Preparation method of nigaxostat intermediate

Abstract

The invention relates to a preparation method of a compound F and a salt thereof. The reaction is as follows: # imgabs0 #. The preparation method comprises the following steps: (1) carrying out condensation reaction on a compound B and a compound C to prepare a compound D; (2) carrying out reduction reaction on the compound D to obtain a compound E; and (3) carrying out nitro reaction on the compound E to prepare a compound F and salt thereof. The method is mild in process condition, simple to operate, high in yield and simple in post-treatment, the product can be obtained only through a crystallization purification mode, three wastes are reduced, the problems that in the prior art, methyl ester is reduced into aldehyde, the reaction needs ultralow temperature, selectivity is not easy to control, and excessive reduction is easy are solved, hydrogenation and salt forming reactions are ingeniously integrated into a one-pot method, and the method is suitable for industrial production. The hydrochloride crystal form of the compound F with high yield and high purity is successfully prepared; the crystal form is stable in property, good in reproducibility and easy to realize industrial production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 1-(2-methyl-1-(neobutylamino)propan-2-yl)-1H-imidazole-4-amine, belonging to the field of drug intermediate synthesis. Background Art

[0002] Nigasetastat is an oral γ-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 nigasetastat as the first dedicated drug for the treatment of recurrent / refractory desmoid tumors.

[0003] 1-(2-methyl-1-(neobutylamino)propan-2-yl)-1H-imidazole-4-amine is an important intermediate in the synthesis of nitrestat; the specific structure is shown below:

[0004]

[0005] Patent WO2005092864A1 discloses the following preparation method:

[0006]

[0007] The method prepares 1-(2-methyl-1-(neobutylamino)propan-2-yl)-1H-imidazole-4-amine through three steps of reaction. The method requires ester group reduction at ultra-low temperature. The inventors repeated the route and found that it was difficult to control the selectivity and was prone to over-reduction, which was not conducive to industrial scale-up. Summary of the invention

[0008] In view of the defects of the prior art, the present invention provides a method for preparing 1-(2-methyl-1-(neobutylamino)propan-2-yl)-1H-imidazole-4-amine and its salt. The intermediate prepared by the method is simple, efficient and has a high yield, which greatly reduces the cost and is conducive to large-scale commercial production.

[0009] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0010] The first aspect of the present invention provides a dihydrochloride salt of compound F, the structure of which is shown below:

[0011]

[0012] The second aspect of the present invention provides a crystalline hydrochloride of compound F, the structure of which is shown below:

[0013]

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

[0015] As a further improvement of the present invention, the hydrochloride of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, and 21.51±0.2° in the X-ray powder diffraction pattern detected by Cu-Kα radiation, and has 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°;

[0016] As a further improvement of the present invention, the hydrochloride of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, and 21.51±0.2° in the X-ray powder diffraction pattern detected by Cu-Kα radiation, and has 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°, and 36.11±0.2°;

[0017] As a further improvement of the present invention, the hydrochloride of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, and 21.51±0.2° in the X-ray powder diffraction pattern detected by Cu-Kα radiation, and has 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°, and 36.11±0.2°;

[0018] As a further improvement of the present invention, the hydrochloride of the compound F has an X-ray powder diffraction pattern as shown in the attached specification. Figure 2 shown.

[0019] As further improvements of the present invention, including but not limited to, the hydrochloride of the crystallized compound F of the present invention is stable, has good fluidity, does not agglomerate, clump or wrap the solvent; it provides great convenience in the filtering, storage and transportation links, and further improves the feasibility of industrial production.

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

[0021]

[0022] The following steps are included:

[0023] (1) Compound B and compound C undergo a condensation reaction to prepare compound D;

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

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

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

[0027] Method 1: Compound B is reacted with compound C in an organic solvent in the presence of a condensation agent to obtain compound D;

[0028] Method 2: Compound B and a chlorinating agent are reacted in an organic solvent to obtain an acyl chloride intermediate, which is then reacted with compound C in the presence of an organic base to obtain compound D;

[0029] Method 3: Compound B undergoes a condensation reaction with compound C in an organic solvent in the presence of a condensation agent, an activator and an organic base to obtain compound D;

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

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

[0032] As a further improvement of the present invention, the activator in the method three of step (1) is selected from 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azobenzotriazole (HOAT);

[0033] As a further improvement of the present invention, the molar ratio of compound C in step (1) to the activator in method three is 1:(0.1-1), preferably 1:(0.1-0.5);

[0034] As a further improvement of the present invention, including but not limited to, the chlorination reagent in the second method of 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 invention, the molar ratio of compound B in step (1) to the chlorination reagent in method 2 is 1:(1.05-3), preferably 1:(1.2-2.0);

[0036] As a further improvement of the present invention, a catalyst may be added in the method 2 of step (1), and the catalyst is selected from DMF;

[0037] As a further improvement of the present invention, the amount of catalyst used in the method 2 of step (1) is 0.05-0.5% of the mass of compound B;

[0038] As a further improvement of the present invention, including but not limited to, the organic base in step (1) method 2 or method 3 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 invention, the molar ratio of compound B in step (1) to the organic base in method 2 or method 3 is 1:(1.1-6), preferably 1:(2.5-5);

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

[0041] As a further improvement of the present invention, including but not limited to, the present invention preferably uses an organic solvent, which is mainly selected from the viewpoints of reactivity, selectivity and availability; the organic solvent in step (1) is selected from tetrahydrofuran, dioxane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, acetone, acetonitrile, dimethyl sulfoxide, preferably N,N-dimethylformamide and acetonitrile;

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

[0043] As a further improvement of the present invention, the reaction temperature in step (1) is 0 to 60°C;

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

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

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

[0047] As a further improvement of the present invention, including but not limited to, the reducing agent in step (2) is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, diisobutylaluminum hydride, red aluminum, and borane; preferably sodium borohydride;

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

[0049] As a further improvement of the present invention, including but not limited to, when the reducing agent in step (2) is selected from sodium borohydride, an activator can be added, and the activator is selected from one or more of iodine, Lewis acid, and protonic acid; Lewis acid is preferred;

[0050] As a further improvement of the present invention, including but not limited to, the Lewis acid in step (2) is selected from one or more of boron trifluoride, TiCl4, AlCl3, CaCl2, and ZnCl2; preferably boron trifluoride; for example, boron trifluoride ether solution, boron trifluoride tetrahydrofuran solution;

[0051] As a further improvement of the present invention, including but not limited to, the proton acid in step (2) is selected from one or more of trifluoroacetic acid, sulfuric acid, and hydrochloric acid; preferably trifluoroacetic acid;

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

[0053] As a further improvement of the present invention, including but not limited to, the organic solvent in step (2) is one or more of an ether solvent, a halogenated alkane solvent, an aromatic hydrocarbon solvent, a nitrile solvent and an amide solvent, preferably one or two of an aromatic hydrocarbon solvent and an ether solvent; the amide solvent may be N,N-dimethylformamide; the ether solvent may be one or more of tetrahydrofuran, methyltetrahydrofuran and dioxane, preferably tetrahydrofuran; the halogenated alkane solvent may be one or more of dichloromethane and dichloroethane, preferably dichloromethane; the aromatic hydrocarbon solvent may be one or two of toluene and pyridine, preferably toluene; the nitrile solvent is preferably acetonitrile;

[0054] As a further improvement of the present invention, including but not limited to, the present invention preferably uses an organic solvent, which is mainly selected from the viewpoints of reactivity, selectivity and ease of acquisition; the organic solvent in 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 invention, the volume of the organic solvent in step (2) is 1 to 15 times the mass of the compound D in mL; preferably 6 to 12 times;

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

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

[0058] As a further improvement of the present invention, after the reaction of step (2) is completed, an alkaline solution, preferably a 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 invention, including but not limited to, the nitro reduction reaction in step (3) comprises: compound E is subjected to a reduction reaction in an organic solvent in the presence of a metal catalyst and a hydrogen source to prepare compound F, and hydrogen chloride gas is introduced to prepare a hydrochloride of compound F;

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

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

[0062] As a further improvement of the present invention, 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 invention, including but not limited to, the mass g 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 invention, including but not limited to, the present invention preferably uses an organic solvent, which is mainly selected from the viewpoints of reactivity, selectivity and ease of acquisition; 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 invention, the volume of the organic solvent in step (3) is 1 to 15 times the mass of compound E in mL; preferably 3 to 12 times;

[0066] As a further improvement of the present invention, the reaction temperature in step (3) is 25 to 45°C;

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

[0068] As a further improvement of the present invention, including but not limited to, the nitro reduction reaction in step (3) comprises: adding an organic solvent, compound E, a metal catalyst and a hydrogen source into a kettle, reacting under pressure until the raw material is completely converted, filtering, passing hydrogen chloride gas into the filtrate to gradually precipitate the product, filtering, and drying the filter cake to obtain a hydrochloride salt of solid compound F.

