A process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate

Abstract

The present application relates to the technical field of pharmaceutical chemistry, and particularly to a preparation method of 6-cyano-5-hydroxy-3-oxohexanoate.The preparation method of 6-cyano-5-hydroxy-3-oxohexanoate comprises the following steps: carrying out a first reaction of cyanoacetaldehyde, divinyl ketone, alcohol and a catalyst in an organic solvent to obtain the 6-cyano-5-hydroxy-3-oxohexanoate.By adopting the reaction of cyanoacetaldehyde, divinyl ketone and alcohol, the 6-cyano-5-hydroxy-3-oxohexanoate is synthesized by one-step method, the process route is shortened, the steps are less, and the operation is simple;the use of toxic cyanide and alkali metal reagents is avoided, and the 6-cyano-5-hydroxy-3-oxohexanoate can be obtained at high yield and high purity.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly to a preparation method of 6-cyano-5-hydroxy-3-oxohexanoate. BACKGROUND

[0002] Atorvastatin calcium is the effective component of Lipitor, a blood lipid-lowering drug. Atorvastatin calcium is a cholesterol synthesis inhibitor, and its function is to reduce the amount of cholesterol, especially low-density lipoprotein cholesterol, in blood circulation. Atorvastatin is mainly used for the treatment of coronary heart disease, hyperlipidemia and atherosclerotic diseases.

[0003] 6-cyano-5-hydroxy-3-oxohexanoate is a core intermediate of atorvastatin calcium, and has an important influence on the preparation cost and process advancement of atorvastatin calcium, and plays a decisive role in the synthesis of the chiral drug group of dihydroxyhexanoic acid.

[0004] In the prior art, the synthesis method of 6-cyano-5-hydroxy-3-oxohexanoate includes the following two kinds: the first kind is to use 4-chloro-3-hydroxy-butyric acid ethyl ester as a raw material, and then substitute chlorine by using potassium cyanide or hydrocyanic acid by chemical or biological method, and then perform Claisen condensation with α-lithium acetic acid tert-butyl ester to obtain. This method is generally used for industrial production, and its disadvantage is that 4-chloro-3-hydroxy-butyric acid ethyl ester is expensive; cyanide is a toxic chemical that needs a special warehouse and the cost of cyanide-containing wastewater treatment is extremely high; the reaction temperature is relatively low, the reaction time is long, and the lithium reagent is sensitive to moisture, which increases the danger. The second kind is to use 3-hydroxy-4-chlorobutyronitrile as a raw material, generate 6-chloro-5-hydroxy-3-oxohexanoate by using a metal zinc reagent, and then perform a substitution reaction by using cyanide. This method needs to use toxic cyanide.

[0005] In view of this, the present application is proposed. SUMMARY

[0006] The present application aims to provide a preparation method of 6-cyano-5-hydroxy-3-oxohexanoate, which synthesizes 6-cyano-5-hydroxy-3-oxohexanoate by one-step method, shortens the process route, avoids the use of toxic cyanide and alkali metal reagents, and can obtain 6-cyano-5-hydroxy-3-oxohexanoate with high yield and high purity.

[0007] In order to achieve the above-mentioned purpose of the present application, the following technical scheme is adopted:

[0008] The present application provides a preparation method of 6-cyano-5-hydroxy-3-oxohexanoate, including the following steps:

[0009] cyanacetaldehyde, diketene, alcohol and catalyst are used in the first reaction in an organic solvent to obtain the 6-cyano-5-hydroxy-3-oxohexanoate.

[0010] Further, the alcohol includes at least one of t-butyl alcohol, methanol, ethanol and isopropyl alcohol.

[0011] Further, the catalyst includes a first catalyst or a second catalyst;

[0012] The first catalyst includes a Lewis acid;

[0013] The second catalyst is mainly used in the second reaction with a Lewis acid and a Schiff base.

[0014] Further, the Lewis acid includes at least one of trifluoroacetic acid, boron trifluoride, titanium tetrachloride, titanium tetramethyl alcohol, titanium tetraethyl alcohol, titanium tetraisopropyl alcohol and titanium tetra-t-butyl alcohol.

[0015] And / or, the Schiff base includes at least one of bis-salicylaldehyde ethylenediamine, bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexanediamine and (((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(amino-methylene)bis(methane-methylene))diphenol.

[0016] Further, the temperature of the second reaction is -78-60℃.

[0017] Preferably, the temperature of the second reaction is -10-25℃.

