CN117326977A - Preparation method of 6-cyano-5-hydroxy-3-oxo caproate - Google Patents

Abstract

The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of 6-cyano-5-hydroxy-3-oxo caproate. The invention relates to a preparation method of 6-cyano-5-hydroxy-3-oxo caproate, which comprises the following steps: the cyanoacetaldehyde, the diketene, the alcohol and the catalyst are subjected to a first reaction in an organic solvent to obtain the 6-cyano-5-hydroxy-3-oxo caproate. According to the invention, the reaction of cyanoacetaldehyde, diketene and alcohol is adopted to synthesize the 6-cyano-5-hydroxy-3-oxo-hexanoate by a one-step method, so that the process route is shortened, the steps are few, and the operation is simple; avoiding the use of toxic cyanide and alkali metal reagent, and obtaining the 6-cyano-5-hydroxy-3-oxo caproate with high yield and high purity.

Description

A kind of preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester

Technical field

The present invention relates to the technical field of medicinal chemistry, and in particular to a preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester.

Background technique

Atorvastatin calcium is the active ingredient in the lipid-lowering drug Lipitor. Atorvastatin calcium is a cholesterol synthesis inhibitor. The function of atorvastatin calcium is to reduce the amount of cholesterol in the blood circulation, especially the amount of low-density lipoprotein cholesterol. Atorvastatin is mainly used for the treatment of coronary heart disease, hyperlipidemia and atherosclerotic disease.

6-cyano-5-hydroxy-3-oxohexanoic acid ester is the core intermediate of atorvastatin calcium, which has an important impact on the preparation cost and technological advancement of atorvastatin calcium. The synthesis of sexual pharmacophore groups plays a decisive role.

In the prior art, the synthesis methods of 6-cyano-5-hydroxy-3-oxohexanoate include the following two types: the first one uses 4-chloro-3-hydroxy-butyric acid ethyl ester as raw material, It is obtained by using potassium cyanide or hydrocyanic acid as raw material to replace chlorine through chemical or biological methods, and then performing Claisen condensation with α-lithium tert-butyl acetate. This method is commonly used in industrial production. Its disadvantages are that 4-chloro-3-hydroxy-butyric acid ethyl ester is expensive; cyanide is a highly toxic chemical that requires a special warehouse and the treatment cost of cyanide-containing wastewater is extremely high; the reaction temperature is low , the reaction time is long, and the lithium reagent is sensitive to moisture, which increases the risk. The second method is to use 3-hydroxy-4-chlorobutanol as raw material, react with metallic zinc reagent to generate 6-chloro-5-hydroxy-3-oxohexanoic acid ester, and then use cyanide for substitution reaction. This method requires the use of highly toxic cyanide.

In view of this, the present invention is proposed.

Contents of the invention

The object of the present invention is to provide a preparation method of 6-cyano-5-hydroxy-3-oxohexanoate, which synthesizes 6-cyano-5-hydroxy-3-oxohexanoate in one step, shortening The process route is simplified; the use of toxic cyanide and alkali metal reagents is avoided, and 6-cyano-5-hydroxy-3-oxohexanoic acid ester can be obtained with high yield and high purity.

In order to achieve the above objects of the present invention, the following technical solutions are adopted:

The invention provides a preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester, which includes the following steps:

Cyanoacetaldehyde, diketene, alcohol and catalyst are reacted in an organic solvent for the first time to obtain the 6-cyano-5-hydroxy-3-oxohexanoic acid ester.

Further, the alcohol includes at least one of tert-butyl alcohol, methanol, ethanol and isopropyl alcohol.

Further, the catalyst includes a first catalyst or a second catalyst;

The first catalyst includes a Lewis acid;

The second catalyst is mainly obtained by performing a second reaction between a Lewis acid and a Schiff base.

Further, the Lewis acid includes at least one of trifluoroacetic acid, boron trifluoride, titanium tetrachloride, tetramethyltitanium alkoxide, tetraethyltitanium alkoxide, tetraisopropyltitanium alkoxide and tetratert-butyltitanium alkoxide. A sort of;

And/or, the Schiff base includes bissalicylaldehyde ethylenediamine, bis(3,5-di-tert-butylsalicylene)-1,2-cyclohexanediamine and (((1S, At least one of 2S)-1,2-diphenylethane-1,2-diyl)bis(aminomethylene)bis(methylmethylene))diphenol.

