CN108689866B - Synthesis method of (R) -3-aminobutanol - Google Patents
Synthesis method of (R) -3-aminobutanol Download PDFInfo
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- CN108689866B CN108689866B CN201710219841.5A CN201710219841A CN108689866B CN 108689866 B CN108689866 B CN 108689866B CN 201710219841 A CN201710219841 A CN 201710219841A CN 108689866 B CN108689866 B CN 108689866B
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Abstract
The invention discloses a method for synthesizing (R) -3-aminobutanol. The method adopts (R) -3-aminobutyric acid as a raw material, the raw material is subjected to one-step reduction by borohydride and protonic acid, a crude product is distilled to obtain a product with good chemical purity and optical purity, and the product yield can reach about 80%. According to the invention, the yield is greatly improved, the cost is reduced, and the large-scale production is easy to realize, so that the method is safe, safe and effective and has small safety risk.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals.
Background
Dolutegravir (formula I) was developed by the U.S. griseofulvin smith corporation and was approved by the U.S. FDA for marketing on 12/8/2013. Dolutegravir is a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor that blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration by binding to the integrase active site and is useful in combination with other antiretroviral drugs for the treatment of HIV-1 infections in children over 12 years of age and weighing at least 40 kg.
The currently reported synthesis methods of dolutegravir mainly comprise two major types, one is that maltol is used as a raw material, and the synthesis methods are disclosed in documents US8129385, US8217034, US8552187 and WO 2015001572; the other is synthesized by taking substituted ethyl methyl acetoacetate as a raw material, and is shown in documents WO2015111080, WO2011119566 and WO 2012018065. Both synthetic routes, although starting from different starting materials, use the same intermediate (R) -3-aminobutanol (formula II).
The synthesis method of the dolutegravir key intermediate (R) -3-aminobutanol comprises the following steps: chiral source synthesis, see Tetrahedron, 2005, p9031-41, chemical resolution method, see US2011275855, chiral induction method, j, org, chem, 1977, p1650-52, US 20037373723, biocatalysis method, see Tetrahedron Asymmetry, 1999, p2213-24, and asymmetric catalytic hydrogenation method, see CN 104370755. These methods either have the disadvantages of complicated operation, low yield, long line, or high cost.
Among them, document CN104370755 reports a method of reducing (R) -3-aminobutyric acid with sodium borohydride and lewis acid, but the yield is low, and the use of lewis acid such as anhydrous zinc chloride which is very hygroscopic brings inconvenience to the storage and production operations of the reagent. In addition, documents WO2014140059, US20060030610, US20050054701, Journal of Heterocyclic Chemistry, 2007, p1465-73 and the like report a method of reducing (R) -3-aminobutyric acid to (R) -3-aminobutanol with lithium aluminum hydride, and documents WO2006085149, WO2013187467 report a method of reducing (R) -3-aminobutanoic acid to (R) -3-aminobutanol with borane. The latter two disadvantages are that lithium aluminum hydride and borane are expensive, and lithium aluminum hydride is very active in property and can explode when meeting water, so that safety risk exists and the large-scale production is difficult; the borane is extremely toxic and can be spontaneously combusted, and has great safety risk.
Disclosure of Invention
In order to overcome the defects of complex operation, low yield, long line, high cost, high toxicity and the like in the prior art, the invention discloses a novel method for synthesizing (R) -3-aminobutanol. The method adopts (R) -3-aminobutyric acid as a raw material, sodium borohydride and protonic acid are reduced into a product in one step, the crude product is distilled to obtain a product with chemical purity and optical purity both higher than 99%, and the yield is about 80%. Compared with similar documents, the method has the advantages that the yield is greatly improved, the cost is reduced, the operation is easy, and the large-scale production is easy to realize. Meanwhile, the use of lithium aluminum hydride and borane which have high safety risk and high price is avoided. In contrast, the method of the invention has extremely low safety risk and is a safe and effective method. Specifically, the method comprises the following characteristics:
in a solvent, (R) -3-aminobutyric acid is used as a raw material, and is subjected to reduction reaction with borohydride in the presence of protonic acid to obtain (R) -3-aminobutanol.
The borohydride is selected from one or two of sodium borohydride and potassium borohydride.
The protonic acid is selected from one or more of concentrated sulfuric acid, trifluoroacetic acid and methanesulfonic acid.
The solvent is selected from tetrahydrofuran or ethylene glycol dimethyl ether.
Wherein, the molar ratio of (R) -3-aminobutyric acid, borohydride and protonic acid is 1: 1.5-3.0: 1.0 to 3.0, preferably 1: 2: 1.05.
wherein the reaction temperature is 0-60 ℃.
The reduction reaction comprises the following steps: under the protection of nitrogen, adding the borohydride and (R) -3-aminobutyric acid into a reaction bottle 1, adding tetrahydrofuran, and cooling for later use; dripping concentrated sulfuric acid into a reaction bottle 2 containing tetrahydrofuran solution to prepare tetrahydrofuran sulfate solution; then slowly dripping a tetrahydrofuran sulfate solution in the reaction bottle 2 into a reaction bottle 1 containing borohydride and (R) -3-aminobutyric acid, and absorbing tail gas by using sodium hydroxide; after the dropwise addition is finished, heating to react until the raw materials disappear, adding a sodium hydroxide solution to quench the reaction, and then separating and concentrating to obtain the (R) -3-aminobutanol.
The reduction reaction comprises the following steps: adding the borohydride into a reaction bottle 1 under the protection of nitrogen, adding tetrahydrofuran, and cooling for later use; dripping concentrated sulfuric acid into a reaction bottle 2 containing tetrahydrofuran solution to prepare tetrahydrofuran sulfate solution; then slowly dripping a tetrahydrofuran sulfate solution in the reaction bottle 2 into the reaction bottle 1 containing borohydride, and absorbing tail gas by sodium hydroxide; after the dropwise addition is finished, adding (R) -3-aminobutyric acid in batches, heating to react until the raw materials disappear, adding a sodium hydroxide solution to quench the reaction, and then separating and concentrating to obtain (R) -3-aminobutanol.
The reduction reaction comprises the following steps: under the protection of nitrogen, adding the borohydride and (R) -3-aminobutyric acid into a reaction bottle 1, adding tetrahydrofuran, and cooling for later use; dripping concentrated sulfuric acid into a reaction bottle 2 containing glycol dimethyl ether solution to prepare glycol dimethyl ether solution of sulfuric acid; then slowly dripping the sulfuric acid glycol dimethyl ether solution in the reaction bottle 2 into the reaction bottle 1 containing borohydride and (R) -3-aminobutyric acid, and absorbing tail gas by using sodium hydroxide; after the dropwise addition is finished, heating to react until the raw materials disappear, adding a sodium hydroxide solution to quench the reaction, and then separating and concentrating to obtain the (R) -3-aminobutanol.
The reduction reaction comprises the following steps: and (3) under the protection of nitrogen, adding the borohydride and (R) -3-aminobutyric acid into a reaction bottle, adding tetrahydrofuran, and cooling with ice water. Then slowly dropwise adding trifluoroacetic acid, and absorbing tail gas by sodium hydroxide. After the dropwise addition is finished, heating to react until the raw materials disappear, adding sodium hydroxide to quench the reaction, and then separating and concentrating to obtain the (R) -3-aminobutanol.
The reduction reaction comprises the following steps: and (3) under the protection of nitrogen, adding the borohydride and (R) -3-aminobutyric acid into a reaction bottle, adding tetrahydrofuran, and cooling with ice water. Then slowly dripping methanesulfonic acid, and absorbing tail gas by sodium hydroxide. After the dropwise addition is finished, heating to react until the raw materials disappear, adding a sodium hydroxide solution to quench the reaction, and then separating and concentrating to obtain the (R) -3-aminobutanol.
Detailed Description
Example 1:
under the protection of nitrogen, 90g of sodium borohydride and 100g of (R) -3-aminobutyric acid are added into a reaction bottle 1, 1L of tetrahydrofuran is added, and the mixture is cooled by ice water for later use. Adding 200mL of tetrahydrofuran into the reaction bottle 2, cooling in an ice-water bath, and slowly dropwise adding concentrated sulfuric acid into the reaction bottle 2 to prepare a tetrahydrofuran solution of sulfuric acid. And slowly dripping the tetrahydrofuran sulfate solution in the reaction bottle 2 into the reaction bottle 1, and absorbing tail gas by using a sodium hydroxide solution. After the dropwise addition, the temperature is raised to 60 ℃ for reaction until the raw materials disappear. Adding sodium hydroxide solution to quench the reaction, standing for layering, and distilling an organic phase to recover tetrahydrofuran; extracting the water phase with chloroform, combining the extracts, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and distilling the crude product under reduced pressure to obtain the product. Yield: 74.3%, purity: 99.7%, ee: 99.6%.
Example 2:
120g of sodium borohydride and 124g of (R) -3-aminobutyric acid are added to a reaction bottle under the protection of nitrogen, 1.5L of tetrahydrofuran is added, and the mixture is cooled by ice water. 506g of trifluoroacetic acid was slowly added dropwise to the reaction flask, and the off-gas was absorbed by sodium hydroxide solution. After the dropwise addition, the temperature is raised to 20 ℃ for reaction until the raw materials disappear. Adding sodium hydroxide solution to quench the reaction, standing for layering, and distilling the organic phase to recover tetrahydrofuran. Extracting the water phase with chloroform, combining the extracts, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and distilling the crude product under reduced pressure to obtain the product. Yield: 84.3%, purity: 99.5%, ee: 99.6%.
Example 3:
under the protection of nitrogen, 45g of sodium borohydride and 60g of (R) -3-aminobutyric acid are added into a reaction bottle 1, 1L of tetrahydrofuran is added, and the mixture is cooled by ice water for later use. And adding ethylene glycol dimethyl ether into the reaction bottle 2, cooling in an ice-water bath, and slowly dropwise adding 62g of concentrated sulfuric acid into the reaction bottle 2 to prepare the ethylene glycol dimethyl ether solution of sulfuric acid. Slowly dripping the sulfuric acid glycol dimethyl ether solution in the reaction bottle 2 into the reaction bottle 1, and absorbing tail gas by using a sodium hydroxide solution. After the dropwise addition, the temperature is raised for reaction until the raw materials disappear. Adding sodium hydroxide solution to quench the reaction, standing for layering, and distilling the organic phase to recover tetrahydrofuran. Extracting the water phase with chloroform, combining the extracts, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and distilling the crude product under reduced pressure to obtain the product. Yield: 73.3%, purity: 99.47%, ee: 99.8%.
Example 4:
under the protection of nitrogen, 54g of potassium borohydride is added into the reaction bottle 1, tetrahydrofuran is added, and ice water is used for cooling for standby. Adding 1L of tetrahydrofuran into the reaction bottle 2, cooling in ice water bath, and slowly dropwise adding 60g of concentrated sulfuric acid into the reaction bottle 2 to prepare a tetrahydrofuran solution of sulfuric acid. And slowly dripping the tetrahydrofuran sulfate solution in the reaction bottle 2 into the reaction bottle 1, and absorbing tail gas by using a sodium hydroxide solution. After the dropwise addition is finished, stirring is continuously carried out until the reaction is completed, then 52g of (R) -3-aminobutyric acid is added in batches, and the temperature is raised for reaction until the raw materials disappear. Adding sodium hydroxide solution to quench the reaction, standing for layering, and distilling an organic phase to recover tetrahydrofuran; extracting the water phase with chloroform, combining the extracts, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and distilling the crude product under reduced pressure to obtain the product. Yield 83%, purity: 99.6%, ee: 99.9%.
Example 5:
under the protection of nitrogen, 90g of potassium borohydride and 75g of (R) -3-aminobutyric acid are added into a reaction bottle, tetrahydrofuran is added, and the mixture is cooled by ice water. 350g of methanesulfonic acid is slowly added into the reaction flask dropwise, and the tail gas is absorbed by sodium hydroxide solution. After the dropwise addition, the temperature is raised for reaction until the raw materials disappear. Adding sodium hydroxide solution to quench the reaction, standing for layering, and distilling the organic phase to recover tetrahydrofuran. Extracting the water phase with chloroform, combining the extracts, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and distilling the crude product under reduced pressure to obtain the product. Yield 80.2%, purity: 99.7%, ee: 99.6%.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (1)
1. A method for preparing (R) -3-aminobutanol, characterized by: under the protection of nitrogen, adding 120g of sodium borohydride and 124g of (R) -3-aminobutyric acid into a reaction bottle, adding 1.5L of tetrahydrofuran, and cooling with ice water; slowly dripping 506g of trifluoroacetic acid into the reaction bottle, and absorbing tail gas by using a sodium hydroxide solution; after the dropwise addition is finished, heating to 20 ℃ for reaction until the raw materials disappear; adding sodium hydroxide solution to quench the reaction, standing for layering, and distilling an organic phase to recover tetrahydrofuran; extracting the water phase with chloroform, combining the extracts, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and distilling the crude product under reduced pressure to obtain the product.
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| CN110818578A (en) * | 2019-10-25 | 2020-02-21 | 西安凯立新材料股份有限公司 | Catalytic hydrogenation synthesis method of chiral aminobutanol |
| CN113336655A (en) * | 2020-12-30 | 2021-09-03 | 江西迪赛诺制药有限公司 | Preparation method of (R) -3-aminobutanol |
| CN114853624A (en) * | 2021-04-07 | 2022-08-05 | 青岛贞开生物医药技术有限公司 | Preparation method of 4-amino-1-butanol and N-protected derivative thereof |
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| JPH07228556A (en) * | 1994-02-17 | 1995-08-29 | Nippon Chemiphar Co Ltd | Production of 2-aminobenzyl alcohol derivative |
| CN101128421A (en) * | 2004-12-22 | 2008-02-20 | 神经化学（国际）有限公司 | Methods and compositions for treating amyloid-related diseases |
| WO2011161690A1 (en) * | 2010-06-23 | 2011-12-29 | Symed Labs Limited | Processes for the preparation of (+)-n,n-dimethyl-2-[1-(naphthalenyloxy) ethyl] benzene methanamine and intermediates thereof |
| CN103664660A (en) * | 2013-12-04 | 2014-03-26 | 苏州永健生物医药有限公司 | Synthesis method of dapoxetine hydrochloride |
| CN104370755A (en) * | 2014-08-18 | 2015-02-25 | 江西隆莱生物制药有限公司 | Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid |
| JP2015131803A (en) * | 2013-12-13 | 2015-07-23 | 大正製薬株式会社 | Medicament comprising heteroaromatic ring methyl cyclic amine derivative |
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- 2017-04-06 CN CN201710219841.5A patent/CN108689866B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07228556A (en) * | 1994-02-17 | 1995-08-29 | Nippon Chemiphar Co Ltd | Production of 2-aminobenzyl alcohol derivative |
| CN101128421A (en) * | 2004-12-22 | 2008-02-20 | 神经化学（国际）有限公司 | Methods and compositions for treating amyloid-related diseases |
| WO2011161690A1 (en) * | 2010-06-23 | 2011-12-29 | Symed Labs Limited | Processes for the preparation of (+)-n,n-dimethyl-2-[1-(naphthalenyloxy) ethyl] benzene methanamine and intermediates thereof |
| CN103664660A (en) * | 2013-12-04 | 2014-03-26 | 苏州永健生物医药有限公司 | Synthesis method of dapoxetine hydrochloride |
| JP2015131803A (en) * | 2013-12-13 | 2015-07-23 | 大正製薬株式会社 | Medicament comprising heteroaromatic ring methyl cyclic amine derivative |
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