阅读说明：本技术 一种制备(r)-3-氨基丁醇的方法 (Method for preparing (R) -3-aminobutanol ) 是由 李一清 李振琦 李天新 于 2019-09-12 设计创作，主要内容包括：本发明提供了一种制备(R)-3-氨基丁醇的方法,包括：(1)提供4-羟基-2-丁酮,并对其进行氨化还原,得到消旋的3-氨基丁醇；(2)(S)-扁桃酸和消旋的3-氨基丁醇反应,得到拆分后的扁桃酸盐；(3)拆分后的扁桃酸盐经碱化处理获得产物(R)-3-氨基丁醇。本发明通过还原氨化、成盐拆分制备(R)-3-氨基丁醇的过程,操作简便且反应低危险低污染；所得(R)-3-氨基丁醇纯度高达99.9％(GC法)。(The invention provides a method for preparing (R) -3-aminobutanol, which comprises the following steps: (1) providing 4-hydroxy-2-butanone, and carrying out ammoniation reduction on the 4-hydroxy-2-butanone to obtain racemic 3-aminobutanol; (2) (S) -mandelic acid reacts with racemic 3-aminobutanol to obtain resolved mandelate; (3) the separated mandelate is subjected to alkalization treatment to obtain the product (R) -3-aminobutanol. The method prepares the (R) -3-aminobutanol by reduction ammoniation and salifying resolution, has simple and convenient operation, low reaction risk and low pollution; the purity of the obtained (R) -3-aminobutanol reaches 99.9 percent (GC method).)

1. A method of preparing (R) -3-aminobutanol comprising:

(1) providing 4-hydroxy-2-butanone, and ammoniating and reducing the butanone to obtain racemic 3-aminobutanol;

(2) (S) -mandelic acid reacts with racemic 3-aminobutanol to obtain resolved mandelate;

(3) the separated mandelate is subjected to alkalization treatment to obtain the product (R) -3-aminobutanol.

2. The method of claim 1, wherein the molar ratio of 4-hydroxy-2-butanone to ammonia gas in the ammoniation step is 1: 3-1:4.

3. The method of claim 1, wherein the ammoniation is performed in a polar solvent.

4. The method of claim 1, wherein the reduction in step (1) is a heterogeneous catalytic reduction reaction.

5. The method of claim 1, wherein the racemic 3-aminobutanol is purified by distillation.

6. The process of claim 1, wherein the solvent used for the reaction of (S) -mandelic acid and racemic 3-aminobutanol is a polar solvent.

7. The process of claim 1, wherein the salt formation reaction temperature of (S) -mandelic acid and racemic 3-aminobutanol is from 70 to 80 ℃.

8. The method of claim 1, wherein the basifying step is performed in an alcohol solution.

9. The process of claim 1 wherein the product (R) -3-aminobutanol is distilled to obtain purified (R) -3-aminobutanol.

Technical Field

The invention belongs to the field of fine chemical engineering, and particularly relates to a preparation method of high-purity (R) -3-aminobutanol.

Background

(R) -3-aminobutanol is a key intermediate for synthesizing anti-AIDS drug Dolutegravir (structural formula 1). Dolutegravir was developed by the gilantin smith corporation under the trade name tivacay. The documents mol.Phamacol.,2011,80(4): 565-. Compared with the anti-HIV/AIDS drug Latiravir and Dolutergravir in the visador, the Dolutergravir has the same level of curative effect, and simultaneously does not need to be combined with a drug promoter. Thus, in 2013, month 2, the U.S. Food and Drug Administration (FDA) announced an accelerated review and approved for marketing on day 13, month 8, 2013.

In addition, Journal of Organic chemistry, 1977,42:1650, reports that (R) -3-aminobutanol is a key intermediate of 4-methylcyclophosphoramide, an anticancer drug; terahydron Lett, 1988,29:231, reported to be derivatized as a beta-lactam, an important intermediate in the synthesis of penem antibiotics.

Structural formula 1. Dolutegravir (Dolutegravir)

Regarding the synthesis method of (R) -3-aminobutanol, the prior art mainly carries out synthesis by a chemical resolution method, a chiral raw material synthesis method, a chemical induction method, a preparative chromatography method and an enzyme reduction method, and the corresponding methods and the defects thereof are shown as follows.