[0018] Further, the organic solvent includes at least one of dichloromethane, toluene and tetrahydrofuran.

[0019] Further, the molar ratio of the cyanacetaldehyde, the diketene and the alcohol is 1:(0.8-1.2):(0.8-2);

[0020] And / or, the molar ratio of the cyanacetaldehyde and the catalyst is 1:(0.001-0.1).

[0021] Further, the temperature of the first reaction is -75-60℃.

[0022] Preferably, the temperature of the first reaction is -10-25℃.

[0023] Preferably, the time of the first reaction is 2-30h.

[0024] Further, after the first reaction, it further includes adding hydrochloric acid solution to the reaction system for quenching, collecting the organic phase, and then sequentially performing washing, liquid separation and concentration to obtain the 6-cyano-5-hydroxy-3-oxohexanoate.

[0025] Further, the temperature of the quenching is -7-60℃.

[0026] Preferably, the temperature of the quenching is 0-45℃.

[0027] Compared with the prior art, the present application has the following advantages:

[0028] 1. The present application synthesizes 6-cyano-5-hydroxy-3-oxohexanoate by one-step method through the reaction of cyanoacetaldehyde, diacetylene ketone and alcohol, shortens the process route, reduces the reaction steps, and improves the yield and product purity, the yield can reach more than 90%, and the product purity can reach more than 99%.

[0029] 2. The preparation method of the present application avoids the use of toxic cyanide, thereby avoiding the generation of cyan-containing wastewater; and avoids the use of alkali metal reagents, thereby improving the quality of the product, and the prepared product is stable in quality. DETAILED DESCRIPTION

[0030] The technical solutions of the present application will be described clearly and completely in combination with the specific embodiments, but those skilled in the art will understand that the following described embodiments are part of the embodiments of the present application, rather than all the embodiments, and are only used to illustrate the present application, and should not be regarded as limiting the scope of the present application. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without making creative efforts are within the scope of protection of the present application. The specific conditions are not specified in the embodiments, and are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not specified by the manufacturer, and are all conventional products that can be purchased on the market.

[0031] The preparation method of one 6-cyano-5-hydroxy-3-oxohexanoate of the embodiments of the present application will be described in detail below.

[0032] In some embodiments of the present application, a preparation method of 6-cyano-5-hydroxy-3-oxohexanoate is provided, which comprises the following steps:

[0033] The cyanoacetaldehyde, diacetylene ketone, alcohol and catalyst are subjected to a first reaction in an organic solvent to obtain 6-cyano-5-hydroxy-3-oxohexanoate.

[0034] The present application synthesizes 6-cyano-5-hydroxy-3-oxohexanoate by one-step method through the reaction of cyanoacetaldehyde, diacetylene ketone and alcohol, shortens the process route, reduces the reaction steps, and greatly simplifies the synthesis process.

[0035] The preparation method of the present application has high yield, which can reach more than 90%; and the prepared 6-cyano-5-hydroxy-3-oxohexanoate has high purity, which can reach more than 99%.

[0036] The preparation method of the present application avoids the use of toxic cyanide, such as HCN, KCN, etc., and avoids the generation of cyan-containing wastewater.

[0037] The existing synthesis method, such as using α-lithioacetate and 4-cyano-3-hydroxybutyric acid ethyl ester to react to generate 6-cyano-5-hydroxy-3-oxohexanoate, the excess lithium reagent will continuously react with the product to generate by-products, thereby reducing the product quality; the preparation method of the present application avoids the use of alkali metal reagent, thereby improving the product quality.

[0038] The product prepared by the preparation method of the present application has stable quality, such as the 6-cyano-5-hydroxy-3-oxohexanoate tert-butyl ester prepared by the preparation method of the present application can be directly used for subsequent production of atorvastatin.

[0039] The preparation method of the present application has high production efficiency and short production time.

[0040] In some embodiments of the present application, the alcohol includes at least one of tert-butyl alcohol, methanol, ethanol and isopropyl alcohol.

[0041] When the alcohol is tert-butyl alcohol, the obtained product is 6-cyano-5-hydroxy-3-oxohexanoate tert-butyl ester; when the alcohol is methanol, the obtained product is 6-cyano-5-hydroxy-3-oxohexanoate methyl ester; when the alcohol is ethanol, the obtained product is 6-cyano-5-hydroxy-3-oxohexanoate ethyl ester; when the alcohol is isopropyl alcohol, the obtained product is 6-cyano-5-hydroxy-3-oxohexanoate isopropyl ester.

[0042] In some embodiments of the present application, the catalyst includes a first catalyst or a second catalyst.

[0043] The first catalyst includes a Lewis acid.

[0044] The second catalyst is mainly obtained by a second reaction of a Lewis acid and a Schiff base.

[0045] In the preparation method of the present application, when the catalyst is a Lewis acid of the first catalyst, the obtained product is an achiral compound; when the catalyst is a second catalyst mainly obtained by a second reaction of a Lewis acid and a Schiff base, the obtained product is a chiral compound.

[0046] In some embodiments of the present application, the Lewis acid includes at least one of trifluoroacetic acid, boron trifluoride, titanium tetrachloride, titanium tetramethyl alcohol, titanium tetraethyl alcohol, titanium tetraisopropyl alcohol and titanium tetra-t-butyl alcohol.

[0047] In some embodiments of the present application, the Schiff base comprises at least one of bis-salicylaldehyde ethylenediamine, bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine and (((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(amino- methylene)bis(methanemethylene))diphenol.

[0048] In some embodiments of the present application, the method for preparing the second catalyst comprises the following steps:

[0049] The Lewis acid and the Schiff base are subjected to a second reaction in an organic solvent to obtain the second catalyst.

[0050] In some embodiments of the present application, the molar ratio of the Lewis acid and the Schiff base is 1:(0.8-2); typically but not limitedly, for example, the molar ratio of the Lewis acid and the 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 formed by any two of them.

[0051] In some embodiments of the present application, the temperature of the second reaction is -78-60°C; typically but not limitedly, 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 formed by any two of them; preferably, the temperature of the first reaction is -10-25°C, more preferably, the temperature of the second reaction is 20-25°C.

[0052] In some embodiments of the present application, the time of the second reaction is 0.5-1.5h; preferably, the time of the second reaction is 1h.

[0053] In some embodiments of the present application, the organic solvent comprises at least one of dichloromethane, toluene and tetrahydrofuran. The organic solvent in the first reaction and the second reaction is selected from the above-mentioned reagents.

[0054] In some embodiments of the present application, the molar ratio of the cyanoacetaldehyde, the diacetylene and the alcohol is 1:(0.8-1.2):(0.8-2); typically but not limitedly, for example, the molar ratio of the cyanoacetaldehyde and the diacetylene can be 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2 or a range value formed by any two of them; the molar ratio of the cyanoacetaldehyde and the alcohol can be 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2 or a range value formed by any two of them.

[0055] In some embodiments of the present application, the molar ratio of cyanoacetaldehyde to catalyst is 1:(0.001-0.1); typically but not exclusively, for example, the molar ratio of cyanoacetaldehyde to catalyst can be 1:0.001, 1:0.01, 1:0.05, 1:0.1, or a range value formed by any two of them.

[0056] In some embodiments of the present application, the usage ratio of cyanoacetaldehyde to organic solvent is 1g:1-10mL.

[0057] In some embodiments of the present application, the temperature of the first reaction is -75-60°C; typically but not exclusively, 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 formed by any two of them; preferably, the temperature of the first reaction is -10-25°C; more preferably, the temperature of the first reaction is 20-25°C.

[0058] In some embodiments of the present application, the time of the first reaction is 2-30h; typically but not exclusively, for example, the time of the first reaction can be 2h, 5h, 10h, 15h, 20h, 22h, 24h, 26h, 28h, 30h, or a range value formed by any two of them; preferably 20-30h.

[0059] In some embodiments of the present application, after the first reaction, further comprising: adding hydrochloric acid solution to the reaction system for quenching, collecting the organic phase, and then sequentially performing washing, liquid separation, and concentration to obtain 6-cyano-5-hydroxy-3-oxohexanoate.

[0060] In the preparation method of the present application, only a simple post-treatment process is required after the reaction, and a high-purity product can be obtained.

[0061] In some embodiments of the present application, the temperature of quenching is -7-60°C; typically but not exclusively, for example, the temperature of quenching can be -7°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, or a range value formed by any two of them; preferably, the temperature of quenching is 0-45°C.

[0062] In some embodiments of the present application, the concentration of the hydrochloric acid solution is 0.9-1.1M.

[0063] In some embodiments of the present application, the washing includes washing the organic phase with water.

[0064] The features and performances of the present application are further described in detail below in combination with examples.

[0065] Example 1

[0066] This embodiment provides a method for preparing tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate, and the synthetic route is as follows:

[0067]

[0068] Specifically, it includes the following steps:

[0069] S1. Add 600 mL of dichloromethane, 113 g of tetraisopropyl titanium oxide and 106 g of disalicylic acid ethylenediamine to a sample flask and stir at 0 °C for 1 h to obtain a reaction solution containing the catalyst.

[0070] S2. Add 276g of cyanoacetaldehyde to the above reaction solution containing the catalyst, slowly add 370g of diketene, stir at -20℃ for 4h, then add 600g of tert-butanol, stir for 24h; then quench the reaction by adding 600mL of 1M hydrochloric acid solution at 0℃. After quenching, allow the mixture to stand and separate into layers, collect the organic phase, wash the organic phase with 200mL of water, separate the liquid and obtain the organic phase, concentrate the organic phase to dryness, and obtain 826g of yellow oily substance, which is tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate. The yield is 91%, and the purity of the product is 99.1% according to HPLC analysis.

[0071] Example 2

[0072] This embodiment provides a method for preparing tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate, comprising the following steps:

[0073] 45.6 g of trifluoroacetic acid and 276 g of cyanoacetaldehyde were added to 600 mL of dichloromethane, followed by the slow addition of 370 g of diketene. The mixture was stirred at -20 °C for 4 h, then 600 g of tert-butanol was added, and the mixture was stirred for 24 h. The mixture was then quenched at 0 °C with 600 mL of 1 M hydrochloric acid solution. After quenching, the mixture was allowed to stand and separate into layers. The organic phase was collected, washed with 200 mL of water, and separated into liquid and liquid phases. The organic phase was concentrated to dryness to obtain 820 g of a yellow oily substance, which was tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate. The yield was 90%, and the purity of the product was 99.5% according to HPLC analysis.

[0074] Example 3

[0075] The preparation method of tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate provided in this embodiment is the same as in Example 1, except that tetraisopropyl titanium oxide is replaced with titanium tetrachloride, and bis(3,5-di-tert-butylsalicylic acid)-1,2-cyclohexanediamine is replaced with bis(3,5-di-tert-butylsalicylic acid)-1,2-cyclohexanediamine. The yield of butyl 6-cyano-5-hydroxy-3-oxohexanoate is 94%, and the purity of the product is 98.8% according to HPLC analysis.

[0076] Example 4

[0077] The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester provided in this example refers to Example 1, except that the mass of titanium tetraisopropoxide is 11 g and the mass of bis-salicylaldehyde ethylenediamine is 12 g. The yield of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester is 90%, and the product purity is 98.9% analyzed by HPLC.

[0078] Example 5

[0079] The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester provided in this example refers to Example 1, except that 370 g of divinyl ketone is slowly added and stirred at 25°C for 4 h. The yield of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester is 89%, and the product purity is 97.9% analyzed by HPLC.

[0080] Example 6

[0081] The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester provided in this example refers to Example 1, except that 370 g of divinyl ketone is slowly added and stirred at 25°C for 4 h. The yield of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester is 89%, and the product purity is 97.9% analyzed by HPLC.

[0082]

[0083] Specifically, it includes the following steps:

[0084] S1, 600 mL of dichloromethane, 113 g of titanium tetraisopropoxide and 106 g of bis-salicylaldehyde ethylenediamine are added to a reaction flask, stirred at 0°C for 1 h to obtain a reaction solution containing a catalyst;

[0085] S2, 276 g of cyanoacetaldehyde is added to the above reaction solution containing the catalyst, 370 g of divinyl ketone is slowly added, stirred at -20°C for 4 h, then 600 g of methanol is added, stirred for 24 h; then 600 mL of 1M hydrochloric acid solution is added at 0°C for quenching, and after quenching, it is left to stand and separate into layers, the organic phase is collected, washed with 200 mL of water, and after separation, the organic phase is obtained, concentrated to dryness to obtain 705 g of yellow oil, which is 6-cyano-5-hydroxy-3-oxohexanoic acid methyl ester. The yield is 95%, and the product purity is 99.3% analyzed by HPLC.

[0086] Example 7

[0087] The preparation method of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester provided in this example refers to Example 1, except that 370 g of divinyl ketone is slowly added and stirred at 25°C for 4 h. The yield of 6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester is 89%, and the product purity is 97.9% analyzed by HPLC.

[0088]

[0089] Specifically, it includes the following steps:

[0090] S1, 600 mL of dichloromethane, 113 g of titanium tetraisopropoxide and 106 g of bis-salicylaldehyde ethylenediamine were added into a reaction flask, stirred at 0°C for 1 h to obtain a reaction solution containing catalyst;

[0091] S2, 276 g of cyanoacetaldehyde was added into the above reaction solution containing catalyst, 370 g of divinyl ketone was slowly added dropwise, stirred at -20°C for 4 h, then 600 g of ethanol was added, stirred for 24 h; then 600 mL of 1 M hydrochloric acid solution was added at 0°C for quenching, after quenching, the layers were separated after standing, the organic phase was collected, the organic phase was washed with 200 mL of water, after separation, the organic phase was obtained, the organic phase was concentrated to dryness to obtain 780 g of yellow oil, which was 6-cyano-5-hydroxy-3-oxohexanoic acid ethyl ester. The yield was 97%, and the product purity was 99.4% by HPLC analysis.

[0092] Example 8

[0093] This example provides a method for preparing 6-cyano-5-hydroxy-3-oxohexanoic acid isopropyl ester, and the synthesis route is as follows:

[0094]

[0095] Specifically, the following steps are included:

[0096] S1, 600 mL of dichloromethane, 113 g of titanium tetraisopropoxide and 106 g of bis-salicylaldehyde ethylenediamine were added into a reaction flask, stirred at 0°C for 1 h to obtain a reaction solution containing catalyst;

[0097] S2, 276 g of cyanoacetaldehyde was added into the above reaction solution containing catalyst, 370 g of divinyl ketone was slowly added dropwise, stirred at -20°C for 4 h, then 600 g of ethanol was added, stirred for 24 h; then 600 mL of 1 M hydrochloric acid solution was added at 0°C for quenching, after quenching, the layers were separated after standing, the organic phase was collected, the organic phase was washed with 200 mL of water, after separation, the organic phase was obtained, the organic phase was concentrated to dryness to obtain 780 g of yellow oil, which was 6-cyano-5-hydroxy-3-oxohexanoic acid ethyl ester. The yield was 97%, and the product purity was 99.4% by HPLC analysis.

[0098] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application, and are not limited thereto; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions described in the foregoing examples, or make equivalent substitutions for part or all of the technical features; and these modifications or substitutions do not make the essence of the corresponding technical solution deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate, characterized in that, The method comprises the following steps: a first reaction of cyanoacetaldehyde, diketene, an alcohol and a catalyst in an organic solvent to obtain the 6-cyano-5-hydroxy-3-oxohexanoate; the catalyst is a second catalyst, and the second catalyst is obtained by a second reaction of a Lewis acid and a Schiff base; the Lewis acid comprises at least one of titanium tetrachloride, titanium tetramethyl alcohol, titanium tetraethyl alcohol, titanium tetraisopropyl alcohol and titanium tetra-t-butyl alcohol; the Schiff base comprises at least one of bis-salicylaldehyde-ethylenediamine and bis(3,5-di-t-butyl-salicylidene)-1,2-cyclohexanediamine; the alcohol comprises at least one of t-butyl alcohol, methanol, ethanol and isopropyl alcohol.

2. The process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate according to claim 1, characterized in that, The temperature of the second reaction is -78-60 ℃.

3. The process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate according to claim 2, characterized in that, The temperature of the second reaction is -10-25 ℃.

4. The process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate according to claim 1, characterized in that, The organic solvent comprises at least one of dichloromethane, toluene and tetrahydrofuran.

5. The process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate 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); The molar ratio of the cyanoacetaldehyde and the catalyst is 1:(0.001-0.1).

6. The process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate according to claim 1, characterized in that, The temperature of the first reaction is -75-60 ℃.

7. The process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate according to claim 6, characterized in that, The temperature of the first reaction is -10-25 ℃.

8. The process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate according to claim 6, characterized in that, The time of the first reaction is 2-30 h.

9. The method for preparing 6-cyano-5-hydroxy-3-oxohexanoate according to claim 1, characterized in that, After the first reaction, the method further comprises: adding a hydrochloric acid solution to the reaction system for quenching, collecting the organic phase, and then sequentially performing washing, liquid separation and concentration to obtain the 6-cyano-5-hydroxy-3-oxohexanoate.

10. The process for the preparation of 6-cyano-5-hydroxy-3-oxohexanoate according to claim 9, characterized in that, The temperature of the quenching is -7-60 ℃.

11. The method for preparing 6-cyano-5-hydroxy-3-oxohexanoate according to claim 9, characterized in that, The temperature of the quenching is 0-45 ℃.

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