Further, the temperature of the second reaction is -78~60°C.

Preferably, the temperature of the second reaction is -10~25°C.

Further, the organic solvent includes at least one of dichloromethane, toluene and tetrahydrofuran.

Further, the molar ratio of the cyanoacetaldehyde, the diketene and the alcohol is 1: (0.8～1.2): (0.8～2);

And/or, the molar ratio of the cyanoacetaldehyde and the catalyst is 1: (0.001～0.1).

Further, the temperature of the first reaction is -75~60°C.

Preferably, the temperature of the first reaction is -10~25°C.

Preferably, the first reaction time is 2 to 30 hours.

Further, after the first reaction, it also includes: adding hydrochloric acid solution to the reaction system for quenching, collecting the organic phase, washing, liquid separation and concentration in order to obtain the 6-cyano-5-hydroxy- 3-oxohexanoate.

Further, the quenching temperature ranges from -7 to 60°C.

Preferably, the quenching temperature is 0 to 45°C.

Compared with the prior art, the beneficial effects of the present invention are:

1. The present invention synthesizes 6-cyano-5-hydroxy-3-oxohexanoic acid ester in one step by reacting cyanoacetaldehyde, diketene and alcohol, shortening the process route, reducing reaction steps, and improving productivity. The yield and product purity can reach more than 90%, and the product purity can reach more than 99%.

2. The preparation method of the present invention avoids the use of toxic cyanide, thereby avoiding the generation of cyanide-containing wastewater; avoids the use of alkali metal reagents, thereby improving the quality of the product, and the quality of the produced product is stable.

Detailed ways

The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments. However, those skilled in the art will understand that the embodiments described below are some, not all, of the embodiments of the present invention and are only used for illustrative of the invention and should not be construed as limiting the scope of the invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention. If the specific conditions are not specified in the examples, the conditions should be carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not indicated, they are all conventional products that can be purchased commercially.

The following is a detailed description of the preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to the embodiment of the present invention.

In some embodiments of the present invention, a method for preparing 6-cyano-5-hydroxy-3-oxohexanoate is provided, which includes the following steps:

Cyanoacetaldehyde, diketene, alcohol and catalyst are reacted in an organic solvent for the first time to obtain 6-cyano-5-hydroxy-3-oxohexanoic acid ester.

The present invention synthesizes 6-cyano-5-hydroxy-3-oxohexanoate in one step by reacting cyanoacetaldehyde, diketene and alcohol, shortening the process route, reducing reaction steps, and greatly simplifying the synthesis process. .

The preparation method of the present invention has a high yield, which can reach more than 90%; and the purity of the prepared 6-cyano-5-hydroxy-3-oxohexanoic acid ester is high, which can reach more than 99%.

The preparation method of the invention avoids the use of toxic cyanides, such as HCN, KCN, etc., and at the same time avoids the generation of cyanide-containing wastewater.

Existing synthesis methods, such as using α-lithium acetate and ethyl 4-cyano-3-hydroxybutyrate to react to produce 6-cyano-5-hydroxy-3-oxohexanoate, excess lithium The reagents will continuously react with the product to generate by-products, thereby reducing the quality of the product; the preparation method of the present invention avoids the use of alkali metal reagents, thereby improving the quality of the product.

The quality of the product prepared by the preparation method of the present invention is stable. For example, the 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester prepared by the preparation method of the present invention can be directly used in the preparation of atorvatin. Subsequent production.

The preparation method of the present invention has high production efficiency and short time required.

In some embodiments of the invention, the alcohol includes at least one of tert-butyl alcohol, methanol, ethanol and isopropyl alcohol.

When the alcohol is tert-butyl alcohol, the product obtained is tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate; when the alcohol is methanol, the product obtained is 6-cyano-5-hydroxy- 3-oxohexanoic acid methyl ester; when the alcohol is ethanol, the product obtained is 6-cyano-5-hydroxy-3-oxohexanoic acid ethyl ester; when the alcohol is isopropyl alcohol, the product obtained is 6 -Isopropyl cyano-5-hydroxy-3-oxohexanoate.

In some embodiments of the invention, the catalyst includes a first catalyst or a second catalyst;

The first catalyst includes a Lewis acid;

The second catalyst is mainly obtained by the second reaction of Lewis acid and Schiff base.

In the preparation method of the present invention, when the catalyst uses the first catalyst Lewis acid, the product obtained is an achiral compound; when the catalyst uses the second catalyst mainly obtained by the second reaction of Lewis acid and Schiff base, the product obtained For chiral compounds.

In some embodiments of the invention, the Lewis acids include trifluoroacetic acid, boron trifluoride, titanium tetrachloride, tetramethyltitanium alkoxide, tetraethyltitanium alkoxide, tetraisopropyltitanium alkoxide, and tetratert-butylalcohol At least one of titanium.

In some embodiments of the invention, Schiff bases include bissalicylaldehyde ethylenediamine, bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine, and (( At least one kind of (1S,2S)-1,2-diphenylethane-1,2-diyl)bis(aminomethylene)bis(methylmethylene))diphenol.

In some embodiments of the present invention, the preparation method of the second catalyst includes the following steps:

Lewis acid and Schiff base perform a second reaction in an organic solvent to obtain a second catalyst.

In some embodiments of the present invention, the molar ratio of Lewis acid and Schiff base is 1: (0.8-2); typical but not limiting, for example, the molar ratio of Lewis acid and Schiff base can be 1:0.8 , 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2 or a range value composed of any two of them.

In some embodiments of the present invention, the temperature of the second reaction is -78~60°C; typical but not limiting, for example, the temperature of the second reaction can be -78°C, -60°C, -50°C, - 40°C, -30°C, -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C or a range value consisting of any two of them; preferably, the first The temperature of the reaction is -10~25°C. More preferably, the temperature of the second reaction is 20~25°C.

In some embodiments of the present invention, the second reaction time is 0.5-1.5 h; preferably, the second reaction time is 1 h.

In some embodiments of the invention, the organic solvent includes at least one of dichloromethane, toluene and tetrahydrofuran. The organic solvents used in the first reaction and the second reaction are selected from the above reagents.

In some embodiments of the present invention, the molar ratio of cyanoacetaldehyde, diketene and alcohol is 1: (0.8～1.2): (0.8～2); typical but non-limiting, for example, cyanoacetaldehyde and diketene The molar ratio of cyanoacetaldehyde and alcohol can be 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2 or any two of them; the molar ratio of cyanoacetaldehyde and alcohol can be 1:0.8, 1 : 0.9, 1:1, 1:1.1, 1:1.2 or a range value composed of any two of them.

In some embodiments of the present invention, the molar ratio of cyanoacetaldehyde to the catalyst is 1: (0.001~0.1); typical but not limiting, for example, the molar ratio of cyanoacetaldehyde to the catalyst can be 1:0.001 , 1:0.01, 1:0.05, 1:0.1 or a range value composed of any two of them.

In some embodiments of the present invention, the usage ratio of cyanoacetaldehyde and organic solvent is 1g:1-10mL.

In some embodiments of the present invention, the temperature of the first reaction is -75~60°C; typical but not limiting, for example, the temperature of the first reaction can be -75°C, -60°C, -50°C, - 40°C, -30°C, -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C or a range value consisting of any two of them; preferably, the first The temperature of the reaction is -10~25°C; more preferably, the temperature of the first reaction is 20~25°C.

In some embodiments of the present invention, the first reaction time is 2 to 30h; typical but not limiting, for example, the first reaction time can be 2h, 5h, 10h, 15h, 20h, 22h, 24h, 26h , 28h, 30h or a range value consisting of any two of them; preferably 20 to 30h.

In some embodiments of the present invention, after the first reaction, it also includes: adding hydrochloric acid solution to the reaction system for quenching, collecting the organic phase, washing, liquid separation and concentration in order to obtain 6-cyano-5- Hydroxy-3-oxohexanoate.

In the preparation method of the present invention, only a simple post-treatment process is required after the reaction to obtain a high-purity product.

In some embodiments of the present invention, the quenching temperature is -7~60°C; typical but not limiting, for example, the quenching temperature can be -7°C, 10°C, 20°C, 30°C, 40°C , 50°C, 60°C, or a range of any two thereof; preferably, the quenching temperature is 0 to 45°C.

In some embodiments of the present invention, the concentration of the hydrochloric acid solution is 0.9-1.1M.

In some embodiments of the invention, washing includes washing the organic phase with water.

The features and performance of the present invention will be described in further detail below with reference to examples.

