Title of Invention	"AN IMPROVED PROCESS FOR THE SIMULTANEOUS PREPARATION OF A MIXTURE OF MENTHONES AND MENTHOLS FORM THYMOL"
Abstract	An improved process for simultaneous preparation of a mixture of menthones and menthols from thymol which comprises hydrogenating 0.5- 10 mmols of thymol in presence of 25-75 mg of Rh/alumina catalyst and 0.5-10 mmoles of an additive selected from ß -cyclodextrin (ß-CD) and its derivatives such as herein described, at a hydrogen pressure ranging from 0.5-3 atmospheres, at a temperature ranging between 10° C to 40° C and for a time period ranging between 5-10h , recovering 83% to 96% menthones and menthols by conventional manner such as herein described.

Title of Invention

"AN IMPROVED PROCESS FOR THE SIMULTANEOUS PREPARATION OF A MIXTURE OF MENTHONES AND MENTHOLS FORM THYMOL"

Abstract

An improved process for simultaneous preparation of a mixture of menthones and menthols from thymol which comprises hydrogenating 0.5- 10 mmols of thymol in presence of 25-75 mg of Rh/alumina catalyst and 0.5-10 mmoles of an additive selected from ß -cyclodextrin (ß-CD) and its derivatives such as herein described, at a hydrogen pressure ranging from 0.5-3 atmospheres, at a temperature ranging between 10° C to 40° C and for a time period ranging between 5-10h , recovering 83% to 96% menthones and menthols by conventional manner such as herein described.

