A preparation method of (S)-3-aminobutyronitrile hydrochloride

Abstract

The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing (S)-3-aminobutyronitrile hydrochloride, which specifically comprises the following steps: 1) Step 1: (S)-(4-hydroxybutyl-2-yl)carbamic acid tert-butyl ester reacts with manganese dioxide to synthesize (S)-(4-oxobutyl-2-yl)carbamic acid tert-butyl ester; 2) Step 2: (S)-(4-oxobutyl-2-yl)carbamic acid tert-butyl ester prepared in step 1 and hydroxylamine hydrochloride are catalyzed by zinc chloride to synthesize (S)-3-aminobutyronitrile hydrochloride. The invention has the following beneficial effects: the total reaction yield is high, the obtained (S)-3-aminobutyronitrile hydrochloride has high purity, the operation is simple, the reaction time is short, the reaction conditions are mild, no cyanide is required to participate in the reaction, thereby reducing the production cost, and facilitating large-scale production, avoiding the cyanide endangering the safety of the staff during the production process.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing (S)-3-aminobutyronitrile hydrochloride. Background Art

[0002] (S)-3-Aminobutyronitrile hydrochloride is a chiral compound. As a chiral inducer, it plays an important role in organic synthesis. It can also be used as a pharmaceutical intermediate and has a good market prospect.

[0003] Patent WO2024137426 introduces a method for preparing (S)-3-aminobutyronitrile hydrochloride. This method uses sodium cyanide in the preparation process. Sodium cyanide is a highly toxic substance, and the production operation risk is high, which is not suitable for safe production. At the same time, patent CN118420491A discloses a method for preparing (S)-3-aminobutyronitrile hydrochloride. L-aminopropanol is used as a raw material, and alkoxycarbonylation, acylation, cyanation, and removal of alkoxycarbonyl reactions are carried out in sequence to obtain (S)-3-aminobutyronitrile hydrochloride. Although the cyanation reaction of this method does not use sodium cyanide, the reaction yield and product purity are both low, and the reaction steps are complicated, making it difficult to use for large-scale industrial production. Therefore, how to develop a method for preparing (S)-3-aminobutyronitrile hydrochloride that does not require cyanide to participate in the reaction, has high reaction yield and product purity, and has simple reaction steps has become an urgent problem to be solved. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for preparing (S)-3-aminobutyronitrile hydrochloride.

[0005] The present invention relates to a method for preparing (S)-3-aminobutyronitrile hydrochloride, which specifically comprises the following steps:

[0006] 1) Step 1: Synthesis of (S)-tert-butyl (4-oxobutan-2-yl)carbamate:

[0007] Adding (S)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester and manganese dioxide to a reaction solvent, heating first and then keeping the temperature for reaction, filtering the reaction solution after the reaction is completed, washing the filter cake to obtain a primary mother liquor, adding activated carbon to the primary mother liquor for decolorization, filtering the decolorized primary mother liquor, washing the filter cake to obtain a secondary mother liquor, and concentrating the secondary mother liquor under reduced pressure until no fraction is obtained to obtain (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester;

[0008] 2) Step 2: Synthesis of (S)-3-aminobutyronitrile hydrochloride:

[0009] The (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester, zinc chloride and hydroxylamine hydrochloride prepared in step 1 are added to the reaction solvent, and the temperature is first increased and then kept for reaction. After the reaction is completed, the reaction solution is concentrated under reduced pressure until no fraction is produced, and methanol is added for pulping after cooling. The reaction solution is filtered after cooling again, and the filter cake is washed and dried to obtain (S)-3-aminobutyronitrile hydrochloride.

[0010] Preferably, the synthetic route is as follows:

[0011] .

[0012] Preferably, in the step 1, the molar ratio of the (S)-tert-butyl (4-hydroxybutan-2-yl)carbamate to manganese dioxide is 1:1 to 1.5.

[0013] Preferably, in step 1, the reaction solvent is dichloromethane, petroleum ether, hexane or acetone.

[0014] Preferably, in step 1, the temperature is raised to 20-40° C. and the reaction time is kept at this temperature for 18-20 hours.

[0015] Preferably, in step 1, the mass of the activated carbon is 2% to 8% of the mass of the (S)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester.

[0016] Preferably, in the step 2, the molar ratio of the (S)-tert-butyl (4-oxobutan-2-yl)carbamate, zinc chloride and hydroxylamine hydrochloride is 1:0.02-0.08:1-1.3.