Example 1

This embodiment provides a preparation method for tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate. The synthesis route is as follows:

Specifically, it includes the following steps:

S1. Add 600 mL of methylene chloride, 113 g of titanium tetraisopropyl alkoxide and 106 g of bissalicylaldehyde ethylenediamine into the reverse sample bottle, and stir at 0°C for 1 hour to obtain a reaction solution containing the catalyst;

S2. Add 276g cyanoacetaldehyde to the above reaction solution containing the catalyst, slowly add 370g diketene dropwise, stir for 4 hours at -20°C, then add 600g tert-butanol, stir for 24 hours; then add 600mL concentration at 0°C Quench with 1M hydrochloric acid solution. After quenching, let stand and separate. Collect the organic phase. Wash the organic phase with 200 mL of water. Obtain the organic phase after liquid separation. Concentrate the organic phase to dryness to obtain 826g of yellow oil, which is 6-Cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester. The yield was 91%. After HPLC analysis, the product purity was 99.1%.

Example 2

This embodiment provides a preparation method for tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate, which includes the following steps:

Add 45.6g trifluoroacetic acid and 276g cyanoacetaldehyde to 600mL methylene chloride, slowly add 370g diketene dropwise, stir at -20°C for 4h, then add 600g tert-butyl alcohol, stir for 24h; then at 0°C, add Quench 600 mL of hydrochloric acid solution with a concentration of 1M. After quenching, let it stand and separate. Collect the organic phase. Wash the organic phase with 200 mL of water. After separation, the organic phase is obtained. The organic phase is concentrated to dryness to obtain 820g of yellow oil. That is tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate. The yield was 90%. After HPLC analysis, the product purity was 99.5%.

Example 3

The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester provided in this example is referred to Example 1. The only difference is that titanium tetraisopropyl alkoxide is replaced by titanium tetrachloride. , replacing bis-salicylicaldehyde ethylenediamine with bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine. The yield of 6-cyano-5-hydroxy-3-oxohexanoic acid butyl ester was 94%. After HPLC analysis, the product purity was 98.8%.

Example 4

The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester provided in this example is referred to Example 1, the only difference is that the mass of titanium tetraisopropyl alkoxide is 11g, dihydrate The mass of ethylenediamine acetal is 12g. The yield of 6-cyano-5-hydroxy-3-oxohexanoic acid butyl ester was 90%. After HPLC analysis, the product purity was 98.9%.

Example 5

The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester provided in this example is referred to Example 1. The only difference is that 370g of diketene is slowly added dropwise at 25°C and stirred for 4 hours. The yield of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester was 89%. After HPLC analysis, the product purity was 97.9%.

Example 6

This embodiment provides a preparation method for methyl 6-cyano-5-hydroxy-3-oxohexanoate. The synthesis route is as follows:

Specifically, it includes the following steps:

S1. Add 600 mL of methylene chloride, 113 g of titanium tetraisopropyl alkoxide and 106 g of bissalicylaldehyde ethylenediamine into the reverse sample bottle, and stir at 0°C for 1 hour to obtain a reaction solution containing the catalyst;

S2. Add 276g cyanoacetaldehyde to the above reaction solution containing the catalyst, slowly add 370g diketene dropwise, stir at -20°C for 4h, then add 600g methanol, stir for 24h; then add 600ml at 0°C with a concentration of 1M Quench the hydrochloric acid solution. After quenching, let it stand for layering. Collect the organic phase. Wash the organic phase with 200 mL of water. Obtain the organic phase after liquid separation. Concentrate the organic phase to dryness to obtain 705g of yellow oil, which is 6- Methyl cyano-5-hydroxy-3-oxohexanoate. The yield was 95%. After HPLC analysis, the product purity was 99.3%.

Example 7

This embodiment provides a preparation method for ethyl 6-cyano-5-hydroxy-3-oxohexanoate. The synthesis route is as follows:

Specifically, it includes the following steps:

S1. Add 600 mL of methylene chloride, 113 g of titanium tetraisopropyl alkoxide and 106 g of bissalicylaldehyde ethylenediamine into the reverse sample bottle, and stir at 0°C for 1 hour to obtain a reaction solution containing the catalyst;

S2. Add 276g cyanoacetaldehyde to the above reaction solution containing the catalyst, slowly add 370g diketene dropwise, stir for 4h at -20°C, then add 600g ethanol, stir for 24h; then add 600mL at a concentration of 1M at 0°C Quench the hydrochloric acid solution. After quenching, let stand and separate. Collect the organic phase. Wash the organic phase with 200 mL of water. Obtain the organic phase after liquid separation. Concentrate the organic phase to dryness to obtain 780g of yellow oil, which is 6- Cyano-5-hydroxy-3-oxohexanoic acid ethyl ester. The yield was 97%. After HPLC analysis, the product purity was 99.4%.