Full Text	This invention relates to an improved process for simultaneous preparation of a mixture menthones and menthols from thymol. This invention particularly relates to simultaneous preparation of menthones and menthols from thymol using ß-CD and its drivatives. Thymol is present to the extent of about 49.6% in Origanum tyttanthwn (L.A.El'chibekova and G.K.Nikonov, Prir.Soedin. 1986, 2, 247). Satureia thymbra L oil is another such essential oil which contains thymol (36.7%) along with p-cumene (34.6%) and carvacrol (22.4%) (S.M Philianos, T.Andriopoulou-AntranassouIa and A.Loukis, Int.J.Crude Drug Res. 1984, 22(4), 145). Besides, thymol is present in number of volatile oils from Thymus specis such as Thymus transcaucasicus (F.Y.Kasumov and S.I. Gavrenkova, Dokl.Akad.Nauk Az.SSR), Thymus cilicus, Thymus revolutus, and Thymus zygioides (F.LMericli and M.Tanker., Planta Med. 1986, 4, 340). Cyclodextrins are known to form inclusion compounds with a wide variety of organic molecules. Cyclodextrins also mimic enzymes whereby they have been shown to catalyse a wide variety of organic reactions. The included guest molecule exhibit regiospecificity and stereoselectivity in certain reactions when they were subjected to reagents ( M.M.Maheswaran and S.Divakar, J.Sci. Ind.Res., 1994, 53, 924). Earlier it was shown by us that ß-cyclodextrin (ß-CD) and its derivatives effectively alter the product distribution of reduction products of menthone with various reducing agents like sodium dithionite (R.Ravichandran and S.Divakar, J.Mol.Catal.,1994, 93.L247) and sodium borohydride (S.Divakar, M.S.Narayan and A.K.Shaw, Indian J.Chem., 1993, 32B, 387). Reduction by hydrogenation of thymol in solid state could be accomplished under mild conditions, using Rh/alumina (R.Lamartine; R.Perrin; G.Bertholon and C.R.Seances, Acad. Sci. Ser. C. 1980, 291(8) 219-25). However the yields of menthones and menthols were not found to be much (60-65%). Rh/alumina has been extensively used as a hydrogenation catalyst for the reduction of aromatic double bonds. In menthol alone eight optically active isomers are possible. However it is seldom that all the isomers are detected in the mixture. Invariably two most common isomers frequently encountered are menthol and neomenthol. In case of essential oils containing menthone also reduction under various conditions result in the formation of various isomers of epimeric alcohols (L.Szente, J.Szeitli and L. T. Chau., J.Inclusion. Phenomenon., 1987, 5,439; T.C. Chang and H.Ling Su, C.Y.H. Pao, 1977, 6, 67). The major drawbacks in the hydrogenation of thymol are as follows. In hydrogenation processes where very high ratios of menthol to neomenthol were observed, high pressures (greater than 1 atm.) and high temperatures(22°C-130°C) were usually employed (P.Bako, L.Fenichel, L.Toke, L.Szente and J.Szejtli, Proc.Int.Sym.Cyclodextrins, 4th, 1988, 519). At normal pressures, the ratios of menthol/neomenthol obtained from hydrogenation are usually low (5.6 with an yield of 70-80%). Brude and Van Dolahi (V.R.Brude and R.W.Van Dolahi, Ind.Eng.Chem. 1947, 39, 1157) have reported 81% trans-menthol and 60-70% dl-menthol when hydrogenated at 200°C and 800-1400 PSI pressure. At higher temperatures menthones were also formed. Hydrogenation over cobalt catalyst at 180°C and 900 PSI gave 2.7% neomenthol, 9.8% neoisomenthol, 2.7% menthol and 84.7% isomenthol (J.H.William and R.M.Donald. U.S. 1968,3,405,185). In almost all the cases menthols formed are racemic. The main objectives of the present invention are to develop an improved process for the preparation of mentfiones and menthols from thymol avoiding the drawbacks present in the hitherto known process. The present invention provides a process where the yields of epimeric alcohols are enhanced when an inclusion complex of thymol with ß-cyclodextrin are subjected to hydrogenation using Rh\alumina. New principles underlying the invention are the thymol forms inclusion complex in the presence of ß-cyclodextrin in different stoichiometric proportions. Formation of inclusion complexes expose only certain portions of the reactive center for hydrogenation in such a manner that product alcohols with specific disposition of groups around the reactive carbon centres are evolved with stereoselectivity of a very high order. This property is made use of in the production of menthols and hence desirable product distribution according to the process of the present invention. Other new findings are: 1. ß-Cyclodextrin can be recovered and reused. 2. Stoichiometry and binding constant value of the inclusion complexes of thymol with pVcyckxiextrin were determined from UV-visible spectrophotometric measurements. Accordingly the present invention provides an improved process for simultaneous preparation of a mixture of menthones and menthols from thymol which comprises hydrogenating 0.5-10 mmols of thymol in presence of 25 - 75 mg of Rh\alumina catalyst and 0.5-10 mmoles of an additive selected from ß - cyclodextrin (ß-CD) and its derivatives such as herein described, at a hydrogen pressure ranging from 0.5-3 atmospheres , at a temperature ranging between 10 ° C to 40 ° C and for a time period ranging between 5 - 10 h , recovering 83% to 96% menthones and menthols by conventional manner such as herein described. In an embodiment of the present invention, the aromatic compound other than thymol such as p-tertiarybutyl phenol, p-cymene, cumene can also be used. In another embodiment of the invention the catalyst used is Rh\alumina in the range 5-50% of thymol. In yet another embodiment of the invention the additives used are various derivatives from compounds such as ß-cyclodextrin, ß-cyclodextrin-polymer, HPp% CD.and DMjJ-CD in equimolar proportion to thymol. ß-CD-polymer, DMß-CDand HPß-CD were prepared according to the procedures of Shaw etal.