[0069] As further improvements of the present invention, including but not limited to, the present invention skillfully integrates hydrogenation and salt-forming reactions into a one-pot process, successfully preparing a high-yield, high-purity hydrochloride crystal form of compound F, and the crystal form has stable properties and good reproducibility; the preparation method is simple and easy, the product quality is excellent, and it is very easy to realize industrial production;

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

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

[0072]

[0073] Where R is selected from C 1-6 Straight chain alkyl or branched chain alkyl;

[0074] The following steps are included:

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

[0076] As a further improvement of the present invention, including but not limited to, the hydrolysis agent 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 invention, 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 invention, including but not limited to, the preferred solvent of the present invention is mainly selected from the viewpoints of reactivity, environmental protection and easy availability; 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 invention, including but not limited to, the mass amount g of the solvent in the hydrolysis reaction is 1 to 10 times the mass amount g of the compound A; preferably 1.5 to 5 times;

[0080] As a further improvement of the present invention, the reaction temperature of the hydrolysis reaction is 5 to 60°C, preferably 10 to 40°C;

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

[0082] The fifth aspect of the present invention also provides a method for preparing nigasstat: using the dihydrochloride of compound F of the first aspect or the second aspect of the present invention to prepare nigasstat, or comprising obtaining compound F and its salt by the preparation method of compound F and its salt of the third aspect or the fourth aspect of the present invention, and compound F and its salt are further prepared to obtain nigasstat.

[0083] Beneficial technical effects of the present invention:

[0084] 1) Process innovation and high yield: The present invention uses 2-methyl-2-(4-nitro-1H-imidazole-1-yl) propionic acid methyl ester as the starting material, and synthesizes 1-(2-methyl-1-(neobutylamino)propan-2-yl)-1H-imidazole-4-amine and its salt through hydrolysis, condensation, reduction and hydrogenation, with a cumulative yield of up to 76% and a purity of more than 98%. This process significantly reduces production costs and promotes the promotion of industrial production;

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

[0086] 3) Clever application of one-pot method: The present invention cleverly integrates hydrogenation and salt-forming reactions into a one-pot method, and successfully prepares a high-yield, high-purity hydrochloride crystal of compound F. After the crystal is dried by forced air at 50-55°C for 24 hours and then left to stand for 10 days, its XPRD spectrum shows that the crystal properties are stable and have good reproducibility. The preparation method is simple and easy, the product quality is excellent, and it is very easy to realize industrial production, thus solving the problem that the free base compound F will be unstable for about 20 hours regardless of whether it is under nitrogen protection or not;

[0087] 4) Superior hydrochloride stability: The hydrochloride of compound F of the present invention exhibits superior stability to other salts and has good fluidity without agglomeration, agglomeration or solvent inclusion, which provides great convenience in filtration, storage and transportation, further improving the feasibility of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 The product obtained in Example 12 of the present invention 1 H-NMR spectrum;

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

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

[0091] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

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

[0093] Example 1: Preparation of Compound B

[0094]

[0095] Add water (200g) and sodium hydroxide (18.8g, 469.06mmol, 1.0eq) to a three-necked flask, stir and dissolve, cool to 20-30°C, add compound A (100g, 469.06mmol, 1.0eq) at 20-30°C, continue stirring for 2 hours, and take samples to confirm that the raw material conversion is complete. Add DCM (100mL) and extract twice, retain the aqueous phase, add 54g of 36% hydrochloric acid at 10-20°C in the aqueous phase, and stir for 2 hours. Filter by suction, and dry the filter cake at 40-50°C with forced air for 16 hours to obtain an off-white solid compound B (85.9g, yield 92%, purity 97.7%).

[0096] Example 2: Preparation of Compound B

[0097] Add water (400g) and sodium hydroxide (75g, 4.0eq) to a three-necked flask, stir and dissolve, cool to 20-30°C, add compound A (100g, 469.06mmol, 1.0eq) at 20-30°C, continue stirring for 2 hours, and take samples to confirm that the raw material conversion is complete. Add DCM (100mL) and extract twice, retain the aqueous phase, add 108g of 36% hydrochloric acid at 10-20°C in the aqueous phase, and stir for 2 hours. Filter by suction, and dry the filter cake at 40-50°C for 16 hours to obtain an off-white solid compound B (89.7g, yield 96%, purity 97.0%).

