Optically active compounds and process for producing thereof

Abstract: The present invention provides optically active compounds and a process for producing the optically active compounds by a biochemical method in which specific compounds having hydroxyl or acyloxy groups are reacted with esters in the presence of hydrolase. The compounds have the following general formula: wherein R¹, R² and R³ are selected from alkyl groups having 1-4 carbon atoms and phenyl groups, X is selected from a hydrogen atom and - -R, R is selected from alkyl groups having 1-20 carbon atoms, and C* indicates an asymmetric carbon atom.

Description: The present invention relates to optically active compounds which are used as optically active compounds such as physiological active compounds, functional materials and so on, and a process for producing thereof. Compounds represented by the general formula: wherein R¹, R² and R³ are selected from alkyl groups having 1-4 carbon atoms and phenyl groups, X is selected from a hydrogen atom and and R is selected from alkyl groups having 1-20 carbon atoms, have not been known as optically active compounds, but as racemates. The compounds represented by the above general formula (II) are useful chemical compounds as starting materials for pharmaceuticals, agricultural chemicals and the like, and as intermediates. However, the compounds have optical isomers, and in many cases they do not sufficiently exhibit their useful characteristics because they are not obtained as pure compounds. Accordingly, it has been required to obtain preponderantly pure R- or S-compounds. For the above reasons, and in order to obtain an optically active substance, it is necessary to optically resolve a racemate (itself typically obtained by a synthetic chemical technique), to conduct an asymmetric synthesis, or to convert from an optically active starting material by stereochemical synthetic method. In many cases, the process is troublesome and disadvantageous industrially. Similar compounds to the above compounds represented by the general formula (II) are synthesized as starting materials of prostaglandin (M. Nishizawa, M. Yamada and R. Noyori, Tetrahedron Letters, 22 , 247(1981)). However, alkyl chains of the compounds of the present invention are different from those of the above compounds, so that the optically active compounds of the present invention have not been obtained by the conventional methods. Accordingly, it is desired to develop a technique for obtaining optically active compounds of the present invention by an industrially advantageous method. The inventors of the present invention carried out research for obtaining optically active alcohols and esters thereof by an advantageous industrial method. They found new optically active compounds and a process for producing thereof from racemates represented by the above general formula (II). Namely, the present invention provides an optically active R- or S-compound represented by the general formula: wherein R¹, R² and R³ are selected from alkyl groups having 1-4 carbon atoms and phenyl groups, X is selected from a hydrogen atom and R is selected from alkyl groups having 1-20 carbon atoms, and C* indicates an asymmetric carbon atom. The present invention also provides a process for producing optically active compounds represented by the above formula (I) which comprises using by hydrolase, reacting the (R,S)-compound represented by the above formula (II) and an ester to perform a transesterification reaction under substantially anhydrous conditions, and resolving to an optically active compound which contains richly either the R- or S-compound and correspondingly the ester produced from the S- or R-compound. According to the method of the present invention, the reaction is conducted under anhydrous conditions. This method does not require the use of a small amount of water or a lower alcohol instead of the water, and a side reaction does not occur such as hydrolysis of obtained esters and esters of starting compounds, and formation of undesirable esters, so that the enzyme is stably kept in organic solvent and easily separated after the reaction and re-used. Furthermore, as the enzyme is directly used and reacted in organic solvent, the method can be kept free from contamination by unwanted microorganisms. Accordingly, there is no necessity for preparing special equipment, antiseptics, sterilization treatment, etc. It is possible to conduct the reaction in an open system. Further, the reaction may be conducted in the same or less quantity of solvent in comparison with common organic synthetic reactions in high substrate concentration. The following description illustrates this invention more specifically. Compounds used in the present invention are the (R,S)-compounds represented by the above general formula (II). The compounds are characterized by having a triple bond in the formula and available as synthetic substances. It is also enough to use esters, preferably triglycerides, which are commercially available without any difficulty. Triacetin, tripropionin, tributyrin tristearin, trilaurin, trimyristin, triolein, etc, can be exemplified as the triglycerides. As for other esters, methyl propionate, ethyl butyrate, ethyl stearate, trichloroethyl laurate, butyl laurate, ethylene glycol diacetate, etc, can be used. The hydrolase which is used in this invention has the ability to catalyze a transesterification reaction preferentially between the R- or S-compound and the ester when the enzyme is used with the (R,S)-compound, and the enzyme can be used regardless its class. For example, a lipase, lipoprotein lipase, esterase, etc., are preferable. The following table shows commercially available enzymes that can be used in the present reaction. In addition to these enzymes, microoganisms which produce the enzymes having the above ability can be used regardless of their species and genus. As such microorganisms, the genera Arthrobacter, Acromobacter, Alcaligenes, Aspergillus, Chromobacterium, Candida, Mucor, Pseudomonas, Rhizopus, etc, can be exemplified. The enzymes produced from these microorganisms can be used also. In practice of the present invention, (R,S)-alcohols and esters such as triglycerides can be used without any particular treatments. The reaction is typically conducted by mixing an (R,S)-alcohol with an ester, preferably a triglyceride, if necessary adding an organic solvent such as heptane or toluene when the alcohol is slightly soluble in the ester, and contacting efficiently the mixture with an enzyme. The reaction temperature is suitably 20 to 70°C and especially preferably 30 to 45°C. The reaction time is widely variable, say 5 to 2000 hours. The reaction time can be shortened by elevating the reaction temperature or using an enzyme having high activity (large numbers of units) or lowering the substrate concentration. The (R,S)-alcohol which is a substrate and the ester are suitably mixed in the ratio 1:0.5 to 1:2 by mole, and preferably 1:1.1 to 1:1.5 by mole. After the transesterification reaction, the enzyme can be removed by conventional filter operation and used again, as it is. The filtrate can be separated into an optically active alcohol and an ester, respectively, for instance by distillation or column chromatography. The obtained ester is hydrolyzed in an alkali or acid solution to derive the optically active alcohol which is an antipode of the above alcohol. By the above described process, the optically active R- and S-alcohol can be obtained. When the (R,S)-acyloxy compound is used as substrate instead of (R,S)-alcohol, the same method can be used. The merits of this invention are as follows. (1) Unnecessary hydrolysis of esters scarcely occurs because the transesterification reaction is substantially conducted under the conditions of no water. (2) The enzyme can be easily recovered and re-used. (3) No special equipment and materials are used because the reaction can be performed under the conditions of relatively lower temperatures and an open system. (4) Optically active substances having high purity are obtained by a one-step reaction. (5) In spite of the biochemical reaction, the substrate concentration can be increased and big reaction vessels are unnecessary, because a buffer solution and the like are not required in the reaction. Using 1-butyne-3-ol as a starting racemate of the present invention, the alcohol is reacted with 3,4-dihydropyran in the presence of pyridinium p-toluenesulfonate and its hydroxy group is protected by tetrahydropyranylation. The protected compound is then tri-substituted sililation by a conventional method. The tetrahydropyranyl group of the product is deprotected by pyridinium p-toluenesulfonate in ethanol and the racemic compound (II) is obtained. The resulting racemate is optically resolved by the process of the present invention and the compound of the present invention is obtained. The following examples illustrate this invention more specifically, but these will not always be precise in practical applications. Example 1 (i) Production of 3-(2′-tetrahydropyranyloxy)-1-butyne To a cooled solution of 88.6g of 1-butyne-3-ol and 50g of 3,4-dihydropyran in 300ml dichloromethane at 0°C, 200ml of a dichlorometane solution of 5g pyridinium p-toluenesulfonate was added dropwise, stirred for one hour under ice-cold conditions, then stirred for one hour at room temperature, and permitted to stand for one night. The solution was cooled in ice, 3g of sodium bicarbonate was added to the solution. After stirring the solution for one hour, dichloromethane was removed under reduced pressure. 200 ml of heptane was added to the residue and the solution was chromatographed over silica gel. After the solvent was removed, 164.6g of 3-(2′-tetrahydropyranyloxy)-1-butyne having the boiling point of 50-51°C/5Torr was obtained by reduced distillation. (ii) Production of 1-trimethylsilyl-3-(2′-tetrahydropyranyloxy)-1-butyne To a cooled solution of 80g of 3-(2′-tetrahydropyranyloxy)-1-butyne in 300ml of tetrahydrofuran at 10°C, 300ml of a tetrahydrofuran solution of ethyl magnesium bromide which is prepared from 62g of bromoethane was added dropwise for one hour. At the conclusion of the addition, the solution was refluxed for 1.5 hours and cooled. To the solution, a solution of 56.5g of chlorotrimethyl silane in 200ml of tetrahydrofuran was added dropwise for one hour, and permitted to stand for one night. The solution was cooled and 400ml of aqueous solution of 55g of ammonium chloride was added dropwise. The products were extracted with n-heptane. The obtained organic layer was washed with water until it was neutral, and dried. The resulting compounds were concentrated and distilled under reduced pressure. 99g of 1-trimethylsilyl-3-(2′-tetrahydropyranyloxy)-1-butyne having the boiling point of 93-95°C/6Torr was obtained. (iii) Production of (R,S)-1-trimethylsilyl-1-butyne-3-ol To a solution of 45.3g of 1-trimethylsilyl-3-(2′-tetrahydropyranyloxy)-1-butyne in 100ml of ethanol, 2.5g of pyridinium p-toluenesulfonate was added and stirred for 4.5 hours at 55°C. The reaction mixtures were purified by chromatographed over silica gel under reduced pressure and the solvent was removed. 17.5g of (R,S)-1-trimethylsilyl-1-butyne-3-ol having the boiling point of 72-80°C/25Torr was obtained. (iv) Optical resolution Ten grammes of enzyme (produced by Amano pharmaceutical Co. Ltd., lipase "Amano CES"), 14.2g (0.1mol) of (R,S)-1-trimethylsilyl-1-butyne-3-ol and 28.6g (0.11 mol) of tripropionin were charged into three-necked flask and reacted with stirring for six days at 35°C. After the reaction was stopped, the enzyme was removed by filtration and the desired compounds were isolated from the filtrate by distillation under reduced pressure. As the result, 6g of optically active 1-trimethylsilyl-1-butyne-3-ol (rotation α D =+1.2°(neat, 1cm cell)) and 1.5g of optically active 1-trimethylsilyl-1-butyne-3-yl propionate (specific rotation [α] D =+59°(cl.0, CHCl₃)) were obtained. The obtained compounds were identified by structure analysis with NMR. Example 2 Using the same optical resolution method as used in Example 1, 50g of lipase "Amano CES", 71g (0.5mol) of (R,S)-1-trimethylsilyl-1-butyne-3-ol and 151g (0.5 mol) of tributyrin were charged into three-necked flask and reacted as described in Example 1. As the result, 25g (yield 70%) of optically active S-1-trimethylsilyl-1-butyne-3-ol (specific rotation [α] D ²⁶ -19°(c4.0, CHCl₃)) and R-1-trimethylsilyl-1-butyne-3-yl butyrate were obtained. The obtained compounds were identified by structure analysis with NMR.

Claims: An optically active R- or S-compound characterized in that the compound is represented by the general formula: wherein R¹, R² and R³ are selected from alkyl groups having 1-4 carbon atoms and phenyl groups, X is selected from a hydrogen atom and R is selected from alkyl groups having 1-20 carbon atoms, and C* indicates an asymmetric carbon atom. A compound as claimed in claim 1, wherein the compound represented by the formula (I) is optically active 1-trimethylsilyl-1-butyne-3-ol. A compound as claimed in claim 1, wherein the compound represented by the formula (I) is optically active 1-trimethylsilyl-1-butyne-3-yl propionate. A compound as claimed in claim 1, wherein the compound represented by the formula (I) is optically active 1-trimethylsilyl-1-butyne-3-yl butyrate. A process for producing an optically active R- or S-compound represented by the general formula: wherein R¹, R² and R³ are selected from alkyl groups having 1-4 carbon atoms and phenyl groups, X is selected from a hydrogen atom and R is selected from alkyl groups having 1-20 carbon atoms, and C* indicates an asymmetric carbon atom, characterized in that the process comprises using a hydrolase, reacting under substantially anhydrous conditions an ester and an (R,S)-compound represented by the general formula: wherein R¹, R² and R³ are selected from alkyl groups having 1-4 carbon atoms and phenyl groups, X is selected from a hydrogen atom and R is selected from alkyl groups having 1-20 carbon atoms, to effect a transesterification reaction, and resolving to an optically active compound which contains richly either the R- or S-compound and correspondingly the ester produced from the S- or R-compound. A process as claimed in claim 5, wherein the hydrolase is Lipase AP originated from Aspergillus niger , Lipase M from Mucor javanicus , Lipase P fom Pseudomonus fluorescens , Lipase CES from Pseudomonus sp , Lipase CE from Humicola lanuginosa , Lipase F-AP from Rhizopus javanicus , Lipase II from Porcine pancreas , Lipase VIII from Geotrichum candidum , Lipase X from Rhizopus delamar , Lipase from Chromobacterium viscosum , Paratase A from Aspergillus niger , or Lipase from Rhizopus niveus . A process as claimed in claim 6, wherein the hydrolase is Lipase CES from Pseudomonus sp . A process as claimed in claims 5, 6 or 7, wherein the starting ester is a triglyceride. A process as claimed in claim 8, wherein the starting ester is tripropionin or tributyrin. A process as claimed in claim 8 or 9, wherein the (R,S)-compound represented by the formula (II) is (R,S)-1-trimethylsilyl-1-butyne-3-ol.

Inventors: KANEOYA MASAKAZU, UCHIDA MANABU, YOSHIDA NAOYUKI, KANEOYA, MASAKAZU, UCHIDA, MANABU, YOSHIDA, NAOYUKI
Applicants: CHISSO CORP, CHISSO CORPORATION
Application year: 1988
Main classification: C12P9
IPC codes: C12P41, C07F7, C12P9