Chemical resolution method

In the patent US: 2011/0275855A1A1, Breuer et al reported a method for obtaining (R) -3-aminobutanol by resolving racemic 3-aminobutanol with (S) -mandelic acid (3). Optically active (S) -mandelic acid (3) and racemic aminobutanol (2) are stirred and reacted in an isopropanol aqueous solution at the temperature of 20-80 ℃, precipitated and crystallized, vacuum dried to form (R) -3-aminobutyrate mandelate (4), and then dissolved in morpholine, and distilled at the temperature of 93 ℃ under 26mbar to obtain the product (R) -3-aminobutanol. Because of the greater water solubility of (R) -3-aminobutanol, researchers have not employed a method of free base followed by organic extraction, but used 4- (2-hydroxyethyl) morpholine (5) as the solvent and base. The yield of the method reaches 84 percent, the ee value reaches 99.6 percent, but the method has the defect that the morpholine impurities are difficult to remove and the purity is influenced.

Heterocyclic Lett.,2015,5(2):241-244, reported Srinivasa et al use D- (-) -tartaric acid (7) instead of (S) -mandelic acid (3) to react with racemic 3-aminobutanol to give the product (R) -3-aminobutanol (6). But the subsequent treatment used basic potassium carbonate free and acetonitrile extraction, so that the product with greater water solubility was lost.

(II) chiral raw material synthesis method

Tetrahedron,2005,61(38): 9031-. The derivative (11) undergoes wolff rearrangement and hydrolysis to produce the product (R) -3-aminobutanol (6) and the intractable byproduct lactone (12). The disadvantage of this process is that large amounts of reagents are used which are unsuitable for industrialization and give rise to intractable by-products.

(III) chemical induction method

The chemical induction method is one of the methods for completing the introduction of the chiral center by adding an induction chiral reagent at an early stage. The production of (R) -3-aminobutanol (6) by inducing chiral phenethylamine (13) and ethyl crotonate (14) was studied by Kinas et al in J.org.chem.,1977,42(9):1650-1652 as early as 1977. However, this method has low stereoselectivity and low yield (7.8%), and lithium aluminum hydride and palladium on carbon used are not favorable for controlling industrial cost.

Volkmar in the patent US:2003/0073723A1 made an improvement by using a more sterically hindered N-benzyl-1-phenylethylamine (15) instead of chiral phenylethylamine and a more sterically hindered t-butyl crotonate (16) instead of ethyl crotonate (14) to increase stereoselectivity by steric hindrance. The reaction is carried out at the temperature of minus 78 ℃, n-butyl lithium is used as alkali, lithium aluminum hydride is used as a reducing agent, and the product (R) -3-aminobutanol (6) is obtained by palladium hydroxide hydrogenation reduction. The method improves selectivity and yield to 28%, but uses high-cost and high-safety potential reagents such as n-butyl lithium in the process.

In patent CN106748816A, mailogfei and the like utilize a condensation reaction of ethyl acetoacetate (18) and chiral phenethylamine (13) in a toluene solution to obtain a compound (1R) -3- (1' -methylbenzylamine) -2-butenoic acid ethyl ester (19), and then the compound is reduced by the combined action of sodium borohydride and pyridine hydrobromide to obtain a free compound (20). Compound (20) is salified in an ethyl acetate solution containing hydrochloric acid, and resolved in a mixture of acetone and absolute ethanol (V acetone: V ethanol ═ 4: 1) to give compound (21). Reducing sodium borohydride to obtain a compound (22), removing benzyl under the action of palladium carbon, and finally adding (S) -mandelic acid for recrystallization and washing a methanol solution of sodium methoxide and ethyl acetate to obtain a product (R) -3-aminobutanol (6). The method finally obtains chiral purity as high as 100%, but the yield is not high, and the difficulty of industrial implementation is increased by the operation of repeated recrystallization purification. Whereas the ratio of the R-S isomer of compound (21) after salt formation resolution is only 82: 18, this step is to meet the requirements of selective synthesis.

(IV) preparative chromatography

In patent WO 2014/009447A1, Bodil takes racemic 3-aminobutyric acid (23) as a raw material, and Chz-Cl is used for protecting the amino group of the 3-aminobutyric acid (23). A set of racemates 24 and 25 obtained by borane reduction in the ratio 1: 1. then separating the racemate by chiral preparative high performance liquid chromatography, and finally reducing palladium carbon to obtain the product (R) -3-aminobutanol (6), wherein the yield is 94%. But this method is not suitable for industrial scale-up.

