(S)-aminonitrile hydrochloride compound and preparation method thereof

Abstract

The invention provides an (S)-aminonitrile hydrochloride compound and a preparation method thereof, and belongs to the technical field of medicine synthesis and preparation, the preparation method comprises the following steps: under inert conditions, S1, mixing a compound 1, 4-dimethylaminopyridine, pyridine and a reaction solvent, and adding paratoluensulfonyl chloride for reaction to obtain a compound 2; s2, mixing the compound 2 with a reaction solvent, and adding sodium cyanide for reaction to obtain a compound 3; s3, putting a magnesium rod into a reaction bottle, and dropwise adding a methanol solution of the compound 3 at room temperature for reaction to obtain a compound 4; and S4, mixing the compound 4 with an HCl organic solvent for reaction to obtain a target compound 5, namely the (S)-aminonitrile hydrochloride compound. The (S)-aminonitrile hydrochloride compound and the preparation method thereof provided by the invention have the advantages of high conversion rate, high yield, short steps, simple operation and low cost, and are suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis and preparation technology, specifically relating to a (S)-aminonitrile hydrochloride compound and its preparation method. Background Technology

[0002] Iblisse, an oral GLP-1 small molecule agonist developed by Eli Lilly, is used to treat obesity and type 2 diabetes. Currently in Phase III clinical trials, it is the most advanced oral GLP-1 receptor agonist. (S)-3-aminobutyronitrile hydrochloride, as an intermediate for iblisse, has significant market demand. However, current conventional methods for synthesizing (S)-3-aminobutyronitrile hydrochloride are complex, involve numerous steps, have poor intermediate stability, and are costly. To meet market demand, new, efficient, and concise synthetic methods need to be developed.

[0003] Patent application CN116390926A discloses a method for synthesizing (S)-3-aminobutyronitrile hydrochloride. This route uses compound 1-A as the starting material, and through substitution with MsCl and Boc reaction, compound 2-A is prepared. Compound 2-A is then cyanided to obtain compound 3-A, and compound 3-A is further de-Boc-treated to obtain the target product compound 4-A. The reaction route is shown below: , The shortcomings of this route are as follows: it uses a toxic reagent (MsCl) and the Boc group has poor stability, resulting in low yield and high process cost.

[0004] In summary, the existing technology has obvious shortcomings. Therefore, it is of great significance to develop a method for preparing (S)-aminonitrile hydrochloride compounds that has high conversion rate, high yield, short steps, simple operation, low cost, and is suitable for industrial production. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a (S)-aminonitrile hydrochloride compound and its preparation method. This preparation method features high conversion rate, high yield, short steps, simple operation, low cost, and suitability for industrial production.

[0006] The technical solution of this invention to solve the above-mentioned technical problems is as follows: A method for preparing (S)-aminonitrile hydrochloride compounds, the preparation method comprising the following steps: S1. Under inert conditions, compound 1, 4-dimethylaminopyridine, pyridine and reaction solvent were mixed and p-toluenesulfonyl chloride was added to react and give compound 2. S2. Under inert conditions, compound 2 obtained in step S1 is mixed with the reaction solvent, and sodium cyanide is added to react and compound 3 is obtained. S3. Under inert conditions, magnesium strips are placed in a reaction flask, and a methanol solution of compound 3 obtained in step S2 is added dropwise at room temperature to react and obtain compound 4. S4. Under inert conditions, compound 4 obtained in step S3 is mixed with HCl organic solvent and reacted to obtain target compound 5, which is (S)-aminonitrile hydrochloride compound.

[0007] Furthermore, the synthetic process route of this preparation method is as follows: , Where R is any one of Me, Et, OMe, and OEt.

[0008] Furthermore, in step S1, the molar ratio of compound 1, p-toluenesulfonyl chloride, 4-dimethylaminopyridine, and pyridine is 1.0:(2.0~2.5):(0.1~0.5):(2.0~2.5).

[0009] Furthermore, in step S2, the molar ratio of compound 2 to sodium cyanide is 1.0:(1.0~3.0).

[0010] Furthermore, in step S3, the molar ratio of compound 3 to magnesium strip is 1.0:(1.0~8.0).