(P.E.Shaw, and B.S.Buslig, J.Agric. Food Chem., 1986, 34, 834), Szejtli etal. (J.Szejtli, A.Liptak, I. Jodal, P.Fugedi, P.Nanasi and A Neszmelyi, Starch/Starke, 1980, 32, 165) and Pitha et.al (J.Pitha, J.Milecki, W.Fales, L.Parall and K.Uekama, IntJ.Pham, 1981,29,79) respectively. A typical procedure employed for the hydrogenation reaction is as follows. A mixture of thymol (5-10 mmoles) along with about 0.5-10 mmoles of ß-cyclodextrin and its derivatives and Rh\alumina (25-75mg) were ground well and transfered to hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 0.5 to 3 atmospheres between 10°C to 40°C for about 5-10 h. The product was worked out from the reaction mixture by filtering the Rh\alumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. The process of the invention is described in detail in the examples given below which are illustrative only and should not be construed to limit the scope of the invention. Example 1 Thymol (0.667mmoles) and Rh/alumina (50mg) were ground to a fine powder and transfered to a hydrogenation apparatus(of capacity 225ml). The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the RhNalumina catalyst, after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. The above described control reaction resulted in 76.8% menthols with a menthol/neomenthol(M/N) ratio of 5.6 (Table. 1). Example 2 Thymol (0.667 mmoles), ß-CD (0.07mmoles) and Rh/alumina'(50mg) were ground to a fine powder and transfered to a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the RhNalumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. The above reaction containing 0.1 equivalent ß-CD (to thymol) gave rise to a menthol/neomenthol ratio of 6.3 with 94.6% total epimeric alcohols (Table. 1). Example 3 Thymol (0.667 mmoles), ß-CD (0.14mmoles) and Rh/alumina (50mg) were ground to a fine powder and transfered to a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 hour. The product was worked out from the reaction mixture filtering the Rh\alumina catalyst, after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. The above reaction containing 0.2 equivalent of BCD gave rise to a M/N ratio of 6.0 with 91.5% total epimeric alcohols. Example 4 Thymol (0.667 mmoles), ß-CD (0.28 mmoles) and Rh/alumina (50mg) were ground to a fine powder and transfered to a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the Rh\alumina catalyst, after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. When the J5-CD concentration was increased to 0.4 (above reaction) and 0.7equivalents, the M/N ratio was found to be 5.5 and 4.7 with 80.4 and 70.0% of total epimeric alcohols respectively. Thus an increase in ß-CD concentration caused an increase in total menthols when compared to control (76.9%) at all the molar equivalents of ß-CD (0.1 to 1.0) employed. However at the same molar equivalence range, the percentage of alcohols formed decreased from 94.6% to 83.6%. Example 5 A mixture of thymol (0.667 mmoles), ß-CD-polymer (0.67 mmoles) and Rh\alumina (50 mg) was taken as fine powder in a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the RhNalumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. Hydrogenation in presence of 1 equivalent ß-CD- polymer resulted in an increase in M/N ratio of 6.2 with increase in total percentage of epimeric alcohols to about 83.6% with respect to ß-CD and control. Example 6 A mixture of thymol (0.667 mmoles), HPß-CD (0.133 mmoles) and 50 mg of RhNalumina were taken as fine powder in a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the RhNalumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. Hydrogenation in presence of 0.2 equivalent HPß-CD, resulted in a M/N ratio of 5.5 with a drastic decrease in total percent of epimeric alcohols (from 76.8% to 16.7%) compared to control and increase in formation of menthones to 80.9% . Example 7 A mixture of thymol (0.667 mmoles), HPß-CD (0.33 rnmoles) and 50mg of RhAalumina were taken as fine powder in a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the Rh\alumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. When the concentration of HPß-CD were 0.5 and 1.0 equivalents, the values of M/N were found to be 2.3(for both concentrations) with increase in menthols to 89.9% and 95.8% respectively. Thus, an increase in concentration of HPß-CD resulted increase in total percentage of menmols(compare examples 6 and 7). Example 8 A mixture of thymol (0.667 mmoles), DMp-CD (0.33 mmoles) and 50mg of Rh/alumina were taken as fine powder in a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the Rh\alumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product. Hydrogenation in presence of 0.5 equivalent DMß-CD resulted increase in