[0098] Example 3: Preparation of Compound B

[0099] Add water (400g) to a three-necked flask, stir and dissolve lithium hydroxide monohydrate (78.7g, 4.0eq), cool to 20-30°C, add compound A (100g, 469.06mmol, 1.0eq) at 20-30°C, continue stirring for 2 hours, and take samples to confirm that the raw material conversion is complete. Add DCM (100mL) and extract twice, retain the aqueous phase, and add 108g of 36% hydrochloric acid at 10-20°C in the aqueous phase, and stir for 2 hours. Filter by suction, and dry the filter cake at 40-50°C for 16 hours to obtain an off-white solid compound B (90.5g, yield 96.4%, purity 98.2%).

[0100] Example 4: Preparation of Compound D

[0101]

[0102] DMF (250mL) was added to a three-necked flask, followed by compound B (50g, 251.05mmol, 1.0eq), and CDI (42.8g, 263.60mmol, 1.05eq) was added in batches at a temperature of 30-35°C, and stirring was continued for 2 hours. Compound C (26.3g, 301.26mmol, 1.2eq) was then added dropwise at this temperature. Stir at 30-35°C for 18 hours, and sampling was performed to confirm that the raw material conversion was complete. The reaction solution was added dropwise to water (750g), cooled to 0-10°C, and stirred for 2 hours. Filtered by suction, the filter cake was dried at 50-55°C with forced air for 24 hours to obtain an off-white powder solid compound D (59.3g, yield 88%).

[0103] Example 5: Preparation of Compound D

[0104] Add acetonitrile (250mL) to a three-necked flask, add compound B (50g, 251.05mmol, 1.0eq) under nitrogen protection, control the temperature at 30-35°C, add CDI (42.8g, 263.60mmol, 1.05eq) in batches, and continue stirring for 2 hours. Then add compound C (26.3g, 301.26mmol, 1.2eq) dropwise at this temperature. Stir for 18 hours at 30-35°C, and take samples to confirm that the raw material conversion is complete. Add the reaction solution dropwise to water (750g), cool to 0-10°C, stir for 2 hours, filter, and dry the filter cake at 50-55°C with forced air for 24 hours to obtain an off-white powder solid (55.9g, yield 83%).

[0105] Example 6: Preparation of Compound D

[0106] Add acetonitrile (500mL) to a three-necked flask, add compound B (50g, 251.05mmol, 1.0eq) under nitrogen protection, add compound C (26.3g, 301.26mmol, 1.2eq), HOBT (10.2g, 75.31mmol, 0.3eq), DIPEA (146g, 1.13mol, 4.5eq) at a temperature of 10-20°C, cool to 0-10°C, add BOP (133.2g, 301.26mmol, 1.2eq) in batches. Stir at 5-15°C for 18 hours, take a sample to confirm that the raw material is completely converted. Add the reaction solution dropwise to water (750g), cool to 0-10°C and stir for 2 hours, filter, and dry the filter cake at 50-55°C for 24 hours to obtain an off-white powder solid (61.3g, yield 91%).

[0107] Example 7: Preparation of Compound E

[0108]

[0109] THF (1.5L) was added to the three-necked flask, sodium borohydride (63.5g, 1.68mol, 3eq) was added under nitrogen protection, and a boron trifluoride ether solution (276mL, 2.24mol, 4eq) was added dropwise at a temperature of 0-10°C, and stirring was continued at 0-10°C for 1 hour; the temperature was raised to 30-40°C, and compound D (150g, 559.05mmol, 1.0eq, dissolved in 450g of THF) was added dropwise, and stirring was continued at 30-40°C for 18 hours. The sampling control confirmed that the raw material conversion was complete, and 20% NaOH solution was slowly added dropwise, and the mixture was separated after stirring at 30-40°C for 5 hours. The organic phase was concentrated to a small volume for crystallization, filtered, and the filter cake was dried by forced air at 50-55°C for 24 hours to obtain an off-white powder solid compound E (130.8g, yield 92%, purity 99%).

[0110] Example 8: Preparation of Compound E

[0111] THF (1.5L), compound D (150g, 559.05mmol, 1.0eq) were added to a three-necked flask, sodium borohydride (63.5g, 1.68mol, 3eq) was added under nitrogen protection, and a boron trifluoride ether solution (276mL, 2.24mol, 4eq) was added dropwise at a temperature of 0-10°C, and stirred at 0-10°C for 1h; the temperature was raised to 30-40°C and stirred for 18 hours. The sampling control confirmed that the raw material conversion was complete, and a 20% NaOH solution was slowly added dropwise, and the mixture was separated after stirring at 30-40°C for 5 hours. The organic phase was concentrated to a small volume for crystallization, filtered, and the filter cake was dried at 50-55°C for 24 hours to obtain an off-white powder solid compound E (122.3g, yield 86%, purity 99%).

