Method for preparing dipeptide compound

Abstract

The present invention relates to a method for preparing a dipeptide compound. The method is easily implemented and provides a high total yield; and obtained products have a low impurity content that can be easily purified, and the quality of each intermediate can be easily controlled, making the method applicable to industrial production.

Description

Preparation method of dipeptide compound TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical industry, and particularly relates to a preparation method of a dipeptide compound. BACKGROUND

[0002] At present, the mortality rate of cardiovascular and cerebrovascular diseases ranks second in the world, among which thromboembolism is the main cause of a high proportion of cardiovascular and cerebrovascular diseases, and the incidence, prevalence and mortality increase with age. With the increasing aging of the population, the incidence of such diseases is on the rise.

[0003] Currently, there are mainly two types of oral anticoagulants on the market: direct thrombin inhibitors and direct factor Xa inhibitors. Dabigatran etexilate is the only oral effective direct thrombin inhibitor approved for marketing at present, and clinical studies have proved that the drug can effectively replace warfarin to become one of the preferred drugs for preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation and preventing postoperative deep vein embolism events. Due to the aging of the population and the rising incidence of cardiovascular and cerebrovascular diseases, a convenient, selective and orally bioavailable thrombin inhibitor for the treatment of thrombosis has become an attractive target.

[0004] CN113195515A discloses that dipeptide compounds are used for mediating the activity of trypsin-like serine proteases, and the compounds can be used as anticoagulants or trypsin-like serine protease inhibitors, thereby treating thromboembolic diseases and other related cardiovascular diseases. A group of dipeptide compounds I are disclosed in CN113195515A:

[0005] wherein, R 1 is unsubstituted or substituted C 1-6 alkyl; R 2 is unsubstituted or substituted C 1-12 alkyl.

[0006] Some specific compounds disclosed in CN113195515A are as follows:

[0007] CN113195515A further discloses two preparation methods of the compounds, both of which need to go through the step of column chromatography, which is not conducive to industrial production. In view of the good drug development prospect of the compound I, it is necessary to further study the industrial production method suitable for the compound I. SUMMARY

[0008] The present application provides a preparation method of the compound I, comprising the following steps:

[0009] (4) reacting compound VI with compound N in a first reaction, and then with Boc20 in a second reaction to obtain compound VII, wherein the first reaction is carried out in an acid binding agent and a first solvent, and the second reaction is carried out in a second solvent,

[0010] (5) deprotecting compound VII to obtain compound I, wherein the reaction is carried out in an acid solution and a solvent,

[0011] wherein, R 1 is an optionally substituted C 1-6 alkyl, R 2 is an optionally substituted C 1-12 alkyl; and X is halogen.

[0012] In some embodiments, R 1 is unsubstituted C 1-6 alkyl, in some embodiments, R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl; in some embodiments, R 1 is methyl, ethyl, propyl or t-butyl.

[0013] In some embodiments, R 2 is unsubstituted straight chain or branched C 1-6 alkyl; in some embodiments, R 2 is ethyl, n-propyl, i-propyl, n-butyl, n-pentyl or n-hexyl.

[0014] In some embodiments, X is Cl or Br.

[0015] In some embodiments, compound I is one of the following compounds I-1 to I-6:

[0016] In some embodiments, the method for preparing compound VI comprises the following steps:

[0017] (3) deprotecting compound V to obtain compound VI, wherein the reaction is carried out in an acid solution and a solvent,

[0018] In some embodiments, the method for preparing compound V comprises the following steps:

[0019] (2) reacting compound IV with compound M to obtain compound V, wherein the reaction is carried out in an acid binding agent and a solvent,

[0020] In some embodiments, the method of preparing compound IV comprises the following steps:

[0021] (1) deprotecting compound III to obtain compound IV, wherein the reaction is carried out in a catalyst / hydrogen and a solvent,

[0022] In some embodiments, in step (1), the catalyst is selected from one or more of platinum oxide, palladium hydroxide, palladium black or palladium on carbon.

[0023] In some embodiments, in step (1), a drying agent is optionally added, which is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate and molecular sieves.

[0024] In some embodiments, in step (1), the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol and tetrahydrofuran, preferably methanol and / or ethanol.

[0025] In some embodiments, in step (1), the catalyst is used in an amount ranging from 0.01 to 1, preferably from 0.04 to 0.1, relative to the weight of compound III; in some embodiments, in step (1), the drying agent is used in an amount ranging from 0 to 1, preferably from 0.05 to 0.1, relative to the weight of compound III.

[0026] In some embodiments, in step (1), the reaction temperature is from -10°C to 60°C, preferably from 0°C to 10°C.

[0027] In some embodiments, in step (1), the reaction pressure is from 0.1 MPa to 3 MPa, preferably from 0.1 MPa to 0.4 MPa.

[0028] In some embodiments, in step (2), a catalyst is optionally added, which is 4-dimethylaminopyridine or N,N-dimethylformamide, preferably 4-dimethylaminopyridine.

[0029] In some embodiments, in step (2), the acid binding agent is selected from at least one of trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, 2-methylpyridine, N-methylmorpholine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide, preferably N-methylmorpholine and / or N,N-diisopropylethylamine.

[0030] In some embodiments, in step (2), the solvent is at least one selected from the group consisting of dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, toluene, dioxane, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide, preferably dichloromethane.

[0031] In some embodiments, in step (2), the amount of the catalyst is in the range of 0-1 by weight relative to compound M, preferably 0.05-0.2; the molar ratio of compound IV to acid-binding agent is 1:(1-3), preferably 1:(1.1-1.5); and the temperature of the reaction is -10-40°C, preferably -10-20°C.

[0032] In some embodiments, in step (2), after the reaction is quenched, the organic phase is washed, concentrated, dissolved in ethyl acetate, and then dropped into n-heptane for crystallization.

[0033] In some embodiments, in step (3), the acid is trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid, acetic acid, hydrogen chloride, sulfuric acid, hydrobromic acid or phosphoric acid, preferably hydrogen chloride; and in some embodiments, in step (3), the acid solution is selected from the group consisting of acid-containing ethanol solution, acid-containing methanol solution, acid-containing ethyl acetate solution and / or acid-containing dioxane solution, preferably hydrogen chloride ethyl acetate solution.

[0034] In some embodiments, in step (3), the solvent is at least one selected from the group consisting of dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile and ethanol, preferably ethyl acetate and / or ethanol; the concentration of the acid solution is 0.5-4 mol / L; and the molar ratio of compound V to acid is 1:(1-15), preferably 1:(4-10).

[0035] In some embodiments, in step (3), the temperature of the reaction is -20-40°C, preferably -10-10°C, and further preferably 0-10°C.

[0036] In some embodiments, in step (4), the acid-binding agent is at least one selected from the group consisting of trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, 2-methylpyridine, N-methylmorpholine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide, preferably N-methylmorpholine and / or N,N-diisopropylethylamine.