[0011] Furthermore, in step S3, the mass concentration of the methanol solution of compound 3 is 8-12%.

[0012] Furthermore, in step S4, the molar ratio of compound 4 to HCl in the HCl organic solvent is 1.0:(1.0~3.0).

[0013] Furthermore, in step S1, the reaction temperature is -20~80℃; the reaction time is 18~24h.

[0014] Furthermore, in step S2, the reaction temperature is 40~100℃.

[0015] Furthermore, in step S4, the mass concentration of HCl in the HCl organic solvent is 20-30%.

[0016] Furthermore, in step S4, the HCl organic solvent is at least one of the following: an ethyl acetate solution of HCl, a 1,4-dioxane solution of HCl, a methanol solution of HCl, and an ethanol solution of HCl.

[0017] Furthermore, in step S1, the reaction solvent is at least one selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, dichloroethane, and toluene.

[0018] Furthermore, in step S2, the reaction solvent is at least one of N,N-dimethylformamide and dimethyl sulfoxide.

[0019] The present invention also discloses a (S)-aminonitrile hydrochloride compound, which is prepared by the preparation method provided by the present invention.

[0020] The beneficial effects of this invention are: This invention provides a method for preparing (S)-aminonitrile hydrochloride compounds. This method is achieved through steps such as esterification, cyanation, Ts removal, and salt formation. It has advantages such as short route and low cost, and has significant cost competitiveness. At the same time, the reaction conditions are mild, the operation is simple, and it is easy to scale up, making it more suitable for industrial production. Attached Figure Description

[0021] Figure 1 The 1H NMR spectrum of compound 2 in Example 1; Figure 2 The carbon NMR spectrum of compound 2 in Example 1; Figure 3 The 1H NMR spectrum of compound 3 in Example 1; Figure 4 The carbon NMR spectrum of compound 3 in Example 1; Figure 5 The 1H NMR spectrum of compound 5 in Example 1; Figure 6 The image shows the carbon NMR spectrum of compound 5 in Example 1. Detailed Implementation

[0022] The specific embodiments of the present invention will be described in detail below. The present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed herein.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used is for describing particular embodiments only and is not intended to limit the invention.

[0024] In all embodiments of this invention, the inert conditions are provided by nitrogen gas.

[0025] A method for preparing a (S)-aminonitrile hydrochloride compound, which is mainly used in the preparation of the new drug erblisse, an oral GLP-1 small molecule agonist used to treat obesity and type II diabetes. The preparation method includes the following steps: S1. Under inert conditions, compound 1, 4-dimethylaminopyridine, pyridine and reaction solvent were mixed and p-toluenesulfonyl chloride was added to react and give compound 2. S2. Under inert conditions, compound 2 obtained in step S1 is mixed with the reaction solvent, and sodium cyanide is added to react and compound 3 is obtained. S3. Under inert conditions, magnesium strips are placed in a reaction flask, and a methanol solution of compound 3 obtained in step S2 is added dropwise at room temperature to react and obtain compound 4. S4. Under inert conditions, compound 4 obtained in step S3 is mixed with HCl organic solvent and reacted to obtain target compound 5, which is (S)-aminonitrile hydrochloride compound.

[0026] Specifically, the synthesis process route of this preparation method is as follows: , Where R is any one of Me, Et, OMe, and OEt.

[0027] Specifically, in step S1, the molar ratio of compound 1, p-toluenesulfonyl chloride, 4-dimethylaminopyridine, and pyridine is 1.0:(2.0~2.5):(0.1~0.5):(2.0~2.5).

[0028] Specifically, in step S2, the molar ratio of compound 2 to sodium cyanide is 1.0:(1.0~3.0).

[0029] Specifically, in step S3, the molar ratio of compound 3 to magnesium strip is 1.0:(1.0~8.0).

[0030] Specifically, in step S3, the mass concentration of the methanol solution of compound 3 is 8-12%.

[0031] Specifically, in step S4, the molar ratio of compound 4 to HCl in the HCl organic solvent is 1.0:(1.0~3.0).

[0032] Specifically, in step S1, the reaction temperature is -20~80℃; the reaction time is 18~24h.

[0033] Specifically, in step S2, the reaction temperature is 40~100℃.

[0034] Specifically, in step S4, the mass concentration of HCl in the HCl organic solvent is 20-30%.

[0035] Specifically, in step S4, the HCl organic solvent is at least one of the following: an ethyl acetate solution of HCl, a 1,4-dioxane solution of HCl, a methanol solution of HCl, and an ethanol solution of HCl.

[0036] Specifically, in step S1, the reaction solvent is at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, dichloroethane, and toluene.

[0037] Specifically, in step S2, the reaction solvent is at least one of N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

[0038] More specifically, in the embodiments of the present invention, compound 1 is selected as (S)-2-amino-1-propanol as the starting material, and the target compound 5 is finally obtained. This does not limit the technology of the present invention. Any one of (S)-3-aminoethyl-1-propanol, (S)-3-aminomethoxy-1-propanol, and (S)-3-aminoethoxy-1-propanol can be selected as needed.

[0039] Specifically, the preparation steps for compound 1 using (S)-2-amino-1-propanol as the starting material are as follows: (1) Preparation of compound 2, the structural formula of compound 2 is as follows: Under inert conditions, compound (S)-2-amino-1-propanol, 4-dimethylaminopyridine (DMAP), pyridine and reaction solvent were mixed, p-toluenesulfonyl chloride was added, and the mixture was reacted at -20 to 80 °C for 18 to 24 h.

[0040] The post-reaction processing was as follows: hydrochloric acid was added to quench the reaction, the organic phase was separated by standing, the organic phase was washed with water until neutral, the solvent in the organic phase was removed to obtain the crude product, and the crude product was recrystallized to obtain yellow crystalline compound 2.

[0041] Specifically, the recrystallization solvent is at least one of toluene, petroleum ether, n-hexane, n-heptane, methanol, ethanol, and ethyl acetate.

[0042] In this step of the reaction, the amount of pyridine must be in excess to consume the generated byproduct hydrochloric acid in time, thereby shifting the chemical equilibrium of the reaction to the right, promoting the reaction, and increasing the yield.

[0043] (2) Preparation of compound 3, the structural formula of compound 3 is as follows: Under inert conditions, compound 2 and the reaction solvent were mixed, sodium cyanide was added, and the reaction was carried out at 40~100℃.

[0044] The post-processing steps after the reaction were as follows: water was added to quench the reaction, the upper organic phase was separated, the aqueous phase was extracted with solvent, the organic phase was collected, the organic phase was washed with water until neutral, the solvent was removed, and after recrystallization, a white solid compound 3 was obtained.

[0045] Specifically, the extraction solvent is any one of toluene, ethyl acetate, 2-methyltetrahydrofuran, etc.

[0046] Specifically, the recrystallization solvent is at least one of toluene, petroleum ether, n-hexane, n-heptane, methanol, ethanol, and ethyl acetate.

[0047] More specifically, in step (2), the reaction must be carried out in DMF or DMSO, and the reaction does not or barely occurs in other solvents.

[0048] (3) Preparation of compound 4, the structural formula of compound 4 is as follows: Magnesium strips were placed in a reaction flask under inert gas protection, and a methanol solution of compound 3 was added dropwise at room temperature while the reaction was kept at this temperature.

[0049] The post-processing steps after the reaction were as follows: after the reaction was completed, the temperature was lowered, hydrochloric acid was added to quench the reaction, solvent extraction was performed, the organic phase was separated, the organic phase was descaled to remove the solvent, and a yellow oily crude compound 4 was obtained. The crude compound was purified by column chromatography to obtain a refined compound 4. A mixed solvent of ethyl acetate and petroleum ether was selected as the eluent, wherein ethyl acetate accounted for 30% of the total volume of the mixed solvent.

[0050] Specifically, the mass concentration of the methanol solution of compound 3 is 8-12%.