[0112] Example 9: Preparation of Compound E

[0113] THF (1.5L), compound D (150g, 559.05mmol, 1.0eq) were added to a three-necked flask, sodium borohydride (63.5g, 1.68mol, 3eq) was added under nitrogen protection, boron trifluoride tetrahydrofuran solution (340.1mL, 2.80mol, 5eq) was added dropwise at a temperature of 0-10°C, and stirred at 0-10°C for 1 hour; the temperature was raised to 30-40°C and stirred for 18 hours. The sampling control confirmed that the raw material conversion was complete, and 20% NaOH solution was slowly added dropwise. After stirring at 30-40°C for 5 hours, the liquid was separated. The organic phase was concentrated to a small volume for crystallization, filtered, and the filter cake was dried at 50-55°C for 24 hours to obtain an off-white powder solid compound E (128g, yield 90%, purity 99%).

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

[0115]

[0116] THF (500 mL), compound E (100 g, 393.19 mmol, 1.0 eq) and 10 g of 5% palladium carbon were added to the autoclave; hydrogen was replaced three times, pressurized to 20-25 bar, and reacted at 30-40° C. for 18 hours. The sampling control confirmed that the raw material was completely converted, the palladium carbon was filtered, hydrogen chloride gas was passed into the filtrate, the product was gradually precipitated, filtered, and the filter cake was dried at 50-55° C. for 24 hours to obtain the hydrochloride of the off-white powder solid compound F (107.5 g, yield 92%, purity 99.2%).

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

[0118] THF (500 mL), compound E (100 g, 393.19 mmol, 1.0 eq) and 10 g of 5% palladium carbon were added to the autoclave; hydrogen was replaced three times, pressurized to 10-15 bar, and reacted at 30-40 ° C for 18 hours. The sampling control confirmed that the raw material was completely converted, the palladium carbon was filtered, hydrogen chloride gas was passed into the filtrate, and the product was gradually precipitated, filtered, and the filter cake was dried at 50-55 ° C for 24 hours. The material was collected and weighed to obtain the hydrochloride of the off-white powder solid compound F (104.10 g, yield 89.1%, purity 98.3%).

[0119] Example 12: Preparation of the hydrochloride salt of compound F

[0120] Ethyl acetate (500 mL), compound E (100 g, 393.19 mmol, 1.0 eq) and 10 g of 5% palladium on carbon were added to the autoclave; hydrogen was replaced three times, the pressure was increased to 20-25 bar, and the reaction was carried out at 30-40°C for 18 hours. The sampling control confirmed that the raw material conversion was complete, the palladium on carbon was filtered, and hydrogen chloride gas was passed into the filtrate to gradually precipitate the product. The filter cake was dried at 50-55°C for 24 hours to obtain the hydrochloride salt of off-white powder solid compound F (109.9 g, yield 94%, purity 98.8%). Quantification 1 H-NMR spectrum Figure 1 As shown, the XPRD spectrum is as follows Figure 2 shown.

[0121] Comparative Example 1: Preparation of Compound M

[0122]

[0123] Compound A (100 g, 469.06 mmol) was dissolved in 1.0 L DCM, and the temperature was lowered to -80--90° C. with liquid nitrogen. DIBAL-H (1.5 M, 781.77 mL, 1.17 mol) was added dropwise at this temperature. The addition was completed after 0.5 h. The temperature was kept for 15 min. TLC showed that the raw material had reacted completely. 500 mL of ethyl acetate was added dropwise below -70° C., and then 120 mL of water was added dropwise. The temperature was raised to 20-30° C. and stirred for 20 min. Anhydrous sodium sulfate was added to remove water, and the mixture was filtered through diatomaceous earth. 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 oily liquid compound M and compound N. The LCMS content of compound M was 65.77%, and the retention time RT = 0.75 min; the LCMS content of compound N of the over-reduced alcohol was 8.32%, and the retention time RT = 0.78 min; the LCMS spectrum was as follows Figure 3 shown.

