Process for the preparation of a nitraspidast intermediate

Abstract

The application relates to a preparation method of a compound F and a salt of the compound F, and a reaction as follows: comprising the following steps: (1) condensation reaction of compound B and compound C to prepare compound D; (2) reduction reaction of compound D to obtain compound E; (3) nitro reaction of compound E to prepare the compound F and the salt of the compound F. The application has the advantages of mild process conditions, simple operation, high yield, simple post-treatment, product obtained through only a purification mode of crystallization, reduction of "three wastes", and solution of the problems of the prior art, such as the need of ultralow temperature for reduction of methyl ester to aldehyde, difficulty in controlling selectivity, and easy over-reduction, ingenious integration of hydrogenation and salt formation reaction into a one-pot method, successful preparation of a hydrochloride crystal form of the compound F with high yield and high purity, stable crystal form, good reproducibility, and easy realization of industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing 1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-amine, belonging to the field of pharmaceutical intermediates synthesis. BACKGROUND

[0002] Nitarsone is an oral gamma-secretase inhibitor that effectively inhibits the growth of desmoid tumors by blocking the activation of Notch signaling proteins. On November 27, 2023, the U.S. Food and Drug Administration (FDA) approved nitarsone as the first drug specifically for the treatment of recurrent / refractory desmoid tumors.

[0003] 1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-amine is an important intermediate for the synthesis of nitarsone; the specific structure is as follows:

[0004]

[0005] The preparation method disclosed in patent WO2005092864A1 is as follows:

[0006]

[0007] This method prepares 1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-amine through three steps of reaction. The method needs to reduce the ester group at ultra-low temperature. The inventors found that it is difficult to control the selectivity and easy to over-reduce, which is not conducive to industrialization. SUMMARY

[0008] In view of the defects of the prior art, the present application provides a preparation method of 1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-amine and its salt. The intermediate prepared by the method is simple, efficient and high-yielding, greatly reducing the cost and being conducive to commercial mass production.

[0009] To achieve the above technical objectives, the present application adopts the following technical solutions:

[0010] The first aspect of the present application provides a dihydrochloride salt of compound F, the structure of which is as follows:

[0011]

[0012] The second aspect of the present application provides a crystalline hydrochloride salt of compound F, the structure of which is as follows:

[0013]

[0014] As a further improvement of the present application, the hydrochloride salt of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 21.51±0.2° in X-ray powder diffraction pattern measured using Cu-Kα radiation;

[0015] As a further improvement of the present application, the hydrochloride salt of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 21.51±0.2° in X-ray powder diffraction pattern measured using Cu-Kα radiation and one or more of the following characteristic peaks: 13.81±0.2°, 14.41±0.2°, 16.08±0.2°, 22.40±0.2°, 25.66±0.2°, 29.74±0.2°;

[0016] As a further improvement of the present application, the hydrochloride salt of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 21.51±0.2° in X-ray powder diffraction pattern measured using Cu-Kα radiation and one or more of the following characteristic peaks: 13.81±0.2°, 14.41±0.2°, 16.08±0.2°, 17.79±0.2°, 22.40±0.2°, 25.66±0.2°, 25.92±0.2°, 29.74±0.2°, 36.11±0.2°;

[0017] As a further improvement of the present application, the hydrochloride salt of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 21.51±0.2° in X-ray powder diffraction pattern measured using Cu-Kα radiation and one or more of the following characteristic peaks: 13.81±0.2°, 14.07±0.2°, 14.41±0.2°, 16.08±0.2°, 17.79±0.2°, 20.27±0.2°, 22.40±0.2°, 24.25±0.2°, 24.84±0.2°, 25.66±0.2°, 25.92±0.2°, 29.74±0.2°, 36.11±0.2°;

[0018] As a further improvement of the present application, the hydrochloride salt of the compound F has an X-ray powder diffraction pattern substantially as shown in Figure 5 of the accompanying drawings. Figure 2

[0019] ​As a further improvement of the present application, including but not limited to, the hydrochloride salt of the crystalline compound F of the present application is stable, has good fluidity, and does not cake, clump or wrap solvent; provides great convenience in the aspects of filtration, storage and transportation, and further improves the feasibility of industrial production.

[0020] The third aspect of the present application provides a preparation method of compound F and its salt, and the reaction formula is as follows:

[0021]

[0022] The preparation method comprises the following steps:

[0023] (1) Compound B is subjected to condensation reaction with compound C to prepare compound D;

[0024] (2) Compound D is subjected to reduction reaction to obtain compound E;

[0025] (3) Compound E is subjected to nitro reaction to prepare compound F and its salt, for example, dihydrochloride salt;

[0026] As a further improvement of the present application, the step (1) condensation reaction comprises:

[0027] Method one: compound B is subjected to condensation reaction with compound C in an organic solvent in the presence of a condensation agent to obtain compound D;

[0028] Method two: compound B is subjected to acyl chloride reaction with a chlorinating agent in an organic solvent to obtain an acyl chloride intermediate, and compound C is subjected to reaction in the presence of an organic base to obtain compound D;

[0029] Method three: compound B is subjected to condensation reaction with compound C in an organic solvent in the presence of a condensation agent, an activating agent and an organic base to obtain compound D;

[0030] As a further improvement of the present application, including but not limited to, the condensation agent in the method one or method three of the step (1) is selected from one or more of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride EDCI, dicyclohexyl carbodiimide DCC, N,N'-carbonyldiimidazole CDI, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate HCTU, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU, benzotriazole-N,N,N",N"-tetramethyluronium hexafluorophosphate HBTU, benzotriazole-1-yl oxy tris(dimethylamino) phosphonium hexafluorophosphate BOP; preferably N,N'-carbonyldiimidazole CDI and benzotriazole-1-yl oxy tris(dimethylamino) phosphonium hexafluorophosphate BOP;

