IE20040197A1 - Method for separating Cis-3,5-dimethylpiperidine from a mixture of its geometrical isomers - Google Patents

Abstract

Disclosed is a single step process for separating Cis-3,5-dimethylpiperidine from a mixture of its geometrical isomers. The method comprises hydrogenation of 3,5-lutidine in the presence of water and 5% ruthenium on alumina as the catalyst at a predetermined range of temperature and pressure and does not involve the use of any organic solvent.

Description

1. Field of the Invention This invention in general relates to methods, for separating a compound from a mixture of its geometrical isomers. More particularly, the present invention relates to a single step process for separating cis-3,5-dimethylpiperidine from a mixture of cis- and trans -3,5-dimethylpiperidine, without the use of any organic TO solvent. 2. Background of the Invention Methods for separating compounds from mixtures are extremely important, at 15 the laboratory level as well as at the commercial levels. The purity of a compound is dictated to a large extent by the purification step in which a compound is separated from other products of the reaction in which it is produced. The separation of a compound from its isomer, such as Cis- and Trans- isomers is difficult to achieve.

The methods disclosed in the known arts for separating a compound from the mixture of its isomers include preferential salt formation. But this can be expensive and time consuming. It is therefore, important to devise a method for separating cis-3,5-dimethylpiperidine from a mixture of its geometrical isomers in an economical and time-efficient manner. It is against this background the current invention has been brought out whereby an improved one step process has been devised to separate cis-3,5-dimethylpiperidine from a mixture of cisand trans-3,5-dimethylpiperidine without using an organic solvent.

Cis-3,5-dimethylpiperidine is a derivative of piperidine, which is very useful for the preparation of fungicidal agents and plant growth regulating compounds.

IE 0 4 0 1 9 7 Cis-3,5-dimethylpiperidine is also used as an intermediate for pesticidal aminomethylheterocyclic compounds and compounds which modulate feeding behavior and related diseases like obesity, diabetes, cancer (tumor), inflammatory disorders, depression, stress related disorders and Alzheimer’s disease. Further Cis-3,5-dimethylpiperidine is useful in the preparation of C-20Dihydro-deoxy-(cyclic amino)-derivatives of macrolide antibiotics.

Separation of Cis-3,5-dimethylpiperidine from commercially available 4:1 mixture of Cis:trans-3,5-dimethylpiperidine involves a multi-step process that includes heating, filtration, extraction, crystallization and drying. The process further involves use of organic solvents and other chemicals like acids and bases that makes the process time-consuming and uneconomical.

Therefore, there exists the need to devise an improved process for separating Cis-3,5-dimethylpiperidine. The present invention provides for a single step and highly selective process for the separation of cis-3,5-dimethylpiperidine from a mixture of Cis:trans-3,5-dimethylpiperidine. 3. Related Art United States Patent No. 4,138,399 to Holland et al. discloses the preparation of cis-3,5-Dimethylpiperidine Hydrochloride from 3,5-Lutidine by hydrogenation under 1000 psi hydrogen pressure in ethanol using 5% rhodium on carbon as catalyst at room temperature. In this method, organic solvents like hexane and chloroform are used for the further extraction and purification of the product.

United States Patent No. 4,820,695 to Debono et al. and United States Patent No. 4,920,103 to Krist et al. disclose two methods of purification of cis-3,5dimethylpiperidine. One method discloses the addition of o-chlorobenzoyl chloride to a solution containing 3,5-dimethylpiperidine, triethylamine and dichloromethane. The use of hexane and dichloromethane is disclosed to further IE 0 4 0 1 9 7 recrystallize the product to obtain pure cis-amide, and pure cis-3,5dimethylpiperidine is obtained by further refluxing the amide in ethylene glycol and potassium hydroxide and then distilling and collecting the fraction boiling between 100°C and 195°C.

The alternate method of purification of cis-3,5-dimethylpiperidine described in the above-mentioned prior patents discloses the preparation of hydrochloride salt by bubbling HCI gas through the solution of commercial grade 3,5dimethylpiperidine and anhydrous ether. The salt is further treated, employing acetone and diethyl ether to yield cis-3, 5-dimethylpiperidine, contaminated with There are numerous prior art disclosures revealing the commercial use of Cis3,5-dimethylpiperidine, which include United States Patent Numbered 4,713,379; United States Patent Numbered 4,75,5521, United States Patent Numbered 4,826,857, United States Patent Numbered 4,904,656, United States Patent Numbered 4,615,725, United States Patent Numbered 5,177,103, United States Patent Numbered 5,571,930, United States Patent Numbered 4,820,694 and United States Patent Numbered 6,187, 777. 4. Summary of the Invention It is the principal aspect of the present invention to devise an improved method for separating a compound from a mixture of its geometrical isomers, wherein the compound being separated is Cis-3,5-dimethylpiperidine and the mixture from which the compound being separated is a mixture of Cis:trans-3,5dimethylpiperidine.

In accordance with one preferred embodiment, disclosed herein is a single step process for separating cis-3,5-dimethylpiperidine from a mixture of cis- and trans-3,5-dimethylpiperidine wherein no organic solvent is used.