[0124] Comparative Example 2: Preparation of Compound E

[0125]

[0126] Compound A (2.13 g, 9.99 mmol) was dissolved in 20 mL DCM, cooled to -60 °C with liquid nitrogen, and DIBAL-H (1.5 M, 13.3 mL, 19.98 mmol) was added dropwise at this temperature for 0.5 h. The mixture was kept warm for 15 min. TLC showed that the reaction of the raw materials was complete. 10 mL of ethyl acetate was added dropwise below -60 °C, and then 3 mL of water was added dropwise. The mixture was heated to 20-30 °C and stirred for 20 min. Anhydrous sodium sulfate was added to remove water, and the mixture was filtered through diatomaceous earth. 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 DCM, compound C (10.88 g, 125 mmol) and 2 g of 4A activated powder were added, and the mixture was stirred at room temperature for 1 h. NaBH(OAc)3 (4.24 g, 19.98 mmol) was added and stirred at room temperature overnight. The mixture was filtered through diatomaceous earth, 15 mL of saturated sodium carbonate solution was added, the layers were separated, the organic layer was dried and then spin-dried through a column (PE / EA=2:1) ​​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] The preparation process of compound E was prepared by referring to compound M in comparative example 2, using DCM as the reaction solvent, NaBH3CN as the reducing agent, adding materials at 0-10°C, reacting at room temperature, and LCMS detection. The content of compound E was 40%.

[0130] Comparative Example 4: Preparation of Compound F

[0131]

[0132] Ethyl acetate (32 mL) and compound E (4 g, 15.73 mmol, 1.0 eq) were added to the autoclave at 10-20 ° C. After stirring and dissolving, 0.4 g of 5% palladium carbon was added; hydrogen was replaced three times, and the hydrogen was pressurized to 1.2 MPa, and then the temperature was raised to 30-40 ° C for reaction for 3 hours. The sampling control confirmed that the raw material was completely converted, and the palladium carbon was filtered to obtain the reaction solution of compound F. The stability test data are shown in Table 1 below:

[0133] serial number time How to save Reaction solution color LCMS assay 1 0 hours Nitrogen storage Light yellow 79.18％ 2 2 hours Storage without nitrogen brown 78.46％ 3 20 hours Nitrogen storage Light Brown 76.92％ 4 20 hours Storage without nitrogen Dark Brown 68.49％

[0134] It can be seen from Table 1 that the free base compound F is placed under nitrogen protection for 20 hours, and the LCMS content decreases by 2.26%, and the color deepens; when stored without nitrogen, the LCMS shows that the content decreases by 0.42% after 2 hours, and decreases by 10.69% after 20 hours. As time goes by, the color deepens significantly; in summary, the free base compound F will be unstable for more than 2 hours regardless of whether it is protected by nitrogen or not, the content decreases significantly as time goes by, and the impurities increase, which is not conducive to storage.

Claims

1. A dihydrochloride salt of compound F, the structure of which is shown below:

2. A crystalline hydrochloride of compound F, the structure of which is shown below: The hydrochloride of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, and 21.51±0.2° in the X-ray powder diffraction pattern detected by Cu-Kα radiation.

3. The hydrochloride according to claim 1 or 2, characterized in that: The X-ray powder diffraction pattern detected by Cu-Kα radiation has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 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°, 29.74±0.2°; And / or, preferably, the hydrochloride of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 21.51±0.2° and one or more of the following characteristic peaks in the X-ray powder diffraction pattern detected by Cu-Kα radiation: 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°; And / or, preferably, the hydrochloride of the compound F has characteristic peaks at 8.05±0.2°, 16.36±0.2°, 21.23±0.2°, 21.51±0.2° and one or more of the following characteristic peaks in the X-ray powder diffraction pattern detected by Cu-Kα radiation: 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°; And / or, preferably, the hydrochloride salt of compound F has an X-ray powder diffraction pattern as shown in Figure 2 of the specification.

4. A method for preparing compound F and its salt, the reaction formula is as follows: The steps include: (1) Compound B and compound C undergo a condensation reaction to prepare compound D; (2) Compound D is subjected to a reduction reaction to obtain Compound E; (3) Compound E is subjected to nitro reaction to prepare compound F and its salt; for example, dihydrochloride.

5. The preparation method according to claim 4, characterized in that: The condensation reaction in step (1) comprises: Method 1: Compound B is reacted with compound C in an organic solvent in the presence of a condensing agent to obtain compound D; Method 2: Compound B is reacted with a chlorinating agent in an organic solvent to obtain an acyl chloride intermediate, which is reacted with compound C in the presence of an organic base to obtain compound D; Method 3: Compound B undergoes condensation reaction with compound C in an organic solvent in the presence of a condensation agent, an activator and an organic base to obtain compound D.

