PROCESS FOR PREPARING 1,3-DIOXOLANE-4-METHANOL COMPOUNDS

Abstract: A process for preparing easily and economically a 1,3-dioxolane-4-methanol in a racemic form or an optically active form with high purity and in high yield. The process comprises reacting a 3-halogeno-1,2-propanediol (1a) wherein X is halogen atom, or glycidol with an alcohol in a base to prepare a 3-alkoxy-1,2-propanediol and acetalizing it in an acid and hydrogenolysing it in a reduction catalyst to prepare a 1,3-dioxolane-4-methanol of a formula (5) wherein R 1 and R 2 are hydrogen atom, alkyl having 1 to 4 carbon atoms or phenyl, and R 1 and R 2 may form a cycloalkyl ring having 3 to 6 carbon atoms with the adjacent carbon atoms.

Description: The present invention relates to a process for preparation of optically active 1,3-dioxolane-4-methanols useful as an intermediate of medicines, agricultural chemicals, etc. 1,3-Dioxolane-4-methanols are used as an intermediate of medicines, agricultural chemicals, etc. and the following processes for preparation of them are known: (i) A process for preparation of them by reacting glycerin and an acetonide reagent ( Synth. Commun., 22, 2653(1992), (ii) a process for preparation of them from mannitol (Biochem. Prep., 2, 31(1952)), (iii) a process for preparation of them from an ascorbic acid (J. Am. Chem. Soc., 102, 6304(1980), (iv) a process for preparation of them from serine (Japanese Patent Publication B No. 6-62492), (v) an optical resolution of them by using an enzyme (J. Chem. Soc., Perkin Trans. I 23, 3459(1994) and so on. These processes, however, have industrially the following disadvantages: According to the process for preparation of them by reacting glycerin and an acetonide reagent of (i), a mixture of a compound acetalized between positions 1 and 2 and a compound acetalized between positions 1 and 3 is produced and it is fairly difficult to separate each compound from the mixture. According to the method of (ii), because a chemically equivalent amount of lead tetraacetate or sodium hyperiodic acid is used in case of cleavage of 1,2-diol compounds, it takes high costs and in case of preparing an optical isomer, only the (S)-form is obtained because only D-mannitol is present in nature. According to the process for preparation of them from L-ascorbic acid or D-isoascorbic acid of (iii), because a chemically equivalent amount of lead tetraacetate or sodium periodic acid is used, it takes high costs like in case of (ii). According to the method from serine of (iv), in case of preparing an optical isomer, only the (R)-form is obtained because only the (L)-form is present in nature like in case of (ii) and furthermore, in case of reduction of the carboxylic acid, a reagent which is difficult to be dealt with in mass production such as lithium aluminum hydride etc. must be used. According to the process by the biochemically optical resolution method of (v), purity of one of optical isomers is high, but purity of the other is low, and in some cases, in order to separate an optically active alcohol and an optically active ester which are prepared from a racemic alcohol, separation by column chromatography is necessary and therefore, it is not suitable for mass production. Furthermore, any process mentioned above contains many steps and is not practical. Therefore, a more efficient process for preparation of a 1,3-dioxolane-4-methanols was desired. The present inventors engaged extensively in solving above problems, and found a novel process for achieving the above objective compound from an optically active 3-halogeno-1,2-propanediol or glycidol. The present invention relates to a process for preparing an optically active 1,3-dioxolane-4-methanol of the formula wherein R 1 and R 2 are the same or different and are hydrogen atom, alkyl having 1 to 4 carbon atoms or phenyl, and R 1 and R 2 may form a cycloalkyl ring having 3 to 6 carbon atoms with the adjacent carbon atoms, which is characterized in reacting an optically active 3-halogeno-1,2-propanediol of the formula wherein X is halogen atom, or an optically achive glycidol of the formula with a alcohol of the formula ROH wherein R is aralkyl or allyl, in the presence of a base to prepare an optically active 3-alkoxy-1,2-propanediol of the formula wherein R is as defined above, and acetalizing it with an acetalizing agent in the presence of an acid catalyst to prepare an optically active 4-alkoxymethyl-1,3-dioxolane of the formula wherein R, R 1 and R 2 are as defined above, and then subjecting it to hydrogenolysis in the presence of a reduction catalyst. According to the present invention, where an optically active 3-halogeno-1,2-propanediol or glycidol as a starting material is used, there is also obtained an optically active 1,3-dioxolane-4-methanol. The reaction of the present invention is schematically shown as follows. , in the above formulae X, R 1 , R 2 and R are as defined above. Each step is explained in detail as follows. Step (A) A 3-alkoxy-1,2-propanediol of the formula (3) is obtained by reacting a 3-halogeno-1,2-propanediol of the formula (1a) or glycidol of the formula (1b) with an alcohol of the formula (2) in the presence of a base. Preferable examples of the 3-halogeno-1,2-propanediols are 3-chloro-1,2-propanediol and 3-bromo-1,2-propanediol. Examples of the alcohols are ones having an aralkyl group or an allyl group, especially preferably benzyl alcohol and allyl alcohol. The amount of the alcohol is 1 to 4 mole equivalent to the 4-halogenomethyl-1,3-dioxolane or glycidol. Examples of the bases are alkali metal or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, calcium carbonate, etc., alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc., alkali metal or alkaline earth metal hydrides, such as sodium hydride, lithium hydride, calcium hydride, etc., preferably alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc., and alkali metal or alkaline earth metal hydrides, such as sodium hydride, lithium hydride, calcium hydride, etc. Examples of solvents are polar aprotic solvents, such as N,N-dimethylformamide, dimethyl sulfoxide, etc., ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, etc., halogen compounds, such as dichloromethane, 1,2-dichloroethane, etc., water and a mixture of these solvents. The alcohols used as a starting material may serve as a solvent if used in excess. On the other hand, an 3-alkoxy-1,2-propanediol is also prepared by making glycidol from a 3-halogeno-1,2-propanediol and reacting it with an alcohol in the presence of an acid catalyst, but an 2-alkoxy-1,3-propanediol is produced as by-product and this product is very difficult to be separated from an 3-alkoxy-1,2-propanediol because both compounds are very similar in their properties. Therefore, this process is not preferable. Step(B) A 4-alkoxymethyl-1,3-dioxolane of the formula (4) is prepared by reacting the thus obtained 3-alkoxy-1,2-propanediol of the formula (3) with an acetalizing agent in the presence of an acid catalyst. The examples of the acid catalysts are organic acids, such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, camphorsulfonic acid, etc., mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and Lewis acid, such as trifluoroborate etc., preferably p-toluenesulfonic acid, pyridinium p-toluenesulfonate, camphorsulfonic acid and trifluoroborate The amount of the acid catalyst is 0.05 to 0.1 mol equivalent to an 3-alkoxy-1,2-propanediol. For instances of the acetalizing agents, when a compound of the formula (4) wherein R 1 and R 2 are hydrogen atom is prepared, formaldehyde is used, when a compound of the formula (4) wherein R 1 and R 2 are phenyl, benzophenone is used, when a compound of the formula (4) wherein R 1 and R 2 form a 6 membered ring together with the adjacent carbon atoms is prepared, cyclohexanone is used and when a compound of the formula (4) wherein R 1 is phenyl and R 2 is hydrogen is prepared, benzaldehyde is used. When a compound of the formula (4) wherein R 1 and R 2 are methyl is prepared, acetone, 2,2-dimethoxypropane and 2-methoxypropene as an acetalizing agent are preferably used. The examples of solvents are ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., halogen compounds, such as dichloromethane, dichloroethane, etc., acetone and so on. The reaction temperature is from 0°C to refluxing temperature of the solvent. Step(C) A 1,3-dioxolane-4-methanol of the formula (5) is prepared by subjecting the thus obtained 4-alkoxymethyl-1,3-dioxolane of the formula (4) to catalytic hydrogenation under an atmosphere of hydrogen in a solvent. Examples of the solvents are esters, such as ethyl acetate, butyl acetate, etc., ethers, such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc., ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc., alcohols, such as methanol, ethanol, isopropanol, t-butanol, etc., water and a mixture of these solvents. The catalysts are not limited as far as the catalysts used in this field, but preferable ones are metal catalysts, such as palladium, platinum, etc., and palladium is more preferable in view of the yield and economy. Especially about 5 - 10% palladium-carbon powder is better. The amount of the catalyst is preferably 0.5 to 50 weight percent per 4-alkoxymethyl-1,3-dioxolane. Thus obtained a 1,3-dioxolane-4-methanol is prepared in good yield and high purity by usual purification methods, such as distillation in vacuo. By using an optically active 3-halogeno-1,2-propanediol as a starting material, there is obtained an optically active 1,3-dioxolane-4-methanol. A 3-halogeno-1,2-propanediol with high optical purity ( 98% or more than 98 %) is obtainable by methods described in Japanese Patent Publication B No. 4-73998, and No. 4-73999 which were filed by the present applicant. According to the present invention, by using a (R)-3-halogeno-1,2-propanediol or (R)-glycidol, there is obtained a (S)-1,3-dioxolane-4-methanol. A R-form compound is prepared in the same way. By using a 3-halogeno-1,2-propanediol or glycidol with highly optical purity, there is obtained a 1,3-dioxolane-4-methanol with highly optical purity without marked racemization on the reaction. The present invention is explained by the following examples, but it is not limited to these examples. Examples 1 to 5 are cases in variation of the bases used in step(A), of the solvents used in step (A) and of the solvents used in step (C). Example 5 is a case using glycidol as a starting material. Comparative example is an instance showing production of a by-product by reacting glycidol and an alcohol in the presence of an acid catalyst to prepare an 3-alkoxy-1,2-propanediol. Example 1 Benzyl alcohol (32.90g, 0.35 mol) was dropped under ice cooling in a suspension of 60% sodium hydride (5.88g, 0.155 mol) and DMF (150ml). After emission of hydrogen gas, therein a DMF solution(15ml) of (R)-3-chloro-1,2-propanediol (8.535g, 0.078 mol, optical purity 98.7% e.e.) was dropped. The reaction temperature was raised to 60°C and the mixture was stirred under heating for 2 hours. After completion of the reaction the mixture was cooled on ice bath and neutralized with 6% hydrochloric acid. After removal of water and DMF in vacuo, ethyl acetate was added to the residue, the insoluble materials were filtered off and the filtrate was condensed in vacuo. Thereto acetone (750ml) and p-toluenesulfonic acid (0.579g) were added and the solution was stirred for 5 hours at 25°C. After the reaction was over, the mixture was neutralized with triethylamine. After stirring for 5 minutes, acetone was removed in vacuo. The crude product was distilled to give 9.267g of (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 54%, b.p. 110°C at 0.3 mmHg). 10% Palladium-carbon (2.63g) was added to thus obtained (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (9.267g, 41.69 mmol) in ethanol(250ml) and the mixture was stirred for 3 hours at 25°C under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 4.68g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 85%, b.p. 65°C at 3 mmHg, optical purity 97.5% e.e., specific rotation [α] D 20 +10.84° (c=1,MeOH))). Example 2 Benzyl alcohol (60.54g, 0.56mol) was dropped under ice cooling in a suspension of 60% sodium hydride (11.2g, 0.28 mol) and DMF (300ml). After emission of hydrogen gas, therein a DMF solution(25ml) of (R)-3-chloro-1,2-propanediol (15.47g, 0.14 mol, optical purity 98.7% e.e.) was dropped. The reaction temperature was raised to 60°C and the mixture was stirred under heating for 2 2 hours. After completion of the reaction the mixture was cooled on ice bath and neutralized with 6% hydrochloric acid. After removal of water and DMF in vacuo, ethyl acetate was added to the residue, the insoluble materials were filtered off and the filtrate was condensed in vacuo. Thereto acetone (1500ml) and p-toluenesulfonic acid (1.13g) were added and the solution was stirred for 5 hours at 25°C. After the reaction was over, the reaction mixture was neutralized with triethylamine. After stirring for 5 minutes, acetone was removed in vacuo. The crude product was distilled to give 16.228g of (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 52%, b.p. 110°C at 0.3 mmHg). 10% Palladium-carbon (2.7g) was added to thus obtained (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (16.228g, 73.02 mmol) in ethyl acetate(270ml) and the mixture was stirred for 3 hours at 25°C under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 8.78g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 91%, b.p. 70°C at 6 mmHg, optical purity 97.2% e.e., specific rotation [α] D 20 +10.76° (c=1,MeOH))). Example 3 In benzyl alcohol (116.02g, 1.073mol) was dropped 48% sodium hydroxide (18ml) under ice cooling. After dropping the reaction mixture was stirred for 10 minutes and then was heated to 80°C. Therein a benzyl alcohol solution(30ml) of (R)-3-chloro-1,2-propanediol (29.82g, 0.27 mol, optical purity 98.7% e.e.) was dropped. Then the mixture was stirred under heating for 1 hour. After completion of the reaction the mixture was cooled to 25°C and neutralized with 6% hydrochloric acid. The reaction mixture was extracted with ethyl acetate and the extract was washed with satulated brine, dried over anhydrous sodium sulfate and condensed in vacuo. Thereto acetone (450ml) and p-toluenesulfonic acid (0.285g) were added and the solution was stirred for 3 hours at 25°C. After the reaction was over, the mixture was neutralized with triethylamine. After stirring for 5 minutes, acetone was removed in vacuo. The crude product was distilled to give 14.39g of (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 47%, b.p. 120°C at 0.5 mmHg). 10% Palladium-carbon (2.3g) was added to thus obtained (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (14.398g, 64.74 mmol) in ethyl acetate(250ml) and the mixture was stirred for 3 hours at 25°C under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 7.61g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 89%, b.p. 70°C at 6 mmHg, optical purity 97.4% e.e., specific rotation [α] D 20 +10.78° (c=1,MeOH))). Example 4 To benzyl alcohol (600ml) was added dropwise at room temperature 60% sodium hydride (104,4g, 2.60 mol). The reaction temperature was raised to 40°C and therein, (R)-3-chloro-1,2-propanediol (240g, 2.17 mol, optical purity 99.1% e.e.) was dropped. After the reaction at 80°C for 3 hours, acetic acid was added to the reaction mixture and it was stirred for 10 minutes. After removal of excess benzyl alcohol, desalination was carried out by adding acetone. Further acetone (1.4L) and p-toluenesulfonic acid (4.12g) were added thereto and the solution was stirred for 5 hours at 25°C. After the reaction was over, the mixture was neutralized with triethylamine. After stirring for 5 minutes, acetone was removed in vacuo. The crude product was distilled to give 361.7g of (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 75%, b.p. 110°C at 0.3 mmHg, optical purity 98.9% e.e.). 10% Palladium-carbon (120g) was added to (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (361.7g, 1.63 mol) in ethanol(2L) and the mixture was stirred for 3 hours at 25°C under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 189.5g of (S)-2,2-dimethyl-1,3-dioxclane-4-methanol (yield 88%, b.p. 63°C at 2 mmHg, optical purity 98.7% e.e., specific rotation [α] D 20 +11.16° (c=1,MeOH))). Example 5 Benzyl alcohol (65.8g, 0.7mol) was dropped under ice cooling in a suspension of 60% sodium hydride (11.76g, 0.31 mol) and DMF (300ml). After emission of hydrogen gas, therein a DMF solution(30ml) of glycidol (11.556g, 0.156 mol) was dropped. The reaction temperature was raised to 60°C and the mixture was stirred under heating for 2 hours. After completion of the reaction the mixture was cooled on ice bath and neutralized with 6% hydrochloric acid. After removal of water and DMF in vacuo, ethyl acetate was added to the residue, the insoluble materials were filtered off and the filtrate was condensed in vacuo. Thereto acetone (1500ml) and p-toluenesulfonic acid (1.16g) were added and the solution was stirred for 5 hours at 25°C. After the reaction was over, the mixture was neutralized with triethylamine. After stirring for 5 minutes, acetone was removed in vacuo. The crude product was distilled to give 16.692g of (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 48%, b.p. 112°C at 0.3 mmHg). 10% Palladium-carbon (3g) was added to thus obtained (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (16.692g, 74.88 mmol) in ethanol(250ml) and the mixture was stirred for 3 hours at 25°C under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solution was condensed in vacuo. The crude product was distilled to give 8.61g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 87%, b.p. 65°C at 3 mmHg, optical purity 97.8% e.e., specific rotation [α] D 20 +10.92° (c=1,MeOH))). Comparative example Boron trifluoride-diethyl ether complex ( 0,9ml,0.007ml) was dropped in benzyl alcohol (92ml) of glycidol (22.01g, 0.3 mol) on ice bath. After dropping the mixture was stirred for 8 hours at 25°C. After the reaction was over, triethylamine was added thereto and benzyl alcohol was removed in vacuo. The desidue was dissolved in acetone and thereto p-toluenesulfonic acid was added. The mixture was reacted for 8 hours at 25°C. After the completion of the reaction triethylamine was added thereto and acetone was removed in vacuo. The crude product was distilled to give a mixture (43.8g, yield 81%) of 4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane and 5-benzyloxymethyl-2,2-dimethyl-1,3-dioxane. The ratio of the dioxolane and the dioxane was 8 to 1 by analysis with gas chromatography. According to the present invention, 1,3-dioxolane-4-methanols are comparatively simply and economically prepared without expense reagents. An optically active 1,3-dioxolane-4-methanol is prepared with high purity and in good yield.

Claims: A process for preparing an optically active 1,3-dioxolane-4-methanol of the formula wherein R 1 and R 2 are the same or different and are hydrogen atom, alkyl having 1 to 4 carbon atoms or phenyl, and R 1 and R 2 may form a cycloalkyl ring having 3 to 6 carbon atoms with the adjacent carbon atoms, which is characterized in reacting an optically active 3-halogeno-1,2-propanediol of the formula wherein X is a halogen atom, or an optically active glycidol of the formula with an alcohol of the formula ROH wherein R is aralkyl or allyl in the presence of a base to prepare an optically active 3-alkoxy-1,2-propanediol of the formula wherein R is as defined above, and acetalizing it with an acetalizing agent in the presence of an acid catalyst to prepare an optically active 4-alkoxy-1,3-dioxolane of the formula wherein R, R 1 and R 2 are as defined above, and then subjecting it to hydrogenolysis in the presence of a reduction catalyst. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in claim 1 which is characterized in using an optically active 3-halogeno-1,2-propanediol of the formula (1a) as a starting material. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in claim 1 which is characterized in using an optically active glycidol of the formula (1b) as a starting material. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in claim 1 or 2 wherein a halogen atom in the formula (1a) is chlorine atom or bromine atom. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in any one of claims 1 to 4 wherein the base is an alkali metal hydroxide or hydride. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in any one of claims 1 to 5 wherein the alcohol is benzyl alcohol or allyl alcohol. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in any one of claims 1 to 6 wherein the acid catalyst is p-toluenesulfonic acid, pyridinium p-toluenesulfonate, camphorsulfonic acid or trifluoroborate. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in any one of claims 1 to 7 wherein the acetalizing agent is a compound selected from ketones mentioned below, aldehydes mentioned below, dialkoxyacetals of ketones mentioned below and enol ethers of ketones mentioned below; Ketones: acetone, diethyl ketone, benzophenone, cyclohexanone, Aldehyde: formaldehyde, acetoaldehyde, benzaldehyde; Dialkoxyacetals of ketones: 2,2-dimethoxypropane, 2,2-dimethoxypentane, Enol ethers of ketones: 2-methoxypropene. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in claim 8 wherein the acetalizing agent is a compound selected from acetone, 2,2-dimethoxypropane and 2-methoxypropene. The process for preparing an optically active 1,3-dioxolane-4-methanol claimed in any one of claims 1 to 9 wherein the reduction catalyst is a palladium catalyst.

Inventors: FURUKAWA YOSHIRO, HINOUE KAZUMASA, FURUKAWA, YOSHIRO, HINOUE, KAZUMASA
Applicants: DAISO CO LTD, DAISO CO., LTD.
Application year: 1997
Main classification: C07D317
IPC codes: C07D317