IE 0 4 0 ί 9 7 In accordance with one another preferred embodiment, the present invention provides for a single step process for separating cis-3,5-dimethylpiperidine from a mixture of cis- and trans-3,5-dimethylpiperidine wherein the process comprises hydrogenation of 3,5-lutidine in the presence of water and 5% ruthenium on alumina catalyst at high temperature and pressure.

In accordance with one another preferred embodiment, the present invention provides for a single step process for separating cis-3,5-dimethylpiperidine from a mixture of cis- and trans-3,5-dimethylpiperidine, wherein water present in the reaction process favours the Cis-isomer formation and removes predominantly Trans -isomer during the fractional separation.

In accordance with one another preferred embodiment, the present invention provides for a method of producing the pure form of cis-3,5-dimethylpiperidine wherein the method comprises a single step separation process to separate cis3,5-dimethylpiperidine from a mixture of cis- and trans-3,5-dimethylpiperidine by hydrogenating 3,5-lutidine in the presence of water and 5% ruthenium on alumina catalyst at high temperature and pressure and decanting the crude product from the catalyst, recycling the catalyst in batches, carrying out fractional distillation of the crude mass to remove trans-isomer of 3,5dimethylpiperidine as an azeotrope with water, recycling the aqueous phase in the crude and distillation of pure Cis-3,5-dimethylpiperidine.

In accordance with yet another preferred embodiment, disclosed herein is a single step process for separating cis-3,5-dimethylpiperidine from a mixture of cis- and trans-3,5-dimethylpiperidine, wherein the process comprises hydrogenation of 3,5-lutidine in the presence of water ranging from 10-60% by weight ratio of the base, at temperature ranging from 180-220°C, pressure ranging from 30 to 60 Kg/cm2, decanting the crude product from the catalyst; recycling the catalyst in batches for 5 to 20 times, carrying out fractional distillation of the crude mass to remove trans-isomer of-3,5-dimethylpiperidine IE 0 4 0 1 g 7 as an azeotrope with water, recycling the aqueous phase in the crude and distillation of pure Cis-3,5-dimethylpiperidine with 5% trans-isomer.

In accordance with one another preferred embodiment, the present invention provides for a single step separation process for the separation of cis-3,5dimethylpiperidine from a mixture of cis- and trans-3,5-dimethylpiperidine, wherein the process comprises, hydrogenation of 3,5-lutidine in the presence of water and ruthenium on alumina catalyst at 180 to 200°C.

In accordance with yet another preferred embodiment, the present invention provides for a single step separation process for the separation of cis-3,5dimethylpiperidine from a mixture of cis- and trans-3,5-dimethylpiperidine, wherein the process comprises, hydrogenation of 3,5-lutidine in the presence of water and ruthenium on alumina catalyst, wherein the catalyst is about 0.3-2% with respect to 3,5-lutidine.

In accordance with still another preferred embodiment, the present invention provides for a single step separation process, wherein the process comprises, hydrogenation of 3,5-lutidine in the presence of water and ruthenium on alumina catalyst, wherein the catalyst is about 0.5-1% with respect to 3,5-lutidine.

In accordance with yet another preferred embodiment, the present invention provides for a single step separation process, wherein the process comprises, hydrogenation of 3,5-lutidine in the presence of water and ruthenium on alumina catalyst, wherein the quantity of water is 10 to 60% of 3,5-lutidine.

In accordance with one another preferred embodiment, the present invention provides for a single step separation process, wherein the process comprises, hydrogenation of 3,5- lutidine in the presence of water and ruthenium on alumina catalyst, wherein the quantity of water is 20 to 50% of 3,5-lutidine.

IE 0 4 0 19 7 In accordance with yet another preferred embodiment, the present invention provides for a single step separation process, wherein the process comprises, hydrogenation of 3,5-lutidine in the presence of water and ruthenium on alumina catalyst, wherein the pressure is about 30 to 100 kg/cm2, preferably 40 to 70 kg/cm2.

In accordance with another preferred embodiment, the present invention provides for a process, wherein the process comprises hydrogenation of 3,5lutidine in presence of a catalyst, wherein the catalyst can be recyclable for 5-20 times.

. Detailed Description of the Invention The disclosed embodiment of the present invention deals with a process for the separation of cis-3,5-dimethylpiperidine from a mixture of Cis:trans-3,5dimethylpiperidine. The present invention provides single step and highly selective process for the separation of cis-3,5-dimethylpiperidine from a mixture of Cis:trans-3,5-dimethylpiperidine without employing any organic solvent.

The present invention is further illustrated below with reference to the following examples.

Example 1 880gm 3,5-lutidine and 220gm water were charged in a 2 lit. autoclave. To this solution 4.4 gm ruthenium on alumina (5% Ru) was charged. The autoclave was boxed up and flushed with nitrogen gas thrice followed with the flushing by hydrogen gas twice. The autoclave was pressurized with hydrogen gas and the mass was heated to 190 to 200°C. After achieving 190 to 200°C, the hydrogen pressure was increased to 45 to 55 kg/cm2 and pressure was continued till the hydrogen consumption was over. The sample was checked for complete IE 0 4 ο 1 g j conversion of 3,5-lutidine and 1120 gm crude product was obtained. The G.C. analysis showed Cis-81.12 and Trans-17.99 area%. The crude mass was decanted and the catalyst was recycled during hydrogenation.

The crude mass was charged for fractional distillation along with 75 gms of fresh or recycled water in a two meter, 1 inch diameter column, filled with Sulzer packings. The trans isomer was azeotroped and collected in decanter. The organic layer from the decanter, rich in trans isomer, is either used or discarded. The aqueous phase was recycled in the same crude to draw out Trans-isomer predominantly. Trans-3,5-dimethylpiperidine was enriched at the top leaving the cis-isomer predominantly at the bottom. After removal of water, once the transisomer was removed as per the desired limit, cis-3,5-dimethylpiperidine was distilled out. The recovery was 600-630 gm with 4.5% trans-3,5dimethylpiperidine.

Example 2 880 gm 3,5-lutidine was charged in a 2 lit. autoclave, then 4.4 gm ruthenium on alumina (5% Ru) was charged in autoclave. The autoclave was boxed up and flushed with nitrogen gas thrice followed with the flushing by hydrogen gas twice. The autoclave was pressurized with hydrogen gas and the mass was heated to 190 to 200°C. After achieving 190 to 200°C, the hydrogen pressure was increased to 45 to 55 kg/cm2 and pressure was continued till the hydrogen consumption was over. The sample was checked for complete conversion of 3,5lutidine and 1120 gm crude product was obtained. The G.C. analysis showed Cis-68 and Trans-31.2 area%. The crude mass was decanted and the catalyst was recycled during hydrogenation.

The crude mass was charged for fractional distillation along with 75 gms of water in a two meter, 1 inch diameter column, filled with Sulzer packings. The trans isomer was azeotroped and collected in decanter. The organic layer from IE Ο 4 Ο 1 9 7 the decanter, rich in trans isomer, is either used or discarded. The aqueous phase was recycled in the same crude to draw out Trans-isomer predominantly. Trans3,5-dimethylpiperidine was enriched at the top leaving the cis-isomer predominantly at the bottom. After removal of water, once the trans-isomer was removed as per the desired limit, cis-3,5-dimethylpiperidine was distilled out. Appreciable separation of the isomers could not be obtained.

Example 3 880gm 3,5-lutidine and 220gm water were charged in a 2 lit. autoclave. To this solution 4.4 gm ruthenium on alumina (5% Ru) was charged. The autoclave was boxed up and flushed with nitrogen gas thrice followed with the flushing by hydrogen gas twice. The autoclave was pressurized with hydrogen gas and the mass was heated to 190 to 200°C. After achieving 190 to 200°C, the hydrogen pressure was increased to 45 to 55 kg/cm2 and pressure was continued till the hydrogen consumption was over. The sample was checked for complete conversion of 3,5-lutidine and 1120 gm crude product was obtained. The crude mass was decanted and the catalyst was recycled 10 times [Handling loss (0.30.5 gm) of the catalyst was adjusted in each cycle] during hydrogenation. After the eleventh re-cycle of the catalyst, reaction mass obtained showed the presence of 82.0% Cis and 17% Tams Isomer.

Claims (12)

CLAIMS:

1. A method for separating cis-3,5-dimethylpiperidine from a mixture of its geometrical isomers, the method comprising hydrogenating a pyridine derivative in the presence of water and a catalyst at a predetermined range of temperature and pressure.

2. The method according to claim 1, wherein the pyridine derivative is 3,5-lutidine.

3. The method according to claim 2 wherein the 3,5- lutidine is cis3,5 -dimethylpyridine.

4. The method according to claim 1, wherein the catalyst is 5% ruthenium on alumina.

5. The method according to claim 1, wherein the predetermined range of temperature is 180-250°C.

6. The method according to claim 1, wherein the predetermined range of pressure is 30-100 Kg/cm 2 .

7. The method according to claim 3, wherein the catalyst present is in the range of 0.5-2.0% by wei' ratio of the base.

8. The method according to claim 2, wherein the water present is in the range of 10-60% by weight of the base.

9. The method according to claim 1, wherein the catalyst is recycled 10-20 times without affecting the yield. ® Ο 4 Ο 1 g 7

10. The method according to any of claims 1 through to 9 wherein the method is a single-step method.

11. A method of separating cis-3,5-dimethylpiperidine from a 5 mixture of its geometrical isomers, the method comprising: hydrogenating 3,5- lutidine in the presence of water and 5% ruthenium on alumina catalyst at high temperature and pressure; decanting the crude product from the catalyst; recycling the catalyst in batches; 10 distilling the crude mass using a fractionating column to remove transisomer of -3,5-dimethylpiperidine as an azeotrope with water; and recycling the aqueous phase in the crude and distilling the crude to produce pure Cis-3,5-dimethylpiperidine.

12. 15 12. The method according to any of the preceding claims substantially as hereinbefore described with reference to the examples.