6. The preparation method according to claim 4, characterized in that: The condensation reaction in step (1) satisfies one or more of the following conditions: The condensing agent of the method one or the method three is selected from one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDCI, dicyclohexylcarbodiimide DCC, N,N'-carbonyldiimidazole CDI, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate HCTU, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU, benzotriazole-N,N,N",N"-tetramethyluronium hexafluorophosphate HBTU, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate BOP; preferably N,N'-carbonyldiimidazole CDI and benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate BOP; And / or, preferably, the molar ratio of compound B to the condensing agent of method one or method three is 1:(1-3), preferably 1: (1.01～1.5)； And / or, preferably, the activator of the method three is selected from 1-hydroxybenzotriazole HOBT or 1-hydroxy-7-azobenzotriazole HOAT; And / or, preferably, the molar ratio of the compound C to the activator of method three is 1:(0.1-1), preferably 1:(0.1-0.5); and / or, preferably, the chlorination agent of method two is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride; preferably oxalyl chloride; And / or, preferably, the molar ratio of the compound B to the chlorination reagent of method 2 is 1:(1.05-3), preferably 1: (1.2～2.0)； And / or, preferably, in the method 2, a catalyst may be added, and the catalyst is selected from DMF; And / or, preferably, the amount of catalyst used in the method 2 is 0.05-0.5% by mass of compound B; And / or, preferably, the organic base in method 2 or method 3 is selected from one or more of triethylamine, diisopropylethylamine, diisopropylamine, diethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene DBU; preferably diisopropylethylamine; And / or, preferably, the molar ratio of the compound B to the organic base of method 2 or method 3 is 1:(1.1-6), preferably 1:(2.5-5); And / or, preferably, the organic solvent is one or more of an ether solvent, a halogenated alkane solvent, a ketone solvent, an aromatic hydrocarbon solvent, a nitrile solvent, a sulfone solvent and an amide solvent, preferably one or both of a nitrile solvent and an amide solvent; the sulfone solvent is preferably dimethyl sulfoxide; the amide solvent may be one or more of N,N-dimethylformamide, N-methylpyrrolidone and N,N-dimethylacetamide, preferably N,N-dimethylformamide; the ether solvent may be one or more of tetrahydrofuran, methyltetrahydrofuran and dioxane, preferably dioxane; the halogenated alkane solvent may be one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane; the ketone solvent may be acetone; the aromatic hydrocarbon solvent may be one or both of toluene and pyridine, preferably toluene; the nitrile solvent is preferably acetonitrile; And / or, preferably, the organic solvent is selected from tetrahydrofuran, dioxane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, acetone, acetonitrile, dimethyl sulfoxide, preferably N,N-dimethylformamide, acetonitrile; And / or, preferably, the volume dosage of the organic solvent mL is 1 to 15 times the mass dosage of compound B g; preferably 3 to 8 times; And / or, preferably, the reaction temperature is 0 to 60°C; And / or, preferably, the reaction time is 10 to 36 hours, preferably 15 to 24 hours; And / or, preferably, the condensation reaction comprises: compound B undergoes a condensation reaction with compound C in an organic solvent in the presence of CDI to obtain compound D; or compound B undergoes a condensation reaction with compound C in an organic solvent in the presence of HOBT, BOP, and an organic base to obtain compound D; or compound B undergoes an acyl chloride reaction with oxalyl chloride in an organic solvent in the presence of a catalyst to obtain an acyl chloride intermediate, which is reacted with compound C in the presence of an organic base to obtain compound D.

7. The preparation method according to claim 4, characterized in that: The reduction reaction in step (2) comprises: in an organic solvent, in the presence of a reducing agent, performing a reduction reaction on compound D to prepare compound E; The reduction reaction in step (2) satisfies one or more of the following conditions: And / or, preferably, in an organic solvent, compound D is subjected to a reduction reaction to prepare compound E; And / or, preferably, the molar ratio of compound D to reducing agent in the reduction reaction is 1:(1.05-5), preferably 1: (2.5～3.5)； And / or, preferably, the reduction reaction is carried out in a reducing agent, the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, diisobutylaluminum hydride, red aluminum, borane; preferably sodium borohydride; And / or, preferably, when the reducing agent is selected from sodium borohydride, an activator may be added, wherein the activator is selected from one or more of iodine, Lewis acid, and protonic acid; Lewis acid is preferred; And / or, preferably, the Lewis acid is selected from one or more of boron trifluoride, TiCl4, AlCl3, CaCl2, and ZnCl2; Boron trifluoride is preferred; for example, boron trifluoride ether solution, boron trifluoride tetrahydrofuran solution; And / or, preferably, the protonic acid is selected from one or more of trifluoroacetic acid, sulfuric acid, and hydrochloric acid; preferably trifluoroacetic acid; and / or, preferably, the molar ratio of compound D to the activator in the reduction reaction is 1:(1-10), preferably 1: (3.5～5.5)； And / or, preferably, the organic solvent is one or more of an ether solvent, a halogenated alkane solvent, an aromatic hydrocarbon solvent, a nitrile solvent and an amide solvent, preferably one or two of an aromatic hydrocarbon solvent and an ether solvent; the amide solvent may be N,N-dimethylformamide; the ether solvent may be one or more of tetrahydrofuran, methyltetrahydrofuran and dioxane, preferably tetrahydrofuran; the halogenated alkane solvent may be one or more of dichloromethane and dichloroethane, preferably dichloromethane; the aromatic hydrocarbon solvent may be one or two of toluene and pyridine, preferably toluene; the nitrile solvent is preferably acetonitrile; And / or, preferably, the organic solvent is selected from tetrahydrofuran, dioxane, dichloromethane, dichloroethane, N,N-dimethylformamide, toluene, acetonitrile, preferably tetrahydrofuran, toluene; And / or, preferably, the volume amount mL of the organic solvent is 1 to 15 times the mass amount g of compound D; preferably 6 to 12 times; And / or, preferably, the reaction temperature is 0 to 70°C; And / or, preferably, the reaction time is 10 to 30 hours, preferably 15 to 24 hours; And / or, preferably, after the reaction of step (2) is completed, add an alkaline solution, preferably a NaOH solution, stir, separate the liquids, concentrate to 1 / 3, 1 / 4, 1 / 5, 1 / 6 of the original volume, crystallize, filter, and dry the filter cake to obtain solid compound E.

8. The preparation method according to claim 4, characterized in that: The nitro reduction reaction in step (3) comprises: compound E is subjected to a reduction reaction in an organic solvent in the presence of a metal catalyst and a hydrogen source to prepare compound F, and hydrogen chloride gas is introduced to prepare the hydrochloride of compound F; The reduction reaction in step (3) satisfies one or more of the following conditions: And / or, preferably, the reaction hydrogen pressure is selected from 5 to 40 bar, preferably 10 to 25 bar; And / or, preferably, the metal catalyst is selected from one or more of palladium carbon Pd / C, palladium hydroxide Pd(OH)2, platinum carbon Pt / C, preferably palladium carbon Pd / C; And / or, preferably, the metal catalyst is selected from palladium carbon Pd / C, preferably 5% Pd / C or 10% Pd / C; and / or, preferably, the mass g ratio of the compound E to the metal catalyst is 1:(0.05-0.5), preferably 1:(0.08-0.15); and / or, preferably, the organic solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, acetonitrile, preferably tetrahydrofuran, Ethyl acetate; And / or, preferably, the volume dosage of the organic solvent mL is 1 to 15 times the mass dosage of compound E g; preferably 3 to 12 times; And / or, preferably, the reaction temperature is 25 to 45°C; And / or, preferably, the reaction time is 10 to 30 hours, preferably 15 to 24 hours; And / or, preferably, the reaction in step (3) comprises: adding an organic solvent, compound E, a metal catalyst and a hydrogen source into a kettle, reacting under pressure until the raw materials are completely converted, filtering, passing hydrogen chloride gas into the filtrate to precipitate the product, filtering, and drying the filter cake with air at 50-55° C. to obtain the hydrochloride salt of solid compound F.

9. The preparation method according to claim 4, characterized in that: The preparation method of the compound B, the reaction formula is as follows: Where R is selected from C 1-6 Straight chain alkyl or branched chain alkyl; The following steps are included: Compound A is subjected to a hydrolysis reaction in a solvent to prepare compound B; And / or, preferably, 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 an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate and an alkali metal phosphate; And / or, preferably, the hydrolysis reaction further satisfies 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; preferably sodium hydroxide and lithium hydroxide; The solvent for the hydrolysis reaction is selected from ethyl acetate, methyl tert-butyl ether, toluene, isopropyl acetate, water, preferably water; The mass amount g of the solvent in the hydrolysis reaction is 1 to 10 times the mass amount g of compound A; preferably 1.5 to 5 times; The reaction temperature of the hydrolysis reaction is 5 to 60°C, preferably 10 to 40°C; The reaction time of the hydrolysis reaction is 0.5 to 6 hours, preferably 1 to 4 hours.

10. A method for preparing nitrestat, characterized in that: The method of preparing nigasstat using the dihydrochloride of compound F according to any one of claims 1 to 3 or comprising obtaining compound F and its salt by the method for preparing compound F and its salt according to any one of claims 4 to 9, and further preparing nigasstat by compound F and its salt.

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