Search

CN-122010778-A - Preparation method of (S) -3-aminobutyric acid hydrochloride compound

CN122010778ACN 122010778 ACN122010778 ACN 122010778ACN-122010778-A

Abstract

The invention discloses a preparation method of (S) -3-amino butyronitrile hydrochloride compounds, and relates to the technical field of medicine preparation methods. The preparation method comprises the steps of taking (S) -2-methylaziridine as an initial raw material, reacting with sulfonyl chloride in the presence of alkali to obtain an N-sulfonylation intermediate, then adopting diethyl aluminum cyanide to carry out selective ring opening at low temperature, introducing cyano groups to generate a corresponding cyanamide intermediate, removing silicon-based protection by tetra-N-butyl ammonium fluoride, and salifying by hydrogen chloride to obtain a target product. The method has the advantages of mild condition, good selectivity, high yield, convenient mass production and high optical purity of the obtained product, and is suitable for industrial preparation.

Inventors

  • PENG WEI

Assignees

  • 湖南阿斯迪康药业有限公司

Dates

Publication Date
20260512
Application Date
20260410

Claims (10)

  1. 1. The preparation method of the (S) -3-aminobutyric acid hydrochloride compound is characterized in that the preparation method takes (S) -2-methylaziridine and 2- (triphenylsilicon-based) ethane-1-sulfonyl chloride as starting materials, and the (S) -3-aminobutyric acid hydrochloride is prepared through three steps of reaction of upper protecting group, selective ring opening, deprotection and salification; the product in the upper protecting group is (S) -2- (triphenylsilyl) ethane-1-sulfonyl-2-methylaziridine; step two, the product of the selective ring opening is (S) -N- (1-cyano propane-2-yl) -2- (triphenylsilicon-based) ethane-1-sulfonamide; the structure of the (S) -2- (triphenylsilyl) ethane-1-sulfonyl-2-methyl aziridine is as follows: ; The structure of the (S) -N- (1-cyano-propane-2-yl) -2- (triphenylsilyl) ethane-1-sulfonamide is as follows: 。
  2. 2. the method for preparing (S) -3-aminobutyric acid hydrochloride according to claim 1, wherein the synthetic route of the first step is as follows: ; the first step adopts the constraint acid of N, N-diisopropylethylamine; The solvent adopted in the first step is anhydrous dichloromethane; the catalyst adopted in the first step is 4-dimethylaminopyridine; in the first step, the mol ratio of the (S) -2-methylaziridine, the 2- (triphenylsilyl) ethane-1-sulfonyl chloride and the N, N-diisopropylethylamine is 1:1.0-1.1:1.2-1.8.
  3. 3. The method for producing (S) -3-aminobutyric acid hydrochloride according to claim 2, wherein the amount of 4-dimethylaminopyridine is 0.02 to 0.1 times the molar amount of (S) -2-methylaziridine; The reaction temperature of the first step is 0-10 ℃, 2- (triphenylsilicon-based) ethane-1-sulfonyl chloride is dropwise added, and the reaction is carried out for 3-6 hours at 20-30 ℃ in a heat preservation way.
  4. 4. The method for preparing the (S) -3-aminobutyric acid hydrochloride compound according to claim 2, wherein the post-treatment in the first step comprises quenching with saturated aqueous ammonium chloride solution, washing with aqueous citric acid solution, aqueous sodium bicarbonate solution and saturated saline solution, drying with anhydrous magnesium sulfate, and crystallizing and purifying with a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 8-12:1.
  5. 5. The method for preparing (S) -3-aminobutyric acid hydrochloride according to claim 1, wherein the reaction route of the second step is as follows: ; The raw materials of the second step are (S) -2- (triphenylsilyl) ethane-1-sulfonyl-2-methylaziridine and diethyl aluminum cyanide; The dosage of the diethyl aluminum cyanide is 1.1-1.3 equivalent of (S) -2- (triphenylsilyl) ethane-1-sulfonyl-2-methylaziridine; the solvent in the second step is toluene; the second step is carried out under the protection of nitrogen or argon.
  6. 6. The method for preparing (S) -3-aminobutyric acid hydrochloride according to claim 5, wherein in the second step, diethylaluminum cyanide is added dropwise at a temperature of 0-5 ℃, the reaction is carried out for 6-10 hours at a temperature of 35-45 ℃ after the dropwise addition, and the reaction solution is 10% aqueous solution of potassium sodium tartrate to break the aluminum complex.
  7. 7. The method for preparing the (S) -3-aminobutyric acid hydrochloride compound according to claim 6, wherein the post-treatment in the second step comprises ethyl acetate extraction, anhydrous sodium sulfate drying, concentration and pulping and recrystallization by adopting a mixed solvent of methyl tertiary butyl ether and n-heptane with a volume ratio of 1:4-6.
  8. 8. The method for preparing (S) -3-aminobutyric acid hydrochloride according to claim 1, wherein the synthetic route of the third step is as follows: ; step three, taking (S) -N- (1-cyano propane-2-yl) -2- (triphenylsilicon-based) ethane-1-sulfonamide as a raw material; The removing reagent in the third step is tetra-n-butyl ammonium fluoride; The salt forming reagent in the third step is hydrogen chloride-dioxane solution; The solvent in the third step is anhydrous tetrahydrofuran; the dosage of tetra-N-butyl ammonium fluoride is 2.0-2.5 equivalents of (S) -N- (1-cyano propane-2-yl) -2- (triphenylsilicon-based) ethane-1-sulfonamide, the reaction temperature is 40-60 ℃, and the reaction time is 4-8 hours.
  9. 9. The process for preparing (S) -3-aminobutyric acid hydrochloride according to claim 8, wherein in the third step, purified water is added after the reaction, tetrahydrofuran is removed by concentrating under reduced pressure, the by-product of the extraction and separation of triphenylsilicon fluoride is extracted with methyl tert-butyl ether, aqueous phase is back extracted with 1.0M hydrochloric acid, organic phase is washed with dichloromethane, and aqueous phase is combined and lyophilized to obtain crude product.
  10. 10. The preparation method of the (S) -3-aminobutyric acid hydrochloride compound, as claimed in claim 9, is characterized in that the post-treatment in the third step comprises dissolving the freeze-dried crude product in absolute ethyl alcohol, heating to 35-45 ℃, dropwise adding absolute ethyl ether to be slightly turbid under stirring, cooling and crystallizing for 3-5 hours in an ice water bath, filtering and vacuum drying to obtain the pure product of the (S) -3-aminobutyric acid hydrochloride, wherein the optical purity is more than or equal to 99.5%ee.

