GB2239242A - Cyclohexanol derivative - Google Patents
Cyclohexanol derivative Download PDFInfo
- Publication number
- GB2239242A GB2239242A GB9027816A GB9027816A GB2239242A GB 2239242 A GB2239242 A GB 2239242A GB 9027816 A GB9027816 A GB 9027816A GB 9027816 A GB9027816 A GB 9027816A GB 2239242 A GB2239242 A GB 2239242A
- Authority
- GB
- United Kingdom
- Prior art keywords
- trans
- cis
- formula
- carrying
- acetone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- HPXRVTGHNJAIIH-PTQBSOBMSA-N cyclohexanol Chemical class O[13CH]1CCCCC1 HPXRVTGHNJAIIH-PTQBSOBMSA-N 0.000 title 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 238000011065 in-situ storage Methods 0.000 claims abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 2
- 150000004692 metal hydroxides Chemical class 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims 1
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 abstract description 6
- 229960005174 ambroxol Drugs 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000011109 contamination Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- HWAFCRWGGRVEQL-UHFFFAOYSA-N n-(4-hydroxycyclohexyl)acetamide Chemical compound CC(=O)NC1CCC(O)CC1 HWAFCRWGGRVEQL-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- OCTKLEFRMHWSLP-KYZUINATSA-N C(C)(C)=N[C@@H]1CC[C@H](CC1)O Chemical compound C(C)(C)=N[C@@H]1CC[C@H](CC1)O OCTKLEFRMHWSLP-KYZUINATSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- -1 N-isopropylidene-amino Chemical group 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000003407 synthetizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/06—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
- C07C251/08—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton being acyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
4-Trans-(N-isopropylidene-amino)-cyclohexanol of formula I <IMAGE> by hydrolizing 4-cis/trans-acetaminocyclohexanol of formula II, <IMAGE> and reacting the thus-obtained 4-cis/trans-aminocyclohexanol of formula III <IMAGE> with acetone, e.g. in situ. The above compound I is an important intermediate for the preparation of ambroxol, which is a bronchosecretolytic agent.
Description
PROCESS FOR THE PREPARATION OF A NOVEL INTERMEDIATE
TECHNICAL FIELD
The present invention relates to the preparation of novel 4-trans-(N-isopropylidene-amino)-cyclohexanol of formula I
The novel compound of the invention is a valuable intermediate for the preparation of N-(2-amino-3,5-dibromobenzyl)-trans-4aminocyclohexanol, commonly known as ambroxol.
Ambroxol is a very significant and wide-spread bronchosecretolytic agent for the treatment of the respiratory track and bronchial tubes.
SUMMARY OF THE INVENTION
According to the invention 4-trans-(N-isopropylideneamino)-cyclohexanol of formula I is prepared by hydrolyzing 4cis/trans-acetamidocyclohexanol of formula II,
then reacting the 4-cis/trans-aminocyclohexanol of formula III thus obtained in situ with acetone, then recovering the product of formula I from the reaction mixture.
DETAILED DESCRIPTION OF THE INVENTION
The hydrolysis of 4-cis/trans-acetamidocyclohexanol of formula II is carried out in the presence of a strong base in such a solvent which assures the homogeneity of the reaction mixture. Preferably alkaline metal hydroxide, more preferably sodium hydroxide, can be used as a base.
The reaction can be carried out within wide temperature ranges depending on the solvent or solvent mixture used. The preferred temperature range is 90 to 1200C. The reaction is completed within 6 to 18 hours, the 4-cis/transacetamidocyclohexanol of formula II is formed in almost quantitative yield within 8 hours. The product is led into a solvent-solvent extractor together with the reaction medium. The extraction can be carried out continuously with an inert apolar solvent, preferably with a chlorinated hydrocarbon.
The extraction time, depending on the quality and quantity of solvents, amounts to 8 to 16 hours, preferably (when chloroform is used) to 8 hours.
Then the solvent is distilled off, acetone is added to the 4-cis/trans-acetamidocyclohexanol and the mixture is heated at the boiling point of the reaction mixture. The rate of formation of the Schiff-base is relatively high at this temperature, under optimal conditions it is completed within 2 hours.
Upon cooling the reaction mixture, the desired trans-4 (N-isopropyliden-amino)-cyclohexanol selectively precipitates.
The solid product can be separated by filtration or centrifuging.
The 4-trans-(N-isopropylidene-amino)-cyclohexanol is obtained with good yield without any cis-isomer contamination.
This purity has great significance as the quality control standards of pharmaceutical ingredients allow -to a less and less extent the presence of contaminations derived from intermediates, starting materials, side-products, optionally from isomers.
The intermediate of ambroxol production is 4-transaminocyclohexanol which is separated from the cis/trans isomer mixture. Owing to the above quality requirements the formation of cis isomers and by-products is not desired, their complete removal is a very significant task.
The practical way of synthetizing ambroxol is to use a starting material which is free of cis-isomer at the earliest step of the multi-stage synthesis as the purification of the intermediates of the following synthesis steps requires much more work and time and results in higher losses.
The 4-acetamidocyclohexanol can be prepared from pacetamidophenol by catalytic hydrogenation (Ber. Dtsch. Chem.
Ges. 72, 995 /1939/; J. Am. Chem. Soc. 75, 1345 /1953/; Can. J.
Chem. 48, 2065 /1970/). 4-Acetamidocyclohexanol is present in the reaction mixture in the form of cis and trans isomers depending on the steric position of its amino and hydroxyl groups. The ratio of the formed cis/trans isomers is 1:4 to 1:1 depending on the mode of carrying out the reduction.
The separation of isomers is solved by fractional crystallization from different solvents (US patent specification
No. 2,152,960). The most preferred solvents are diethyl ether and acetone.
According to J. Am. Chem. Soc. 75, 1345 (1953) the suitably pure trans isomer can be obtained with a yield of 31 % after 9-fold fractional recrystallization from acetone, while according to the method described in Can. J. Chem. 48, 2065 (1970) the product can be obtained with a yield of only 20-25 % after 4-fold recrystallization from acetone.
The 4-acetamidocyclohexanol prepared by the above methods comprises a significant amount of cis-isomer contamination, as was also proved by our experiments. This contamination results in the corresponding undesired cis-intermediates in the next steps of the synthesis.
The invention is further illustrated by the following, non-limiting examples.
Example 1
Preparation of 4-trans-(N-isopropylidene-amino)-cyclohexanol a) From 4-cis/trans-acetamidocyclohexanol
160 g (4 moles) of sodium hydroxide are dissolved in 640 ml of water then 100 g (0.64 mole) of 4-cis/transacetamidocyclohexanol (trans isomer content: 74 %) are added. The mixture is boiled for 8 hours, whereby a solution is obtained.
Then the solution is cooled to room temperature, led into a continuous solvent-solvent extractor and extracted with 1200 ml of chloroform for 8 hours. The phases are separated, the organic phase is dried over anhydrous magnesium sulfate, filtered with charcoal and the solvent is distilled off.
The thus-obtained crude 4-cis/trans-aminocyclohexanol are boiled for 2 hours in 650 ml (8.87 moles) of acetone. A solution is - obtained from which 4-trans-(N-isopropylidene-amino)cyclohexanol precipitates upon cooling in the form of white crystals.
Yield: 45 g (62 % calculated for the trans-isomer of the starting material)
Melting point: 151 OC.
b) From 4-cis/trans-aminocyclohexanol
34.55 g (0.3 mole) of 4-cis/trans-aminocyclohexanol (trans-isomer content: 60 %) are boiled with 220 ml of acetone for 2 hours. The white 4-trans-(N-isopropylidene-amino)cyclohexanol precipitating from the solution is filtered off and dried. Thus 22.72 g (74 %) of pure trans-isomer are obtained.
Melting point: 151 OC.
Example 2
Preparation of the starting 4-cis/trans-acetamidocyclohexanol
4.5 g of palladium-on-charcoal catalyst wetted with 10 % by volume of water, 0.6 g (0.006 g mole) of potassium acetate dissolved in 10 ml of water and 150 g (0.99 mole) of pacetamidophenol are charged into an acid-resistant autoclave supplied with a turbo stirrer. The volume of the solution is supplemented to 450 ml. The reaction mixture is hydrogenated under a pressure of 5 bar at a temperature of 120-130 OC for about 6 hours. At the end of the reaction the catalyst is filtered off and the aqueous solution is evaporated to dryness.
Thus 155.2 g (99 %) of white, crystalline product are obtained whose trans-isomer content amounts to 74 %.
Melting point: 142 OC.
4-trans(N-isopropylidene-amino)-cyclohexanol may be reacted to form Amrboxol by a process described in a copending Application filed on 21st December, 1990 and claiming priority from Hungarian Patent Application
No. 6745/89.
Claims (11)
1. A process for the preparation of 4-trans-(Nisopropylidene-amino)-cyclohexanol of formula I
w h i c h c o m p r i s e s hydrolizing 4-cis/transacetamidocyclohexanol of formula II,
reacting the thus-obtained 4-cis/trans-aminocyclohexanol of formula III
with acetone (preferably in situ), then recovering the product of formula I thus obtained.
2. A process as claimed in claim 1, w h i c h c o m p r i s e s carrying out the hydrolysis of 4-cis/transacetamidocyclohexanol of formula II with the aid of an alkaline metal hydroxide, preferably sodium hydroxide.
3. A process as claimed in claim 2, w h i c h c o m p r i s e s carrying out the hydrolysis in a solvent ensuring a homogeneous reaction mixture.
4. A process as claimed in claim 3, w h i c h c o m p r i s e s carrying out the hydrolysis in an aqueous medium.
5. A process as claimed in any of claims 2 to 4, w h i c h c o m p r i s e s carrying out the reaction at a temperature of 90 to 120 OC.
6. A process as claimed in any of claims 2 to 5, w h i c h c o m p r i s e s extracting the 4-cis/transaminocyclohexanol of formula III with an inert apolar solvent.
7. A process as claimed in claim 6, w h i c h c o m p r i s e s using a chlorinated hydrocarbon, preferably chloroform, as inert apolar solvent.
8. A process as claimed in claim 1, w h i c h c o m p r i s e s carrying out the reaction of 4-cis/transaminocyclohexanol of formula III with acetone in situ at the boiling point of the reaction mixture.
9. 4-Trans-(N-isopropylidene-amino)-cyclohexanol of formula I.
10. A process of making a compound of the general formula
I substantially as hereinbefore described in Example 1.
11. A process of making a compound of the general Formula
I which comprises reacting 4-cis/trans-aminocyclohexanol of the general Formula III with acetone and recovering the compound of the general Formula I thus obtained.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU896744A HU208949B (en) | 1989-12-22 | 1989-12-22 | Process for producing 4-trans-/4-isopropyliden-amino/-cyclohexanol |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9027816D0 GB9027816D0 (en) | 1991-02-13 |
| GB2239242A true GB2239242A (en) | 1991-06-26 |
| GB2239242B GB2239242B (en) | 1993-07-21 |
Family
ID=10971987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9027816A Expired - Fee Related GB2239242B (en) | 1989-12-22 | 1990-12-21 | Process and the preparation of cyclohexanol derivatives |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPH0592945A (en) |
| AT (1) | AT398969B (en) |
| GB (1) | GB2239242B (en) |
| HU (1) | HU208949B (en) |
| IT (1) | IT1246048B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19745529C1 (en) * | 1997-10-15 | 1999-03-18 | Great Lakes Chem Konstanz Gmbh | Production of trans-4-amino-cyclohexanol from paracetamol |
| US7531567B2 (en) | 2001-05-28 | 2009-05-12 | Serumwerk Bernburg Ag | Use of a medicament containing an effector of the glutathione metabolism together with α-lipoic acid in kidney replacement therapy |
| CN113402402A (en) * | 2021-06-29 | 2021-09-17 | 江西荣兴药业有限公司 | Method for recovering trans-p-aminocyclohexanol from low-concentration waste liquid |
-
1989
- 1989-12-22 HU HU896744A patent/HU208949B/en not_active IP Right Cessation
-
1990
- 1990-12-21 JP JP2412702A patent/JPH0592945A/en active Pending
- 1990-12-21 GB GB9027816A patent/GB2239242B/en not_active Expired - Fee Related
- 1990-12-21 AT AT0261890A patent/AT398969B/en not_active IP Right Cessation
- 1990-12-21 IT IT02250690A patent/IT1246048B/en active IP Right Grant
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19745529C1 (en) * | 1997-10-15 | 1999-03-18 | Great Lakes Chem Konstanz Gmbh | Production of trans-4-amino-cyclohexanol from paracetamol |
| EP0909753A3 (en) * | 1997-10-15 | 2000-10-25 | Great Lakes Chemical Konstanz GmbH | Process for the preparation of trans-4-aminocyclohexanol |
| US7531567B2 (en) | 2001-05-28 | 2009-05-12 | Serumwerk Bernburg Ag | Use of a medicament containing an effector of the glutathione metabolism together with α-lipoic acid in kidney replacement therapy |
| CN113402402A (en) * | 2021-06-29 | 2021-09-17 | 江西荣兴药业有限公司 | Method for recovering trans-p-aminocyclohexanol from low-concentration waste liquid |
| CN113402402B (en) * | 2021-06-29 | 2023-08-18 | 江西荣兴药业有限公司 | Method for recycling trans-p-aminocyclohexanol from low-concentration waste liquid |
Also Published As
| Publication number | Publication date |
|---|---|
| IT9022506A0 (en) | 1990-12-21 |
| ATA261890A (en) | 1994-07-15 |
| AT398969B (en) | 1995-02-27 |
| JPH0592945A (en) | 1993-04-16 |
| HUT58281A (en) | 1992-02-28 |
| IT1246048B (en) | 1994-11-07 |
| GB2239242B (en) | 1993-07-21 |
| GB9027816D0 (en) | 1991-02-13 |
| HU208949B (en) | 1994-02-28 |
| IT9022506A1 (en) | 1992-06-21 |
| HU896744D0 (en) | 1990-03-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19961221 |