total epimeric alcohol to about 80.6% compared to control. The results obtained in the title reaction are summarised in Table 1. Table 4.1 Hydrogenation of thymol over Rhodium/alumina In presence of ß-cyclodextrin and its derivatives* (Table Removed) 8 By GC analysis b Neoisomenthol Although the rates of hydrogen consumption showed slightly less than three equivalents (to thymol) of hydrogen being consumed, Gas Chromatographic analyses showed no unreduced thymol. Small amounts of menthone and isomenthone could be detected during reduction and on storage. Presence of ß-CD and its derivatives, gave rise to other side products, besides ketones and alcohols. In summary, presence of ß-CD and its derivatives significantly affected the relative distribution of reduction products when compared to the control reaction. Thymol purchased from M/S. SD fine chemicals Ltd, India, was used as such. Rh/alumina catalyst (5% Rh) purchased from M/S Aldrich Chemical Company U.K. was employed. ß-Cyclodextrin purchased from M/s Cyclolabs Ltd, Hungary was used. The product analysed was by GC. Gas chromatographic analyses was carried out on Shimadzu GC-15A instrument fitted with 20% carbowax 20M, with 30ml/min nitrogen flow rate was used. The injection and FID detection port temperatures were maintained at 200°C and 240°C, respectively. The column was maintained at 110°C. Retention times: Menthone-6.38 min; isomenthone-7.3 min; neomenthol-10.67 min; neoisomenthol-12.17 min; menthol-13.15 min. Ultraviolet-visible spectroscopy using a Shimadzu UV-240 spectrophotometer at + 20°C was employed for determining the binding constant value of ß-CD with thymol. Thymol solutions were prepared in aqueous ethanol. ß-CD solutions was prepared in thymol solution, from which gradual additions to the thymol solutions were made. Thymol exhibits a strong absorption at 271 nm in aqueous ethanol ( = 2320). With the addition of increasing amounts of ß-CD, the max values increased from 271 nm to 276 nm. Absorption values also increased correspondingly. A titration plot of AA(difference in absorption between thymol and that at a certain concentration of ß-CD) versus [ß-CD]/[Thymol] exhibited an asymptotic curve with 1:2 stoichiometry, indicating formation of a 1:2 complex. The binding constant value was determined by the method of Farmoso (C.Formoso, biochem. Biophy. Res. Commun., 1973, 50, 995). A plot of 1/ AA against 1/[ß-CD] gave a straight line with slope equal to ( AAB.K), where AA is the difference in absorbance between free thymol and its ß-CD complex and K is the binding constant value for the 1:2 complex. A value of 4.80x102 ± 0.2 M-1 was obtained for the thymol ß-CD complex.. The hydrogenation was carried out under ambient conditions. ß-CD and its derivatives employed could be recovered and reused, and the hydrogenation catalyst used is also relatively cheap. Hence, the data presented in this present investigation provides an attractive method for the reduction of thymol into desired ketones or alcohols, by varying the conditions like use or non-use of ß-CD and its hydroxypropyl,dimethyl and polymer derivatives. The main advantages of the invention are: i) At 0.1 equivalent of ß-CD 94.6% menthols was found to be formed. However, Highest conversion was observed at 1 equivalent of HPß-CD which showed 95.8% of formation of menthols. Control showed only 76.8% formation of menthols. ii) Highest alcohol/ketone ratio of 45.5 was observed at 0.1 equivalent of ß-CD and 83.6 at 1 equivalent of BCD. iii) No unreacted thymol could be detected at the end of the reaction. iv) At 0.2 equivalent of HPß-CD 80.9% of menthones was formed. v) At 0.5 equivalent DMß-CD highest proportion of neoisomenthol was observed . vi) Hydrogenation was acheived under mild reaction conditions with an easy work out procedure. vii) ß-CD and its derivatives employed could be recoverd and reused. viii) By regulating the proportion of ß-CD and thymol, the selectivity towards the formation of menthones and menthols can be favourably achieved. We Claim: 1. An improved process for simultaneous preparation of a mixture of menthones and menthols from thymol which comprises hydrogenating 0.5 - 10 mmols of thymol in presence of 25 - 75 mg of Rh\alumina catalyst and 0.5 - 10 mmoles of an additive selected from (3 - cyclodextrin (ß-CD) and its derivatives such as herein described, at a hydrogen pressure ranging from 0.5-3 atmospheres , at a temperature ranging between 10 ° C to 40 ° C and for a time period ranging between 5 - 10 h , recovering 83% to 96% menthones and menthols by conventional manner such as herein described. 2. An improved process as claimed in claims I where in Rh\alumina used in catalytic amounts is in the range of 5-50% of thymol. 3. An improved process as claimed in claims land 2 where in the derivatives of ß -cyclodextrin used is selected from hydroxypropyl-ß-cyclodextrin , heptakis-2,6-di-O-methyl-ß-cyclodextrin and ß-cyclodextrin-polymer . 4. An improved process as claimed in claims land 3 where in the ratio of P-cyclodextrin to thymol ranges from 0.1 - 1.0 preferably at a ratio of 0.1 . 5. An improved process for simultaneous preparation of a mixture of menthones and menthols from thymol substantially as herein described with reference to the examples.

