KR20050105164A - Improved syntheton sythesis - Google Patents

Abstract

The present invention is directed to improved synthesis of commercially important syntetone ACHBs starting from readily available 3-hydroxy-γ-butyrolactone. This reaction uses a single pot method without separation or purification of intermediates. This is advantageous over the methods used in the prior art, which use reagents and conditions that minimize undesirable byproducts and can easily be used on a commercial scale. The product is obtained in high yield and is easily purified to provide an excellent intermediate for further synthesis of pharmaceutically important active substances used in commercially important products such as L-carnitine and HMG-coA reductase inhibitor products such as Lipitor. .

Description

Improved Syntheton Sythesis

The present invention provides commercially important lower alkyl 4-cyano-3- via unisolated intermediate alkyl 4-halo-3-hydroxybutyrate, preferably 4-iodo (AIHB) or 4-bromo (ABHB). Novel one-pot synthesis of hydroxybutyrate (ACHB). In a preferred embodiment, ethyl ester EIHB or EBHB is used. The synthesis is applied to synthesize an optically active or racemic product. This is easily carried out on a commercial scale with reagents that provide the desired end product in high purity, high yields and do not pollute the environment and minimize undesirable side reactions.

Ethyl ester ECHB and intermediates EIHB and EBHB are known compounds, which have been prepared by conventionally reported synthetic methods. Thus, for example, in US Pat. No. 6,114,566 to Hollingsworth et al., (R) -ECHB (Compound 4) is a (S) -EBHB (5) and the corresponding non-isolated optically active 3,4-epoxy. Prepared in three steps starting from (S) -3-hydroxy-γ-butyrolactone (3) via de (6). In the first step, lactone (3) was reacted with 30% hydrogen bromide dissolved in acetic acid at 60 ° C. for 4 hours. Ethanol was added and the reaction mixture was held at a constant temperature for 4-6 hours. The mixture was concentrated and then neutralized and then taken up with toluene and concentrated to give (S) -EBHB at a crude yield of 90%. After distillation, the product of yellow oil was tested with at least 95% purity.

The (S) -EBHB intermediate (5) was treated with NaCN in aqueous ethanol at 50 ° C. The solvent was worked up by rotary evaporation and extracted with ethyl acetate to give (R) -ECHB as a yellow oil with a crude yield of 95%, which was further purified by distillation. The crude yield was high in this method, but it was insufficient for commercial scale. As such, the availability of 30% HBr solutions dissolved in acetic acid is limited on a commercial scale and the work up is complicated by the use of acetic acid. When carried out under the same conditions as used by Hollingsworth et al., The unwanted byproduct ethyl 4-hydroxycrotonate was formed at a yield of 3-10%. Another problem arose during the hydrolysis of the ester-based product with its corresponding acid during the cyanation step. It was also observed that when a low yield of ethyl 4-hydroxycrotonate is produced, the corresponding amount of hydrolysis is increased.

In addition, the use of TMSCl / NaI / CH2Cl2 as ring opening reagents is described in Tetrahedron Letters, 28 (16), 1781-1782 (1987) (Larcheveque, M. and Henrot, S.), Tetrahedron, 46 (12) , 4277-4282 (1990) (Larcheveque, M. and Henrot, S.) and WO9306826. As reported by Larcheveque and Henrot, the ring opening of (S) -3-hydroxybutyrolactone proceeds at different conditions and the iodohydrin product, (S) -ethyl-3-hydroxy-4-iodo Butyrate was obtained. These obtained trimethylsilyl iodide for various purposes, and obtained iodohydrin in moderate yield. However, various problems arise when applying this method to large scales. That is, TMSI is difficult to handle because it is expensive and very reactive. In other publications such as G. Olah (Tetrahedron, 1982, 38, 2225-2227), this kind of reaction is generally known to cause various side reactions and the purification process is complex.

The present invention is directed to an improved synthesis of commercially important syntheton ACHBs starting from the readily available 3-hydroxy-γ-butyrolactone. This reaction uses a single pot method without the isolation or purification of intermediates. This is advantageous compared to the methods used in the prior art because it minimizes undesirable byproducts and uses reagents and conditions that can easily be used on a commercial scale. The product is obtained in high yield and is an excellent intermediate for further synthesis of pharmaceutically important active substances used in commercially important products such as L-carnitine and HMG-coA reductase inhibitor products such as Lipitor® (Atorvastatin, Pfizer). It is easily purified to provide.

In a first step according to the process of the invention, in racemic or optically active form, the starting material 3-hydroxy-γbutyrolactone is subjected to a ring opening reaction using a halide agent. This reaction is obtained in fast, clean and quantitative yields when carried out in the presence of acylating agents and lower alkanols. Suitable halide agents include reagents that provide bromine or iodine, such reagents, for example, hydrogen bromide, hydrogen iodide, trimethylsilyl bromide or iodide in solution or gas form, or preferably hydrochloric acid Alkali metal bromide or iodide such as sodium bromide in the presence of mineral acids such as sulfuric acid, and the like. Suitable acylating agents include lower alkanoyl halides such as acetylchloride or acetyl bromide, alkanoic anhydrides such as acetic anhydride, lower alkyl alkanoates such as ethyl esters of lower aliphatic carboxylic acids, most preferably ethyl acetate or ethyl formate And mixtures thereof. As used herein, the term "lower" means a moiety having from 1 to 4 carbon atoms. Optional reagents useful in the practice of the present invention include lower alkanoyl bromide that provides all functionality. Preferred lower alkanoyl bromide is acetyl bromide. In this reaction, it is most desirable to avoid the use of hydrogen bromide in the presence of acetic acid in order to avoid undesirable side reactions.

The first step can be carried out under any conventional reaction conditions, such conditions are not very limited. Suitable reaction temperatures may range from 0 to 100 ° C. Preferable temperature range is 50-60 degreeC. After the ring opening reaction, the resulting carboxylic acid is esterified in the presence of an alkylating agent such as a lower alkanol, most preferably ethanol to give the desired intermediate product AIHB or ABHB. Both the acylating agent and lower alkyl are present in at least the equivalent molar amount of the other reactants to serve as the solvent of the reaction.

Note that the first step reaction is not performed successfully when using a chlorinating agent such as hydrogen chloride, sodium chloride / hydrogen chloride or trimethylsilyl chloride.

The desired ring opening reaction is carried out in accordance with the process of the present invention to produce AIHB or ABHB in quantitative controlled yield and purity to use the intermediate directly without the need for separation and purification in the next step.

In a second step of the invention, the AIHB or ABHB product obtained in the crude, unseparated first step is reacted with a source of cyanide ions to give the desired product ACHB, most preferably as ethyl ester (ECHB). Suitable cyanide ion sources in this reaction step are alkali metal cyanide, most preferably sodium or potassium cyanide. The cyanation reaction is carried out using the same solvent used in the first step, ie lower alkanols such as ethanol can be present in the aqueous mixture (ethanol to water ratio of 1:10 to 10: 1). As in the first step of the invention, the temperature conditions used are not limited. However, due to the exothermic reaction produced by the addition of cyanide reagents to the AIHB or ABHB intermediates, it is desirable to initiate the reaction at a temperature of about 25 ° C. and maintain the temperature below approximately levels by cooling. After completion of the cyanide ion reagent addition, the reaction mixture may be heated at a temperature of about 35 ° C. for 1 to 24 hours, most preferably about 6 hours.

The pH of the reaction mixture is preferably in the range of 7 to 11, preferably 7.5 to 10.5, most preferably 8 to 9.5. If necessary, the pH can be effectively adjusted by adding a hydrogen halide such as hydrogen iodide or hydrogen bromide. By carrying out the reaction in this way, the reaction with cyanide ions is carried out with EBHB in water under strong base conditions or the water / alcohol mixture (ethyl 4-hydroxycrotonate formation and hydrolysis of esters) is substantially reduced or Or it was unexpectedly found that side reactions occur when they are removed together. Conversely, when the aqueous conditions of the prior art were used, 3 to 10% of byproduct ethyl 4-hydroxycrotonate was observed, with total <2% ethyl by GC peak when the conditions of the invention were used. 4-hydroxycrotonate is observed. It is also an undetectable level of hydrolyzate.

The reaction mixture can then be extracted with a suitable organic solvent or solvent mixture and the reaction solvent can be concentrated up in a conventional manner. The final product is purified by vacuum fractional distillation in batch or continuous mode to provide the desired CHB in high yield and purity suitable for use in commercial scale, pharmaceutical preparation of pharmaceutically important important end products.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which do not limit the present invention.

Example 1

(A) Hydrogen bromide / acetyl chloride / ethyl acetate / ethanol as ring opening reagent

A mixture of 10 g of (S) -3-hydroxy-γ-butyrolactone and 50 ml of ethyl acetate was cooled to 0 ° C. With stirring, 7.7 g of acetylchloride was slowly added. To the ethanol was added 50 ml total of 6N HBr (50 ml EtOH and 24 g (3 eq) HBr) and the mixture was warmed up to 50 ° C. and kept at that temperature for 3 hours. The mixture was concentrated to remove most ethyl acetate. Ethanol, 50 ml, was added to the residue and the resulting solution was stirred at 50 ° C. for 5 hours. The mixture was concentrated to remove most solvent. The resulting product was a slightly yellowish oil and obtained in quantitative yield. However, it is used directly in the next step without further separation or purification.

(B) using hydrogen bromide / ethyl acetate / ethanol as ring opening reagent

To a mixture of 10 g of (S) -3-hydroxy-γ-butyrolactone and 50 ml of ethyl acetate was added 50 ml (50 ml EtOH and 24 g (3 eq) HBr) total of 6N HBr to ethanol. The mixture was warmed up to 50 ° C. and kept at that temperature for 5 hours. The mixture was concentrated to remove most ethyl acetate. Ethanol, 50 ml, was added to the residue and the resulting solution was stirred at 50 ° C. for 5 hours. The mixture was concentrated to remove most solvent. The resulting product was a slightly yellowish oil and obtained in quantitative yield. However, it is used directly in the next step without further separation or purification.

(C) Use of acetic anhydride / ethyl acetate / ethanol / hydrogen bromide as ring opening reagent

To a mixture of 10 g of (S) -3-hydroxy-γ-butyrolactone, 9.2 ml of acetic anhydride and 50 ml of ethyl acetate, 50 ml of total 6N HBr (50 ml EtOH and 24 g (3 eq) HBr)) were added to ethanol. The mixture was warmed up to 50 ° C. and maintained at that temperature for 3 hours. The mixture was concentrated to remove most ethyl acetate. Ethanol, 50 ml, was added to the residue and the resulting solution was stirred at 50 ° C. for 5 hours. The mixture was concentrated to remove most solvent. The resulting product was a slightly yellowish oil and obtained in quantitative yield. However, it can be used directly in the next step without further separation or purification.

(D) using acetyl chloride / ethyl acetate / ethanol / sodium bromide as ring opening reagent

A mixture of 10 g of (S) -3-hydroxy-γ-butyrolactone and 50 ml of ethyl acetate was cooled to 0 ° C. With stirring, 7.7 g of acetylchloride was slowly added. To the ethanol was added 50 ml total of 6N HBr (50 ml EtOH and 24 g (3 eq) HBr) and the mixture was warmed up to 50 ° C. and kept at that temperature for 3 hours. The mixture was concentrated to remove most ethyl acetate. Ethanol, 50 ml, was added to the residue and the resulting solution was stirred at 50 ° C. for 48 h. The mixture was concentrated to remove most solvent. The resulting product was a slightly yellowish oil and obtained in quantitative yield. However, it can be used directly in the next step without further separation or purification.

(E) Acetyl bromide / ethanol as ring opening reagent

A mixture of 100 g of (S) -3-hydroxy-γ-butyrolactone, 136 g of ethanol and 400 ml of ethyl acetate was cooled to 0 ° C. With stirring, 241 g of acetylbromide was added slowly. The mixture was warmed to 50 ° C. and kept at that temperature for 5 hours. The mixture was concentrated to remove most ethyl acetate. Ethanol, 400 ml, was added to the residue and the resulting solution was stirred at 50 ° C. for 5 hours. The resulting product is slightly yellowish and can be concentrated or used directly in the next step without separation or further purification as in Example 2. Yield was quantitative.

Example 2

(A) One-pot method for the preparation of ethyl 4-cyano-3-hydroxybutyrate (ECHB)

To the solution obtained in Example 1 (starting at 20 g of (S) -3-hydroxyGBL), a solution of NaCN was added (addition of additional mineral acid, such as HBr or HCl, if necessary) to adjust the pH to 8-9.5. Can be).

From this the solution was cooled to 25 ° C. A solution of 22.6 g of NaCN dissolved in 40 ml of water was added for 20 minutes. The reaction temperature was maintained at 25 ° C. during the addition. After addition, the reaction mixture was stirred at 25 ° C. for 1 hour. The reaction was heated to 35 ° C. for 6 hours. The solution was cooled to 25 ° C. and extracted twice with 100 ml of methylene chloride. After concentration, 33 g of crude ethyl 4-cyano-3-hydroxybutyrate was obtained. Yields analyzed by quantitative GC have an average product yield of> 80%.

The ECHB product, in R form, was further purified in batch or continuous mode by vacuum fractional distillation. Distillation recovery is> 95%. b.p. 270 ° C (116 ° C / 0.8mmHg)

% e.e.> 98% (by GC, the optical purity of the lactone starting material is maintained)

From the foregoing description of particular implementations of the invention, various modifications, adjustments and improvements will be readily apparent to those skilled in the art. It is understood that all such modifications, adjustments and improvements fall within the scope of the present invention. Accordingly, the foregoing is merely illustrative of the present invention, which does not limit the present invention.

Claims (17)

(a) reacting 3-hydroxy- [gamma] -butyrolactone with a halide agent in the presence of an acylating agent dissolved in a lower alkanol solvent to produce a reaction product comprising lower alkyl 4-halo-3-hydroxybutyrate. Providing (wherein the halo is selected from bromine and iodine), (b) reacting the reaction product of step (a) with cyanide ions in the reaction mixture having a pH of 7 to 11 without separation or purification to lower alkyl 4-cyano-3-hydroxybutyrate having a minimum side reaction product ( Generating ACHB) Method for producing lower alkyl 4-cyano-3-hydroxybutyrate (ACHB) comprising a. The method of claim 1 wherein the halide agent in step (a) is selected from the group consisting of hydrogen bromide, hydrogen iodide, acyl halides, trimethylsilyl halides, and alkali metal halides in solution or gas form. Halide is selected from bromine and iodine. The method of claim 2 wherein the halide agent is liquid hydrogen bromide. The process of claim 1 wherein the acylating agent in step (a) is selected from the group consisting of lower alkanoyl halides, lower alkanoic anhydrides, lower alkyl alkanoates and mixtures thereof. The method of claim 4 wherein the acylating agent is acetyl chloride. 5. The method of claim 4 wherein said acylating agent is acetic anhydride. 5. The method of claim 4 wherein the acylating agent is ethyl acetate or ethyl formate. The method of claim 1 wherein acetyl bromide is provided as the halogenating agent and the acylating agent. The method of claim 1 wherein the source of cyanide ions in step (b) is an alkali metal cyanide. 10. The method of claim 9, wherein the alkali metal cyanide is sodium cyanide. The method of claim 1, wherein step (a) and step (b) are carried out continuously in a single reaction vessel. The method of claim 1 wherein the reaction uses a racemic reactant and produces a racemic product. The method of claim 1, wherein the method uses an optically active reactant and produces an optically active product. The method of claim 13, wherein the process uses a reactant having a (S) -configuration. The process of claim 1 wherein the reaction product of step (a) is ethyl 4-bromo-3-hydroxybutyrate (EBHB) and the final product prepared is ethyl 4-cyano-3-hydroxybutyrate (ECHB). How to feature. The method of claim 1 wherein step (b) is performed at a pH range of 8 to 9.5. The method of claim 1, wherein step (b) is performed in aqueous ethanol.