A preparation method of (R) 3-butyn-2-ol derivative

Abstract

This invention discloses a method for preparing a 3-butyn-2-ol derivative of compound (R) of formula (II) from a 3-butyn-2-one derivative of formula (I) via a reduction reaction, wherein the reduction reaction is an enzyme-catalyzed reduction reaction, and the enzyme is selected from carbonyl reductases. This invention can effectively prepare the target compound and has advantages such as simple operation, environmental friendliness, high yield, high selectivity, and low cost, making it suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a method for preparing a (R) 3-butyn-2-ol derivative. Background Art

[0002] Chiral propargyl alcohol derivatives are important intermediates for the synthesis of natural products such as alkaloids, steroids, and sesquiterpenes.

[0003] The specific structural formula is as follows:

[0004]

[0005] At present, a patent (CN102408313A) has reported the synthesis method of the intermediate, which discloses the following route:

[0006] Racemic 3-butyn-2-ol is used as a raw material, first reacted with phthalic anhydride, and then salified and split with R-phenylethylamine to finally obtain (R) 3-butyn-2-ol. However, in this route, the compound needs to be crystallized and purified several times after salification to obtain the final product. There are also related literature reports on the preparation method of (R) 3-butyn-2-ol derivatives (Thomas Schubert; Werner Hummel; Maria-Regina Kula; Michael Müller. Enantioselective Synthesis of Both Enantiomers of Various Propargylic Alcohols by Use of Two Oxidoreductases. Eur JOC. 2001 (22), 4181-4187.), but these processes have one or more of the following problems: 1) a large amount of high-concentration acid-containing wastewater and waste liquid will be generated during the splitting process; 2) the yield is low, the production cycle is long, and the production cost is increased; 3) the reaction system is too large, the production capacity is low, and it is not suitable for industrial scale-up production. Summary of the invention

[0007] In view of the above problems, the present invention provides a method for preparing a 3-butyn-2-one derivative represented by formula (I) into a (R) 3-butyn-2-ol derivative represented by formula (II):

[0008]

[0009] The R is selected from methyl or ethyl;

[0010] Wherein, when the R is selected from methyl, the enzyme is selected from carbonyl reductase; and the carbonyl reductase is selected from Amano Enzyme Products Co., Ltd. of Japan and is selected from carbonyl reductase K1, carbonyl reductase K2, carbonyl reductase K3 or carbonyl reductase K4;

[0011] or when the R is selected from ethyl, the enzyme is selected from carbonyl reductase; and the carbonyl reductase is selected from Amano Enzyme Products Co., Ltd. of Japan, and is selected from carbonyl reductase K2;

[0012] Further, the temperature of the enzyme catalyzed reaction is 20°C to 60°C, preferably 37°C to 45°C;

[0013] The time for the enzyme catalytic reaction is 12 to 96 hours, preferably 18 to 48 hours.

[0014] Furthermore, the enzyme-catalyzed reaction is carried out in an aqueous solvent system.

[0015] Furthermore, the aqueous solvent is selected from a mixed solvent consisting of phosphate and an organic solvent.

[0016] Furthermore, the organic solvent is selected from methyl tert-butyl ether, isopropyl ether or acetone

[0017] Further, the mass ratio of the compound of formula (I) to the enzyme is 100:1 to 1:1, preferably 30:1 to 10:1;

[0018] Furthermore, the mass ratio of the compound represented by formula (I) to the coenzyme is 10000:1 to 10:1, preferably 1000:1 to 100:1.

[0019] Furthermore, the phosphate solution is a phosphate buffer solution with a pH of 7.2, and in the mixed solvent, the volume ratio of the phosphate buffer solution to the organic solvent is 100:1 to 1:1, preferably 10:1 to 4:1.

[0020] Furthermore, the mass volume ratio of the compound of formula (I) to the solvent is 1:5 to 1:20, preferably 1:10 to 1:15.

[0021] The experimental results show that the present invention can effectively prepare the target compound and has the advantages of simple operation, green environmental protection, high yield, high selectivity and low cost.

[0022] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0023] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0024] In the examples, the enzyme reagents were sourced from Japan's Amano Enzyme Products Co., Ltd., and the coenzymes were sourced from Bontai Biotechnology (Shenzhen) Co., Ltd.

[0025] Example 1

[0026] Preparation of (R)3-butyn-2-ol:

[0027]

[0028] In phosphate buffer (250 mL), 3-butyne-2-one (50 g), carbonyl reductase K1 (2.5 g), coenzyme (NADPH, 0.05 g), methyl tert-butyl ether (62.5 mL), isopropanol (10 mL), stirred at 37 ° C, after 26 hours, the reaction was terminated, methyl tert-butyl ether (250 mL) was added and extracted twice, the organic phases were combined, dried, and spin-dried to obtain 45 g of oil (compound of formula (II)), ee = 99.2%, yield = 90%.

[0029] Example 2

[0030] In phosphate buffer (500 mL), add 3-butyne-2-one (50 g), carbonyl reductase K2 (2.5 g), coenzyme (NADH, 0.5 g), methyl tert-butyl ether (50 mL), isopropanol (10 mL), and react with stirring at 45 ° C. After 18 hours, terminate the reaction, add methyl tert-butyl ether (250 mL) and extract twice. The organic phases are combined, dried, and spin-dried to obtain 42 g of an oily substance (compound of formula (II)), ee = 99.6%, yield = 84%.

[0031] Example 3

[0032] In phosphate buffer (500 mL), add 3-butyne-2-one (50 g), carbonyl reductase K2 (1.6 g), coenzyme (NADH, 0.05 g), methyl tert-butyl ether (50 mL), isopropanol (10 mL), and react with stirring at 45°C. After 38 hours, terminate the reaction, add methyl tert-butyl ether (250 mL) and extract twice. Combine the organic phases, dry, and spin dry to obtain 44 g of an oily substance (compound of formula (II)), ee = 99.6%, yield = 88%.

[0033] Example 4

[0034] In phosphate buffer (750 mL), 3-butyne-2-one (50 g), carbonyl reductase K3 (5 g), coenzyme (0.02 g), isopropyl ether (75 mL), isopropanol (10 mL), stirred at room temperature, after 38 hours, terminate the reaction, add methyl tert-butyl ether (250 mL) and extract twice, combine the organic phases, dry, and spin dry to obtain 41 g of oil (compound of formula (II)), ee = 98.5%, yield = 82%.

[0035] Example 5

[0036] In phosphate buffer (500 mL), add 3-butyne-2-one (50 g), carbonyl reductase K4 (1.6 g), coenzyme (NADPH, 0.1 g), acetone (50 mL), isopropanol (10 mL), stir at room temperature. After 48 hours, terminate the reaction, add methyl tert-butyl ether (250 mL) and extract twice. Combine the organic phases, dry, and spin dry to obtain 43.5 g of oil (compound of formula (II)), ee = 97.5%, yield = 87%.

[0037] Example 6

[0038] Preparation of (R)1-butyn-3-ol:

[0039]

[0040] In phosphate buffer (500 mL), add 1-butyne-3-one (50 g), carbonyl reductase K2 (2.5 g), coenzyme (NADH, 0.5 g), methyl tert-butyl ether (50 mL), isopropanol (10 mL), and react at 45 ° C. After 24 hours, terminate the reaction, add methyl tert-butyl ether (250 mL) and extract twice. Combine the organic phases, dry, and spin dry to obtain 45.3 g of oil (compound of formula (IIb)), ee = 99.4%, yield = 90.6%

[0041] In summary, high-purity alkynol intermediates can be effectively prepared, which has the advantages of simple operation, green environmental protection, high yield, high selectivity, low cost, etc., and can be applied to industrial production.

Claims

1. A method for preparing a 3-butyn-2-ol derivative of a compound (R) of formula (II) from a 3-butyn-2-one derivative of a compound of formula (I), characterized in that The steps include: 1) Using the compound represented by formula (I) as a raw material, in an aqueous solvent system, using isopropanol as a hydrogen source, and subjecting the reduced product to enzyme-catalyzed reduction to obtain a (R) 3-butyn-2-ol derivative; wherein, the R is selected from methyl, the enzyme is selected from carbonyl reductase; and the carbonyl reductase is selected from Amano Enzyme Products Co., Ltd. of Japan, and is selected from carbonyl reductase K1, carbonyl reductase K2, carbonyl reductase K3 or carbonyl reductase K4; Or the R is selected from ethyl, the enzyme is selected from carbonyl reductase; and the carbonyl reductase is selected from Amano Enzyme Products Co., Ltd. of Japan, and is selected from carbonyl reductase K2; The coenzyme is selected from reduced nicotinamide adenine dinucleotide phosphate (NADPH) or nicotinamide adenine dinucleotide (NADH); The enzyme-catalyzed reaction is carried out in an aqueous solvent system; The aqueous solvent is selected from a mixed solvent consisting of a phosphate buffer and an organic solvent; The organic solvent is selected from methyl tert-butyl ether, isopropyl ether or acetone.

2. The method according to claim 1, characterized in that: The temperature of the enzyme catalyzed reaction is 20°C to 60°C; The enzyme catalyzed reaction time is 12 to 96 hours.

3. The method according to claim 1, characterized in that: The mass ratio of the compound represented by formula (I) to the enzyme is 100:1 to 1:1; the mass ratio of the compound represented by formula (I) to the coenzyme is 10000:1 to 10:

1.

4. The method according to claim 1, characterized in that: The phosphate buffer is a phosphate buffer with a pH of 7.

2. In the mixed solvent, the volume ratio of the phosphate buffer to the organic solvent is 100:1 to 1:1.

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