Example 8

This embodiment provides a preparation method for 6-cyano-5-hydroxy-3-oxohexanoic acid isopropyl ester. The synthesis route is as follows:

Specifically, it includes the following steps:

S1. Add 600mL dichloromethane, 113g titanium tetraisopropyloxide and 107g disalicylicaldehyde ethylenediamine into the reverse sample bottle, and stir at 0°C for 1 hour to obtain a reaction solution containing the catalyst;

S2. Add 276g cyanoacetaldehyde to the above reaction solution containing the catalyst, slowly add 370g diketene dropwise, stir for 4 hours at -20°C, then add 600g isopropyl alcohol, stir for 24 hours; then add 600mL concentration at 0°C Quench with 1M hydrochloric acid solution. After quenching, let stand and separate. Collect the organic phase. Wash the organic phase with 200 mL of water. Obtain the organic phase after liquid separation. Concentrate the organic phase to dryness to obtain 810g of yellow oil, which is 6-Cyano-5-hydroxy-3-oxohexanoic acid isopropyl ester. The yield was 95%. After HPLC analysis, the product purity was 99.6%.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention, but not to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: The technical solutions described in the foregoing embodiments can still be modified, or some or all of the technical features can be equivalently replaced; and these modifications or substitutions do not deviate from the essence of the corresponding technical solutions from the technical solutions of the embodiments of the present invention. scope.

Claims (10)

1. A preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester, which is characterized in that it includes the following steps: Cyanoacetaldehyde, diketene, alcohol and catalyst are reacted in an organic solvent for the first time to obtain the 6-cyano-5-hydroxy-3-oxohexanoic acid ester. 2. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to claim 1, characterized in that the alcohol includes tert-butyl alcohol, methyl alcohol, ethanol and isopropyl alcohol. At least one. 3. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to claim 1, characterized in that the catalyst includes a first catalyst or a second catalyst; The first catalyst includes a Lewis acid; The second catalyst is mainly obtained by performing a second reaction between a Lewis acid and a Schiff base. 4. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to claim 3, characterized in that the Lewis acid includes trifluoroacetic acid, boron trifluoride, tetrachloride At least one of titanium, tetramethyltitanium alkoxide, tetraethyltitanium alkoxide, tetraisopropyltitanium alkoxide and tetratert-butyltitanium alkoxide; And/or, the Schiff base includes bissalicylaldehyde ethylenediamine, bis(3,5-di-tert-butylsalicylene)-1,2-cyclohexanediamine and (((1S, At least one of 2S)-1,2-diphenylethane-1,2-diyl)bis(aminomethylene)bis(methylmethylene))diphenol. 5. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to claim 3, characterized in that the temperature of the second reaction is -78~60°C; Preferably, the temperature of the second reaction is -10~25°C. 6. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to claim 1, characterized in that the organic solvent includes at least one of dichloromethane, toluene and tetrahydrofuran . 7. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to claim 1, characterized in that the molar ratio of the cyanoacetaldehyde, the diketene and the alcohol is 1: (0.8～1.2): (0.8～2); And/or, the molar ratio of the cyanoacetaldehyde and the catalyst is 1: (0.001～0.1). 8. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to claim 1, characterized in that the temperature of the first reaction is -75~60°C; Preferably, the temperature of the first reaction is -10~25°C; Preferably, the first reaction time is 2 to 30 hours. 9. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid ester according to claim 1, characterized in that, after the first reaction, it also includes: adding hydrochloric acid solution to the reaction system After quenching and collecting the organic phase, washing, liquid separation and concentration are performed in sequence to obtain the 6-cyano-5-hydroxy-3-oxohexanoic acid ester. 10. The preparation method of 6-cyano-5-hydroxy-3-oxohexanoate according to claim 9, characterized in that the quenching temperature is -7~60°C; Preferably, the quenching temperature is 0 to 45°C.