Full Text

This invention relates to an improved process for simultaneous preparation of a mixture
menthones and menthols from thymol. This invention particularly relates to
simultaneous preparation of menthones and menthols from thymol using ß-CD and its drivatives.
Thymol is present to the extent of about 49.6% in Origanum tyttanthwn (L.A.El'chibekova and G.K.Nikonov, Prir.Soedin. 1986, 2, 247). Satureia thymbra L oil is another such essential oil which contains thymol (36.7%) along with p-cumene (34.6%) and carvacrol (22.4%) (S.M Philianos, T.Andriopoulou-AntranassouIa and A.Loukis, Int.J.Crude Drug Res. 1984, 22(4), 145). Besides, thymol is present in number of volatile oils from Thymus specis such as Thymus transcaucasicus (F.Y.Kasumov and S.I. Gavrenkova, Dokl.Akad.Nauk Az.SSR), Thymus cilicus, Thymus revolutus, and Thymus zygioides (F.LMericli and M.Tanker., Planta Med. 1986, 4, 340).
Cyclodextrins are known to form inclusion compounds with a wide variety of organic molecules. Cyclodextrins also mimic enzymes whereby they have been shown to catalyse a wide variety of organic reactions. The included guest molecule exhibit regiospecificity and stereoselectivity in certain reactions when they were subjected to reagents ( M.M.Maheswaran and S.Divakar, J.Sci. Ind.Res., 1994, 53, 924). Earlier it was shown by us that ß-cyclodextrin (ß-CD) and its derivatives effectively alter the product distribution of reduction products of menthone with various reducing agents
like sodium dithionite (R.Ravichandran and S.Divakar, J.Mol.Catal.,1994, 93.L247) and sodium borohydride (S.Divakar, M.S.Narayan and A.K.Shaw, Indian J.Chem., 1993, 32B, 387).
Reduction by hydrogenation of thymol in solid state could be accomplished under mild conditions, using Rh/alumina (R.Lamartine; R.Perrin; G.Bertholon and C.R.Seances, Acad. Sci. Ser. C. 1980, 291(8) 219-25). However the yields of menthones and menthols were not found to be much (60-65%). Rh/alumina has been extensively used as a hydrogenation catalyst for the reduction of aromatic double bonds. In menthol alone eight optically active isomers are possible. However it is seldom that all the isomers are detected in the mixture. Invariably two most common isomers frequently encountered are menthol and neomenthol. In case of essential oils containing menthone also reduction under various conditions result in the formation of various isomers of epimeric alcohols (L.Szente, J.Szeitli and L. T. Chau., J.Inclusion. Phenomenon., 1987, 5,439; T.C. Chang and H.Ling Su, C.Y.H. Pao, 1977, 6, 67).
The major drawbacks in the hydrogenation of thymol are as follows. In hydrogenation processes where very high ratios of menthol to neomenthol were observed, high pressures (greater than 1 atm.) and high temperatures(22°C-130°C) were usually employed (P.Bako, L.Fenichel, L.Toke, L.Szente and J.Szejtli, Proc.Int.Sym.Cyclodextrins, 4th, 1988, 519). At normal pressures, the ratios of menthol/neomenthol obtained from hydrogenation are usually low (5.6 with an yield of
70-80%). Brude and Van Dolahi (V.R.Brude and R.W.Van Dolahi, Ind.Eng.Chem. 1947, 39, 1157) have reported 81% trans-menthol and 60-70% dl-menthol when hydrogenated at 200°C and 800-1400 PSI pressure. At higher temperatures menthones were also formed. Hydrogenation over cobalt catalyst at 180°C and 900 PSI gave 2.7% neomenthol, 9.8% neoisomenthol, 2.7% menthol and 84.7% isomenthol (J.H.William and R.M.Donald. U.S. 1968,3,405,185). In almost all the cases menthols formed are racemic.
The main objectives of the present invention are to develop an improved process for the preparation of mentfiones and menthols from thymol avoiding the drawbacks present in the hitherto known process. The present invention provides a process where the yields of epimeric alcohols are enhanced when an inclusion complex of thymol with ß-cyclodextrin are subjected to hydrogenation using Rh\alumina.
New principles underlying the invention are the thymol forms inclusion complex in the presence of ß-cyclodextrin in different stoichiometric proportions. Formation of inclusion complexes expose only certain portions of the reactive center for hydrogenation in such a manner that product alcohols with specific disposition of groups around the reactive carbon centres are evolved with stereoselectivity of a very high order. This property is made use of in the production of menthols and hence desirable product distribution according to the process of the present invention. Other new findings are:
1. ß-Cyclodextrin can be recovered and reused.
2. Stoichiometry and binding constant value of the inclusion complexes of thymol with pVcyckxiextrin were determined from UV-visible spectrophotometric measurements.
Accordingly the present invention provides an improved process for simultaneous preparation of a mixture of menthones and menthols from thymol which comprises hydrogenating 0.5-10 mmols of thymol in presence of 25 - 75 mg of Rh\alumina catalyst and 0.5-10 mmoles of an additive selected from ß - cyclodextrin (ß-CD) and its derivatives such as herein described, at a hydrogen pressure ranging from 0.5-3 atmospheres , at a temperature ranging between 10 ° C to 40 ° C and for a time period ranging between 5 - 10 h , recovering 83% to 96% menthones and menthols by conventional manner such as herein described.
In an embodiment of the present invention, the aromatic compound other than thymol such as p-tertiarybutyl phenol, p-cymene, cumene can also be used.