[0031] As a further improvement of the present application, the molar ratio of compound B to the condensing agent of Method I or Method III in step (1) is 1 : (1-3), preferably 1 : (1.01-1.5);

[0032] As a further improvement of the present application, the activating agent of Method III in step (1) is selected from 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT);

[0033] As a further improvement of the present application, the molar ratio of compound C to the activating agent of Method III in step (1) is 1 : (0.1-1), preferably 1 : (0.1-0.5);

[0034] As a further improvement of the present application, including but not limited to, the chlorinating agent of Method II in step (1) is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride; preferably oxalyl chloride;

[0035] As a further improvement of the present application, the molar ratio of compound B to the chlorinating agent of Method II in step (1) is 1 : (1.05-3), preferably 1 : (1.2-2.0);

[0036] As a further improvement of the present application, a catalyst can be added to Method II in step (1), the catalyst is selected from DMF;

[0037] As a further improvement of the present application, the amount of catalyst used in Method II in step (1) is 0.05-0.5% of the mass of compound B;

[0038] As a further improvement of the present application, including but not limited to, the organic base of Method II or Method III in step (1) is selected from one or more of triethylamine, diisopropylethylamine DIPEA, diisopropylamine, diethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene DBU; preferably diisopropylethylamine DIPEA;

[0039] As a further improvement of the present application, the molar ratio of compound B to the organic base of Method II or Method III in step (1) is 1 : (1.1-6), preferably 1 : (2.5-5);

[0040] As a further improvement of the present application, including but not limited to, the step (1) organic solvent is one or more of ether solvents, halogenated alkane solvents, ketone solvents, aromatic hydrocarbon solvents, nitrile solvents, sulfone solvents and amide solvents, preferably one or both of nitrile solvents and amide solvents; the sulfone solvent is preferably dimethyl sulfoxide; the amide solvent can be one or more of N,N-dimethylformamide, N-methyl pyrrolidone and N,N-dimethylacetamide, preferably N,N-dimethylformamide; the ether solvent can be one or more of tetrahydrofuran, methyl tetrahydrofuran and dioxane, preferably dioxane; the halogenated alkane solvent can be one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane; the ketone solvent can be acetone; the aromatic hydrocarbon solvent can be one or both of toluene and pyridine, preferably toluene; the nitrile solvent is preferably acetonitrile;

[0041] As a further improvement of the present application, including but not limited to, the present application preferably selects the organic solvent mainly from the point of view of reactivity, selectivity and ease of obtaining; the step (1) organic solvent is selected from tetrahydrofuran, dioxane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone, toluene, acetone, acetonitrile, dimethyl sulfoxide, preferably N,N-dimethylformamide, acetonitrile;

[0042] As a further improvement of the present application, the volume of the step (1) organic solvent is 1-15 times the mass of compound B; preferably 3-8 times;

[0043] As a further improvement of the present application, the step (1) reaction temperature is 0-60℃;

[0044] As a further improvement of the present application, the step (1) reaction time is 10-36 hours, preferably 15-24 hours;

[0045] As a further improvement of the present application, the step (1) condensation reaction includes: compound B in an organic solvent, CDI is present, compound C is subjected to condensation reaction to obtain compound D; or compound B in an organic solvent, HOBT, BOP, organic base is present, and compound C is subjected to condensation reaction to obtain compound D; or compound B and oxalyl chloride are subjected to acyl chloride reaction in an organic solvent in the presence of a catalyst to obtain an acyl chloride intermediate, and compound C is subjected to reaction in the presence of an organic base to obtain compound D.

[0046] As a further improvement of the present application, the step (2) reduction reaction includes: compound D is subjected to reduction reaction in an organic solvent in the presence of a reducing agent to prepare compound E;

[0047] As a further improvement of the present application, the reducing agent in the step (2) is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, diisobutylaluminum hydride, red aluminum, borane; preferably sodium borohydride;

[0048] As a further improvement of the present application, the molar ratio of compound D to the reducing agent in the step (2) is 1: (1.05-5), preferably 1: (2.5-3.5);

[0049] As a further improvement of the present application, when the reducing agent in the step (2) is selected from sodium borohydride, an activating agent can be added, the activating agent is selected from one or more of elemental iodine, Lewis acid, protonic acid; preferably Lewis acid;

[0050] As a further improvement of the present application, the Lewis acid in the step (2) is selected from one or more of boron trifluoride, TiCl4, AlCl3, CaCl2, ZnCl2; preferably boron trifluoride; for example boron trifluoride ethyl ether solution, boron trifluoride tetrahydrofuran solution;

[0051] As a further improvement of the present application, the protonic acid in the step (2) is selected from one or more of trifluoroacetic acid, sulfuric acid, hydrochloric acid; preferably trifluoroacetic acid;

[0052] As a further improvement of the present application, the molar ratio of compound D to the activating agent in the step (2) is 1: (1-10), preferably 1: (3.5-5.5);

[0053] As a further improvement of the present application, the organic solvent in the step (2) is selected from one or more of ether solvent, halogenated alkane solvent, aromatic hydrocarbon solvent, nitrile solvent and amide solvent; preferably one or two of aromatic hydrocarbon solvent and ether solvent; the amide solvent can be N,N-dimethylformamide; the ether solvent can be one or more of tetrahydrofuran, methyltetrahydrofuran and dioxane, preferably tetrahydrofuran; the halogenated alkane solvent can be one or more of dichloromethane and dichloroethane, preferably dichloromethane; the aromatic hydrocarbon solvent can be one or two of toluene and pyridine, preferably toluene; the nitrile solvent is preferably acetonitrile;

[0054] As a further improvement of the present application, the organic solvent is preferably selected from the viewpoint of reactivity, selectivity and ease of obtaining; the organic solvent in the step (2) is selected from tetrahydrofuran, dioxane, dichloromethane, dichloroethane, N,N-dimethylformamide, toluene, acetonitrile, preferably tetrahydrofuran and toluene;

[0055] As a further improvement of the present application, the volume of the organic solvent in step (2) is 1-15 times, preferably 6-12 times, the mass of compound D;

[0056] As a further improvement of the present application, the reaction temperature in step (2) is 0-70°C;

[0057] As a further improvement of the present application, the reaction time in step (2) is 10-30 hours, preferably 15-24 hours;

[0058] As a further improvement of the present application, after the reaction in step (2) is complete, a basic solution, preferably NaOH solution, is added, stirred, separated, concentrated to 1 / 3, 1 / 4, 1 / 5, 1 / 6 of the original volume, crystallized, filtered, and the filter cake is dried to obtain solid compound E.

[0059] As a further improvement of the present application, including but not limited to, the nitro reduction reaction in step (3) includes: compound E, in the presence of an organic solvent, metal catalyst and hydrogen source, reduction reaction to prepare compound F, and hydrogen chloride gas is introduced to prepare the hydrochloride salt of compound F;

[0060] As a further improvement of the present application, including but not limited to, the hydrogen pressure in step (3) is selected from 5-40 bar, preferably 10-25 bar;

[0061] As a further improvement of the present application, including but not limited to, the metal catalyst in step (3) is selected from one or more of palladium on carbon (Pd / C), palladium hydroxide (Pd(OH)2), platinum on carbon (Pt / C), preferably palladium on carbon (Pd / C);

[0062] As a further improvement of the present application, including but not limited to, the metal catalyst in step (3) is selected from Pd / C, preferably 5% Pd / C or 10% Pd / C;

[0063] As a further improvement of the present application, including but not limited to, the mass ratio of compound E to metal catalyst in step (3) is 1:(0.05-0.5), preferably 1:(0.08-0.15);

[0064] As a further improvement of the present application, including but not limited to, the preferred organic solvent of the present application is selected mainly from the perspectives of reactivity, selectivity and ease of obtaining; the organic solvent in step (3) is selected from methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, acetonitrile, preferably tetrahydrofuran, ethyl acetate;

[0065] As a further improvement of the present application, the volume of the organic solvent in step (3) is 1-15 times the mass of compound E; preferably 3-12 times;

[0066] As a further improvement of the present application, the reaction temperature in step (3) is 25-45℃;

[0067] As a further improvement of the present application, the reaction time in step (3) is 10-30 hours, preferably 15-24 hours;

[0068] As a further improvement of the present application, including but not limited to, the nitro reduction reaction in step (3) includes: adding an organic solvent in a kettle, adding compound E, adding a metal catalyst and a hydrogen source, pressurizing the reaction to complete the conversion of the raw material, filtering, passing hydrogen chloride gas into the filtrate, gradually precipitating the product, filtering, drying the filter cake, and obtaining the hydrochloride salt of solid compound F.

[0069] As a further improvement of the present application, including but not limited to, the present application ingeniously integrates hydrogenation and salt formation into a one-pot method, successfully preparing a high-yield, high-purity hydrochloride salt of compound F with stable crystal form and good reproducibility; the preparation method is simple and easy to implement, the product quality is excellent, and industrial production is extremely easy to achieve;

[0070] As a further improvement of the present application, including but not limited to, the process route solves the problem of using ultra-low temperature and poor selectivity control in patent WO2005092864A1, which is prone to over-reduction.

[0071] The fourth aspect of the present application provides a preparation method of compound B, the reaction is as follows:

[0072]

[0073] wherein R is selected from C 1-6 linear or branched alkyl;

[0074] comprising the following steps:

[0075] Compound A is subjected to a hydrolysis reaction in a solvent to prepare compound B;

[0076] As a further improvement of the present application, including but not limited to, the hydrolysis reagent is an acid or a base; the acid is hydrochloric acid or sulfuric acid, and the base is selected from one or more of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates;

[0077] As a further improvement of the present application, including but not limited to, the base of the hydrolysis reaction is selected from one or more of potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide; preferably sodium hydroxide, lithium hydroxide; for example sodium hydroxide, lithium hydroxide monohydrate;

[0078] As a further improvement of the present application, including but not limited to, the solvent of the hydrolysis reaction is selected from ethyl acetate, methyl tert-butyl ether, toluene, isopropyl acetate, water, preferably water;

[0079] As a further improvement of the present application, including but not limited to, the mass amount of the solvent in the hydrolysis reaction is 1-10 times, preferably 1.5-5 times, the mass amount of compound A;

[0080] As a further improvement of the present application, the reaction temperature of the hydrolysis reaction is 5-60℃, preferably 10-40℃;

[0081] As a further improvement of the present application, the reaction time of the hydrolysis reaction is 0.5-6 hours, preferably 1-4 hours;

[0082] The fifth aspect of the present application also provides a method for preparing nitrasenstat: using the dihydrochloride salt of compound F of the first aspect or the second aspect of the present application to prepare nitrasenstat or using the compound F and its salt obtained by the preparation method of the third aspect or the fourth aspect of the present application to further prepare the compound F and its salt, and then further preparing nitrasenstat.