Description

Preparation method of (S) -3-aminobutyric acid hydrochloride compound Technical Field The invention relates to the technical field of medicine preparation methods, in particular to a preparation method of (S) -3-amino butyronitrile hydrochloride compounds. Background The (S) -3-amino butyronitrile hydrochloride is an important chiral drug intermediate, the structure of the intermediate contains a chiral primary amine center and a terminal cyano group, and the intermediate is a key chiral building block for synthesizing dipeptidyl peptidase-4 (DPP-4) inhibitor antidiabetic drugs (such as sitagliptin and derivatives thereof). The optical purity of the compound directly influences the pharmacological activity and the safety of the final medicine, so that the development of the preparation method with high optical purity and high yield, which is suitable for industrial production, has important economic value and social significance. In the prior art, the preparation of (S) -3-amino butyronitrile hydrochloride mainly adopts an enzymatic resolution method or an enamine reduction method. The enzymatic resolution method generally takes racemate as a raw material and utilizes lipase or acylase to carry out kinetic resolution, but the method has the defects of low theoretical yield upper limit (50% at maximum), high cost of enzyme catalyst, harsh reaction conditions, difficult recycling and the like. The chemical reduction method mostly uses 3-aminobutyric acid as a starting material and performs asymmetric hydrogenation reduction through chiral catalysts (such as ruthenium and rhodium complexes), however, the method usually involves high-pressure equipment, noble metal catalysts have high cost, the products are mostly grease-like substances, the purification is difficult, and the intramolecular cyclization is easy to generate pyrrolidone byproducts or racemization, so that the optical purity is reduced. In addition, the existing technology generally needs multiple column chromatography in the purification process, and the solvent consumption is large, so that the requirement of industrial scale-up production is difficult to meet. Therefore, there is a need to develop a new method for obtaining (S) -3-aminobutyric acid hydrochloride with high optical purity in a high selectivity, which has mild reaction conditions, simple operation, low cost, and is capable of overcoming the technical defects of low yield, difficult purification, easy racemization, unsuitable industrial production and the like in the prior art. Disclosure of Invention The invention aims at solving the problems existing in the prior art and provides a preparation method of (S) -3-aminobutyric acid hydrochloride compounds. The preparation method takes (S) -2-methylaziridine and 2- (triphenylsilyl) ethane-1-sulfonyl chloride as starting materials, and is prepared through three steps of reaction of protecting group loading, selective ring opening, deprotection and salification. In order to achieve the above purpose, the invention adopts the following technical scheme: The preparation method takes (S) -2-methyl aziridine and 2- (triphenylsilicon-based) ethane-1-sulfonyl chloride as starting materials, and the (S) -3-amino butyronitrile hydrochloride is prepared by three steps of reaction of protecting group, selective ring opening, deprotection and salification; the product in the upper protecting group is (S) -2- (triphenylsilyl) ethane-1-sulfonyl-2-methylaziridine; step two, the product of the selective ring opening is (S) -N- (1-cyano propane-2-yl) -2- (triphenylsilicon-based) ethane-1-sulfonamide; the structure of the (S) -2- (triphenylsilyl) ethane-1-sulfonyl-2-methyl aziridine is as follows: ; The structure of the (S) -N- (1-cyano-propane-2-yl) -2- (triphenylsilyl) ethane-1-sulfonamide is as follows: 。 further, the synthetic route of the first step is as follows: ; the first step adopts the constraint acid of N, N-diisopropylethylamine; The solvent adopted in the first step is anhydrous dichloromethane; the catalyst adopted in the first step is 4-dimethylaminopyridine; in the first step, the mol ratio of the (S) -2-methylaziridine, the 2- (triphenylsilyl) ethane-1-sulfonyl chloride and the N, N-diisopropylethylamine is 1:1.0-1.1:1.2-1.8. Further, the dosage of the 4-dimethylaminopyridine is 0.02-0.1 times of the molar quantity of the (S) -2-methylaziridine; The reaction temperature in the first step is 0-10 ℃,2- (triphenylsilicon-based) ethane-1-sulfonyl chloride is dropwise added, and the reaction is carried out for 3-6 hours at 20-30 ℃ in a heat preservation way. Further, the post-treatment in the first step comprises quenching by saturated ammonium chloride aqueous solution, washing by citric acid aqueous solution, sodium bicarbonate aqueous solution and saturated saline solution, drying by anhydrous magnesium sulfate, and crystallizing and purifying by adopting a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 8-12:1. Further,