[0017] Preferably, in step 2, the reaction solvent is N,N-dimethylformamide, toluene or xylene.

[0018] Preferably, in the step 2, the temperature is raised to 80-120° C., and the reaction time is kept warm for 2-4 hours; the temperature is lowered to 25-30° C.; the volume of the methanol is measured in milliliters, the mass of the (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester is measured in grams, and the volume of the methanol is 0.5-1.5 times the mass of the (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester; the temperature is lowered to 0-5° C. again, and the temperature of the solvent used for washing the filter cake is controlled at 0-5° C.

[0019] Preferably, the total yield of the two-step reaction is greater than 85%, and the purity of the (S)-3-aminobutyronitrile hydrochloride is greater than 99.0%.

[0020] Compared with the prior art, the advantages and positive effects of the present invention are:

[0021] (1) The method for preparing (S)-3-aminobutyronitrile hydrochloride has a high total reaction yield, and the obtained (S)-3-aminobutyronitrile hydrochloride has high purity, thereby reducing the production cost;

[0022] (2) The preparation method of (S)-3-aminobutyronitrile hydrochloride is simple to operate and has a short reaction time, which reduces labor costs and is convenient for large-scale production;

[0023] (3) The preparation method of (S)-3-aminobutyronitrile hydrochloride has mild reaction conditions, so that the reaction performance will not be affected when it is scaled up to industrial production scale;

[0024] (4) The method for preparing (S)-3-aminobutyronitrile hydrochloride does not require cyanide to participate in the reaction, thereby avoiding the danger of cyanide to the safety of workers during the production process and reducing the harm to the environment. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the following is a brief introduction to the drawings required for describing the embodiment:

[0026] Figure 1 This is the NMR spectrum of the (S)-3-aminobutyronitrile hydrochloride provided in Example 1. DETAILED DESCRIPTION

[0027] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention is further described below with reference to the accompanying drawings and embodiments.

[0028] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0029] Example 1

[0030] The following is combined with Figure 1 The present invention is further described as a method for preparing (S)-3-aminobutyronitrile hydrochloride, which specifically comprises the following steps:

[0031] 1) Step 1: Synthesis of (S)-tert-butyl (4-oxobutan-2-yl)carbamate:

[0032] 50.0g of (S)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester and 34.4g of manganese dioxide were added to 200ml of dichloromethane, stirred evenly, and then heated to 25°C. Stirred and kept warm for 20h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with 25ml of dichloromethane to obtain a primary mother liquor. 2.5g of activated carbon was added to the primary mother liquor for decolorization for 1h, and then filtered. The filter cake was washed with 50ml of dichloromethane to obtain a secondary mother liquor. The secondary mother liquor was concentrated under reduced pressure until no fraction was produced to obtain 43.5g of (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester with a purity of 98.6% and a reaction yield of 88.0%.

[0033] 2) Step 2: Synthesis of (S)-3-aminobutyronitrile hydrochloride:

[0034] 43.5 g of tert-butyl (S)-(4-oxobutan-2-yl)carbamate prepared in step 1, 1.0 g of zinc chloride and 17.7 g of hydroxylamine hydrochloride were added to 130 ml of toluene, stirred evenly, heated to 100°C, stirred and kept warm for 2 h, and monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure until no fraction was produced, cooled to 30°C, 50 ml of methanol was added for 0.5 h, cooled to 5°C, stirred for 1 h, filtered, and the filter cake was washed with 25 ml of 5°C methanol. The filter cake was dried at 55°C to obtain 27.5 g of (S)-3-aminobutyronitrile hydrochloride with a purity of 99.2% and a reaction yield of 98.3%.

[0035] Example 2

[0036] A method for preparing (S)-3-aminobutyronitrile hydrochloride, specifically comprising the following steps:

[0037] 1) Step 1: Synthesis of (S)-tert-butyl (4-oxobutan-2-yl)carbamate:

[0038] 100.0g of (S)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester and 45.9g of manganese dioxide were added to 400ml of acetone, stirred evenly, and then heated to 40°C. Stirred and kept warm for 18h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with 50ml of acetone to obtain a primary mother liquor. 8.0g of activated carbon was added to the primary mother liquor for decolorization for 1h, and then filtered. The filter cake was washed with 100ml of acetone to obtain a secondary mother liquor. The secondary mother liquor was concentrated under reduced pressure until no fraction was produced to obtain 88.9g of (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester with a purity of 98.3% and a reaction yield of 89.9%.