[0083] The present application has the beneficial technical effects:

[0084] 1) Process innovation and high efficiency: the present application uses 2-methyl-2-(4-nitro-1H-imidazol-1-yl) propyl acetate as the starting material, and synthesizes 1-(2-methyl-1-(neoxinylamino) prop-2-yl)-1H-imidazol-4-amine and its salt through hydrolysis, condensation, reduction and hydrogenation steps, with a cumulative yield of up to 76% and a purity of more than 98%. This process significantly reduces production costs and promotes the popularization of industrialized production;

[0085] 2) Mild process conditions and simple operation: the process conditions of the present application are mild, the operation is simple, and the yield is high. In addition, the post-treatment method of crystallization purification greatly reduces the generation of "three wastes". At the same time, it solves the problems of ultra-low temperature conditions, difficulty in selective control and over-reduction required in the reduction of methyl ester to aldehyde in the prior art, and is suitable for large-scale production;

[0086] 3) Ingenious application of one-pot method: the present application ingeniously integrates hydrogenation and salt formation into one-pot method, successfully preparing the hydrochloride salt of compound F with high yield and high purity. After 24 hours of air-drying at 50-55℃, and 10 days of standing, the XPRD pattern of the crystal form shows that the crystal form is stable and has good reproducibility. The preparation method is simple and easy to operate, the product quality is excellent, and the industrial production is extremely easy to realize, thereby solving the problem that the free base compound F is unstable for about 20 hours whether under nitrogen protection or not;

[0087] 4) Superior stability of hydrochloride salt: the compound F hydrochloride salt of the present application shows superior stability to other salts, and has good flowability, and will not cake, clump or wrap solvent. It provides great convenience in the aspects of filtration, storage and transportation, and further improves the feasibility of industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0088] Figure 1 X-ray powder diffraction (XPRD) pattern of the product obtained in Example 12 of the present application; 1 H-NMR spectrum;

[0089] Figure 2 X-ray powder diffraction (XPRD) pattern of the product obtained in Example 12 of the present application;

[0090] Figure 3 LCMS spectrum of the mixed product obtained in Comparative Example 1 of the present application. DETAILED DESCRIPTION

[0091] The preparation method of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[0092] The experimental methods used in the following examples are conventional methods unless otherwise specified; the reagents, materials, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0093] Example 1: Preparation of compound B

[0094]

[0095] Into a three-necked flask, add water (200 g), sodium hydroxide (18.8 g, 469.06 mmol, 1.0 eq) and stir until dissolved. Cool to 20-30 °C, and then add compound A (100 g, 469.06 mmol, 1.0 eq) while maintaining the temperature at 20-30 °C. Continue stirring for 2 hours. Take a sample and confirm that the starting material has been completely converted. Extract twice with DCM (100 mL) each time, and retain the aqueous phase. While maintaining the temperature at 10-20 °C, add 36% hydrochloric acid (54 g) dropwise. Stir for 2 hours. Filter, and dry the filter cake at 40-50 °C for 16 hours to obtain compound B (85.9 g, 92% yield, 97.7% purity) as a white solid.

[0096] Example 2: Preparation of compound B

[0097] Into a three-necked flask, add water (400 g), sodium hydroxide (75 g, 4.0 eq) and stir until dissolved. Cool to 20-30 °C, and then add compound A (100 g, 469.06 mmol, 1.0 eq) while maintaining the temperature at 20-30 °C. Continue stirring for 2 hours. Take a sample and confirm that the starting material has been completely converted. Extract twice with DCM (100 mL) each time, and retain the aqueous phase. While maintaining the temperature at 10-20 °C, add 36% hydrochloric acid (108 g) dropwise. Stir for 2 hours. Filter, and dry the filter cake at 40-50 °C for 16 hours to obtain compound B (89.7 g, 96% yield, 97.0% purity) as a white solid.

[0098] Example 3: Preparation of compound B

[0099] Into a three-necked flask, add water (400 g), lithium hydroxide monohydrate (78.7 g, 4.0 eq) and stir until dissolved. Cool to 20-30 °C, and then add compound A (100 g, 469.06 mmol, 1.0 eq) while maintaining the temperature at 20-30 °C. Continue stirring for 2 hours. Take a sample and confirm that the starting material has been completely converted. Extract twice with DCM (100 mL) each time, and retain the aqueous phase. While maintaining the temperature at 10-20 °C, add 36% hydrochloric acid (108 g) dropwise. Stir for 2 hours. Filter, and dry the filter cake at 40-50 °C for 16 hours to obtain compound B (90.5 g, 96.4% yield, 98.2% purity) as a white solid.

[0100] Example 4: Preparation of compound D

[0101]

[0102] A three-necked flask was charged with DMF (250 mL), then compound B (50 g, 251.05 mmol, 1.0 eq), CDI (42.8 g, 263.60 mmol, 1.05 eq) was added portionwise at 30-35 °C, and stirring was continued for 2 h. Then compound C (26.3 g, 301.26 mmol, 1.2 eq) was added dropwise at the same temperature. Stirring was continued at 30-35 °C for 18 h, and the sample was taken for in-process control to confirm complete conversion of the starting material. The reaction solution was added dropwise to water (750 g), and stirring was continued at 0-10 °C for 2 h. Filtration was performed, and the filter cake was dried at 50-55 °C under air draft for 24 h to obtain compound D (59.3 g, yield 88%) as a white powder.

[0103] Example 5: Preparation of compound D

[0104] A three-necked flask was charged with acetonitrile (250 mL), then compound B (50 g, 251.05 mmol, 1.0 eq) was added under nitrogen protection, CDI (42.8 g, 263.60 mmol, 1.05 eq) was added portionwise at 30-35 °C, and stirring was continued for 2 h. Then compound C (26.3 g, 301.26 mmol, 1.2 eq) was added dropwise at the same temperature. Stirring was continued at 30-35 °C for 18 h, and the sample was taken for in-process control to confirm complete conversion of the starting material. The reaction solution was added dropwise to water (750 g), and stirring was continued at 0-10 °C for 2 h. Filtration was performed, and the filter cake was dried at 50-55 °C under air draft for 24 h to obtain a white powder (55.9 g, yield 83%).

[0105] Example 6: Preparation of compound D

[0106] A three-necked flask was charged with acetonitrile (500 mL), then compound B (50 g, 251.05 mmol, 1.0 eq) was added under nitrogen protection, compound C (26.3 g, 301.26 mmol, 1.2 eq), HOBT (10.2 g, 75.31 mmol, 0.3 eq), DIPEA (146 g, 1.13 mol, 4.5 eq) were added at 10-20 °C, and BOP (133.2 g, 301.26 mmol, 1.2 eq) was added portionwise at 0-10 °C. Stirring was continued at 5-15 °C for 18 h, and the sample was taken for in-process control to confirm complete conversion of the starting material. The reaction solution was added dropwise to water (750 g), and stirring was continued at 0-10 °C for 2 h. Filtration was performed, and the filter cake was dried at 50-55 °C under air draft for 24 h to obtain a white powder (61.3 g, yield 91%).

[0107] Example 7: Preparation of compound E

[0108]

[0109] Into a 3-necked flask, THF (1.5 L) was added, under nitrogen protection, sodium borohydride (63.5 g, 1.68 mol, 3 eq), and compound D (150 g, 559.05 mmol, 1.0 eq) was added. Compound D was dissolved in 450 g of THF. Compound D was added dropwise at 0-10 °C. The reaction was stirred for 1 h at 0-10 °C. The reaction was stirred for 18 h at 30-40 °C. The reaction was sampled and analyzed. The reaction was complete. 20% NaOH solution was added dropwise. The reaction was stirred for 5 h at 30-40 °C. The reaction was sampled and analyzed. The reaction was complete. The organic phase was concentrated to a small volume. The product was crystallized. The product was filtered. The filter cake was dried at 50-55 °C for 24 h. Compound E was obtained as a white powder (130.8 g, 92% yield, 99% purity).

[0110] Example 8: Preparation of compound E

[0111] Into a 3-necked flask, THF (1.5 L) was added, under nitrogen protection, sodium borohydride (63.5 g, 1.68 mol, 3 eq), and compound D (150 g, 559.05 mmol, 1.0 eq) was added. Compound D was dissolved in 450 g of THF. Compound D was added dropwise at 0-10 °C. The reaction was stirred for 1 h at 0-10 °C. The reaction was stirred for 18 h at 30-40 °C. The reaction was sampled and analyzed. The reaction was complete. 20% NaOH solution was added dropwise. The reaction was stirred for 5 h at 30-40 °C. The reaction was sampled and analyzed. The reaction was complete. The organic phase was concentrated to a small volume. The product was crystallized. The product was filtered. The filter cake was dried at 50-55 °C for 24 h. Compound E was obtained as a white powder (130.8 g, 92% yield, 99% purity).

[0112] Example 9: Preparation of compound E

[0113] Into a 3-necked flask, THF (1.5 L) was added, under nitrogen protection, sodium borohydride (63.5 g, 1.68 mol, 3 eq), and compound D (150 g, 559.05 mmol, 1.0 eq) was added. Compound D was dissolved in 450 g of THF. Compound D was added dropwise at 0-10 °C. The reaction was stirred for 1 h at 0-10 °C. The reaction was stirred for 18 h at 30-40 °C. The reaction was sampled and analyzed. The reaction was complete. 20% NaOH solution was added dropwise. The reaction was stirred for 5 h at 30-40 °C. The reaction was sampled and analyzed. The reaction was complete. The organic phase was concentrated to a small volume. The product was crystallized. The product was filtered. The filter cake was dried at 50-55 °C for 24 h. Compound E was obtained as a white powder (130.8 g, 92% yield, 99% purity).

[0114] Example 10: Preparation of hydrochloride salt of compound F

[0115]

[0116] A 500 mL autoclave was charged with THF (500 mL), compound E (100 g, 393.19 mmol, 1.0 eq), 5% palladium on carbon (10 g); hydrogen was replaced three times, pressurized to 20-25 bar, and reacted at 30-40 °C for 18 hours. The sample was taken for in-process control to confirm complete conversion of the starting material. The palladium on carbon was filtered, and hydrogen chloride gas was passed through the filtrate to gradually precipitate the product. The product was filtered, and the filter cake was dried at 50-55 °C under a blast of air for 24 hours to obtain the hydrochloride salt of compound F as a white powder (107.5 g, 92% yield, 99.2% purity).

[0117] Example 11: Preparation of the hydrochloride salt of compound F

[0118] A 500 mL autoclave was charged with THF (500 mL), compound E (100 g, 393.19 mmol, 1.0 eq), 5% palladium on carbon (10 g); hydrogen was replaced three times, pressurized to 20-25 bar, and reacted at 30-40 °C for 18 hours. The sample was taken for in-process control to confirm complete conversion of the starting material. The palladium on carbon was filtered, and hydrogen chloride gas was passed through the filtrate to gradually precipitate the product. The product was filtered, and the filter cake was dried at 50-55 °C under a blast of air for 24 hours to obtain the hydrochloride salt of compound F as a white powder (107.5 g, 92% yield, 99.2% purity).

[0119] Example 11: Preparation of the hydrochloride salt of compound F

[0120] A 500 mL autoclave was charged with THF (500 mL), compound E (100 g, 393.19 mmol, 1.0 eq), 5% palladium on carbon (10 g); hydrogen was replaced three times, pressurized to 20-25 bar, and reacted at 30-40 °C for 18 hours. The sample was taken for in-process control to confirm complete conversion of the starting material. The palladium on carbon was filtered, and hydrogen chloride gas was passed through the filtrate to gradually precipitate the product. The product was filtered, and the filter cake was dried at 50-55 °C under a blast of air for 24 hours to obtain the hydrochloride salt of compound F as a white powder (107.5 g, 92% yield, 99.2% purity). 1 The H-NMR spectrum is shown in Figure 1 The XPRD spectrum is shown in Figure 2 .

[0121] Comparative Example 1: Preparation of compound M

[0122]

[0123] Compound A (100 g, 469.06 mmol) was dissolved in 1.0 L DCM, cooled to -80 ~ -90 °C with liquid nitrogen, DIBAL-H (1.5 M, 781.77 mL, 1.17 mol) was added dropwise at this temperature, 0.5 h dropwise, 15 min after the reaction, TLC showed that the raw material was reacted completely, 500 mL of ethyl acetate was added dropwise below -70 °C, and then 120 mL of water was added. After being stirred at 20 ~ 30 °C for 20 min, anhydrous sodium sulfate was added to remove water, filtered with diatomite, and the filter cake was washed with about 500 mL of ethyl acetate / methanol = 5:1. The filtrate was collected and concentrated to dryness to obtain 93 g of a mixture of brown red oil liquid compound M and compound N. The LCMS content of compound M was 65.77%, the retention time RT = 0.75 min; the LCMS content of the over-reduced alcohol compound N was 8.32%, the retention time RT = 0.78 min; the LCMS spectrum is shown in Figure 3 .

[0124] Comparative Example 2: Preparation of compound E

[0125]

[0126] Compound A (2.13 g, 9.99 mmol) was dissolved in 20 mL of DCM, cooled to -60 °C with liquid nitrogen, DIBAL-H (1.5 M, 13.3 mL, 19.98 mmol) was added dropwise at this temperature, 0.5 h dropwise, 15 min after the reaction, TLC showed that the raw material was reacted completely, 10 mL of ethyl acetate was added dropwise below -60 °C, and then 3 mL of water was added. After being stirred at 20 ~ 30 °C for 20 min, anhydrous sodium sulfate was added to remove water, filtered with diatomite, and the filter cake was washed with about 50 mL of ethyl acetate / methanol = 5:1. The filtrate was collected and concentrated to dryness, dissolved in 20 mL of DCM, and then compound C (10.88 g, 125 mmol) and 2 g of 4A activated powder were added. After being stirred at room temperature for 1 h, NaBH(OAc)3 (4.24 g, 19.98 mmol) was added and stirred at room temperature overnight. After filtration with diatomite, 15 mL of saturated sodium carbonate solution was added, the layers were separated, the organic layer was dried and rotary evaporated, and then column chromatography (PE / EA = 2:1) was performed to obtain 580 mg of yellow solid compound E, with a yield of 22.8%.

[0127] Comparative Example 3: Preparation of compound E

[0128]

[0129] Referring to the preparation process of compound M in Comparative Example 2, DCM was used as the reaction solvent, NaBH3CN was used as the reducing agent, and the raw materials were added at 0 ~ 10 °C. After being reacted at room temperature, LCMS detection showed that the content of compound E was 40%.

[0130] Comparative Example 4: Preparation of compound F

[0131]

[0132] Compound E (4 g, 15.73 mmol, 1.0 eq) was dissolved in ethyl acetate (32 mL) in an autoclave at 10-20 °C, and then 5% palladium-carbon (0.4 g) was added. Hydrogen was replaced for three times, and the hydrogen pressure was increased to 1.2 MPa. Then the temperature was increased to 30-40 °C, and the reaction was carried out for 3 hours. The sample was taken for control to confirm that the starting material was completely converted. The palladium-carbon was filtered, and the reaction solution of compound F was obtained. The stability test data are shown in Table 1 below:

[0133] Number Time Preservation method Color of reaction solution LCMS content 1 0 hours Preservation under nitrogen Light yellow 79.18％ 2 2 hours Preservation without nitrogen Brown 78.46％ 3 20 hours Preservation under nitrogen Light brown 76.92％ 4 20 hours Preservation without nitrogen Dark brown 68.49％

[0134] As shown in Table 1 above, the content of free base compound F decreased by 2.26% after being placed for 20 hours under nitrogen protection, and the color deepened. When not stored under nitrogen protection, the content decreased by 0.42% after being placed for 2 hours, and the content decreased by 10.69% after being placed for 20 hours. With the extension of time, the color deepened obviously. In summary, free base compound F is unstable for more than 2 hours whether under nitrogen protection or not. The content decreases obviously with the extension of time, and the impurities increase, which is not conducive to storage.

Claims

1. A method for preparing compound F and salts thereof, the reaction formula is shown as follows: comprising the following steps: (1) condensation reaction of compound B with compound C to prepare compound D; (2) reduction reaction of compound D to obtain compound E; (3) nitro reduction reaction of compound E to prepare compound F and salts thereof; the step (1) condensation reaction comprises: Method I: condensation reaction of compound B with compound C in an organic solvent in the presence of a condensing agent to obtain compound D; Method II: acyl chloride reaction of compound B with a chlorinating agent in an organic solvent to obtain an acyl chloride intermediate, and reaction of the acyl chloride intermediate with compound C in the presence of an organic base to obtain compound D; Method III: condensation reaction of compound B with compound C in an organic solvent in the presence of a condensing agent, an activating agent and an organic base to obtain compound D; the condensing agent in the Method I or Method III is selected from one or more of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), dicyclohexyl carbodiimide (DCC), N, N'-carbonyldiimidazole (CDI), 6-chlorobenzotriazole-1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HCTU), 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N, N, N'', N''-tetramethyluronium hexafluorophosphate (HBTU) and benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) ; the activating agent in the Method III is selected from 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azobenzotriazole (HOAT). the step (1) condensation reaction meets one or more of the following conditions: the molar ratio of compound B to the condensing agent in the Method I or Method III is 1: (1-3) ; the molar ratio of compound C to the activating agent in the Method III is 1: (0.1-1) ; the molar ratio of compound B to the chlorinating agent in the Method II is 1: (1.05-3), and the chlorinating agent is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride; the Method II adds a catalyst, and the catalyst is selected from DMF; the organic base in the Method II or Method III is selected from one or more of triethylamine, diisopropylethylamine, diisopropylamine, diethylamine, pyridine, N-methylmorpholine and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) ; the molar ratio of compound B to the organic base in the Method II or Method III is 1: (1.1-6). ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 2. The method of claim 1, wherein: ​ ​ ​ ​ ​ ​ ​ The organic solvent is one or more of ether solvents, halogenated alkane solvents, ketone solvents, aromatic hydrocarbon solvents, nitrile solvents, sulfone solvents and amide solvents; the sulfone solvent is dimethyl sulfoxide; the amide solvent is one or more of N,N-dimethylformamide, N-methylpyrrolidone and N,N-dimethylacetamide; the ether solvent is one or more of tetrahydrofuran, methyltetrahydrofuran and dioxane; the halogenated alkane solvent is one or more of dichloromethane, dichloroethane and chloroform; the ketone solvent is acetone; the aromatic hydrocarbon solvent is one or both of toluene and pyridine; and the nitrile solvent is acetonitrile. The volume of the organic solvent is 1-15 times the mass of compound B. The reaction temperature is 0-60°C. The reaction time is 10-36 hours.

3. The method of claim 2, wherein: The step (1) condensation reaction satisfies one or more of the following conditions: The molar ratio of compound B to the condensing agent of method one or method three is 1: (1.01-1.5); The molar ratio of compound C to the activating agent of method three is 1: (0.1-0.5); The molar ratio of compound B to the chlorinating agent of method two is 1: (1.2-2.0), and the chlorinating agent is selected from oxalyl chloride; The catalyst of method two is used in an amount of 0.05-0.5% of the mass of compound B; The organic base of method two or method three is selected from diisopropylethylamine; The molar ratio of compound B to the organic base of method two or method three is 1: (2.5-5); The organic solvent is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, acetone, acetonitrile and dimethyl sulfoxide; The volume of the organic solvent is 3-8 times the mass of compound B. The reaction time is 15-24 hours.

4. The method of claim 1, wherein: The step (1) condensation reaction includes: condensation of compound B with compound C in the presence of CDI in an organic solvent to obtain compound D; or condensation of compound B with compound C in the presence of HOBT, BOP and an organic base in an organic solvent to obtain compound D; or acyl chloride reaction of compound B with oxalyl chloride in the presence of a catalyst in an organic solvent to obtain an acyl chloride intermediate, and reaction of the acyl chloride intermediate with compound C in the presence of an organic base to obtain compound D.

5. The method of claim 1, wherein: The step (2) reduction reaction includes: reduction of compound D in the presence of a reducing agent in an organic solvent to prepare compound E.

6. The preparation method according to claim 5, characterized in that, The step (2) reduction reaction satisfies one or more of the following conditions: The molar ratio of compound D to the reducing agent in the reduction reaction is 1: (1.05-5); The reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, diisobutylaluminum hydride, red aluminum and borane; When the reducing agent is sodium borohydride, an activating agent is added, the activating agent is selected from one or more of the following: elemental iodine, Lewis acid, and protonic acid; the Lewis acid is selected from one or more of the following: boron trifluoride, TiCl4, AlCl3, CaCl2, and ZnCl2; the protonic acid is selected from one or more of the following: trifluoroacetic acid, sulfuric acid, and hydrochloric acid; The molar ratio of compound D to the activating agent in the reduction reaction is 1: (1-10) ; The organic solvent is one or more of the following: ether solvent, halogenated alkane solvent, aromatic hydrocarbon solvent, nitrile solvent, and amide solvent; the amide solvent is N,N-dimethylformamide; the ether solvent is one or more of the following: tetrahydrofuran, methyltetrahydrofuran, and dioxane; the halogenated alkane solvent is one or more of the following: dichloromethane and dichloroethane; the aromatic hydrocarbon solvent is one or both of the following: toluene and pyridine; the nitrile solvent is acetonitrile; The volume of the organic solvent is 1-15 times the mass of compound D; The reaction temperature is 0-70°C; The reaction time is 10-30 hours; After the reaction in step (2) is complete, a basic solution is added, stirring, liquid separation, concentration to 1 / 3, 1 / 4, 1 / 5, 1 / 6 of the original volume, crystallization, filtration, drying of the filter cake, to obtain solid compound E.

7. The production method according to claim 6, wherein The reduction reaction in step (2) satisfies one or more of the following conditions: The molar ratio of compound D to the reducing agent in the reduction reaction is 1: (2.5-3.5) ; The reducing agent is sodium borohydride; When the reducing agent is sodium borohydride, an activating agent is added, the activating agent is selected from one or more of the following: Lewis acid; the Lewis acid is boron trifluoride; The molar ratio of compound D to the activating agent in the reduction reaction is 1: (3.5-5.5) ; The organic solvent is selected from the following: tetrahydrofuran, dioxane, dichloromethane, dichloroethane, N,N-dimethylformamide, toluene, and acetonitrile; The volume of the organic solvent is 6-12 times the mass of compound D; The reaction time is 15-24 hours; After the reaction in step (2) is complete, a NaOH solution is added, stirring, liquid separation, concentration to 1 / 3, 1 / 4, 1 / 5, 1 / 6 of the original volume, crystallization, filtration, drying of the filter cake, to obtain solid compound E.

8. The method of claim 1, wherein: The nitro reduction reaction in step (3) includes: compound E, in the presence of an organic solvent, a metal catalyst, and a hydrogen source, reduction reaction to prepare compound F, and hydrogen chloride gas is introduced to prepare the hydrochloride salt of compound F.

9. The method of claim 8, wherein, The nitro reduction reaction in step (3) satisfies one or more of the following conditions: The hydrogen source is hydrogen gas, and the hydrogen gas pressure is selected from 5-40 bar; The metal catalyst is selected from one or more of the following: palladium on carbon Pd / C, palladium hydroxide Pd(OH)2, and platinum on carbon Pt / C; The mass ratio of compound E to the metal catalyst is 1: (0.05-0.5) ; The organic solvent is selected from the following: methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, and acetonitrile; The volume of the organic solvent mL is 1-15 times the mass of compound E g; The reaction temperature is 25-45℃; The reaction time is 10-30 hours; The step (3) reaction includes: adding an organic solvent in a kettle, adding compound E, adding a metal catalyst and a hydrogen source, pressurizing the reaction until the raw material is completely converted, filtering, passing hydrogen chloride gas into the filtrate, precipitating the product, filtering, and drying the filter cake at 50-55℃ with a blast to obtain a solid hydrochloride salt of compound F.

10. The method of claim 9, wherein, The step (3) nitro reduction reaction meets one or more of the following conditions: The reaction hydrogen pressure is selected from 10-25 bar; The metal catalyst is selected from palladium on carbon Pd / C; The mass g ratio of compound E to metal catalyst is 1: (0.08-0.15); The organic solvent is selected from tetrahydrofuran and ethyl acetate; The volume of the organic solvent mL is 3-12 times the mass of compound E g; The reaction time is 15-24 hours.

11. The method of claim 1, wherein: The preparation method of compound B is shown in the following reaction formula: wherein R is selected from C 1-6 linear or branched alkyl; Comprising the following steps: Compound A is subjected to a hydrolysis reaction in a solvent to prepare compound B; The hydrolysis reaction is carried out in an acid or a base; the acid is selected from hydrochloric acid or sulfuric acid, and the base is selected from one or more of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates.

12. The method of claim 11, wherein, The hydrolysis reaction also meets one or more of the following conditions: The base of the hydrolysis reaction is selected from one or more of potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, and sodium hydroxide; The solvent of the hydrolysis reaction is selected from ethyl acetate, methyl tert-butyl ether, toluene, isopropyl acetate, and water; The mass of the solvent g used in the hydrolysis reaction is 1-10 times the mass of compound A g; The reaction temperature of the hydrolysis reaction is 5-60℃; The reaction time of the hydrolysis reaction is 0.5-6 hours. The mass of the solvent g used in the hydrolysis reaction is 1.5-5 times the mass of compound A g.

13. The method of claim 12, wherein, The salt of compound F is selected from a hydrochloride salt of compound F.

14. The method of claim 1, wherein: The hydrochloride salt of compound F is a dihydrochloride salt; 15. The method of claim 14, wherein: The X-ray powder diffraction pattern of the hydrochloride salt of compound F detected using Cu-Kα radiation has characteristic peaks at 2θ of 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, and 21.51±0.2°. 。 16. The method of claim 14, wherein: The X-ray powder diffraction pattern of the hydrochloride salt of compound F detected using Cu-Kα radiation has characteristic peaks at 2θ of 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, and 21.51±0.2° and one or more of the following characteristic peaks: 13.81±0.2°, 14.41±0.2°, 16.08±0.2°, 22.40±0.2°, 25.66±0.2°, and 29.74±0.2°.

17. The method of claim 16, wherein: ​ 18. The method of claim 17, wherein: The hydrochloride salt of the compound F has an X-ray powder diffraction pattern with peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 21.51±0.2° when measured using Cu-Kα radiation and one or more of the following characteristic peaks: 13.81±0.2°, 14.41±0.2°, 16.08±0.2°, 17.79±0.2°, 22.40±0.2°, 25.66±0.2°, 25.92±0.2°, 29.74±0.2°, 36.11±0.2°.

19. The method of claim 18, wherein: The hydrochloride salt of the compound F has an X-ray powder diffraction pattern with peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 21.51±0.2° when measured using Cu-Kα radiation and one or more of the following characteristic peaks: 13.81±0.2°, 14.07±0.2°, 14.41±0.2°, 16.08±0.2°, 17.79±0.2°, 20.27±0.2°, 22.40±0.2°, 24.25±0.2°, 24.84±0.2°, 25.66±0.2°, 25.92±0.2°, 29.74±0.2°, 36.11±0.2°.

20. The method of claim 19, wherein: The hydrochloride salt of the compound F has an X-ray powder diffraction pattern as shown in Figure 2.

21. A process for the preparation of nitrasiphat, characterized by: The preparation method of the compound F and the salt thereof by any one of claims 1-20, the compound F and the salt thereof are further prepared into nitrasenstat.

Images