In another embodiment of the invention the catalyst used is Rh\alumina in the range 5-50% of thymol.
In yet another embodiment of the invention the additives used are various derivatives from compounds such as ß-cyclodextrin, ß-cyclodextrin-polymer, HPp% CD.and DMjJ-CD in equimolar proportion to thymol.
ß-CD-polymer, DMß-CDand HPß-CD were prepared according to the procedures of Shaw etal.(P.E.Shaw, and B.S.Buslig, J.Agric. Food Chem., 1986, 34,
834), Szejtli etal. (J.Szejtli, A.Liptak, I. Jodal, P.Fugedi, P.Nanasi and A Neszmelyi, Starch/Starke, 1980, 32, 165) and Pitha et.al (J.Pitha, J.Milecki, W.Fales, L.Parall and K.Uekama, IntJ.Pham, 1981,29,79) respectively.
A typical procedure employed for the hydrogenation reaction is as follows. A mixture of thymol (5-10 mmoles) along with about 0.5-10 mmoles of ß-cyclodextrin and its derivatives and Rh\alumina (25-75mg) were ground well and transfered to hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 0.5 to 3 atmospheres between 10°C to 40°C for about 5-10 h. The product was worked out from the reaction mixture by filtering the Rh\alumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
The process of the invention is described in detail in the examples given below which are illustrative only and should not be construed to limit the scope of the invention.
Example 1
Thymol (0.667mmoles) and Rh/alumina (50mg) were ground to a fine powder and transfered to a hydrogenation apparatus(of capacity 225ml). The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering
the RhNalumina catalyst, after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
The above described control reaction resulted in 76.8% menthols with a menthol/neomenthol(M/N) ratio of 5.6 (Table. 1).
Example 2 Thymol (0.667 mmoles), ß-CD (0.07mmoles) and Rh/alumina'(50mg) were ground to a fine powder and transfered to a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the RhNalumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
The above reaction containing 0.1 equivalent ß-CD (to thymol) gave rise to a menthol/neomenthol ratio of 6.3 with 94.6% total epimeric alcohols (Table. 1).
Example 3
Thymol (0.667 mmoles), ß-CD (0.14mmoles) and Rh/alumina (50mg) were ground to a fine powder and transfered to a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 hour. The product was worked out from the reaction mixture filtering the Rh\alumina catalyst, after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
The above reaction containing 0.2 equivalent of BCD gave rise to a M/N ratio of 6.0 with 91.5% total epimeric alcohols.
Example 4
Thymol (0.667 mmoles), ß-CD (0.28 mmoles) and Rh/alumina (50mg) were ground to a fine powder and transfered to a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the Rh\alumina catalyst, after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
When the J5-CD concentration was increased to 0.4 (above reaction) and 0.7equivalents, the M/N ratio was found to be 5.5 and 4.7 with 80.4 and 70.0% of total epimeric alcohols respectively. Thus an increase in ß-CD concentration caused an increase in total menthols when compared to control (76.9%) at all the molar equivalents of ß-CD (0.1 to 1.0) employed. However at the same molar equivalence range, the percentage of alcohols formed decreased from 94.6% to 83.6%.
Example 5 A mixture of thymol (0.667 mmoles), ß-CD-polymer (0.67 mmoles) and Rh\alumina (50 mg) was taken as fine powder in a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the RhNalumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
Hydrogenation in presence of 1 equivalent ß-CD- polymer resulted in an increase in M/N ratio of 6.2 with increase in total percentage of epimeric alcohols to about 83.6% with respect to ß-CD and control.
Example 6
A mixture of thymol (0.667 mmoles), HPß-CD (0.133 mmoles) and 50 mg of RhNalumina were taken as fine powder in a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the RhNalumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
Hydrogenation in presence of 0.2 equivalent HPß-CD, resulted in a M/N ratio of 5.5 with a drastic decrease in total percent of epimeric alcohols (from 76.8% to 16.7%) compared to control and increase in formation of menthones to 80.9% .
Example 7 A mixture of thymol (0.667 mmoles), HPß-CD (0.33 rnmoles) and 50mg of RhAalumina were taken as fine powder in a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by filtering the Rh\alumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
When the concentration of HPß-CD were 0.5 and 1.0 equivalents, the values of M/N were found to be 2.3(for both concentrations) with increase in menthols to 89.9% and 95.8% respectively. Thus, an increase in concentration of HPß-CD resulted increase in total percentage of menmols(compare examples 6 and 7).
Example 8
A mixture of thymol (0.667 mmoles), DMp-CD (0.33 mmoles) and 50mg of Rh/alumina were taken as fine powder in a hydrogenation apparatus. The flask was filled with hydrogen gas after evacuation of air and set for hydrogenation at a pressure of 1.0 atm. for about 8 h. The product was worked out from the reaction mixture by
filtering the Rh\alumina catalyst after addition of ether to the hydrogenation reaction mixture and evaporating the solvent to recover the product.
Hydrogenation in presence of 0.5 equivalent DMß-CD resulted increase in total epimeric alcohol to about 80.6% compared to control. The results obtained in the title reaction are summarised in Table 1.
Table 4.1 Hydrogenation of thymol over Rhodium/alumina In presence of ß-cyclodextrin and its derivatives*

(Table Removed)
8 By GC analysis b Neoisomenthol
Although the rates of hydrogen consumption showed slightly less than three equivalents (to thymol) of hydrogen being consumed, Gas Chromatographic analyses showed no unreduced thymol.
Small amounts of menthone and isomenthone could be detected during reduction and on storage. Presence of ß-CD and its derivatives, gave rise to other side products, besides ketones and alcohols. In summary, presence of ß-CD and its derivatives significantly affected the relative distribution of reduction products when compared to the control reaction.
Thymol purchased from M/S. SD fine chemicals Ltd, India, was used as such. Rh/alumina catalyst (5% Rh) purchased from M/S Aldrich Chemical Company U.K. was employed. ß-Cyclodextrin purchased from M/s Cyclolabs Ltd, Hungary was used. The product analysed was by GC. Gas chromatographic analyses was carried out on Shimadzu GC-15A instrument fitted with 20% carbowax 20M, with 30ml/min nitrogen flow rate was used. The injection and FID detection port temperatures were maintained at 200°C and 240°C, respectively. The column was maintained at 110°C. Retention times: Menthone-6.38 min; isomenthone-7.3 min; neomenthol-10.67 min; neoisomenthol-12.17 min; menthol-13.15 min.
Ultraviolet-visible spectroscopy using a Shimadzu UV-240 spectrophotometer at + 20°C was employed for determining the binding constant value of ß-CD with
thymol. Thymol solutions were prepared in aqueous ethanol. ß-CD solutions was prepared in thymol solution, from which gradual additions to the thymol solutions were made. Thymol exhibits a strong absorption at 271 nm in aqueous ethanol ( = 2320). With the addition of increasing amounts of ß-CD, the max values increased from 271 nm to 276 nm. Absorption values also increased correspondingly. A titration plot of AA(difference in absorption between thymol and that at a certain concentration of ß-CD) versus [ß-CD]/[Thymol] exhibited an asymptotic curve with 1:2 stoichiometry, indicating formation of a 1:2 complex. The binding constant value was determined by the method of Farmoso (C.Formoso, biochem. Biophy. Res. Commun., 1973, 50, 995). A plot of 1/ AA against 1/[ß-CD] gave a straight line with slope equal to ( AAB.K), where AA is the difference in absorbance between free thymol and its ß-CD complex and K is the binding constant value for the 1:2 complex. A value of 4.80x102 ± 0.2 M-1 was obtained for the thymol ß-CD complex..
The hydrogenation was carried out under ambient conditions. ß-CD and its derivatives employed could be recovered and reused, and the hydrogenation catalyst used is also relatively cheap. Hence, the data presented in this present investigation provides an attractive method for the reduction of thymol into desired ketones or alcohols, by varying the conditions like use or non-use of ß-CD and its hydroxypropyl,dimethyl and polymer derivatives.
The main advantages of the invention are:
i) At 0.1 equivalent of ß-CD 94.6% menthols was found to be formed. However,
Highest conversion was observed at 1 equivalent of HPß-CD which showed 95.8% of
formation of menthols. Control showed only 76.8% formation of menthols.
ii) Highest alcohol/ketone ratio of 45.5 was observed at 0.1 equivalent of ß-CD and 83.6
at 1 equivalent of BCD.
iii) No unreacted thymol could be detected at the end of the reaction.
iv) At 0.2 equivalent of HPß-CD 80.9% of menthones was formed.
v) At 0.5 equivalent DMß-CD highest proportion of neoisomenthol was observed .
vi) Hydrogenation was acheived under mild reaction conditions with an easy work out
procedure.
vii) ß-CD and its derivatives employed could be recoverd and reused.
viii) By regulating the proportion of ß-CD and thymol, the selectivity towards the
formation of menthones and menthols can be favourably achieved.

We Claim:
1. An improved process for simultaneous preparation of a mixture of menthones and menthols from thymol which comprises hydrogenating 0.5 - 10 mmols of thymol in presence of 25 - 75 mg of Rh\alumina catalyst and 0.5 - 10 mmoles of an additive selected from (3 - cyclodextrin (ß-CD) and its derivatives such as herein described, at a hydrogen pressure ranging from 0.5-3 atmospheres , at a temperature ranging between 10 ° C to 40 ° C and for a time period ranging between 5 - 10 h , recovering 83% to 96% menthones and menthols by conventional manner such as herein described.
2. An improved process as claimed in claims I where in Rh\alumina used in catalytic amounts is in the range of 5-50% of thymol.
3. An improved process as claimed in claims land 2 where in the derivatives of ß -cyclodextrin used is selected from hydroxypropyl-ß-cyclodextrin , heptakis-2,6-di-O-methyl-ß-cyclodextrin and ß-cyclodextrin-polymer .
4. An improved process as claimed in claims land 3 where in the ratio of P-cyclodextrin to thymol ranges from 0.1 - 1.0 preferably at a ratio of 0.1 .
5. An improved process for simultaneous preparation of a mixture of menthones and menthols from thymol substantially as herein described with reference to the examples.

Documents:

2153-del-1998-abstract.pdf

2153-del-1998-claims cancelled.pdf

2153-del-1998-claims.pdf

2153-del-1998-complete specifiction (granted).pdf

2153-del-1998-correspondence-others.pdf

2153-del-1998-correspondence-po.pdf

2153-del-1998-description (complete).pdf

2153-del-1998-form-1.pdf

2153-del-1998-form-2.pdf

2153-del-1998-form-3.pdf

2153-del-1998-form-9.pdf

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Patent Number

190583

Indian Patent Application Number

2153/DEL/1998

PG Journal Number

32/2003

Publication Date

09-Aug-2003

Grant Date

15-Mar-2004

Date of Filing

24-Jul-1998

Name of Patentee

COUNCIL OF SCEINTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI 110001, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	SOUNDAR DIVAKAR	CENTRAL FOOD TECHNOLOGICAL RESEARCH INSTITUTE, MYSORE, INDIA
2	PALANISWAMY RAVI	CENTRAL FOOD TECHNOLOGICAL RESEARCH INSTITUTE, MYSORE, INDIA

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA