylformamide or N,N-dimethylacetamide; The molar ratio of the compound of formula III to the compound of formula II is 1:0.8, 1:1.0, 1:1.2, 1:1.29, 1:1.3, 1:1.35, 1:1.4, 1:1.5, 1:2.0, or a range between any two of the above ratios, preferably 1:0.8-2.0, more preferably 1:1.0-1.5, more preferably 1:1.2-1.5, further preferably 1:1.2-1.4, most preferably 1:1.29-1.3, most preferably 1:1.3-1.4, and most preferably 1:1.35-1.5; The molar ratio of the compound of formula III to the catalyst is 1:0.0001, 1:0.0005, 1:0.005, 1:0.009, 1:0.01, 1:0.011, 1:0.014, 1:0.015, 1:0.05, 1:0.1, 1:0.2 or a range between any two of the above ratios, preferably 1:0.0001-0.2, more preferably 1:0.0005-0.1, more preferably 1:0.005-0.05, further preferably 1:0.005-0.015, most preferably 1:0.009-0.011, most preferably 1:0.01-1:0.014, and most preferably 1:0.011-0.015; The ligand and the catalyst are different substances. The catalyst is calculated as palladium. The molar ratio of the catalyst to the ligand is 1:0.8-4, preferably 1:1-4, more preferably 1:0.8-2, more preferably 1:1-2, further preferably 1:0.9-1.1, and most preferably 1:1; The volume mass ratio of the solvent to the compound of formula III (mL:g) is 1:0.01-0.3, preferably 1:0.03-0.2, more preferably 1:0.05-0.2, more preferably 1:0.08-0.15, further preferably 1:0.1-0.15, most preferably 1:0.09-0.11, and most preferably 1:0.1-0.12; The reaction temperature of the preparation method is 0°C to 100°C, preferably 0°C to 80°C, more preferably 25°C to 60°C, and even more preferably 45°C to 60°C; The reaction time of the preparation method is 1h, 1.8h, 2h, 2.2h, 4h, 10h, 18h or a range between any two of the above values, preferably 1h to 18h, more preferably 1h to 10h, more preferably 1h to 4h, most preferably 1.8h to 2.2h, and most preferably 1h to 2h. A method for preparing a compound of formula VI or a salt thereof, characterized by comprising the following steps: (1) The compound of formula II and the compound of formula III react in a solvent in the presence of a catalyst and a ligand to obtain the compound of formula I; (2) reacting the compound of formula I with isoamyl nitrite in a solvent in the presence of a buffer system to obtain compound V; (3) removing the protecting group from the compound of formula V to obtain the compound of formula VI or its salt,
Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, R ² is halogen, and PG is an amino protecting group. The preparation method according to claim 5, wherein the compound II has the structural formula shown in Formula II-A, the compound I has the structural formula shown in Formula I-A, the compound V has the structural formula shown in Formula V-A, and the compound VI has the structural formula shown in Formula VI-A.
Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, and PG is an amino protecting group. The preparation method according to any one of claims 5-6, wherein The R ⁰ is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl, more preferably methyl; Said R ¹ is fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine, more preferably bromine or iodine, and more preferably iodine; Said R ² is fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine, more preferably bromine or iodine, and more preferably iodine; The PG is tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimide, p-methoxybenzyl, benzyl, benzyloxycarbonyl or t-methoxycarbonyl, preferably tert-butyloxycarbonyl, p-methoxybenzyl or benzyl, more preferably tert-butyloxycarbonyl; The reaction conditions of step (1) are as described in claim 4. The preparation method according to any one of claims 5 to 7, wherein The compound of formula VI or its salt is a compound of formula VI or its hydrochloride, preferably a compound of formula VI or its dihydrochloride, more preferably the dihydrochloride of compound VI; The buffer system in step (2) is composed of an acid and a salt having a corresponding acid ion, wherein the acid is acetic acid, formic acid, phosphoric acid or potassium dihydrogen phosphate, preferably acetic acid, phosphoric acid or potassium dihydrogen phosphate, more preferably acetic acid or potassium dihydrogen phosphate, and further preferably acetic acid; In step (2), the buffer system is a combination of acetic acid and potassium acetate, a combination of formic acid and sodium formate, a combination of phosphoric acid and sodium phosphate, or potassium dihydrogen phosphate, preferably a combination of acetic acid and potassium acetate, a combination of phosphoric acid and sodium phosphate, or potassium dihydrogen phosphate, more preferably a combination of acetic acid and potassium acetate, or a combination of phosphoric acid and sodium phosphate, and more preferably a combination of acetic acid and potassium acetate; The solvent in step (2) is one or a mixed solvent of two or more of ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene, dioxane