[0037] In some embodiments, in step (4), the first solvent is at least one selected from the group consisting of methanol, ethanol, dichloromethane, tetrahydrofuran, dioxane, acetonitrile and N,N-dimethylformamide, preferably dichloromethane and / or ethanol.

[0038] In some embodiments, in step (4), the second solvent is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, toluene, butanone, ethyl acetate, dioxane, methyl tert-butyl ether, isopropyl ether, acetonitrile, preferably ethyl acetate.

[0039] In some embodiments, in step (4), the molar ratio of compound VI to compound N is 1:(1-3), preferably 1:(1.5-2.5);

[0040] In some embodiments, in step (4), the molar ratio of compound VI to amino protecting agent Boc20 is 1:(1-3), preferably 1:(1.1-1.6);

[0041] In some embodiments, in step (4), the molar ratio of compound VI to acid binding agent is 1:(1-5), preferably 1:(3-4);

[0042] In some embodiments, in step (4), the temperature of the first reaction is -20°C-40°C, preferably 0°C-10°C; the temperature of the second reaction is -20°C-40°C, preferably 10°C-20°C;

[0043] In some embodiments, step (4) comprises the following steps: after the first reaction, a first acid or a solution of the first acid is added to adjust the pH to ≤5, water and a second solvent are added for extraction, the aqueous phase is adjusted to pH ≥7 and then extracted again with the second solvent, the organic phases are combined, di-tert-butyl dicarbonate is added dropwise, and a second reaction is performed.

[0044] In some embodiments, the first acid is one or more of trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid, acetic acid, hydrogen chloride, sulfuric acid, hydrobromic acid or phosphoric acid, preferably hydrogen chloride.

[0045] In some embodiments, in step (4), the solution of the first acid is one or more of an ethanolic solution of the acid, a methanolic solution of the acid, an ethyl acetate solution of the acid, or a dioxane solution of the acid, preferably an ethyl acetate solution of hydrogen chloride;

[0046] In some embodiments, step (4) comprises the following steps: dissolving compound VI in a first solvent, adding part of the acid-binding agent dropwise to pH≥7 at a first reaction temperature, then adding the rest of the acid-binding agent, then adding compound N, after the reaction is complete, adding a first acid or a solution of the first acid to adjust pH≤5, adding water and a second solvent to extract, adjusting the pH of the aqueous phase to≥7 and then extracting with a second solvent again, combining the organic phases, adding di-tert-butyl dicarbonate dropwise, and reacting completely at a second reaction temperature; the reaction solution is washed with an aqueous solution of a second acid, the organic phase is collected, and the compound VII is obtained after post-treatment.

[0047] The second acid is one or more of citric acid, potassium dihydrogen phosphate, carbonic acid, or phenol.

[0048] In some embodiments, in step (5), the acid is one or more of trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid, acetic acid, hydrogen chloride, sulfuric acid, hydrobromic acid, or phosphoric acid, preferably hydrogen chloride; in some embodiments, in step (5), the acid solution is selected from an acid-containing ethanol solution, an acid-containing methanol solution, an acid-containing ethyl acetate solution, and / or an acid-containing dioxane solution, preferably an ethyl acetate solution of hydrogen chloride;

[0049] In some embodiments, in step (5), the solvent is selected from at least one of dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, acetonitrile, and ethanol, preferably ethyl acetate and / or ethanol;

[0050] In some embodiments, in step (5), the concentration of the acid solution is 0.5-4 mol / L; the molar ratio of compound VII to acid is 1:(1-10).

[0051] In some embodiments, in step (5), the temperature of the reaction is -20℃-40℃, preferably 0-10℃.

[0052] The second aspect of the present application provides a preparation method of compound I-1, comprising the following steps:

[0053] (5) deprotecting compound VII-1 to obtain compound I-1, wherein the reaction is carried out in an acid solution and a solvent; the acid solution is an ethyl acetate solution of hydrogen chloride, the solvent is ethyl acetate or ethanol, the concentration of the acid solution is 0.5-4 mol / L, the molar ratio of compound VII-1 to acid is 1:(1-10), and the temperature of the reaction is -10℃-20℃;

[0054] In some embodiments, the molar ratio of compound VII-1 to acid is 1:(1-10), and the reaction further comprises the following post-processing steps: after the reaction is complete, the product is concentrated, and then ethyl acetate is added to the product while controlling the temperature at 0-10°C, the product is filtered, the solid is dissolved in water, and then ethyl acetate is added, the pH is adjusted to 7-8 using sodium bicarbonate, the organic phase is concentrated and dried, and the resulting compound I-1 is a free base, and the preferred configuration is shown in structure I-1.

[0055] In some embodiments, the molar ratio of compound VII-1 to acid is 1:(2-2.5), and the reaction further comprises the following post-processing steps: after the reaction is complete, the product is filtered, dried, and the resulting compound I-1 is a hydrochloride salt, and the preferred configuration is shown in structure I-1c,

[0056] In some embodiments, the molar ratio of compound VII-1 to acid is 1:(3-10), and the reaction further comprises the following post-processing steps: after the reaction is complete, the product is filtered, ethyl acetate is added to the product while controlling the temperature at 0-10°C, the product is filtered, and dried, and the resulting compound I-1 is a dihydrochloride salt, and the preferred configuration is shown in structure I-1b,

[0057] In some embodiments, the method for preparing compound VII-1 comprises the following steps:

[0058] (4) dissolving compound VI-1 in a first solvent and ethyl bromoacetate to perform a first reaction, and then performing a second reaction with Boc2O in a second solvent to obtain compound VII-1, wherein the first reaction is performed in an acid binding agent and a solvent; the acid binding agent is N-methylmorpholine and / or N,N-diisopropylethylamine, the first solvent is ethanol, and the temperature of the first reaction is -20°C to 40°C; the second reaction solvent is ethyl acetate, the temperature of the second reaction is 10°C to 20°C, and the molar ratio of compound VI-1 to ethyl bromoacetate, Boc2O, and the acid binding agent is 1:(1.5-2.5):(1.1-1.6):(3-4),

[0059] In some embodiments, the method for preparing compound VI-1 comprises the following steps:

[0060] (2) reacting compound IV with chloroformic acid n-propyl ester to obtain compound V-1, wherein the reaction is carried out in a catalyst, an acid binding agent and a solvent, the catalyst is 4-dimethylamino pyridine, the acid binding agent is N-methyl morpholine and / or N,N-diisopropyl ethyl amine, and the solvent is dichloromethane; the amount of the catalyst is 0.05-0.2 by weight of compound IV, the molar ratio of compound IV to the acid binding agent is 1:(1.1-1.5), and the reaction temperature is -10-20°C; the molar ratio of compound IV to chloroformic acid n-propyl ester is 1:(1.1-1.5),

[0061] (3) deprotecting compound V-1 to obtain compound VI-1, wherein the reaction is carried out in an acid solution and a solvent, the acid solution is hydrogen chloride ethyl acetate solution, the solvent is ethyl acetate and / or ethanol, the concentration of the acid solution is 0.5-4 mol / L, the molar ratio of compound V-1 to the acid is 1:(4-10), and the reaction temperature is -10-10°C,

[0062] In some embodiments, step (4) comprises the following steps: dissolving compound VI-1 in ethanol, adding part of N,N-diisopropyl ethyl amine dropwise to pH≥7 at 0-10°C, adding the rest of diisopropyl ethyl amine, then adding ethyl bromoacetate dropwise, after the reaction is completed, adding hydrogen chloride ethyl acetate solution to adjust pH≤5, adding water and ethyl acetate to carry out extraction, adjusting the pH of the water phase to pH≥7, then extracting with ethyl acetate again, combining the organic phases, adding di-tert-butyl dicarbonate dropwise, and allowing the reaction to complete at 10-20°C, washing the reaction solution with citric acid aqueous solution, collecting the organic phase, and then treating to obtain compound VII-1. Advantages:

[0063] The method of the present application has the advantages of less impurities, simple post-treatment and purification steps, effective removal of by-products, no need for column chromatography, no loss of product on silica gel column, high reaction yield, easy detection and control of the quality of intermediates, and suitability for industrial production. DETAILED DESCRIPTION

[0064] The present application is further illustrated by the following specific embodiments, which are intended to be illustrative only, and are not intended to limit the present application in any way. Any modification or change easily made by those skilled in the art to the present application will fall within the scope of the present application. Unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Moreover, the laboratory operation steps used herein are conventional steps widely used in the corresponding fields. Meanwhile, in order to better understand the present application, the definitions and explanations of the related terms are provided as follows.

[0065] The terms "having," "containing," and "including" are to be construed in an open-ended fashion, that is as describing one or more elements or steps without excluding any other element or step, whether or not explicitly described.

[0066] In the present invention, all ranges recited are inclusive of the ranges' endpoints, unless otherwise indicated.

[0067] In the present invention, unless otherwise indicated, % is percent by weight / weight (w / w).

[0068] In the present invention, unless otherwise indicated, any numerical values, such as recited concentrations or concentration ranges, are understood to be modified in all instances by the term "about." Thus, a numerical value typically includes ±10% of the recited value.

[0069] In the present invention, "optionally" or "optionally" means that the subsequently described event or circumstance can or can not occur, and this description includes both the occurrence and non-occurrence of the event or circumstance.

[0070] The term "pharmaceutically acceptable salt of a compound" refers to a salt that is biologically or otherwise pharmaceutically acceptable, meaning that the salt does not cause any undesirable physiological effects (e.g., is neither toxic nor deleterious) when administered in sufficient amounts to a recipient thereof. Pharmaceutically acceptable salts of Compound I include addition salts of pharmaceutically acceptable inorganic acids and organic acids. Examples of suitable organic acids include, but are not limited to, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, propionic acid, fumaric acid, oxalic acid, citric acid, and examples of suitable inorganic acids include, but are not limited to, such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid.

[0071] The term "solvate" refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of the solute).

[0072] In the present invention, unless specifically indicated otherwise, a compound encompasses within its scope its free base, pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically substituted derivatives, and the like. The compounds of the present invention can also exist in a hydrate or solvate form.

[0073] In the present invention, unless specifically indicated otherwise, a structural formula refers to the specific structure or configuration shown by the structural formula.

[0074] For example, in the present invention, "Structural Formula I" refers to the structure directly corresponding to Structural Formula I; "Compound I" encompasses the free base, pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically substituted derivatives, and the like shown by Structural Formula I.

[0075] The compounds of the present application can have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present application are included within the present application. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are encompassed by the present application.

[0076] The term "tautomer" refers to isomers of a molecule in which a proton moves rapidly between two positions, resulting in functional group isomerism. The compounds of the present application contain amidine structures in which the imine and amino groups can interconvert to form tautomers, i.e.

[0077] For example, the free base of Compound I exists as two different tautomers, as shown in the following structural formulas:

[0078] For example, the free base of Compound I-1 exists as two tautomers, as shown in the following structural formulas:

[0079] Under the conditions of the present application, the predominant tautomer of the free base of Compound I-1 is as shown in the following structural formula:

[0080] The term "alkyl" refers to straight chain or branched chain saturated hydrocarbon chains. The term "Cx-yalkyl" refers to straight chain or branched chain saturated hydrocarbons containing x to y carbon atoms. For example, "C1-6alkyl" refers to straight chain or branched chain saturated hydrocarbons containing 1 to 6 carbon atoms. C 1-6 Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylpentyl.

[0081] The term "unsubstituted" refers to the absence of substituents from the group of substituents to which the modified group is modified. For example, an unsubstituted straight chain C 1～6 Alkyl groups include methyl, ethyl, n-propyl, n-butyl (n-C4H9), n-pentyl (n-C5H 11 ), n-hexyl (n-C6H 13 ); unsubstituted branched chain C 1～6 Alkyl groups include, but are not limited to, i-propyl, s-butyl, i-butyl, t-butyl, i-pentyl, neopentyl, 2-methylpentyl, and 3-methylpentyl.

[0082] The term "substituted" means that the group being modified is either unsubstituted or substituted with one or more substituents within the limits of the valence of the group. "Substituents" can each independently be selected from hydroxy, carboxy, halogen, alkyl, alkoxy, aryl, heteroaryl, acyl, sulfonyl, sulfhydryl (-SH), alkylthio, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cyano, ester, or trifluoromethyl, and the substituents can be further substituted. For example, "substituted alkyl" includes alkyl groups substituted with one or more groups independently selected from hydroxy, carboxy, halogen (e.g., F, Cl, Br), alkyl (e.g., C1-6alkyl), heteroalkyl (e.g., C1-6heteroalkyl), alkoxy (e.g., C1-6alkoxy), aryl (e.g., phenyl), heteroaryl (e.g., 5- or 6-membered heteroaryl), acyl, sulfonyl, SH, alkylthio, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cyano, ester, and trifluoromethyl.

[0083] The term "the deacid reagent" refers to a reagent used to neutralize the protons in the reaction system, which can reduce the effect of acid on the reaction. Commonly used deacid reagents are generally organic or inorganic bases.

[0084] In the present application, a method for preparing a compound of formula I is provided, comprising the following steps:

[0085] wherein R 1 , R 2 and X are as defined above.

[0086] wherein step (1) is typically carried out by hydrogenation in the presence of a suitable catalyst and one or more suitable solvents, optionally with the addition of a drying agent, and the catalyst can be selected from hydrogenation catalysts such as palladium, platinum, rhodium, nickel, etc., and preferably platinum oxide, palladium hydroxide, palladium black, palladium on carbon, etc. The amount of catalyst used is in the range of 0.01-1 w / w relative to the weight of the compound of formula III, and preferably 0.04-0.1 w / w, for example 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 6%, 7%, 8%, 9%, 10%, or any range therebetween.

[0087] In the active carbon-supported metal catalyst, the amount of catalyst is calculated in terms of the amount of metal. For example, in palladium on carbon, the amount of catalyst is calculated in terms of the amount of palladium metal.

[0088] The weight percentage of palladium in the palladium on carbon used in the present application can be 3%-10%, for example 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any range therebetween. In some embodiments, the catalyst is 7% palladium on carbon, and the amount of palladium is 4.4% relative to the weight of the compound of formula III.

[0089] The palladium hydroxide used in the present application can be palladium hydroxide supported on activated carbon, wherein the weight percentage of palladium hydroxide can be 5% to 20%, for example 5%, 10%, 15%, 20% or any range therebetween.

[0090] In step (1), the solvent used for the reaction is selected from methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran or a mixture thereof, wherein methanol and / or ethanol is preferred.

[0091] In step (1), the reaction temperature can be -10°C to 60°C, wherein 0°C to 10°C is preferred.

[0092] In step (1), the reaction pressure can be about 0.1 MPa to 3 MPa, wherein 0.1 MPa to 0.4 MPa is preferred, for example 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa or any range therebetween.

[0093] Step (2) is usually carried out in the presence of one or more suitable acid binding agents and one or more suitable solvents, optionally with the addition of a catalyst. The catalyst can be selected from, for example, 4-dimethylaminopyridine, DMF and the like, preferably 4-dimethylaminopyridine. The amount of catalyst used is 0 to 1 w / w, preferably 0.05 to 0.2 w / w, for example 0.05 w / w, 0.06 w / w, 0.07 w / w, 0.08 w / w, 0.09 w / w, 0.1 w / w, 0.15 w / w, 0.2 w / w, relative to the weight of compound IV.

[0094] In step (2), the molar ratio of compound IV to compound M can be 1:1 to 1:3, wherein 1:1.1 to 1:1.5 is preferred, for example 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or any range therebetween.

[0095] In step (2), the acid binding agent is selected from trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, 2-methylpyridine, N-methylmorpholine, 4-dimethylaminopyridine and the like organic bases, or potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide and the like inorganic bases; preferably N-methylmorpholine and / or N,N-diisopropylethylamine. The molar ratio of compound IV to acid binding agent can be 1:1 to 1:3, wherein 1:1.1 to 1:1.5 is preferred, for example 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or any range therebetween.

[0096] In step (2), the solvent used in the reaction is selected from dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, toluene, dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof, wherein dichloromethane is preferred.

[0097] In step (2), the reaction temperature can be -10°C to 40°C, preferably -10°C to 20°C.

[0098] In step (2), the following steps are also included: after the reaction is quenched, the organic phase is washed and concentrated, dissolved in ethyl acetate, and then n-heptane is added dropwise for crystallization.

[0099] Step (3) is usually carried out in the presence of a suitable acid and one or more suitable solvents. The acid is selected from organic acids such as trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid, or inorganic acids such as hydrogen chloride, sulfuric acid, hydrobromic acid or phosphoric acid, preferably an organic solution of hydrogen chloride is used for the deprotection reaction; the organic solution of hydrogen chloride is selected from ethanol solution of hydrogen chloride, methanol solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride or dioxane solution of hydrogen chloride, preferably ethyl acetate solution of hydrogen chloride, the concentration of which is 0.5-4 mol / L, for example 0.5 mol / L, 1 mol / L, 1.5 mol / L, 2 mol / L, 2.5 mol / L, 3 mol / L, 3.5 mol / L, 4 mol / L or any range therebetween. The molar ratio of the compound of formula V to the acid can be 1:1-1:15, preferably 1:4-1:10, for example 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 or any range therebetween.

[0100] In step (3), the solvent used in the reaction is selected from dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, ethanol or a mixed solvent thereof, wherein ethyl acetate, ethanol or a mixed solvent thereof is preferred.

[0101] In step (3), the reaction temperature can be -20°C to 40°C, preferably -10°C to 10°C, for example -10°C to 0°C, 0-5°C, 5-10°C or any range therebetween.

[0102] Step (4) reacts compound VI with compound N, followed by treatment with Boc2O to provide compound VII:

[0103] wherein R 1 and R 2 X is halogen, as defined above.

[0104] wherein compound VI can be in the form of its salt, compound VI is usually salified with an inorganic or organic acid, such as an organic acid, for example trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid, acetic acid, propionic acid, fumaric acid, oxalic acid, citric acid, etc., or an inorganic acid, for example hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid, etc., preferably the hydrochloride salt of compound VI (molar ratio 1 : 1 or 1 : 2).

[0105] In step (4), the molar ratio of compound VI to compound N can be 1 : 1 to 1 : 3, wherein preferably 1 : 1.5 to 1 : 2.5, for example 1 : 1.5, 1 : 2.0, 1 : 2.1, 1 : 2.2, 1 : 2.3, 1 : 2.4, 1 : 2.5 or any range therebetween.

[0106] In step (4), the molar ratio of compound VI to amino protecting agent Boc2O can be 1 : 1 to 1 : 3, wherein preferably 1 : 1.1 to 1 : 1.6, for example 1 : 1.1, 1 : 1.2, 1 : 1.3, 1 : 1.4, 1 : 1.5, 1 : 1.6 or any range therebetween.

[0107] wherein, step (4) is usually reacted in the presence of one or more suitable acid binding agents and one or more suitable solvents. The acid binding agent is selected from trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, 2-methylpyridine, N-methylmorpholine, 4-dimethylaminopyridine and the like organic bases, or potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide and the like inorganic bases; preferably N-methylmorpholine or N,N-diisopropylethylamine. The molar ratio of compound VI to the acid binding agent can be 1 : 1 to 1 : 5, wherein preferably 1 : 3 to 1 : 4, for example 1 : 3, 1 : 3.25, 1 : 3.4, 1 : 3.5, 1 : 3.75, 1 : 4 or any range therebetween.

[0108] In step (4), the solvent used for the reaction is selected from methanol, ethanol, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or a mixed solvent thereof, wherein preferably dichloromethane and / or ethanol.

[0109] In step (4), the reaction temperature can be -20 °C to 40 °C, wherein preferably -10 °C to 20 °C.

[0110] Step (5) is typically carried out in the presence of a suitable acid and one or more suitable solvents. The acid is selected from trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid and other organic acids, or hydrogen chloride, sulfuric acid, hydrogen bromide or phosphoric acid and other inorganic acids, in some embodiments an organic solution of hydrogen chloride; the organic solution of hydrogen chloride is selected from ethanol solution of hydrogen chloride, methanol solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride, dioxane solution of hydrogen chloride, in some embodiments ethyl acetate solution of hydrogen chloride with a concentration of 0.5-4 mol / L, for example 0.5 mol / L, 1 mol / L, 1.5 mol / L, 2 mol / L, 2.5 mol / L, 3 mol / L, 3.5 mol / L, 4 mol / L or any range therebetween. The molar ratio of compound of formula VII to acid can be 1:1-1:10, wherein 1:4-1:10 is preferred, for example 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 or any range therebetween.

[0111] In step (5), the solvent used for the reaction is selected from dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, acetonitrile, ethanol or a mixture thereof, wherein ethyl acetate, acetonitrile or a mixture thereof is preferred.

[0112] In step (5), the reaction temperature can be -20°C-40°C, wherein 0°C-10°C is preferred.

[0113] The free base of compound I exists in two different tautomers as shown below:

[0114] The corresponding salts of compound I can also exist as salts of different tautomers.

[0115] For example, the free base of compound I-1 exists in two different tautomers as shown below:

[0116] During the research of the present application, it was confirmed that the free base, mono-hydrochloride salt and di-hydrochloride salt of compound I-1 exist as which tautomer is dominant, respectively. According to the results of one-dimensional and two-dimensional nuclear magnetic resonance, the following is confirmed:

[0117] Free base:

[0118] Mono-hydrochloride salt:

[0119] Di-hydrochloride salt:

[0120] CN113195515A prepares compound I-1 from N-tert-butoxycarbonyl-D-leucyl-L-prolyl-[(4- carbamimidoyl)benzyl]amide, including the following steps: 1) acylation by reacting compound IV and benzyl chloroformate to obtain compound V-1, and obtaining a solution of compound V-1 after column chromatography; 2) directly performing the next Boc protection reaction on the solution obtained in step 1) to obtain compound VI-1; 3) directly reacting compound VI-1 with ethyl bromoacetate, stirring at 50°C for 8h, after the reaction is completed, the crude product is purified by column chromatography, and then hydrochloric acid is used for acidification to obtain a hydrochloride salt. Compound I-1 hydrochloride salt is prepared from compound IV, three steps of reaction, two column chromatography post-treatment steps, and the total yield is 59%.

[0121] The technical method has many problems in process scale-up research. For example, the solution obtained after column chromatography in step 1) has a large volume, and directly performing the second step reaction has low industrial operation efficiency; in step 3), the crude product after the reaction of compound VI-1 with ethyl bromoacetate is an oil, and there is a certain loss in the column loading process, and the product is easy to produce more hydrolysis impurities after contacting with silica gel, and the separation yield is low. Overall, this method needs to go through two column chromatography, and the column chromatography has long time, complicated operation, large solvent consumption, uncontrollable product quality, and cannot meet the requirements of industrialization.

[0122] In the process of preparing compound V-1 from compound IV by acylation in the method of the present application, a specific solvent is used for crystallization, no column chromatography is needed, high-purity compound V-1 is obtained, compound V-1 is deprotected to obtain compound VI-1, then Boc protection is introduced in the step of preparing I-1 from compound VI-1, through adjustment of the process route, combined with extraction, washing, concentration and other post-treatment steps, high-purity compound V-1 is first prepared, then the Boc protecting group is removed, and high-purity compound I-1 is obtained through simple post-treatment. Although the steps of the reaction route increase, the content of impurities produced is reduced, and the by-products in the reaction can be effectively removed through simple post-treatment and purification steps, the overall route does not need column chromatography step, the loss of product on the silica gel column is avoided, the reaction yield is high, and in some embodiments of the present application, the total yield of five-step reaction is as high as 66% or more, and the purity is more than 99%. The method is easy to implement, the quality of intermediates is easy to detect and control, the product quality obtained through kilogram-scale amplification is controllable, so high-quality compound I-1 can be stably and continuously provided for use as a pharmaceutical API, and the method is suitable for industrial production.

[0123] Regarding the quantitative analysis in the present embodiment, high performance liquid chromatography (HPLC) method is used for detection.

[0124] HPLC detection conditions:

[0125] Column: C18 reversed-phase chromatography column

[0126] Mobile phase A: Ammonium acetate aqueous solution: acetonitrile = 90:10 (%V / V)

[0127] Mobile phase B: Ammonium acetate aqueous solution: acetonitrile = 20:80 (%V / V)

[0128] Wavelength: 245 nm

[0129] Flow rate: 1.0 mL / min

[0130] Example 1: Preparation of compound IV

[0131] Into a reaction flask was added 25 g of compound III, 100 mL of methanol, 1.0 g of 7% wet palladium-carbon, 1.3 g of anhydrous magnesium sulfate, replaced with nitrogen, replaced with hydrogen, and then reacted at a temperature of 0-5°C and a pressure of 0.2±0.02 MPa until no hydrogen was absorbed, TLC showed that the reaction was complete, filtered, the filtrate was concentrated to dryness, and the material was dried to obtain compound IV, which was used in the next step reaction at a theoretical yield of 100%.

[0132] ESI-MS (m / z): 460.2970 (M+H).

[0133] Example 2: Preparation of compound IV

[0134] Into a reaction flask was added 25 g of compound III, 100 mL of methanol, 1.0 g of 7% wet palladium-carbon, 1.3 g of anhydrous magnesium sulfate, replaced with nitrogen, replaced with hydrogen, and then reacted at a temperature of 0-5°C and a pressure of 0.2±0.02 MPa until no hydrogen was absorbed, TLC showed that the reaction was complete, filtered, the filtrate was concentrated to dryness, and the material was dried to obtain compound IV, which was used in the next step reaction at a theoretical yield of 100%.

[0135] ESI-MS (m / z): 460.2970 (M+H).

[0136] Example 3: Preparation of compound IV

[0137] Into a reaction flask was added 25 g of compound III, 100 mL of methanol, 1.0 g of 7% wet palladium-carbon, 1.3 g of anhydrous magnesium sulfate, replaced with nitrogen, replaced with hydrogen, and then reacted at a temperature of 0-5°C and a pressure of 0.2±0.02 MPa until no hydrogen was absorbed, TLC showed that the reaction was complete, filtered, the filtrate was concentrated to dryness, and the material was dried to obtain compound IV, which was used in the next step reaction at a theoretical yield of 100%.

[0138] ESI-MS (m / z): 460.2970 (M+H).

[0139] Example 4: Preparation of compound V-1

[0140] Into a reaction flask was added 75 mL of dichloromethane, 15.0 g of compound IV, 0.8 g of 4-dimethylaminopyridine, 4.87 g of N,N-diisopropylethylamine was added under nitrogen protection at 0-10 °C, then 6.6 g of n-hexyl chloroformate was added dropwise, after the reaction was completed, ammonia water was added dropwise for quenching, after the separation of layers, the organic phase was washed with potassium bisulfate aqueous solution, saturated brine, then dried with magnesium sulfate, filtered, the filtrate was concentrated, dissolved in ethyl acetate, then n-heptane was added dropwise for crystallization, suction filtration, and drying to obtain compound V-1, yield 17.2 g, yield 89.7%.

[0141] ESI-MS (m / z): 588.3785 (M+H).

[0142] Example 5: Preparation of compound V-1

[0143] Into a reaction flask was added 50 mL of dichloromethane, 10.0 g of compound IV, 2 g of 4-dimethylaminopyridine, 2.9 g of N-methylmorpholine was added under nitrogen protection at 0-10 °C, then 4.3 g of n-hexyl chloroformate was added dropwise, after the reaction was completed, ammonia water was added dropwise for quenching, after the separation of layers, the organic phase was washed with potassium bisulfate aqueous solution, saturated brine, then dried with magnesium sulfate, filtered, the filtrate was concentrated, dissolved in ethyl acetate, then n-heptane was added dropwise for crystallization, suction filtration, and drying to obtain compound V-1, yield 11.3 g, yield 88.6%.

[0144] ESI-MS (m / z): 588.3785 (M+H).

[0145] Example 6: Preparation of compound V-1

[0146] Into a reaction flask was added 20 kg of dichloromethane, 3.09 kg of compound IV, 0.22 kg of 4-dimethylaminopyridine, 1.28 kg of N,N-diisopropylethylamine was added under nitrogen protection at 0-10 °C, then 1.60 kg of n-hexyl chloroformate was added dropwise, after the reaction was completed, ammonia water was added dropwise for quenching, after the separation of layers, the organic phase was washed with potassium bisulfate aqueous solution, saturated brine, then dried with magnesium sulfate, filtered, the filtrate was concentrated, dissolved in ethyl acetate, then n-heptane was added dropwise for crystallization, suction filtration, and drying to obtain compound V, yield 3.48 kg, yield 88.1%.

[0147] ESI-MS (m / z): 588.3785 (M+H).

[0148] Example 7: Preparation of compound VI-1

[0149] Into a reaction flask was placed ethyl acetate 12 mL, absolute ethanol 5 mL, 10.0 g of compound V, stirred to dissolve, temperature controlled at 0-10 °C, 30 mL of hydrogen chloride / ethyl acetate (3M) was added dropwise, after the dropwise addition was completed, the reaction was allowed to proceed for 3-24 hours, after the reaction was completed, the reaction mixture was concentrated to dryness, to obtain compound VI, which was not isolated, and the yield was calculated as 100% of the theoretical value.

[0150] ESI-MS (m / z): 488.3259 (M+H).

[0151] Example 8: Preparation of compound VI-1

[0152] Into a reaction flask was placed ethyl acetate 3.58 kg, absolute ethanol 1.33 kg, 3.32 kg of compound V, stirred to dissolve, temperature controlled at 0-10 °C, 13.28 kg of hydrogen chloride / ethyl acetate (3M) was added dropwise, after the dropwise addition was completed, the reaction was allowed to proceed for 3-24 hours, after the reaction was completed, the reaction mixture was concentrated to dryness, to obtain compound VI-1, which was not isolated, and the yield was calculated as 100% of the theoretical value.

[0153] ESI-MS (m / z): 488.3259 (M+H).

[0154] Example 9: Preparation of compound VII-1

[0155] Into a reaction flask was placed absolute ethanol 28 mL, 7.0 g of compound VI-1, stirred to dissolve, temperature controlled at 0-10 °C, 3.29 g of N,N-diisopropylethylamine was added dropwise, the pH was measured to be >7, 2.47 g of N,N-diisopropylethylamine was added, then 3.4 g of ethyl bromoacetate was added dropwise, after the reaction was completed, 28 g of hydrogen chloride / ethyl acetate solution (3M) was added dropwise, 100 g of water was added, 60 g of ethyl acetate was added to wash, 60 g of ethyl acetate was added to the water layer, 10% potassium bicarbonate aqueous solution was used to adjust the pH to >11, the organic phase was collected by separation, 3.28 g of di-tert-butyl dicarbonate was added dropwise, the reaction was allowed to proceed at 15-20 °C until it was complete, the reaction solution was washed with 80 g of 10% citric acid aqueous solution, the organic phase was collected by separation, the organic phase was washed with saturated brine, the organic phase was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated, to obtain 6.7 g of compound VII-1 as an oil, with a yield of 79.8%.

[0156] ESI-MS (m / z): 674.4094 (M+H).

[0157] Example 10: Preparation of compound VII-1

[0158] To the reaction flask was added 28 mL of anhydrous ethanol, 7.0 g of compound VI-1, stirred to dissolve, temperature controlled at 5-10 °C, 2.6 g of N-methylmorpholine was added dropwise, pH was measured to be >7, 2.0 g of N-methylmorpholine was added, then 5.01 g of ethyl bromoacetate was added dropwise, after the reaction was completed, 28 g (3M) of hydrogen chloride ethyl acetate solution was added dropwise, 100 g of water was added dropwise, 60 g of ethyl acetate was added for washing, 10% potassium bicarbonate aqueous solution was added to adjust pH >11, the layers were separated, the organic phase was collected, 3.92 g of di-tert-butyl dicarbonate was added dropwise, and the reaction was completed at 15-20 °C, the reaction solution was washed with 80 g of 10% citric acid aqueous solution, the layers were separated to obtain the organic phase, which was washed with saturated brine, the organic phase was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 6.6 g of compound VII-1 oil with a yield of 78.5%.

[0159] ESI-MS (m / z): 674.4094 (M+H).

[0160] Example 11: Preparation of compound VII-1

[0161] To the reaction flask was added 10 kg of anhydrous ethanol, 3.17 kg of compound VI-1, stirred to dissolve, temperature controlled at 5-10 °C, 1.56 kg of N,N-diisopropylethylamine was added dropwise, pH was measured to be >7, 1.18 kg of N,N-diisopropylethylamine was added, then 1.82 kg of ethyl bromoacetate was added dropwise at 5-10 °C, after the reaction was completed, 10 kg (3M) of hydrogen chloride ethyl acetate solution was added dropwise, 70 kg of water was added, 40 kg of ethyl acetate was added for washing, 10% potassium bicarbonate aqueous solution was added to adjust pH >7, the layers were separated, the organic phase was collected, 2.2 kg of di-tert-butyl dicarbonate was added dropwise, and the reaction was completed at 15-20 °C, the reaction solution was washed with 80 kg of 10% citric acid aqueous solution, the layers were separated to obtain the organic phase, which was washed with saturated brine, the organic phase was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 2.92 kg of compound VII-1 oil with a yield of 76.7%.

[0162] ESI-MS (m / z): 674.4094 (M+H).

[0163] Example 12: Preparation of free base of compound I-1

[0164] Into a 50 mL reaction flask, add acetonitrile 1.58 g, 2.0 g of compound VII-1, 5.4 g of ethyl acetate, stir and dissolve, control temperature at 0-10 °C, drop 5.56 g of hydrogen chloride / ethyl acetate (3M), keep warm until the reaction is complete, filter, get wet product, add ethyl acetate to control temperature at 0-10 °C, slurry, filter, dissolve the solid with water, add ethyl acetate, adjust pH to 7-8 with sodium bicarbonate, separate the layers, concentrate the organic phase to get wet product, dry to get 1.58 g of free base of compound I-1, yield 92.9%, purity ≥ 99%.

[0165] ESI-MS (m / z): 574.3590 (M+H).

[0166] Example 13: Preparation of compound I-1

[0167] Into a 50 mL reaction flask, add acetonitrile 1.58 g, 2.0 g of compound VII-1, 5.4 g of ethyl acetate, stir and dissolve, control temperature at 0-10 °C, drop 5.56 g of hydrogen chloride / ethyl acetate (3M), keep warm until the reaction is complete, filter, get wet product, add ethyl acetate to control temperature at 0-10 °C, slurry, filter, dissolve the solid with water, add ethyl acetate, adjust pH to 7-8 with sodium bicarbonate, separate the layers, concentrate the organic phase to get wet product, dry to get 1.58 g of free base of compound I-1, yield 92.9%, purity ≥ 99%.

[0168] ESI-MS (m / z): 574.3590 (M+H).

[0169] Example 14: Preparation of compound I-1

[0170] Into a 50 mL reaction flask, add acetonitrile 1.58 g, 2.0 g of compound VII-1, 5.4 g of ethyl acetate, stir and dissolve, control temperature at 0-10 °C, drop 5.56 g of hydrogen chloride / ethyl acetate (3M), keep warm until the reaction is complete, filter, get wet product, add ethyl acetate to control temperature at 0-10 °C, slurry, filter, dissolve the solid with water, add ethyl acetate, adjust pH to 7-8 with sodium bicarbonate, separate the layers, concentrate the organic phase to get wet product, dry to get 1.58 g of free base of compound I-1, yield 92.9%, purity ≥ 99%.

[0171] ESI-MS (m / z): 610.3327 (M+H).

[0172] Example 15: Preparation of compound I-1

[0173] Into a 50 mL reaction flask, add acetonitrile 1.58 g, 2.0 g of compound VII-1, 5.4 g of ethyl acetate, stir and dissolve, control temperature at 0-10 °C, drop 5.56 g of hydrogen chloride / ethyl acetate (3M), keep warm until the reaction is complete, filter, get wet product, add ethyl acetate to control temperature at 0-10 °C, slurry, filter, dissolve the solid with water, add ethyl acetate, adjust pH to 7-8 with sodium bicarbonate, separate the layers, concentrate the organic phase to get wet product, dry to get 1.58 g of free base of compound I-1, yield 92.9%, purity ≥ 99%.

[0174] ESI-MS (m / z): 610.3327 (M+H).

[0175] Example 16: Preparation of dihydrochloride salt of compound I-1

[0176] Into a 250 mL reaction flask, acetonitrile 10.0 g, 10.0 g of compound VII-1, 36.0 g of ethyl acetate were added, stirred and dissolved, temperature was controlled at 0-10 °C, 40 g of hydrogen chloride / ethyl acetate (3M) was added dropwise, and the reaction was allowed to complete, then filtered to obtain the wet product, which was slurried in ethyl acetate at 0-10 °C, filtered, and dried to obtain 8.9 g of dihydrochloride salt of compound I-1, with a yield of 92.7% and a purity of ≥99%.

[0177] While the present application has been described with reference to example embodiments, it will be understood by those skilled in the art that various changes in form and details can be made therein without departing from the spirit and scope of the application. The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the principles, and the scope of the application set forth in the claims.

Claims

1. A process for the preparation of a compound I, characterized in that comprising the following steps: (4) subjecting compound VI to a first reaction with compound N, and a second reaction with Boc20, to obtain compound VII, wherein the first reaction is carried out in an acid binding agent and a first solvent, and the second reaction is carried out in a second solvent, (5) deprotecting compound VII to obtain compound I, wherein the reaction is carried out in an acid solution and a solvent, wherein R 1 is optionally substituted C 1-6 alkyl, R 2 is optionally substituted C 1-12 alkyl; and X is halo.

2. The production method according to claim 1, characterized by, further comprising the following steps: (3) deprotecting compound V to produce compound VI, wherein the reaction is carried out in an acid solution and a solvent, 3. The method of claim 2, wherein, further comprising the following steps: (2) reacting compound IV with compound M to yield compound V, wherein the reaction is carried out in an acid binding agent and a solvent, 4. The production method according to claim 3, characterized by, further comprising the following steps: (1) deprotecting compound III to yield compound IV, wherein the reaction is carried out in a catalyst / hydrogen and a solvent, 5. The production method according to any one of claims 1 to 4, characterized by, R 1 is unsubstituted C 1-6 alkyl, preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl, more preferably methyl, ethyl, propyl or t-butyl; R 2 is unsubstituted straight-chain or branched-chain C 1-6 alkyl, preferably ethyl, n-propyl, i-propyl, n-butyl, n-pentyl or n-hexyl; X is Cl or Br.

6. The production method according to any one of claims 1 to 4, characterized by, Compounds I are the following compounds I-1 to I-6:

7. The production method according to any one of claims 1 to 4, characterized by, Step (4) comprises the following steps: after the first reaction, a first acid or a solution of the first acid is added to adjust pH≤5, water and a second solvent are added for extraction, the aqueous phase is adjusted to pH≥7 and then extracted with the second solvent again, the organic phases are combined, di-tert-butyl dicarbonate is added dropwise, and a second reaction is carried out.

8. The production method according to any one of claims 1 to 4, characterized by, In step (4), the acid-binding agent is selected from at least one of trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, 2-methylpyridine, N-methylmorpholine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide, preferably N-methylmorpholine and / or N,N-diisopropylethylamine; or In step (4), the first solvent is selected from at least one of methanol, ethanol, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, and N,N-dimethylformamide, preferably dichloromethane and / or ethanol; or In step (4), the second solvent is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, toluene, butanone, ethyl acetate, dioxane, methyl tert-butyl ether, isopropyl ether, acetonitrile, preferably ethyl acetate; or In step (4), the molar ratio of compound VI to compound N is 1:(1-3), preferably 1:(1.5-2.5); or In step (4), the molar ratio of compound VI to amino protecting agent Boc2O is 1:(1-3), preferably 1:(1.1-1.6); or In step (4), the molar ratio of compound VI to acid-binding agent is 1:(1-5), preferably 1:(3-4); or In step (4), the temperature of the first reaction is -20℃-40℃, preferably 0℃-10℃; the temperature of the second reaction is -20℃-40℃, preferably 10℃-20℃; or In step (5), the acid is one or more of trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid, acetic acid, hydrogen chloride, sulfuric acid, hydrobromic acid, or phosphoric acid, preferably hydrogen chloride; or In step (5), the acid solution is selected from an acid-containing ethanol solution, an acid-containing methanol solution, an acid-containing ethyl acetate solution, and / or an acid-containing dioxane solution, preferably an ethyl acetate solution of hydrogen chloride; or In step (5), the solvent is selected from at least one of dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, acetonitrile, and ethanol, preferably ethyl acetate and / or ethanol; or In step (5), the concentration of the acid solution is 0.5-4 mol / L; or In step (5), the molar ratio of compound VII to acid is 1:(1-10); or In step (5), the temperature of the reaction is -20℃-40℃, preferably 0-10℃.