[0051] More specifically, the initiation of step (3) is very important. The initiation phenomenon is that the magnesium strip changes from bright silver to grayish white. This is mainly controlled by the dropping temperature of the methanol solution of compound 3. It must be controlled at room temperature of 20~30℃. When the temperature is controlled too low, the reaction will not be initiated smoothly, affecting the subsequent reaction. When the temperature is controlled slightly higher, a violent exothermic phenomenon will occur, causing the material to surge.

[0052] Specifically, the extraction solvent is any one of toluene, dichloromethane, ethyl acetate, or 2-methyltetrahydrofuran.

[0053] (4) Preparation of target compound 5, the structural formula of compound 5 is as follows: Under inert conditions, compound 4 and anhydrous ethanol were added to a three-necked flask, and an ethanol solution of HCl was added dropwise while stirring at room temperature. The reaction was carried out at room temperature.

[0054] The post-processing steps after the reaction were as follows: the temperature was lowered to 0-5℃ and filtered under pressure, and the crude product was washed with anhydrous ethanol at 0-5℃ to obtain the crude product; anhydrous ethanol was added to dissolve the crude product at room temperature, the temperature was lowered to 0-5℃, the mixture was stirred for 1 hour, filtered under pressure, and the filter cake was dried to obtain a white solid, which is the refined product of target compound 5.

[0055] Example 1 The preparation method of (S)-2-aminonitrile hydrochloride compound includes the following steps: (1) Preparation of compound 2, the structural formula of compound 2 is as follows: Under inert conditions, 7.5 g (0.10 mol) of compound (S)-2-amino-1-propanol, 2.5 g (0.02 mol) of 4-dimethylaminopyridine, 17.4 g (0.22 mol) of pyridine and 30.0 g of dichloromethane were added to a three-necked flask and mixed. The temperature was controlled at 20~30℃, and a solution prepared with 38.2 g (0.22 mol) of p-toluenesulfonyl chloride and 76.3 g of dichloromethane was added dropwise. After the addition was completed, the reaction was carried out at 20~30℃ for 24 h.

[0056] The post-reaction processing was as follows: dilute hydrochloric acid was added to quench the reaction, the organic phase was separated by standing, the organic phase was washed with water until neutral, and the solvent in the organic phase was removed under reduced pressure at 30-40℃ to obtain the crude product. The crude product was recrystallized with 76.6g of ethanol, filtered under reduced pressure at 0-5℃, and the resulting filter cake was dried under reduced pressure at 50℃ to obtain 34.5g of yellow crystalline compound 2. The purity was 98% (HPLC test), and the yield was 90.0%.

[0057] The NMR data analysis of compound 2 is as follows: 1 H-NMR (400MHz, CDCl3): δ=7.667-7.714 (t, 4H), δ=7.241-7.325 (dd, 4H), δ=4.937-4.957 (d, 1H), δ=3.891-3.927 (dd, 1H), δ=3.793-3.831 (dd, 1H), δ=3.432-3.551 (m, 1H), δ=2.394-2.425 (d, 6H), δ=1.030-1.046 (d, 3H) ppm. 13 C-NMR(101MHz, CDCl3): δ=145.277, 143.706, 137.477, 132.427, 130.070, 129.859, 128.019, 127.080, 72.527, 48.446, 21.749, 21.606, 17.983ppm.

[0058] (2) Preparation of compound 3, the structural formula of compound 3 is as follows: Under inert conditions, 61.5 g (0.187 mol) of compound 2 and 246.0 g of N,N-dimethylformamide were added to a three-necked flask and mixed. 20.2 g (0.411 mol) of sodium cyanide was added at 20-30 °C, and the mixture was heated to 40-45 °C and reacted for 20 h.

[0059] The post-reaction processing was as follows: 1000g of water was added for quenching, the upper organic phase was separated, the aqueous phase was extracted with toluene, allowed to stand and separated, the organic phase was collected, washed with water until neutral, and the solvent was removed under reduced pressure at 60-70℃ to obtain crude compound 3. This crude compound 3 was recrystallized with 69.0g of toluene, filtered under reduced pressure at 0-5℃, and the filter cake was dried under reduced pressure at 50℃ to obtain 27.6g of purified compound 3. The purity was 99%, and the yield was 80.0%.