or methyl tert-butyl ether, preferably ethyl acetate, isopropyl acetate, toluene, tetrahydrofuran or methyl tert-butyl ether, more preferably ethyl acetate, isopropyl acetate or toluene, and more preferably ethyl acetate or toluene; In the step (2), the molar ratio of the salt, calculated as a monovalent acid ion, to the compound of formula I is 1:1-4, preferably 1:1.5-2, more preferably 1:1.2-1.3, and most preferably 1:1.25; In the step (2), the molar ratio of the acid, calculated as hydrogen ion, to the compound of formula I is 1:1-4, preferably 1:1-2, more preferably 1:1.4-1.6, and most preferably 1:1.5; In step (2), the molar ratio of the compound of formula I to isoamyl nitrite is 1:1-2, preferably 1:1.05-1.5, more preferably 1:1.05-1.2; In step (2), the volume mass ratio (mL:g) of the solvent to the compound of formula I is 1:0.03-0.3, preferably 1:0.03-0.2, more preferably 1:0.06-0.1; In the step (2), the isoamyl nitrite can be added dropwise, and the temperature during the addition includes but is not limited to 0°C to 50°C, 10°C to 30°C or 15°C to 25°C; The reaction temperature after the dropwise addition of isoamyl nitrite in step (2) is 40°C, 50°C, 60°C, 70°C, 80°C, or a range between any two of the above values; preferably 40°C to 80°C, more preferably 50°C to 80°C, more preferably 40°C to 70°C, more preferably 50°C to 70°C, and most preferably 60°C to 70°C; After the addition of isoamyl nitrite in step (2) is completed and the temperature is raised to 60-70° C., the reaction time is 0.5-16 h, preferably 0.5-8 h, more preferably 1-4 h, and even more preferably 1.8-2.2 h; After the dropwise addition of isoamyl nitrite in step (2) is completed, the reaction time after heating to 40-50°C is 0.5h-16h, preferably, the reaction time after heating to 40-50°C is 5h-16h, more preferably, the reaction time after heating to 40-46°C is 8h-16h, more preferably, the reaction time after heating to 40-46°C is 10h-16h, and most preferably, the reaction time after heating to 40-46°C is 12h-16h. The preparation method according to any one of claims 5 to 8, wherein In step (3), the PG group is removed in the reaction reagent; In step (3), the PG group is tert-butyloxycarbonyl, and the reaction reagent is acetyl chloride, thionyl chloride, oxalyl chloride or methanol hydrochloric acid solution, preferably acetyl chloride, thionyl chloride or methanol hydrochloric acid solution, more preferably acetyl chloride or methanol hydrochloric acid solution; In step (3), the PG group is tert-butyloxycarbonyl, and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, 4 mol/L hydrochloric acid methanol solution, or 30% hydrochloric acid methanol solution, preferably 2 mol/L hydrochloric acid methanol solution; In step (3), when the PG group is tert-butyloxycarbonyl and the reaction reagent is a 2 mol/L hydrochloric acid methanol solution, the volume mass ratio (mL:g) of the reaction reagent to the compound of formula V is 1:0.02-0.3, preferably 1:0.05-0.3, and more preferably 1:0.1-0.25; In step (3), when the PG group is tert-butyloxycarbonyl and the reaction reagent is a 2 mol/L hydrochloric acid methanol solution, the reaction temperature is 0°C to 50°C, preferably 10°C to 40°C, and more preferably 15°C to 25°C; In step (3), when the PG group is tert-butyloxycarbonyl and the reaction reagent is 2 mol/L hydrochloric acid methanol solution, the reaction time is 0.5 h to 8 h, preferably 1 h to 4 h, and more preferably 1.8 h to 2.2 h; In step (3), the PG group is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the molar ratio of the compound of formula V to acetyl chloride is 1:3-15, preferably 1:3-10, more preferably 1:3-8, more preferably 1:3-7, further preferably 1:4-6, and most preferably 1:4.9-5.1; In step (3), the PG group is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the solvent is methanol, dioxane, ethyl acetate, dichloromethane or isopropyl acetate, preferably acetyl chloride, and the solvent is methanol, dioxane, ethyl acetate or dichloromethane, more preferably methanol or dioxane, and more preferably methanol; In the step (3), the PG group is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, the mass volume ratio (kg:L) of the compound of formula V to the solvent is 1:3-15, preferably 1:3-10, more preferably 1:3-8, more preferably 1:4-6, and most preferably 1:4.9-5.1. In the step (3), the PG group is tert-butyloxycarbonyl, the reaction reagent is acetyl chloride, and the reaction time is 2h-16h, preferably 2h-10h, more preferably 2h-7h, more preferably 3h-5h, and most preferably 3.9-4.1h. The preparation method according to any one of claims 1 to 9, characterized in that the compound of formula II can be obtained by reacting a compound of formula IV with zinc powder in a solvent under the action of an initiator,
Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, and PG is an amino protecting group. The preparation method according to claim 10, wherein the compound of formula IV has the structural formula shown in formula IV-A, and the compound of formula II has the structural formula shown in formula II-A,
Wherein, R ⁰ is C1-C4 alkyl, R ¹ is halogen, and PG is an amino protecting group. The preparation method according to any one of claims 10-11, wherein The R ⁰ is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl, more preferably methyl; Said R ¹ is fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine, more preferably bromine or iodine, and more preferably iodine; The PG is tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimide, p-methoxybenzyl, benzyl, benzyloxycarbonyl or t-methoxycarbonyl, preferably tert-butyloxycarbonyl, p-methoxybenzyl or benzyl, more preferably tert-butyloxycarbonyl; The initiator is one or a mixture of two or more of dibromoethane, trimethylsilyl chloride, and iodine; The solvent is one or a mixture of two or more selected from N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N-methylpyrrolidone or N,N-dimethylacetamide, preferably a mixture of one or more selected from N,N-dimethylformamide, 2-methyltetrahydrofuran, N-methylpyrrolidone or N,N-dimethylacetamide, more preferably a mixture of one or more selected from N,N-dimethylformamide, N-methylpyrrolidone or N,N-dimethylacetamide, further preferably N,N-dimethylformamide or N,N-dimethylacetamide; The volume mass ratio of the solvent to the compound of formula IV (mL:g) is 1:0.02, 1:0.06, 1:0.1, 1:0.12, 1:0.18, 1:0.2, 1:0.24, 1:0.26, 1:0.29, 1:0.35, 1:0.4, 1:0.6, or a range between any two of the above ratios, preferably 1:0.02-0.6, more preferably 1:0.06-0.4, more preferably 1:0.1-0.4, further preferably 1:0.12-0.35, most preferably 1:0.24-0.35, most preferably 1:0.18-0.26, and most preferably 1:0.2-0.29; The molar ratio of the compound of formula IV to zinc powder is 1:1.2, 1:1.5, 1:2, 1:3, 1:3.3, 1:4, 1:5, 1:6 or a range between any two of the above ratios, preferably 1:1.2-6, more preferably 1:2-5, more preferably 1:1.2-4, more preferably 1:1.2-3.3, more preferably 1:3-4, and most preferably 1:1.2-1.8; In some embodiments of the present invention, the molar ratio of the zinc powder to the total amount of the initiator is 1:0.02-0.2, preferably 1:0.02-0.15, more preferably 1:0.02-0.1, more preferably 1:0.02-0.08, and most preferably 1:0.03-0.07; The initiator is dibromoethane and trimethylsilyl chloride, wherein the molar ratio of zinc powder to dibromoethane is 1:0.001-0.1, preferably 1:0.01-0.05, more preferably 1:0.02-0.05, and most preferably 1:0.03-0.04; The initiator is dibromoethane and trimethylsilyl chloride, and the molar ratio of zinc powder to trimethylsilyl chloride is 1:0.001-0.1, preferably 1:0.01-0.05, more preferably 1:0.015-0.05; most preferably 1:0.018-0.021; The activation temperature of the dibromoethane is 50°C to 120°C, preferably 70°C to 100°C, and the activation time is 0.25h to 4h, preferably 0.25h to 2h, more preferably 0.25h to 1h; The initiator is trimethylsilyl chloride, and the molar ratio of zinc powder to trimethylsilyl chloride is 1:0.02-0.2, preferably 1:0.02-0.15, more preferably 1:0.02-0.1, more preferably 1:0.02-0.05, and most preferably 1:0.03-0.05; The reaction temperature of the preparation method is 0°C to 120°C, preferably 15°C to 90°C, more preferably 20°C to 60°C, more preferably 20°C to 40°C, and most preferably 20°C to 35°C; The reaction time of the preparation method is 0.5 h to 8 h, preferably 0.5 h to 4 h, more preferably 1 h to 3 h, further preferably 1.8 to 2.2 h, and the reaction time includes the feeding time. A compound of formula I, characterized in that it has the following structure:
Wherein, R ⁰ is C1-C4 alkyl; PG is tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl. The compound according to claim 13, wherein the compound of formula I has the structural formula shown in formula I-A,
Wherein, R ⁰ is C1-C4 alkyl; PG is tert-butyloxycarbonyl, 2-biphenyl-2-propyloxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl. The compound according to claim 13-14, wherein Said R ⁰ is methyl or ethyl, preferably methyl, preferably ethyl; The PG is tert-butyloxycarbonyl, p-methoxybenzyl or benzyl, preferably tert-butyloxycarbonyl, preferably 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl, more preferably p-methoxybenzyl or benzyl. A compound of formula V, characterized in that it has the following structure:
Wherein, R ⁰ is C1-C4 alkyl; PG is 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl. The compound according to claim 16, wherein the compound of formula V has the structural formula shown in formula V-A,
Wherein, R ⁰ is C1-C4 alkyl; PG is 2-biphenyl-2-propoxycarbonyl, phthalimide, p-methoxybenzyl, benzyl or 2-methoxycarbonyl. The compound according to claims 16-17, wherein the R ⁰ is methyl or ethyl, preferably methyl; and the PG is p-methoxybenzyl or benzyl.