9. The preparation method according to claim 7, characterized in that, In step (4), the first acid is one or more of trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid, acetic acid, hydrogen chloride, sulfuric acid, hydrobromic acid, or phosphoric acid, preferably hydrogen chloride; or In step (4), the solution of the first acid is one or more of an acid in ethanol, an acid in methanol, an acid in ethyl acetate, or an acid in dioxane, preferably an ethyl acetate solution of hydrogen chloride.

10. The production method according to any one of claims 2 to 4, characterized by, In step (3), the acid is one or more of trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, formic acid, acetic acid, hydrogen chloride, sulfuric acid, hydrobromic acid, or phosphoric acid, preferably hydrogen chloride; or In step (3), the acid solution is selected from an acid-containing ethanol solution, an acid-containing methanol solution, an acid-containing ethyl acetate solution, and / or an acid-containing dioxane solution, preferably an ethyl acetate solution of hydrogen chloride; or In step (3), the solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, and ethanol, preferably ethyl acetate and / or ethanol; or In step (3), the concentration of the acid solution is 0.5-4 mol / L; or In step (3), the molar ratio of the compound V to the acid is 1:(1-15), preferably 1:(4-10).

11. The production method according to claim 3 or 4, characterized by, In step (2), a catalyst is optionally added, and the catalyst is 4-dimethylaminopyridine or N,N-dimethylformamide, preferably 4-dimethylaminopyridine; or In step (2), the acid-binding agent is selected from at least one of trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, 2-methylpyridine, N-methylmorpholine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide, preferably N-methylmorpholine and / or N,N-diisopropylethylamine; or In step (2), the solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, toluene, dioxane, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, preferably dichloromethane; or In step (2), the amount of the catalyst is in the range of 0-1 relative to the weight of the compound M, preferably 0.05-0.2; or In step (2), the molar ratio of the compound IV to the acid-binding agent is 1:(1-3), preferably 1:(1.1-1.5); or In step (2), the temperature of the reaction is -10°C-40°C, preferably -10°C-20°C. Step (2) further comprises the following steps: after the reaction is quenched, the organic phase is washed and concentrated, ethyl acetate is added for dissolution, and then n-heptane is added dropwise for crystallization.

12. The production method according to claim 3 or 4, characterized by, In step (1), the catalyst is selected from one or more of platinum oxide, palladium hydroxide, palladium black, or palladium on carbon; or 13. The preparation method according to claim 4, characterized in that, In step (1), a drying agent is optionally added, and the drying agent is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, and molecular sieves; or In step (1), the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, and tetrahydrofuran, preferably methanol and / or ethanol; or In step (1), the amount of the catalyst is in the range of 0.01-1 relative to the weight of the compound III, preferably 0.04-0.1; or In step (1), the molar ratio of the compound III to the catalyst is 1:(0.01-1), preferably 1:(0.04-0.1). ​ In step (1), the amount of the drying agent is in the range of 0-1 parts by weight relative to compound III, preferably 0.05-0.1 parts by weight; or In step (1), the temperature of the reaction is -10-60°C, preferably 0-10°C; or In step (1), the pressure of the reaction is 0.1-3 MPa, preferably 0.1-0.4 MPa.

14. A process for the preparation of compound I-1 characterized in that, comprising the following steps: (5) deprotecting compound VII-1 to obtain compound I-1, wherein the reaction is carried out in an acid solution and a solvent; the acid solution is hydrogen chloride in ethyl acetate, the solvent is ethyl acetate or ethanol, the concentration of the acid solution is 0.5-4 mol / L, the molar ratio of compound VII-1 to the acid is 1:(1-10), and the reaction temperature is -10°C-20°C; The preparation method of compound VII-1 comprises the following steps: (4) the compound VI-1 is dissolved in a first solvent to carry out a first reaction with ethyl bromoacetate, and then a second reaction with Boc2O in a second solvent to obtain the compound VII-1, wherein the first reaction is carried out in an acid binding agent and a solvent; the acid binding agent is N-methylmorpholine and / or N,N-diisopropylethylamine, the first solvent is ethanol, the temperature of the first reaction is-20℃-40℃; the second reaction solvent is ethyl acetate, the temperature of the second reaction is 5℃-20℃, and the molar ratio of the compound VI-1 to ethyl bromoacetate, Boc2O, the acid binding agent is 1:(1.5-2.5):(1.1-1.6):(3-4), The preparation method of compound VI-1 comprises the following steps: (2) reacting compound IV with chloroformic acid n-propyl ester to obtain compound V-1, wherein the reaction is carried out in a catalyst, an acid binding agent and a solvent, the catalyst is 4-dimethylamino pyridine, the acid binding agent is N-methyl morpholine and / or N,N-diisopropyl ethyl amine, and the solvent is dichloromethane; the amount of the catalyst is 0.05-0.2 by weight based on compound IV, the molar ratio of compound IV to the acid binding agent is 1:(1.1-1.5), and the reaction temperature is -10-20°C; the molar ratio of compound IV to chloroformic acid n-propyl ester is 1:(1.1-1.5), (3) deprotecting compound V-1 to obtain compound VI-1, wherein the reaction is carried out in an acid solution and a solvent, the acid solution is hydrogen chloride in ethyl acetate, the solvent is ethyl acetate and / or ethanol, the concentration of the acid solution is 0.5-4 mol / L, the molar ratio of compound V-1 to the acid is 1:(4-10), and the reaction temperature is -10°C-10°C, 15. The method of claim 14, wherein, Step (4) comprises the following steps: dissolving compound VI-1 in ethanol, adding part of N,N-diisopropylethylamine dropwise to pH≥7 at 0-10°C, then adding the rest of diisopropylethylamine, and then adding ethyl bromoacetate dropwise; after the reaction is completed, adding hydrogen chloride ethyl acetate solution to adjust pH≤5, adding water and ethyl acetate to perform extraction, adjusting the pH of the water phase to pH≥7, and then extracting with ethyl acetate again; combining the organic phases, adding di-tert-butyl dicarbonate dropwise, and allowing the reaction to be completed at 10-20°C; washing the reaction solution with an aqueous citric acid solution, collecting the organic phase, and performing post-treatment to obtain compound VII-1.

Images