Title of Invention

AN IMPROVED PROCESS FOR PREPARATION OF 4-ISOPROPYL CYCLOHEXANE CARBOXYLIC ACID

Abstract The invention is related to a process for preparing 4-isopropyl cyclohexane earboxylic acid of formula (I) comprising hydrogenating cumic acid of formula (II) in presence of ruthenium catalyst in alkaline aqueous solution followed by acid treatment.
Full Text

Title :
Process for preparation of 4-isopropyl cyclohexane carboxylic acid
Applicant : Divi's Laboratories Limited
Inventors :
Bolneni Nageswara Rao, Mutyala Krishnaji Rao, Mandava Satyanarayana and Banala Ramesh
Abstract:
The invention is related to a process for preparing 4-isopropyl cyclohexane carboxylic acid of formula (I) comprising hydrogenating cumic acid of formula (II) in presence of ruthenium catalyst in alkaline aqueous solution followed by

eld of Invention :
The present invention relates to an improved process for the preparation of 4-isopropyl cyclohexane carboxylic acid of formula I .More particularly the invention relates to an improved process for the preparation of trans isomer of 4-isopropyl cyclohexane carboxylic acid of the formula la.

The 4-Isopropyl cyclohexane carboxylic acid of the formula I and its derivatives are important intermediates in the manufacturing of liquid crystals, perfumes and medicines (US Patent 5831118). The trans isomeric form of 4-isopropyl cyclohexane carboxylic acid of the formula la is an important intermediate for the preparation of the antidiabetic drug, Nateglinide of the formula II [Japanese Patent Publication A.No. 63 -54321 (1988)].

The process for the preparation of 4-isopropyl cyclohexane carboxyHc acid of the formula I from cumic acid of formula III.


is disclosed in EP No. 0196222. The method comprises of hydrogenation of cumic acid in acetic acid medium, in the presence of platinum oxide as catalyst, filtration of the unused catalyst and concentration of the filtrate under reduced pressure to a solid state, which is further subjected to distillation under reduced pressure to obtain the compound of formula I.
This process has following disadvantages :
Platinum oxide used in the process is not recoverable and is a highly expensive catalyst. An additional step of removal of acetic acid is required to obtain the product. Therefore the process is not economical and is not viable for commercial production
Moreover the platinum oxide catalyst leads to a high proportion of cis'-isomer which is not useful in the synthesis of nateglinide.
Another method for the preparation of the compound of formula I is reported in J.Chem.SocAlAS (1939). In this method, the compound was prepared by hydrogenating cumic acid of formula III using Raney Nickel as catalyst at 200°C under 200 atmospheric pressure (- 200 kg/sq cm) in aqueous alkaline solution, followed by treatment with hydrochloric acid to liberate the free acid.

The drawbacks of this process are :
Raney Nickel is a highly flammable material and is hazardous to handle on an industrial scale, requiring special facilities and care. Recovery of Raney Nickel is also subject to these limitations because of its high flammable nature.
High temperature condition (200°C) and high pressure of hydrogen (200 atmph) are prone to problems of safety, besides demanding high energy consumption.
Japanese Patent 8134020 discloses reduction of some substituted alkyl benzoic acid esters using various catalysts like palladium -carbon, rhodium -carbon and ruthenium -carbon. However, none of the compounds described in the patent are directly useful for the preparation of nateglinide.
Objectives of the invention :
It is therefore the main objective of the present invention to provide an improved process for the preparation of 4-isopropyl cyclohexane carboxylic acid of the formula I especially the isomeric form of the formula la which is simple , economical and environment friendly
Another objective of the present invention is to provide an improved process for the preparation of 4-isopropyl cyclohexane carboxylic acid of the formula I especially the isomeric form of the formula la which does not use platinum oxide as catalyst
Still another objective of the present invention is to provide an improved process for the preparation of 4-isopropyl cyclohexane carboxyhc acid of the formula I which does not use Raney Nickel as catalyst
Another objective of the present invention is to provide an improved process for the preparation of 4-isopropyl cyclohexane carboxylic acid of the formula I especially the isomeric form of the formula I a which uses milder conditions of temperature and pressure.

Accordingly the present invention provides an improved process for the preparation of 4-isopropyl cyclohexane carboxylic acid of formula I especially the isomeric form of the formula la which comprises: (a) hydrogenating 4-isopropyl benzoic acid of formula III in the presence of ruthenium catalyst in an alkaline medium at a hydrogen pressure in the range of 20 to 30 atmospheres (equivalent to 20 to 30 kg/sq.cm) and at a temperature in the range of 120 to 130°C, until consumption of hydrogen ceases, (b) acidifying the resulting reaction mixture with a mineral acid to about pH 2, (c) extracting the resulting product with an organic solvent (d) evaporating the solvent (e) distilling residual product under reduced pressure, (f) thermally isomerising the product with or without a solvent, (g) extracting the resulting product enriched with trans isomeric form with a solvent to remove the cis_ isomeric form and (h) isolating the residual trans isomeric form of the compound of formula la by crystallisation.

Description of the present invention :
Cumic acid of formula III is dissolved in aqueous sodium hydroxide solution or potassium hydroxide solution and wet ruthenium on charcoal catalyst (amounting to about 0.25 % of cumic acid charged) is added. The ruthenium catalyst which can be used is selected from Ruthenium on charcoal or Ruthenium on graphite or Ruthenium on alumina, preferably ruthenium on carbon.
This suspension is charged in a hydrogenator and compound of formula III reduced at about 20 to 30 atmospheres of hydrogen pressure (about 20 -30 kg/ sq.cm.) and maintained at a

temperature of 120 to 130°'C until hydrogen consumption ceases. For acidification mineral acid such as hydrochloric acid or sulfuric acid is used
The catalyst is then filtered off, the filtrate acidified to liberate free 4-isopropyl cyclohexane carboxylic acid, which is extracted into an organic solvent. The organic solvent which can be used in step ( c ) may be selected from organic esters, preferably ethyl acetate.. After removing the solvent by distillation, the product is recovered from the residue by high vacuum distillation, subjected to thermal epimerisation with or without solvent. Solvent diphenyl ether is found to be suitable. The predominant trans isomeric form (-75% of the mixture) recovered by selective extraction of the cis isomeric form with a solvent in which it is soluble but the trans isomeric form is sparingly soluble. By way of examples of the solvents which can be used in step (g) may be selected from C6 to C8 hydrocarbons, preferably n-hexane. The resulting trans isomer of the formula I a is found to have high purity (GC : 99%; m.p. 89 -90°C). The thermal isomerisation in step (f) may be effected at the refluxing temperature of 4-isopropyl cyclohexane carboxylic acid {- 200°C) without using any solvent. The thermal isomerisation in step (f) may also be carried out alternatively using diphenyl ether at the refluxing temperature of about 210X.
The details of the invention are given in the Example given below, which is provided only for illustration and therefore it should not be construed to limit the scope of the invention.
Example 1. Preparation of 4-isopropyl cyclohexane carboxylic acid :
Cumic acid (75 gm) is dissolved in aqueous sodium hydroxide solution (10 % w/v, 310 mL). To the resulting clear solution, 7.5 gm of 5 % ruthenium on charcoal (50% wet) is added and hydrogenated (20 -30 atmosphere of hydrogen pressure) using autoclave at a temperature in the range of 120 -130°C. After cessation of hydrogen consumption, the unused catalyst is filtered at ambient temperature (25 -30°C). The alkaline filtrate is adjusted to pH 2 with hydrochloric acid and the product is extracted with ethyl acetate (3 x 100 mL). Ethyl acetate solution containing the cis-trans mixture of 4-isopropyl cyclohexanecarboxylic is dried (Na2S04) and

concentrated to obtain 59 gm of the cis-trans mixture of 4-isopropyl cyclohexane carboxylic acid. The cis-trans mixture is purified by high vacuum distillation at 1 mm Hg to obtain 54 gm of 99 % pure cis-trans mixture of 4-isopropyl cyclohexane carboxylic acid as liquid.
NMR (CDCI3) : 6 2.05-2.10 (bd, 2H), 2.0 (m, IH), 1.80 -1.81 (bd, 2H), 1.02-1.52 (m, 6H), 0.84 (s, 3H), 0.87 (s, 3H).
The liquid compound containing cis-trans mixture of 4-isopropyl cyclohexane carboxylic is isomerized (epimerized) as follows :
The liquid compound is refluxed under nitrogen atmosphere for 24 hrs to obtain predominantly transform of formula la and cooled to ambient temperature. The resulting liquid is treated with n-hexane (50 mL) and cooled at -10 to 0°C. The desired compound trans -4-isopropyl cyclohexane carboxylic acid crystallizes. The crystals are filtered, dried at 30°C under vacuum to obtain 99 % pure trans 4-isopropyl cyclohexane carboxylic acid (m.p. 89 - 90°C).
The hexane filtrate obtained is used either for recovery of the cis form (formula I b) or to repeat epimerisation and recovery of additional quantity of the trans - form of compound la.
Example 2. Preparation of 4-isopropyl cyclohexane carboxylic acid :
Cumic acid (75 gm) is dissolved in aqueous sodium hydroxide solution (10 % w/v, 310 mL). To the resulting clear solution, 7.5 gm of 5 % ruthenium on charcoal (50% wet) is added and hydrogenated (20 -30 atmosphere of hydrogen pressure) using autoclave at a temperature in the range of 120 -130°C. After cessation of hydrogen consumption, the unused catalyst is filtered at ambient temperature (25 -30°C). The alkaline filtrate is adjusted to pH 2 with hydrochloric acid and the product is extracted with ethyl acetate (3 x 100 mL). Ethyl acetate solution containing the cis-trans mixture of 4-isopropyl cyclohexane carboxylic acid is dried (Na2S04) and concentrated to obtain 59 gm of the cis-trans mixture of 4-isopropyl cyclohexane carboxylic. The cis-trans mixture is purified by high vacuum distillation at 1 mm Hg to obtain 54 gm of 99 % pure cis-trans mixture of 4-isopropyl cyclohexane carboxylic acid as liquid.

NMR (CDCI3): 5 2.05-2.10 (bd, 2H), 2.0 (m, IH), 1.80 -1.81 (bd, 2H), 1.02-1.52 (m, 6H), 0.84 (s, 3H), 0.87 (s, 3H).
The liquid compound containing cis-trans mixture of 4-isopropyl cyclohexane carboxyUc acid is isomerized (epimerized) as follows :
The epimerisation is carried out in diphenyl ether as solvent at its refluxing temperature - 210°C) for about 20 hrs, followed by distillation of the solvent under reduced pressure. The resulting mass is leached with hexane (50 mL) at -10 to 0°C to remove the cis form. The remaining crystalline trans - 4 - isopropyl cyclohexane carboxylic acid is recovered and dried at 30°C under vacuum to obtain 99% pure trans 4 -isopropyl cyclohexane carvoxylic acid ( m.p. 89-90°C)
The hexane filtrate obtained is used either for recovery of the cis form (formula lb) or to repeat epimerisation and recovery of additional quantity of the trans - form of compound la.
• Advantages of the present invention :
1. The process uses only non-hazardous and inexpensive ruthenium catalyst thereby making
the process safe and environmentally friendly
2.The process employs only moderate temperature of between 120 -130°C and moderate
pressure of 20 to 30 kg /sq cm (equivalent to 20 to 30 atmospheres of hydrogen pressure).
thereby making the process not only simple but also economical
3.The unused catalyst can be recovered and can be reused without loss of its activity or the
yield of the end product thereby further making the process economical
4.The trans isomeric form is recovered in good yield (-75 %) and high purity ( 99 %)




WE CLAIM
1. An improved process for the preparation of 4-isopropyl cyclohexane carboxylic acid of formula I especially the isomeric form of the formula la which comprises: (a) hydrogenating 4-isopropyl benzoic acid of formula III in the presence of ruthenium catalyst in an alkaline medium at a hydrogen pressure in the range of 20 to 30 atmospheres (equivalent to 20 to 30 kg/sq.cm) and at a temperature in the range of 120 to 130°C, until consumption of hydrogen ceases, (b) acidifying the resulting reaction mixture with a mineral acid to about pH 2, (c) extracting the resulting product with an organic solvent (d) evaporating the solvent (e) distilling residual product under reduced pressure, (f) thermally isomerising the product with or without a solvent (g), extracting the resulting product enriched with trans isomeric form with a solvent to remove the cis_ isomeric form of the formula I b and (h) isolating the residual trans isomeric form of the compound of formula I a by crystaUization

2. A process as per Claim 1 wherein the ruthenium catalyst used is selected from
Ruthenium on charcoal or Ruthenium on graphite or Ruthenium on alumina, preferably
ruthenium on carbon.
3. A process as claimed in claims 1 & 2 wherein the alkaline medium is achieved by using
sodium or potassium hydroxide.

4. A process as claimed in claims 1 to 3 wherein for acidification a mineral acid such as
hydrochloric acid or sulfuric acid .is used
5. A process as claimed in claims 1 to 4 wherein the organic solvent used in step (c) is
selected from organic esters, preferably ethyl acetate.
6. A process as claimed in claims 1 to 5 wherein the thermal isomerisation in step (f) is
effected at the refluxing temperature of the product 4-isopropyl cyclohexane carboxylic
acid (at a temperature of- 200*^) without using any solvent.
7. A process as claimed in claims 1 to 5 wherein the thermal isomerisation in step (f) is
carried out using diphenyl ether at the refluxing temperature of about 210°C.
8. A process as claimed in claims 1 to 7 wherein the solvent used for removing the cis_
isomer in step ( g) is selected from C6 to Cg hydrocarbons, preferably n-hexane.
9. An improved process for the preparation of 4-isopropyl cyclohexane carboxylic acid of formula I especially the isomeric form of the formula la substantially as herein described with reference to the Examples .



Documents:

124-che-2004 abstract granted.pdf

124-che-2004 claims granted.pdf

124-che-2004 description (complete) granted.pdf

124-che-2004-abstract.pdf

124-che-2004-claims.pdf

124-che-2004-correspondnece-others.pdf

124-che-2004-correspondnece-po.pdf

124-che-2004-description(complete).pdf

124-che-2004-form 1.pdf

124-che-2004-form 19.pdf

abs-124-che-2004.jpg


Patent Number 227456
Indian Patent Application Number 124/CHE/2004
PG Journal Number 10/2009
Publication Date 06-Mar-2009
Grant Date 07-Jan-2009
Date of Filing 19-Feb-2004
Name of Patentee DIVI'S LABORATORIES LIMITED
Applicant Address 7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD 500 016,
Inventors:
# Inventor's Name Inventor's Address
1 MUTYALA KRISHNAJI RAO DIVI'S LABORATORIES LIMITED, 7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD 500 016,
2 MANDAVA SATYANARAYANA DIVI'S LABORATORIES LIMITED, 7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD 500 016,
3 BANALA RAMESH DIVI'S LABORATORIES LIMITED, 7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD 500 016,
4 BOLNENI NAGESWARA RAO DIVI'S LABORATORIES LIMITED, 7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD 500 016,
PCT International Classification Number N/A
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA