Description A PROCESS FOR THE SYNTHESIS OF 3-HYDROXY-GAMMA-BUTYROLACTONE [1] TECHNICAL FIELD [2] [3] The present invention relates to a process for the synthesis of 3-hydroxy-y-butyrolactone of the folowing formula (1) : [4] [5] [6] which is racemic or optical active form. Specifically, the present invention relates to a process for preparing 3-hydroxy-y-butyrolactone in high yield by using 4-chloro-3-hydroxy-butyronitrile as starting material, which is useful as an in- termediate for medicines such as L-carnitine, atorvastatin, etc. and is used for various purposes (refer to US 5,473, 104).

[7] BACKGROUND ART [8] [9] In the literature, the following methods for the preparation of 3-hydroxy-y- butyrdactone have been known: (1) a synthetic method comprising 7 steps starting from isoascorbic acid or ascorbic acid as starting material (Synthesis, 1987,570-573), (2) a method reducing diethyl malic acid esters with boran-dmethyl sulfide and cydizng the resulted hydroxy esters in the presence of an acid (Chemistry Letters, 1984,1389-1392), (3) a method cydiang 4-t-butyloxy-3-hydroxy butanoic acid esters in the presence of an acid (Synthesis, 1986, (1), 37-40), (4) a method preparing 3, 4-hydroxy butanoic acid derivatives from carbohydrate and cyclizing the same (US 6,329, 311), and (5) a method oxidizing 3,4-unsaturated butanoic acid derivatives in the presence of metal catalyst and subsequent cydization of the intermedate (EP 1 302 469).

[10] However, in the above methods, method (1) is too complicated since the operation process is composed of 7 steps and the yield is also too low. Method (2) has dis- advantages that boran-dmethyl sulfide is expensive and a high level of precaution is required while handling it. Method (3) is simple, but a large amount of trifuoroacetic acid should be used. Method (4) is advantageous in that the final product is simply prepared from carbohydrate, but the separation process of the titled product and yield thereof are not dsdosed. Ch the other hand, method (5) provides a convenient process using metal catalyst and hydrogen peroxide, but has a drawback that particular caution is needed in dealing with hydrogen peroxide due to excessive exotherm.

[11] [12] Furthermore, as for methods known in the prior art using natural starting materials such as carbohydrates or an organic acid, only one enantiomer is accessible and so it is difficult to obtain unnatural enantiomer. Also, evenin the case thatunnatural enantiomer may be available, the cost is usually more expensive than that of the natural one.

[13] DISCLOSURE OF THE INVENTION [14] [15] Having the above background of the reported arts, the present inventors in- vestigated an efficient synthesis of 3-hydroxy-y-butyrolactone which is simple, economical, and suitable for commercial mass production. Thus, the purpose of the present invention is to provide a process enabling commercial mass supply and producing both enantiomersselectivelyin low costs. Specifically, the purpose of the present invention is to provide a process comprising : (1) preparing 4-chloro-3-hydroxy-butyronitrile from epichlorohydrinunder the slightly modfied conditions of a known method [J. Amer. Chem. Soc. 2002.124. 1307], (2) treating 4-chloro-3-hydroxy-butyronitrile with an acidc aqueous solution to provide crude 3-hydroxy-y-butyrdactone in a straightforward manner, and (3) conducting direct pu- rification of the reaction mixture to give 3-hydroxy-y-butyrolactone in high purity and yield.

[16] BEST MODE FOR CARRYING OUT THE INVENTION [17] [18] The present invention relates to a process for preparing the (R) -, (S) -or racemic compound represented by the following formula (1), [19] [20] [21] characterized in comprising the steps of, [22] [23] (a) hydrolyang nitrile group of the (R) -, (S) -or racemic compound of the following formula (2) [24] [25] [26] by heating the above compound in acidcaqueous solution to give the compound of the following formula (3) [27] [28] [29] which maintains stereochemical integrity of the asymmetric carbon atom, and [30] [31] (b) neutralizng the above reaction solution with base.

[32] [33] The above reaction can be described by the following reaction scheme (1), [34] [35] [36] in which, [37] CNECH means 4-chloro-3-hydroxy-butyronitrile, CL ACID means 4-chloro-3-hydroxy-butanoic acid, and HGB means 3-hydroxy-y-butyrolactone.

[38] [39] Hereinafter, the present invention wl be described in detail.

[40] [41] Compared with the precedents, the present invention is a simple and economical process. The present invention comprises: (1) the reaction of (R) -, (S) -or racemic epichlorohydrine with metal cyanide to provide (R) -, (S) -or racemic 4-chloro-3-hydroxy-butyronitrile, (2) subsequent hydrolysis by the treatment of acidic aqueous solution to give 4-chloro-3-hydroxy butanoic acid [step (a) ], (3) neutralization of the resulting product by base without a particular separation process to cause lac- tonization [step (b) ], and (4) the final dstilation of the residue obtained by a con- ventional separation process, to give high purity of 3-hydroxy-y-butyrolactone.

[42] [43] In the above process, for the step (a), any common acids that could hydrdyze the nitrile group are desirable. Among them, a typical inorganic acid such as hydrochloric acid, hydroiodc acid, sulfuric acid, etc. is preferable. Among the above acids, hy- drochloric acid or sulfuric acid are more preferable since they are easy to obtain at low prices. When hydrochloric acid is used, 35% or more of hydrochloric acid is preferable to increase productivity. Ch the other hand, as for the mole ratio of acid used in the reaction, 1 equivalent is sufficient theoreticaly, but more than 1 equivalent is proper to reduce the reaction time, and 1.3 to 3 mole equivalent to the compound of the above formula (2) is preferable. The reaction temperature is within the range of room temperature to 100 °C. As the amount of acid used in the reaction is increased, the reaction temperature does not have to be increased, but to reduce the reaction time, the preferable reaction temperature is in the range of 50 °C to 100 °C. Therefore, the preferable reaction system is to react 1.3 to 3 mole equivalent of concentrated hy- drochloric acid to 4-chloro-3-hydroxy butyronitrie at the range of 50 °C to 100 °C.

[44] [45] In the step (b), 3-hydroxy-y-butyrolactone is prepared by cooling and neutralizng the mixture resulted from the reaction of step (a). The base that can be used in the step (b) indudes NaOH, KOH, Na CO, or K CO, but preferably NaOH or KOH. The base 2 3 2 3 used in the neutralization can be added in the form of solid or aqueous solution of a suitable concentration. However, a conventional 50% NaOH is preferable because a higher concentration of NaOH is advantageous to increase productivity. The amount of base used in the reaction is suitable to adjust the pH range of the reaction system into 4 to 11, preferably 5 to 9, more preferably 6 to 8. In neutralizing the reaction solution, the reaction temperature affects the qualityof the product. When the neutralization temperature is high, furan-2- (5H)-one is produced, and thus it is preferable to maintain the reaction temperature as low as possible. A preferable temperature is about 30 °C or less, more preferably 10 °C to 20 °C, and most preferably 5 °C to 10 °C.

[46] [47] In the present invention, 3-hydroxy-y-butyrolactone can be separated from the reaction mixture by extracting with ethyl acetate, acetonitrile, isopropanol, acetone, and n-butanol, respectively or with a mixture of solvent thereof. Or, the titled compound could be easily obtained by concentrating the reaction solution under the reduced pressure, precipitating inorganic substance by suspending the concentrated solution in ethyl acetate, isopropanol, acetone, methylethylketone, respectively, and removing the above inorganic substance by filtration. In the above process, if ammonium chloride precipitated by coding the reaction solution at low temperature is removed by filtration after completing the reaction of step (a), the amount of base required for the neutralization may be reduced more. Also, in this process, it is ad- vantageous to filter NaCl produced by cydization reaction before concentrating under the reduced pressure.

[48] [49] Hereinafter, the present invention will be more specifically ilustrated by the fdlowing examples. However, the following examples should not be construed as limiting the scope of the present invention in any way.

[50] [51] Example 1: Preparation of (S)-3-hydroxy-y-butyrolactone [52] [53] (S)-4-chloro-3-hydroxy butyronitrile (10 g, 83.6 mmd) was mixed with 16.7 mL of concentrated hydrochloric acid, and the resulting reaction solution was heated to 60 °C. Upon completing the hydrolysis reaction, the reaction solution was coded in iced bath, and 50% of sodium hydroxide was added dropwise to the reaction solution to adjust pH 7.5. The reaction mixture was extracted with 25mL of acetonitrile 5 times, and the organic layer was concentrated under reduced pressure to obtain 6.4 g of (S)-3-hydroxy-y-butyrolactone.

[54] Yield : 88.8% [55] Optical purity (GC): 100% ee [56] [57] Example 2: Preparation of (S)-3-hydroxy-y-butyrolactone [58] [59] (S)-4-chbro-3-hydroxy butyronitrile (800 g, 6. 69mol) was mixed with 0.9 kg of concentrated hydrochloric acid, and the reaction solution was heated to 70 °C. Upon completing the hydrolysis reaction, the reaction solution was cooled to 10 °C, and 50% of sodum hydroxide was added dropwise to the reaction solution to adjust the pH to 7.7. The reaction mixture was extracted with 2.5 L of n-butanol twice. The organic layer was concentrated under reduced pressure, diluted with 0.5 L of ethyl acetate, and the formed solid was filtered. The filtrate was concentrated to provide 545 g of (S)-3-hydroxy-y-butyrolactone.

[60] Yield : 80.0% [61] Optical purity (GC): 100% ee [62] [63] Example 3: Rcemic-3-hydroxy-y-butyrdactone [64] [65] Racemic-4-chloro-3-hydroxy butyronitrile (920 g, 7.7 mol) was mixed with 1.28 kg of concentrated hydrochloric acid, and the reaction mixture was heated to 70 °C.

Upon completing the hydrolysis reaction, the reaction solution was cooled to 0 °C, and 1. 3kg of acetone was added. The precipitated ammonium chloride was filtered, and the filter cake was rewashed with 0.9 kg of acetone. To the collected filtrate was added dropwise 50% of sodium hydroxide to adjust the pH to 7.7. The precipitated NaCl was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with 2. 5L of acetone, and the formed solid was filtered. The filtrate was con- centrated under reduced pressure to give 775 g of 3-hydroxy-y-butyrolactone. The above 3-hydroxy-y-butyrdactone was distilled under the reduced pressure to give 600 g of the product as cdorless or light yellow oi.

[66] Yield : 83.0% [67] INDUSTRIAL APPLICABILITY [68] [69] According to the present invention, a high purity of 3-hydroxy-y-butyrolactone is prepared economicaly and simply. Hydrolysis of 4-chloro-3-hydroxy butyronitrile in the acid condtions and subsequent neutralization provided 3-hydroxy-y- butyrdactone in high purity and yield. When an opticaly active form of 4-chloro-3-hydroxy butyronitrile is used, the complete retention of the optical integrity was observed.