[0060] The NMR data analysis of compound 3 is as follows: 1 H-NMR (400MHz, CDCl3): δ=7.748-7.769 (d, 2H), δ=7.304-7.323 (d, 2H), δ=5.199-5.218 (d, 1H), δ=3.544-3.640 (m, 1H), δ=2.496-2.616 (m, 2H), δ=2.419 (s, 3H), δ=1.195-1.211 (d, 3H) ppm. 13 C-NMR (101MHz, CDCl3): δ=144.118, 137.132, 130.060, 127.109, 116.884, 46.290, 26.369, 21.634, 20.379ppm.

[0061] (3) Preparation of compound 4, the structural formula of compound 4 is as follows: 5.4 g (0.224 mol) of magnesium strip was placed in a three-necked flask under inert gas protection. Nitrogen was used to purge the mixture for 0.5 h. A mixture of 7.7 g (0.032 mol) of compound 3 and 77.0 g of methanol was added dropwise with stirring at room temperature. After the addition was complete, the mixture was stirred at half the volume for 24 h at room temperature.

[0062] The post-reaction processing was as follows: After the reaction, the mixture was cooled, quenched with dilute hydrochloric acid, and the pH of the system was adjusted to 7-8. The mixture was then extracted with dichloromethane solvent to separate the organic phase. The organic phase was descaled to remove the solvent, yielding a yellow oily crude compound 4. The crude compound was purified by column chromatography to obtain a refined compound 4. A mixed solvent of ethyl acetate and petroleum ether was used as the eluent, with ethyl acetate comprising 30% of the total volume of the mixed solvent. The purity was 99%, and the yield was 88%.

[0063] (4) Preparation of target compound 5, the structural formula of compound 5 is as follows: Under inert conditions, 8.4 g (0.10 mol) of compound 4 and 16.8 g of anhydrous ethanol were added to a three-necked flask, and 45.6 g (0.25 mol) of 20% hydrogen chloride ethanol solution was added dropwise with stirring at room temperature. The reaction was carried out at room temperature for 2 h.

[0064] The post-reaction processing was as follows: the mixture was cooled to 0-5℃ and filtered under pressure, then washed with anhydrous ethanol at 0-5℃ to obtain the crude product; anhydrous ethanol was added again at room temperature for dissolution, the mixture was cooled to 0-5℃, stirred for 1 hour, filtered under pressure, and the filter cake was dried to obtain a white solid, which was the purified target compound 5. The purity was 99%, and the yield was 99%.

[0065] The melting point of the product was tested by differential scanning calorimetry (DSC): 170.63-182.46-187.23℃.

[0066] The NMR data of the product are as follows: 1 H-NMR (400MHz, CDCl3): δ=3.690-3.770 (m, 1H), δ=2.842-3.031 (dd, 2H), δ=1.383-1.400 (d, 3H)ppm. 13 C-NMR (101MHz, CDCl3): 117.105, 44.326, 22.660, 17.456ppm.

[0067] Example 2 The preparation of a (S)-2-aminonitrile hydrochloride compound is carried out in Example 2 using the same preparation method as in Example 1, except that the amounts and reaction conditions of each step are different.

[0068] In step (1), under inert conditions, 7.5 g (0.10 mol) of compound (S)-2-amino-1-propanol, 1.25 g (0.01 mol) of 4-dimethylaminopyridine, 15.8 g (0.20 mol) of pyridine and 30.0 g of dichloromethane were added to a three-necked flask and mixed. The temperature was controlled at -20~0℃, and a solution prepared with 38.2 g (0.22 mol) of p-toluenesulfonyl chloride and 76.3 g of dichloromethane was added dropwise. After the addition was completed, the reaction was carried out at -20~0℃ for 24 h.

[0069] The post-processing was the same as in Example 1, and the final purity of compound 2 was 95%, with a yield of 88%.

[0070] In step (2), under inert conditions, 61.5 g (0.187 mol) of compound 2 and 246.0 g of DMSO were added to a three-necked flask and mixed. 9.19 g (0.187 mol) of sodium cyanide was added at 20-30 °C and the mixture was reacted at 60-80 °C for 20 h.

[0071] The post-processing was the same as in Example 1. The final purity of compound 3 was 98%, and the yield was 80%.

[0072] In step (3), 0.77 g (0.032 mol) of magnesium strip was placed in a three-necked flask under inert gas protection, nitrogen was used to purge for 0.5 h, and a mixture of 7.7 g (0.032 mol) of compound 3 and 77.0 g of methanol was added dropwise with stirring at room temperature. After the addition was completed, the reaction was stirred at room temperature for 24 h.

[0073] The post-processing was the same as in Example 1, and the final purity of compound 4 was 98%, with a yield of 85%.

[0074] The dosage and operation of step (4) are the same as in Example 1.

[0075] Example 3 The preparation of a (S)-2-aminonitrile hydrochloride compound is carried out in Example 2 using the same preparation method as in Example 1, except that the amounts and reaction conditions of each step are different.

[0076] In step (1), under inert conditions, 7.5 g (0.10 mol) of compound (S)-2-amino-1-propanol, 6.25 g (0.05 mol) of 4-dimethylaminopyridine, 19.8 g (0.25 mol) of pyridine and 30.0 g of dichloromethane were added to a three-necked flask and mixed. The temperature was controlled at 70~80℃, and a solution prepared with 38.2 g (0.22 mol) of p-toluenesulfonyl chloride and 76.3 g of dichloromethane was added dropwise. After the addition was completed, the reaction was carried out at 70~80℃ for 24 h.

[0077] The post-processing was the same as in Example 1. The final purity of compound 2 was 97%, and the yield was 88%.

[0078] In step (2), under inert conditions, 61.5 g (0.187 mol) of compound 2 and 246.0 g of N,N-dimethylformamide were added to a three-necked flask and mixed. 27.57 g (0.561 mol) of sodium cyanide was added at 20-30 °C and heated to 80-100 °C for 20 h.

[0079] The post-processing was the same as in Example 1, and the final purity of compound 3 was 98%, with a yield of 82%.

[0080] In step (3), 6.2 g (0.256 mol) of magnesium strip was placed in a three-necked flask under inert gas protection, and nitrogen was used to purge for 0.5 h. A mixture of 7.7 g (0.032 mol) of compound 3 and 77.0 g of methanol was added dropwise with stirring at room temperature. After the addition was completed, the reaction was stirred at room temperature for 24 h.

[0081] The post-processing was the same as in Example 1. The final purity of compound 4 was 98%, and the yield was 89%.

[0082] The dosage and operation of step (4) are the same as in Example 1.

[0083] Comparative Example 1 The preparation of a (S)-2-aminonitrile hydrochloride compound: Comparative Example 1 uses the same preparation method as Example 1, except that in step (1), the amount of pyridine used is 7.9g, which is less than the range set by the present invention. The purity of the final compound 2 is 63%, and the yield is 52%.

[0084] A comparison of the data results from Comparative Example 1 and Example 1 shows that when the amount of pyridine used is less than the range set in this invention, the purity and yield of compound 2 will both decrease. This is because pyridine has the effect of promoting the reaction to proceed in the forward direction.

[0085] Comparative Example 2 The preparation of a (S)-2-aminonitrile hydrochloride compound was carried out in Comparative Example 2 using the same preparation method as in Example 1, except that in step (1), the reaction was carried out at -40 to -30°C. The purity of compound 2 was 81%, and the yield was 75%.

[0086] A comparison of the data results from Comparative Example 2 and Example 1 shows that when the reaction temperature is lower than the range set in this invention, both the purity and yield of compound 2 will decrease. This is because a decrease in reaction temperature will lead to a decrease in reaction rate.

[0087] Comparative Example 3 The preparation of a (S)-2-aminonitrile hydrochloride compound was carried out using the same preparation method as in Example 1 in Comparative Example 4, except that step (2) was not performed when the solvent was replaced with any one of toluene, tetrahydrofuran, or anhydrous ethanol.

[0088] It can be seen that in Comparative Example 4, when the solvent is replaced with a solvent other than that required by the present invention in step (2), the reaction does not proceed. This is because compound 2 and sodium cyanide can be well dispersed and effectively collide with each other in solvents other than DMF or DMSO systems provided in the present invention, and other solvents cannot serve as the dispersion system for this step of the reaction.

[0089] Comparative Example 4 The preparation of a (S)-2-aminonitrile hydrochloride compound: Comparative Example 5 uses the same preparation method as Example 1, except that in step (3), compound 3 is directly added to the methanol reaction system, which will make the reaction very violent and cause a rushing phenomenon.

[0090] Comparative Example 5 The preparation of a (S)-2-aminonitrile hydrochloride compound was carried out using the same preparation method as in Example 1 in Comparative Example 6, except that in step (3), a methanol solution of compound 3 was added dropwise under ice-water bath conditions at 0°C, which caused the reaction in step (3) to not proceed.

[0091] This invention provides a method for preparing (S)-aminonitrile hydrochloride compounds. This method is achieved through steps such as esterification, cyanation, Ts removal, and salt formation. It has advantages such as short route and low cost, and has significant cost competitiveness. At the same time, the reaction conditions are mild, the operation is simple, and it is easy to scale up, making it more suitable for industrial production.

[0092] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are exhaustively listed. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0093] For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention, and these modifications and improvements are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the appended claims.

Claims

1. A process for the preparation of (S)-amino cyanohydrin hydrochloride characterized by, The preparation method comprises the following steps: S1, under inert conditions, mixing compound 1, 4-dimethylaminopyridine, pyridine and a reaction solvent, adding p-toluenesulfonyl chloride to react, to obtain compound 2; S2, under inert conditions, mixing compound 2 obtained in step S1 and a reaction solvent, adding sodium cyanide to react, to obtain compound 3; S3, under inert conditions, putting a magnesium strip into a reaction bottle, and adding a methanol solution of compound 3 obtained in step S2 dropwise at room temperature to react, to obtain compound 4; S4, under inert conditions, mixing compound 4 obtained in step S3 with HCl organic solvent to react, to obtain target compound 5, i.e. (S)-aminocyanide hydrochloride.

2. The process for the preparation of (S)-amino cyanide hydrochloride according to claim 1, characterized in that, In step S1, the molar ratio of the compound 1, the p-toluenesulfonyl chloride, the 4-dimethylaminopyridine and the pyridine is 1.0: (2.0-2.5): (0.1-0.5): (2.0-2.5).

3. The process for the preparation of (S)-amino cyanide hydrochloride according to claim 1, characterized in that, In step S2, the molar ratio of the compound 2 and the sodium cyanide is 1.0: (1.0-3.0).

4. The process for preparing (S)-amino cyanide hydrochloride according to claim 1, wherein the process is characterized by, In step S3, the molar ratio of the compound 3 and the magnesium strip is 1.0: (1.0-8.0). The mass concentration of the methanol solution of compound 3 is 8-12%.

5. The process for the preparation of (S)-amino cyanide hydrochloride according to claim 1, characterized in that, In step S4, the molar ratio of the compound 4 and HCl in the HCl organic solvent is 1.0: (1.0-3.0).

6. The process for the preparation of (S)-amino cyanide hydrochloride according to claim 1, characterized in that, In step S1, the reaction temperature is -20-80 DEG C; and the reaction time is 18-24 h.

7. The process for the preparation of (S)-amino cyanide hydrochloride according to claim 1, characterized in that, In step S2, the reaction temperature is 40-100 DEG C.

8. The process for the preparation of (S)-amino cyanide hydrochloride according to claim 1, characterized in that, In step S4, the mass concentration of HCl in the HCl organic solvent is 20-30%; The HCl organic solvent is at least one of an ethyl acetate solution of HCl, a 1,4-dioxane solution of HCl, a methanol solution of HCl and an ethanol solution of HCl.

9. The process for the preparation of (S)-amino cyanide hydrochloride according to claim 1, characterized in that, In step S1, the reaction solvent is at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, dichloroethane and toluene; In step S2, the reaction solvent is at least one of N,N-dimethylformamide and dimethyl sulfoxide.

10. A compound of the formula (S)-amino cyanohydrin hydrochloride, characterized by, The preparation method is prepared according to any one of claims 1-9.

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