[0039] 2) Step 2: Synthesis of (S)-3-aminobutyronitrile hydrochloride:

[0040] 88.9g of (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester prepared in step 1, 5.2g of zinc chloride and 43.5g of hydroxylamine hydrochloride were added to 250ml of N,N-dimethylformamide, stirred evenly, heated to 80℃, stirred and kept warm for 3h, and monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure until no fraction was produced, cooled to 25℃, added with 90ml of methanol for 0.5h, cooled to 0℃ and stirred for 1h, filtered, and the filter cake was washed with 45ml of 0℃ methanol, and dried at 55℃ to obtain 56.2g of (S)-3-aminobutyronitrile hydrochloride with a purity of 99.0% and a reaction yield of 98.1%.

[0041] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes for application in other fields. However, any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing (S)-3-aminobutyronitrile hydrochloride, characterized in that: The specific steps include: Step 1: Synthesis of (S)-tert-butyl (4-oxobutan-2-yl)carbamate: Adding (S)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester and manganese dioxide to a reaction solvent, heating first and then keeping the temperature for reaction, filtering the reaction solution after the reaction is completed, washing the filter cake to obtain a primary mother liquor, adding activated carbon to the primary mother liquor for decolorization, filtering the decolorized primary mother liquor, washing the filter cake to obtain a secondary mother liquor, and concentrating the secondary mother liquor under reduced pressure until no fraction is obtained to obtain (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester; Step 2: Synthesis of (S)-3-aminobutyronitrile hydrochloride: The (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester, zinc chloride and hydroxylamine hydrochloride prepared in step 1 are added to the reaction solvent, the temperature is first raised and then the temperature is kept for reaction. After the reaction is completed, the reaction solution is concentrated under reduced pressure until no fraction is obtained, methanol is added to pulp after cooling, the temperature is again lowered and filtered, the filter cake is washed, and the filter cake is dried to obtain (S)-3-aminobutyronitrile hydrochloride; The synthetic route of the preparation method of (S)-3-aminobutyronitrile hydrochloride is as follows: 。 2. The method for preparing (S)-3-aminobutyronitrile hydrochloride according to claim 1, characterized in that: In the step 1, the molar ratio of the (S)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester to manganese dioxide is 1:1 to 1.

5.

3. The method for preparing (S)-3-aminobutyronitrile hydrochloride according to claim 2, characterized in that: In the step 1, the reaction solvent is dichloromethane, petroleum ether, hexane or acetone.

4. The method for preparing (S)-3-aminobutyronitrile hydrochloride according to claim 3, characterized in that: In the step 1, the temperature is raised to 20-40° C. and the reaction time is kept at this temperature for 18-20 hours.

5. The method for preparing (S)-3-aminobutyronitrile hydrochloride according to claim 4, characterized in that: In the step 1, the mass of the activated carbon is 2% to 8% of the mass of the (S)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester.

6. The method for preparing (S)-3-aminobutyronitrile hydrochloride according to claim 5, characterized in that: In the step 2, the molar ratio of the (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester, zinc chloride and hydroxylamine hydrochloride is 1:0.02-0.08:1-1.

3.

7. The method for preparing (S)-3-aminobutyronitrile hydrochloride according to claim 6, characterized in that: In the step 2, the reaction solvent is N,N-dimethylformamide, toluene or xylene.

8. The method for preparing (S)-3-aminobutyronitrile hydrochloride according to claim 7, characterized in that: In the step 2, the temperature is raised to 80-120° C., and the heat preservation reaction time is 2-4 hours; the temperature is lowered to 25-30° C.; the volume of the methanol is measured in milliliters, the mass of the (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester is measured in grams, and the volume of the methanol is 0.5-1.5 times the mass of the (S)-(4-oxobutan-2-yl)carbamic acid tert-butyl ester; the temperature is lowered to 0-5° C. again, and the temperature of the solvent used for washing the filter cake is controlled at 0-5° C.

9. The method for preparing (S)-3-aminobutyronitrile hydrochloride according to claim 8, characterized in that: The total yield of the two-step reaction is greater than 85%, and the purity of the (S)-3-aminobutyronitrile hydrochloride is greater than 99.0%.

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