(V) biological enzyme method

Tetrahedron Asymmedry,1999,10(11):2213-2224, reported that Pascale et al prepared (R) -3-aminobutanol using enzymatic reduction. Ethylacetoacetate is used as a raw material, and is subjected to yeast asymmetric reduction to obtain (S) -ethyl 3-hydroxybutyrate (26), and then is subjected to lithium aluminum hydride reduction to obtain a compound (27). Then the compound (27) is protected by TBDMSCl hydroxyl to obtain a compound (28), and then the compound (29) is obtained by Mitsunobu reaction, and then the compound (30) is obtained by hydrazine hydrate reduction. Finally deprotection with Bu4NF gave the product (R) -3-aminobutanol (6). The method has the disadvantages of complicated process, high reagent cost, high toxicity and difficult industrial scale-up.

Disclosure of Invention

Aiming at the problems of high raw material cost, high toxicity, large potential safety hazard, severe reaction conditions, low product purity, more byproducts, low yield, fussy and tedious process route, unsuitability for industrialization and the like in the preparation of (R) -3-aminobutanol in the prior art, the invention provides the synthesis method which has the advantages of simple process route, low raw material cost, low risk, mild reaction, high chemical and optical purity of the product, high stability and contribution to environmental protection and industrialization.

The invention provides a synthesis method of (R) -3-aminobutanol. The synthetic route is as follows:

the method comprises the following steps:

(1) providing 4-hydroxy-2-butanone, and carrying out ammoniation reduction on the 4-hydroxy-2-butanone to obtain racemic 3-aminobutanol;

(2) (S) -mandelic acid reacts with racemic 3-aminobutanol to obtain resolved mandelate;

(3) the separated mandelate is subjected to alkalization treatment to obtain the product (R) -3-aminobutanol.

In some embodiments of the invention, the molar ratio of 4-hydroxy-2-butanone to ammonia gas in the ammoniation step is 1: 3-1:4.

In some embodiments of the invention, the aminolysis is carried out in a polar solvent. The polar solvent that may be selected herein includes one or more of methanol, ethanol, isopropanol, n-butanol. Although other solvents may also be used to carry out the reaction, practical reactions have shown that other solvents have certain drawbacks in terms of safety and efficiency.

In some embodiments of the invention, the concentration of 4-hydroxy-2-butanone in the polar solvent is 3-4M.

In some embodiments of the invention, the reduction reaction is a reduction reaction involving a heterogeneous hydrogenation catalyst. In one embodiment of the invention, the reduction is a reaction involving raney nickel, and the hydrogen pressure is 1.2 to 1.5MPa, more preferably 1.35 MPa. In another embodiment of the present invention, palladium on carbon is used as the catalyst. In carrying out the above-mentioned reduction reaction, unnecessary disturbances such as replacement of the gas in the reduction system by nitrogen/hydrogen should be avoided, and the corresponding number of times may be 3 times or more to avoid unnecessary disturbances.

In one embodiment of the invention, the ammoniated reduction product is distilled to obtain purified racemic 3-aminobutanol.

In some embodiments of the present invention, the solvent used for the reaction of (S) -mandelic acid and racemic 3-aminobutanol is a polar solvent, and an alcoholic solvent or a ketone solvent may be selected for the above reaction, and in embodiments of the present invention, the selected solvent includes one or more of methanol, ethanol, isopropanol, acetone, and n-butanol.

In some embodiments of the invention, the molar ratio of racemic 3-aminobutanol to (S) -mandelic acid in step (2) is 1: 0.4-1: 0.5.

in some embodiments of the present invention, (S) -mandelic acid is formulated as a solution with a concentration of 0.2-6M and transferred to the reaction system.

In some embodiments of the invention, 4-hydroxy-2-butanone is formulated in a concentration of 0.2-6M solution and transferred to the reaction system.

In some embodiments of the invention, the reaction conditions for (S) -mandelic acid and racemic 3-aminobutanol are from 70 to 80 deg.C, more preferably 75 deg.C.

In some embodiments of the invention, the alkalization step is performed in an alcoholic solution, and optional systems include methanol/sodium methoxide, methanol/potassium methoxide.

In some embodiments of the invention, the product (R) -3-aminobutanol is distilled to obtain purified (R) -3-aminobutanol.

The (R) -3-aminobutanol (6) obtained by the method has the purity of 99.9 percent and the ee value of more than 99.9 percent.

4-hydroxy-2-butanone and ammonia gas are used as raw materials, and Raney nickel is used as a catalyst, so that the cost of the whole synthesis step is reduced; through the processes of reduction ammoniation and salifying resolution, the operation is simple and convenient, the reaction is low in risk and pollution, and the purity of the obtained product (R) -3-aminobutanol reaches 99.9 percent (a GC method).

Detailed Description

The following are examples of the present invention, which are intended to be illustrative of the invention only and not limiting.

The invention provides a synthesis method of (R) -3-aminobutanol. The synthetic route is as follows:

the method comprises the following steps:

(1) reducing and ammoniating the raw material 4-hydroxy-2-butanone to obtain racemic 3-aminobutanol;

(2) salifying and resolving racemic 3-aminobutanol by using (S) -mandelic acid;

(3) adding a methanol solution of sodium methoxide, and removing to obtain the product (R) -3-aminobutanol.

In the above reaction step, involving the use of a solution, the solute may be provided at a concentration of 0.2 to 6M.

In the ammonolysis step (1), the reactants 4-hydroxy-2-butanone and ammonia (NH) can be obtained by ammonolysis₃) The molar ratio of the reaction can be selected from 1: 3-1: 4; the reaction can be carried out by using a polar solvent such as absolute ethyl alcohol; the dissolving and stirring temperature of reactants is controlled to be 0-20 ℃ (preferably 10 ℃); stirring time is 1-2 hours.

In the reduction step of the step (1), products after ammonolysis are transferred into an autoclave without treatment, nitrogen and hydrogen are respectively replaced for three times, the catalyst is recommended to be Raney nickel, the mass ratio of the Raney nickel is 0.08, the reaction temperature is 40-50 ℃ (preferably 45 ℃), the reaction time is 16-20 hours, and the hydrogenation gas pressure is 1.2-1.5MPa, preferably 1.35 MPa; GC control recommends less than 1.00% for 4-hydroxy-2-butanol. This step can be carried out using palladium on carbon and similar catalysts and under similar reaction conditions.

In the product treatment step of the step (1), it is preferable to collect the filtrate by filtration at 20 to 30 ℃ C (preferably 25 ℃ C.) after completion of the reaction, and concentrate the filtrate under reduced pressure at 40 to 45 ℃ C (preferably 45 ℃ C.). More preferably, the product after concentration under reduced pressure is dissolved in toluene again at 100 ℃ and 110 ℃ (preferably 110 ℃), stirred for 3 to 4 hours (preferably 4 hours) and the lower layer is separated, concentrated at 45 to 50 ℃ (preferably 47 ℃), distilled and received at 80 to 120 ℃ to obtain the product compound (32).

Preferably, when the raney nickel mass ratio is 0.08, sufficient reaction in the reaction can be ensured;

preferably, the hydrogenation pressure is 1.2-1.5MPa, and a better reaction result can be obtained under the hydrogenation pressure;

in the (2) step, the molar ratio of the compound (32) to (S) -mandelic acid is 1: 0.4-1: 0.5; the solvent used is a polar solvent, preferably absolute ethanol.

In the step (2), the compound (32) is added dropwise to (S) -mandelic acid over a period of about 1 hour.

In the step (2), the reaction temperature is controlled to be 70-80 ℃ (preferably 75 ℃); then gradually reducing the temperature to 10-15 ℃ (preferably 13 ℃) within 12-24 hours; filtering and pulping repeatedly, collecting filter cake, filtering at 10-15 deg.C (preferably 13 deg.C), and pulping at 80-85 deg.C (preferably 84 deg.C); drying at 45-50 deg.C under normal pressure for 6-10 hr to obtain compound (33).

In the step (2), the crude product obtained by the reaction is filtered, pulped and dried, and a high-purity product can be obtained in a shorter time than when the crude product is directly dried.

In the step (3), the molar ratio of the compound (33) to sodium methoxide is preferably 1: 1, methanol is used as solvent, and other alcohol/base combinations can be selected; the sodium methoxide can be dropwise added by adopting a methanol solution of the sodium methoxide, and the dropwise adding time is 10 to 30 minutes (preferably 20 minutes); the reaction temperature is 60-65 ℃ (preferably 65 ℃); the reaction time is 15-16 hours (preferably 16 hours); cooling to 0-5 deg.C (preferably 2 deg.C) after reaction; filtering the reaction solution at 0-5 deg.C (preferably 2 deg.C); the filtrate is distilled at 120 ℃ and 130 ℃ (preferably 125 ℃) and the fraction is collected to obtain the final product (R) -3-aminobutanol (6). In the process of step (3), the (R) -3-aminobutanol (6) product has a purity of 99.9% and an ee value of more than 99.9% as determined by GC methods commonly used in the art.

The following are corresponding specific examples: