Title of Invention

"AN IMPROVED METHOD FOR THE PREPARATION OF 4-t-BUTYLCYCLOHEXYL ACETATE"

Abstract

The present invention provides an improved method for the preparation of 4-t-butylcyclohexyl acetate comprising the steps of: reacting 4-t-butylcyclohexanol with acetylating agent selected from acetic anhydride and acetic acid in the mole ratio in the range of 1:10-1:20; and refluxing the above reaction mixture with 2-10 ml of solvent selected from pyridine at a temperature in the range of 100 - 115 deg C for a period of 2-6 hours characterized in that the said refluxing is carried out in the presence of an additive selected from the group consisting of beta cyclodextrine, DM beta-CD, HP beta-CD epichlorohydrin polymer and covering the product by known methods.

Full Text

The present invention deals with an improved method for the preparation of 4-t-butylcyclohexyl acetate. The present invention particularly relates to an improved method for the preparation of 4-t-butylcyclohexyl acetate containing more of the trans isomer by using ß-cyclodextrin in the reaction. 4-t-butylcyclohexyl acetate is in practice since 1950's as a fragrance compound in USA. It is used in soap, detergents, creams, lotions and perfumes [Food cosmet. Toxicol., 1978, 16(Supl.l), 657]. The acetate exists as cis and trans isomers. The cis and trans isomers have slightly different flavour notes with the trans isomer having a rich woody odour and the odour of the cis isomer being more intense and more flowery. Reference may be made to Berry, I.K., Robert, L.S. and Joseph, F.Z., Anal.Chem., 1968, 40(4), 727 and Senda, Y., Ishiyama, I. and Imaizumi, S., Bulletin of the chemical society of Japan, 1979, 52(7), 1994 who prepared 4-t-butylcyclohexyl acetate by acetylation of 4-t-butylcyclohexanol. It was found that chemical synthesis did not appreciably change the ratio of the isomers of acetate and alcohol. Reference may be made to Berry, I.K., Robert, L.S. and Joseph, F.Z., Anal.Chem., 1968, 40(4), 727 who found that 4-t-butylcyclohexanol consisted of cis and trans alcohols in the proportion 1:2.5 which corresponded to 28.5 % cis and 71.5 % trans alcohol. Reference may be made to Berry, I.K., Robert, L.S. and Joseph, F.Z., Anal.Chem., 1968, 40(4), 727 who showed that the proportion of cis and trans acetate prepared chemically were reported to be 22.0% cis and 78.0% trans leading to trans / cis ratio of 3.55. Reference may be made to a recent patent on the process for preparing 4-t-butylcyclohexyanol and 4-t-butylcyclohexyl acetate which has been filed in USA US597702 In this case larger content of cis alcohol was prepared and then esterified to get acetate containing more of cis isomer. Major drawback of the existing procedure is that a trans/cis ratio of the acetate of 3.55 is obtained. The trans ester proportion is maintained as the same as that in the alcohol in the esterification processes available. The present method which involves use of p-cyclodextrin and its derivatives in the ester synthesis alters the trans/cis ratio giving rise to more of the trans ester. More of the trans alcohol is converted compared to the cis isomer. This is achieved by inclusion of 4-t-butylcyclohexanol inside p-cyclodextrin cavity which facilitates only the trans alcohol for reaction with acetic anhydride. The cis alcohol is geometrically prevented from reaction with acetic anhydride as as the cis hydroxyl group is present more towards the cavity. In the trans alcohol, the hydroxyl group is exposed and hence is available for the reaction with acetic anhydride. Some amount of cis alcohol remains unreacted while complete reaction with trans alcohol is observed when ß-cyclodextrin is employed. The novelty of the present invention is that use of p-cyclodextrin with reaction lead to more conversion of trans-alcohol giving rise to better trans / cis ratio (maximum trans / cis ratio of 5.49). The main object of the present invention is to provide an improved method for the preparation of 4-t-butylcyclohexyl acetate with higher trans isomer content using p-cyclodextrin. Another object of the present invention is to use cis and trans 4-t-butylcyclohexanol at a proportion of 1:2.3 cis and trans isomer. Still another object of the present invention is to use acetic anhydride or acetic acid as the acetylating agent at 1:10 and 1:20, 4-t-butylcyclohexanol : acetic anhydride proportion. Yet another objetc of the present invention is to use pyridine as the solvent. Still another object of the present invention is to carry out the reaction by refluxing at 100-115°C, preferably at 115°C. Yet another object of the present invention is to carry out the reaction for a period of 2-6 h preferably 2 h. Still another object of the present invention is to use p-cyclodextrin in various proportions as additives in the reaction. Yet another object of the present invention is to use heptakis-2,6-di-0-methyl-ß-cyclodextrin (DMPCD), ß-CD-epichlorohydrin polymer and hydroxypropyl-ß-cyclodextrin as additives in the reaction. Accordingly the present invention provides an improved method for the preparation of 4-t-butylcycohexyl Acetate which comprises reacting 4-t-butylcycohexanol with acetylating agent in the mole ration of 1:10 - 1:20,refluxing the above reaction mixture with 2-10 ml of pyridine with a solvent at a temperature ranging from 100 - 115°C for a period of 2-6 hrs in the presence of an additive selected from the group consisting of beta cyclodextrin, DM beta-CD, HP beta-CD, beta-CD epichlorohydrin polymer and recovering the product by known methods, In an embodiment of the present invention the 4-t-butylcyclohexanol employed contains cis and trans isomers at a proportion of 1:2 to 1:3 . In an embodiment of the present invention the acetylating agent used is selected from acetic anhydride and acetic acid. In an embodiment of the present invention the organic solvent used is pyridine. In an embodiment of the present invention the reaction is carried out preferably for 2hrs. The reaction was carried out in a round bottomed flask by taking 0.78 g (0.005 mole) 4-t-butylcyclohexanol in 5 mL pyridine and 2.55 g (0.025 mole) of acetic anhydride (in case of 1 : 10 equivalent) and 5.1 g (0.05 mole) acetic anhydride (in case of 1 : 20 equivalent) with appropriate equivalents of ß-CD and its derivatives. The reaction mixture was refluxed for 4 h at 115°C and poured into 100 mL cold water. Upper ester layer was extracted with ether and washed with NaHCOa to neutralize the acid and dried with sodium sulfate. The ether layer was then evaporated to get the reaction mixture. The reaction mixture was monitored by gas chromatography using a Carbowax column at 120°C, FID detector at 240°C and injector at 240°C with N2 as the carrier gas at a flow rate of 40 mL per min. The following examples are given by way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention. Example 1 The reaction was carried out in a round bottomed flask by taking 0.78 g (0.005 mole) 4-t-butylcyclohexanol in 5 mL pyridine and 2.55 g (0.025 mole) of acetic anhydride (in case 1:10 4-t-butylcyclohexanol : acetic anhydride) .The reaction mixture was refluxed for 4 h at 115°C and poured into 100 mL cold water. Upper ester layer was extracted with ether and washed with NaHCO3 to neutralize the acid and dried with sodium sulfate. The ether layer was then evaporated to get the reaction mixture. Yield by GC : Total ester 99.0%, cis - 22.1 % and trans -76.9%.Unreacted alcohol is 1.0%, cis - 0.4%, trans - 0.6%. Example 2 The reaction was carried out in a round bottomed flask by taking 0.78 g (0.005 mole) 4-t-butylcyclohexanol in 5 mL pyridine and 2.55 g (0.025 mole) of acetic anhydride (in case 1:10 4-f-butylcyclohexanol : acetic anhydride) with 1.1350g P-CD (0.2 equivalent to 4-t-butylcyclohexanol). The reaction mixture was refluxed for 4 h at 115°C and poured into 100 mL cold water. Upper ester layer was extracted with ether and washed with NaHCO3 to neutralize the acid and dried with sodium sulfate. The ether layer was then evaporated to get the reaction mixture. Yield by GC : Total ester 89.0%, cis - 21.2 % and trans - 67.9%.Unreacted alcohol 11.0%, cis - 3.2 %, trans - 7.8 %. Example 3 The reaction was carried out in a round bottomed flask by taking 0.78 g (0.005 mole) 4-t-butylcyclohexanol in 5 mL pyridine and 2.55 g (0.025 mole) of acetic anhydride (in case 1:10 4-t-butylcyclohexanol : acetic anhydride) with 2.27g ß-CD (0.4 equivalent to 4-t-butylcyclohexanol). The reaction mixture was refluxed for 4 h at 115°C and poured into 100 mL cold water. Upper ester layer was extracted with ether and washed with NaHCO3 to neutralize the acid and dried with sodium sulfate. The ether layer was then evaporated to get the reaction mixture. Yield by GC : Total ester 71.6%, cis - 13.2 % and trans - 58.4%.Unreacted alcohol 28.4%, cis - 8.2 %, trans - 20.2 %. Example 4 The reaction was carried out in a round bottomed flask by taking 0.78 g (0.005 mole) 4-f-butylcyclohexanol in 5 mL pyridine and 2.55 g (0.025 mole) of acetic anhydride (in case 1:10 4-t-butylcyclohexanol : acetic anhydride) with 5.675g ß-CD (1 equivalent to 4-t-butylcyclohexanol). The reaction mixture was refluxed for 4 h at 115°C and poured into 100 mL cold water. Upper ester layer was extracted with ether and washed with NaHCO3 to neutralize the acid and dried with sodium sulfate. The ether layer was then evaporated to get the reaction mixture. Yield by GC : Total ester 87.9%, cis - 13.5 % and trans - 74.4%.Unreacted alcohol 12.1%, cis - 3.5 %, trans - 8.6 %. Example 5 The reaction was carried out in a round bottomed flask by taking 0.78 g (0.005 mole) 4-t-butylcyclohexanol in 5 mL pyridine and 2.55 g (0.025 mole) of acetic anhydride (in case 1:10 4-t-butylcyclohexanol : acetic anhydride) with 0.6655g DMß-CD (0.1 equivalent to 4-t-butylcyclohexanol). The reaction mixture was refluxed for 4 h at 115°C and poured into 100 mL cold water. Upper ester layer was extracted with ether and washed with NaHCO3 to neutralize the acid and dried with sodium sulfate. The ether layer was then evaporated to get the reaction mixture. Yield by GC : Total ester 91.5%, cis - 24.4 % and trans - 67.2%. Unreacted alcohol 8.5%, cis - 2.5 %, trans - 6.0 %. Example 6 The reaction was carried out in a round bottomed flask by taking 0.78 g (0.005 mole) 4-t-butylcyclohexanol in 5 mL pyridine and 5 g (0.025 mole) of acetic anhydride (in case 1:20 4-t-butylcyclohexanol : acetic anhydride) with 5.675gß-CD (1 equivalent to 4-t-butylcyclohexanol). The reaction mixture was refluxed for 4 h at 115°C and poured into 100 mL cold water. Upper ester layer was extracted with ether and washed with NaHCC3 to neutralize the acid and dried with sodium sulfate. The ether layer was then evaporated to get the reaction mixture. Yield by GC : Total ester 89.0%, cis - 13.7 % and trans - 75.3%. Unreacted alcohol 11.0%, cis - 3.5 %, trans - 8.5 %. The main advantages of the invention are 1. The maximum trans / cis ratio of the 4-t-butylcyclohexyl acetate obtained in the presence of 1:1 4-t-butylcyclohexanol : ß-CD was 5.49 2. Almost all the trans alcohol (about 75 %) was converted to the ester in the presence of 1 equivalent of ß-CD. 3. About 50 % of cis alcohol (about 13.5 %) was converted to the ester in the presence o:" 1 equivalent ß-CD. 4. Highest amount of the cis alcohol to cis acetate was observed with 1:0.1 equivalent -t-butylcyclohexanol : ß-CD. 5. ß-CD derivatives also exhibited similar behaviour as ß-CD. We claim: 1. An improved method for the preparation of 4-t-butylcyclohexyl acetate, which comprises the steps of: (a) reacting 4-t-butylcyclohexanol with acetylating agent selected from acetic anhydride and acetic acid in the mole ratio in the range of 1:10-1:20; and (b) refluxing the above reaction mixture with 2-10 ml of solvent selected from pyridine at a temperature in the range of 100 - 115 deg C for a period of 2-6 hours characterized in that the said refluxing is carried out in the presence of an additive selected from the group consisting of beta cyclodextrine, DM beta- CD, HP beta-CD epichlorohydrin polymer and covering the product by known methods. 2. An improve method as claimed in claim 1, wherein 4-t-butylcyclohexanol used contains cis and trans isomers at a proportion in the range of 1:2-l :3. 3. An improve method as claimed in claims 1 and 2, wherein the reaction is carried out preferably for 2 hours. 4. An improved method for the preparation of 4-t-butylcyclohexyl acetate substantially as herein described in description and exemplified in accompanying examples.

Documents:

422-del-2001-abstract.pdf

422-del-2001-claims.pdf

422-del-2001-correspondence-others.pdf

422-del-2001-correspondence-po.pdf

422-del-2001-description (complete).pdf

422-del-2001-form-1.pdf

422-del-2001-form-18.pdf

422-del-2001-form-2.pdf

422-del-2001-form-3.pdf