US2685583A - Hydrogenation process - Google Patents

Description

Patented Aug. 3, 1954 HYDROGENATION PROCESS Joseph Levy, Union, and George Albert Bernotsky, Newark, N. J., assignors to Nopco Chemical Company, Harrison, N. J., a corporation of New Jersey No Drawing. Application September 29, 1949, Serial No. 118,711

20 Claims.

This invention relates to ahydrogenation process and more particularly to a process for the hydrogenation of piperidone compounds to hydroxyp-iperidine compounds.

There are various processes disclosed in' the prior art for producing hydroxypiperidine compounds from piperidones. Such processes are of particular value in. the production of the compound arecoline which is an alkaloid that is utilized by veterinarians as an anthelmintic.

In German Patent No. 485,139, the compound N-methyI-3-carbomethoxy-4-piperidone is reducedto the corresponding 4-hydroxypi-peridine compound by hydrogenation in the presence of a platinum oxide catalyst. This hydrogenation reaction requires a period of approximately 50 hours to accomplish. Also, it requires relatively large amounts of the very expensive platinum oxide catalyst. In an article in J. Gen. Chem. (U. S.S. R.) 11, 934-8 (1941), (C'. A. 37, 381), Dankova et a1. disclosed the hydrogenation of N-methyl-3-carbethoxy-i-piperidone with sodium amalgam. The Dankova procedure is rather impractical and quite cumbersome inasmuch as at least 20 parts ofsodium amalgam are required for each part of piperidone which is to be hydrogenated. Furthermore, sodium amalgam is a difiicult substance to prepare on a large scale and necessitates the handling of large amounts of the expensive and toxic mercury.

Dankova mentions that thereduction may be carried out using. either platinum oxide or Haney nickel as a catalyst. Apparently, however, Dankova considered the sodium amalgam procedure to be the most satisfactory since that procedure was the one he gave in the. detailed description of his process. As pointed out above, the use of platinum oxide as a catalyst is an expensive procedure and requires very long reaction times to complete the hydrogenation. Apparently the use of Raney nickel by Dankova was not,satisfactory or he would have used that in his preferred procedure rather than employing the toxic, expensive and cumbersome sodium amalgam. Ugryumov in Compt. Rend. Acad. Sci, U. S. S. R. 2-3, 48-52 (1940), (C. A. 35, 3644) describes the hydrogenation of N-methyl-3-carbomethoxy-4-piperidone employing a catalyst prepared from an alloy containing 17% nickel and 83% aluminum. was prepared by crushing the alloy to the size of a pea, then treating it for 3 hours with a 2% solution of caustic soda, and thereafter washing it with water to a neutral reaction. The hydrogenation process of Ugryumov isnot set forth in The catalyst of Ugryumov 2 detail as far as results and yields which were obtained are concerned. In this process, the hydrogenation is carried. out on the piperidone ester as the free base in 80% alcohol-20% water solution. Thus a disadvantage of this procedure is that it requires the isolation of the relatively unstable piperidone. ester free base. This compound is rather difiicult to isolate without losses, particularly on a large scale, since it has been shown to readily undergo an irreversible change to a solid material thus reducing the yield of the desired keto ester, e. g. see Cook and Reed, J. C. S.

399 (1945) and Craig and Tarbell, J. A. C. S. 71, 465 (1949).

In copending application Serial No. 724,243, now Patent No. 2,506,458 of Lawrence H. Knox, filed January 24, 1947, a very highly improved process for producing arecol-ine is disclosed and claimed. In that process the hydrogenation of the piperidone compound to a hydroxypiperid-ine was carried out far more satisfactorily than by any of the means disclosed in the prior art. It was foundthat if a small percentage of either the free piperidone or fre piperidine was present in a solution of the hydrochloride salt of the piperidone; the piperidone could be hydrogenated to the hydroxypiperidine inthe presence of a platinum oxide catalyst in a very short time and in the presence of a far smaller amount of platinum oxidev than was required in the proc ess of the German patent referred to above. The hydrogenation process of patent application Serial No. 724,243 although-it is a great advance over the prior art processes for the hydrogenation of N-methyl-3-carbalkoXy-l-piperidones is still a rather expensive procedure inasmuch as it necessitates the use of the very expensive platinum oxide catalyst. In fact the cost of the catalyst makes up a large percentage of the total production cost when the hydrogenation is carried out by that process.

It would be highly desirable if one could employ the very inexpensive Haney nickel catalyst in the hydrogenation of the N-methyl-3-carbalkoxy-4-piperidones to the hydroxypiperidines. McElvain and coworkers in three recent articles, J. A. C. S. 68, 1049 (1946); J. A. C. S. 70, 1826 (1948); and J. A. G. S. 71, 903 (1949), described the reduction of various piperidone compounds with Raney nickel catalysts. Intwo of the procedures of McElvain et 'al., the compounds which were being hydrogenated did not have ester groups thereon while in the other process, the compound whichwas being hydrogenated was N -benzoyl 3 carbethoxy 4 piperidone. This compound, of course, is quite similar to the N- methyl-3-carbalkoxyl piperidones since it has an ester group on the 3 position. In these procedures McElvain and coworkers found it necessary to employ very high pressures, e. g. 2200 lbs/sq. in., and relatively high temperatures, e. g. '75-125 C. Naturally such reaction conditions require relatively elaborate and expensive equipment, particularly for plant operations, in order to carry out the reactions.

It is the object of the present invention to provide an improved procedure for the hydrogenation of N-alkyl-3-carbalkoxy-i-piperidones.

Another object of the invention is to provide a procedure for the hydrogenation of N-methyl- 3-carbalkoxy-e-piperidones which is more economical than previous hydrogenation processes.

A further object of the invention is to provide an improved procedure for the hydrogenation of N-methyl-3-carbalkoxy-1-piperidones wherein the hydrogenation can be carried out at a relatively low pressure and temperature.

Other objects of the invention will in part be obvious and will in part appear hereinafter.

We have discovered that the above and other objects of the invention may be accomplished by dissolving an N-alkyl-3carbalkoxyl-piperidone as the free base in any aromatic or saturated aliphatic hydrocarbon solvent such as benzene, toluene, xylene, cumene, hexane, heptane, octane, nonane, decane, methyl cyclohexane and similar solvents and then hydrogenating the piperidone in the hydrocarbon solvent in the presence of a relatively large amount of Fancy nickel catalyst. It has been found that the free piperidone ester is relatively quite stable in such solvents and very high yields of the desired piperidine compounds are obtained by such a hydrogenation process. Furthermore, the hydro genation may be readily carried out at room temperature and at a relatively low pressure, e. g. from about 2 to about 5 atmospheres.

Raney nickel catalyst is a well known hydrogenation catalyst and descriptions of this catalyst may be found in U. S. Patent No. 1,628,190 of Fancy, in J. A. C. S. 54, 4116 (1932) and in the textbook Organic Syntheses, Volume 21, page 15, published in 1941 by John Wiley and Sons, Inc., New York. In general, this catalyst is prepared from an alloy made up of about 50% of aluminum and about 50% of nickel. The finely powdered alloy is treated with a 20% solution of sodium or potassium hydroxide until the alkali dissolves the aluminum in the alloy leaving the nickel in a finely divided and highly active form. The nickel is then washed several times with water and thereafter stored under water or some other solvent until it is to be used. As is well known, this catalyst is quite cheap as compared to platinum oxide catalysts.

In the process of our invention, any ester of an N-alkyll-piperidone compound having a carboxyl group substituted in the ring may be hydrogenated to the corresponding hydroxypiperidine ester. Preferably we employ our process to convert N-methyl-3-carbalkoxy-4-piperidones to the corresponding N methyl 3 carbalkoxyi-hw droxypiperidines and more particularly we employ our process for converting N-methyl3- carbomethoxyi-piperidone carbethoxy-d-piperidone to the corresponding hydroxypiperidine compounds.

As pointed out above, any aromatic or saturated aliphatic hydrocarbon solvent may be employed in the process of our invention although and N-methyl-3- we prefer that such solvents should be solvents having a boiling point of between about 50 C. and about 180 C. The amount of the hydrocarbon solvent which is employed is not critical although, of course, it should be sufficient to dissolve completely the piperidone ester which is to be hydrogenated.

In carrying out the process of the invention, the solutions of the piperidones in the hydro carbon solvents are preferably obtained without isolating the relatively unstable piperidone bases. In most cases in processes for the production of arecolinc, N methyl-3-carbomethoxy-4-piperidone will be available as the sodium or other alkali metal enolate salt prepared from the condensation of bis-(B-carbomethoxyethyl)- methylamine with an alkali metal condensing agent, such as sodium or potassium or a hydride or methylate thereof. This alkali metal enolate salt may be dissolved in water and the free base liberated by first adding a slight excess over an equivalent amount of an acid such as acetic acid, hydrochloric acid, etc., to the solution followed by adding an excess of a weak alkali such as sodium or potassium carbonate. Thereafter the free base may be extracted from the aqueous medium with a suitable solvent although preferably the solvent which is to be employed in the hydrogenation procedure is utilized as the extracting solvent. The most convenient procedure and the one which we preferably employ in our process to liberate the free base from the sodium or other alkali metal enolate salt of the piperi done ester is to dissolve the sodium or other alkali metal salt of the piperidone ester in water containing an excess of either sodium or potassium bicarbonate preferably keeping the temperature of the mixture at or below about 20 C. so as to minimize any likelihood of a small percentage of the ester groups being saponified during the reaction. The bicarbonate will react with the salt of the piperidone to convert the salt to the free base with the sodium or other alkali metal combining with the bicarbonate to produce a carbonate compound. Thereafter the free base may be readily extracted from the aqueous solution with a solvent such as one of those to be used in the hydrogenation procedure. A very convenient manner in which to accomplish this is to slowly add the alkali metal salt of the condensation product to an aqueous solution of either sodium of potassium bicarbonate containing sufficient bicarbonate to convert all of the piperidone salt to the free base which solution is overlaid with the desired amount of solvent to be used in extracting out the free base. The alkali metal salt is added to this mixture as the mixture is rapidly stirred. Thus the salt reacts almost immediately with the bicarbonate in the aqueous solution and immediately subsequent thereto the free base is extracted from the aqueous solution by the hydrocarbon solvent. In this manner the solvent solution of the relatively unstablepiperidone ester is obtained without the necessity of isolating the free base. On completion of the extraction of the free piperidone ester from the aqueous solution, the solvent solution thereof which is obtained is dried in some suitable manner such as over anhydrous sodium sulfate. To insure complete recovery of the free piperidone, the aqueous solution may be further extracted with a few small portions of the hydrocarbon solvent, which extracts are then combined with the original solvent solution.

- utilized.

' in our process.

'droxypiperidine ester.

tion with some inert salt such as sodium chloride 'orisodium-sulfate or some other inert salt. However, this is not necessary and the free base may be recovered from the aqueous solution merely by extracting the aqueous solution with the desired water-immiscible solvent.

The hydrocarbon solvent solution of the free base is then admixed'with the desired amount of Raney nickel catalyst. A relatively large quantity of Raney nickel catalyst is employed in the process of our invention as compared to the amount of Raney nickel catalyst employed in the usual hydrogenation procedures. Preferably, we

employ about 1 part of Raney nickel catalyst for each 2 parts of the free base which is to be hydrogenated and in all cases at least about 1 part of the catalyst for each 4 parts of free base is employed. If desired, an amount of catalyst equal to the weight of the free base may be used. In carrying out the hydrogenation in accordance with our process, only relatively low hydrogen pressures are required as compared to the prior art hydrogenation procedures.

Thus hydrogen pressures of from about 2 to about 5 atmospheres, i. e. from about to about 75 lbs/sq. in., are suflicient to accomplish the desired hydrogenation although, if desired, moderately' elevated pressures may be employed of course, e. g. about 250 to 300 lbs/sq. in. Furthermore, the hydrogenation can be readily accomplished at room temperature as compared to the relatively high temperatures required in previous processes where Raney nickel catalyst was Of course, if desired, temperatures higher than room temperature can be employed The time required for the hydrogenation reaction to be accomplished by our process is no longer than the time required in many of the prior art processes and is much shorter than the time required in some of the prior art processes. In most cases the desired hydrogenation will be accomplished in .from about 6 to 8 hours. Ifdesired, one may carry out the well known ferric chloride test on the reaction products to determine whether any piperidone ester was not converted to the hy- In this test, a violet coloration is obtained when a small amount of ferric chloride is added to a solution if a compound which exhibits keto-enol tautomerism,

such as one of the piperidone esters, 'is present in the solution.

On completion of the hydrogenation reaction,

"the hydroxypiperidine compound is readily isolated from the hydrogenation reaction mixture by filtering the mixture to remove the catalyst therefrom and then distilling the hydrocarbon solvent, preferably at a reduced pressure. The residue will be the desired hydroxypiperidine ester in a relatively pure form. The pure ester may then be obtained by distilling this crude tion is much-more economical than any of the "prior art procedures. Furthermore, the process of our invention gives very high yieldsxoithe'desired. hydroxypiperidine compound. Although our process is employed principally for the hydrogenation of N-methyl-3-carbomethoxy-14-piperidone to the corresponding hydroxypiperidine compound which hydroxypiperidine compound is subsequently convertedby dehydration to arecoline, it is also highly suitable for the hydrogenation of N-methyl-3-carbethoxyi-piperidone to the corresponding hy roxypiperidine which on dehydration gives homo-arecoline.

For a fuller understanding of the nature and objects ofthe invention, reference maybe .had to the following examples which are given merely as further illustrations of the invention andare not to be construed in a limitingsense:

Example I The dry sodium enolate of N-methyl-3- carbomethoxy-4-piperidone obtained by the cyclization of 0.2 mole of bis-(,B-carbomethoxyethyl)-methylamine with sodium was added with vigorous stirring to a mixture of 20 gms. of sodium sulfate, 30 gms. of sodium bicarbonate and 75 cc. of water overlaid with cc. of toluene. After the enolate was completely dissolved in the mixture, the toluene layer was separated from the aqueous layer. Then the aqueous layer was extracted three times with 35 cc. portions of toluene. The original toluene layer and the toluene extracts were then combined and dried over sodium sulfate, filtered and then treated with hydrogen at about 4 atmospheres pressure in the presence of about 15 gms. of Raney nickel catalyst. Reduction of the N- methyl-3-carbomethoxy-4-piperidone in the toluene proceeded rapidly and after absorption of hydrogen ceased, the catalyst was filtered from the solution and the solvent then removed in vacuo on a steam bath from the hydroxypiperipoint of l23-125 C. at 12 mm.

Example II Another hydrogenation was carried out in essentially the same manner as in Example I except that the amount of catalyst employed was only about 17% of the weight of the free piperidone base. It was found that reduction did not take place with this amount of catalyst and therefore an additional amount of catalyst sumcient to bring the total quantity of catalyst up to about 25% of the weight of the free piperidone base was added. Reduction of the piperidone then proceeded satisfactorily although at an appreciably slower rate than in Example I where the quantityof catalyst was equal to about 50% of the weight of the free piperidone. It is evident, therefore, that it is necessary to employ at least about 1 part of catalyst for each 4 parts of the free piperidone and preferably we employ about 1 part of catalyst for each 2 parts of the'free piperidone.

Example 111 solvent. The naphtha which was employed'had a boiling point of between about 115 and C.

Amixture made up of 75 cc. of water containing gms. of sodium bicarbonate was overlaid with 150 cc. of the naphtha. No sodium sulfate was employed as in Example I to aid in salting out the free piperidone. Two-tenths mole of the dry sodium enolate of N-methyl-3-carbomethoxy-4- piperidone was added to this reaction mixture with stirring, keeping the temperature at or be low room temperature. As soon as all of the soroom temperature and at a hydrogen pressure of about 4 atmospheres.

On completion of the hydrogenation, the catalyst was filtered from the solution and the naphtha then evaporated therefrom in vacuo on a steam bath. The crude product which was obtained was purified by distilling it in vacuo. The pure hydroxypiperidine was obtained in a yield equal to 76% of the theoretical yield.

Example IV In this example the reduction of the piperidone was carried out in xylene. The dry sodium enolate of N-methyl-3-carbomethoxy-4-piperidone obtained by the cyclization of 0.1 mole of -bis-(B-carbomethoxyethyl) methylamine was .added with vigorous stirring to a mixture of 30 cc. of water and 15 gms. of sodium bicarbonate which was overlaid with 100 cc. of xylene, keeping the temperature at or below room temperature. When all of the sodium salt had dissolved in the mixture, the xylene layer was separated therefrom and the aqueous layer was extracted three times with 50 cc. portions of xylene. The combined xylene extracts, including the original xylene layer, were dried over anhydrous sodium sulfate, filtered and then about 7.5 gms. of Raney nickel catalyst were added thereto. The xylene solution was then subjected to hydrogenation at .room temperature under a hydrogen pressure of about 50 lbs/sq. in. gauge pressure. Reduction proceeded quite rapidly with the greater part of the reduction (85%-90%) taking place in about two hours. In order to insure complete reduction, however, the hydrogenation was allowed to proceed for a few hours longer. The catalyst was then filtered from the solution and the xylene removed from the solution by evaporation in 'vacuo on a steam bath. The crude hydroxypi- "peridine was purified by distillation under reduced pressure. A yield of 83.2% of the desired hydroxypiperidine was obtained.

Example V A hydrogenation identical with that of Example IV with the exception that the xylene was replaced with heptane was carried out. It was found, however, that the hydrogenation did not proceed quite as rapidly in the heptane as in the xylene so after about four hours an additional gms. of catalyst was added to the heptane solution. The reduction then proceeded fairly rapidly, giving a yield of the desired hydroxypiperidine of 81%.

Having described our invention what we claim I as new-and desire to secure by Letters Patent is:

1. A process for hydrogenating an N-alkyl-3- carbalkoxy--piperidone to an N-alkyl-S-car balkoxy-4-hydroxypiperidine which comprises dissolving an N-alkyl-3-carbalkoxy-4-piperidone in a solvent selected from the group consisting of aromatic hydrocarbons and saturated aliphatic hydrocarbons, and hydrogenating the piperidone in the solvent solution in the presence of at least about one part of Raney nickel catalyst for each four parts of the piperidone, said hydrogenation being effected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

2. A process for hydrogenating N-methyl-3- carbomethoxy-i-piperidone to N-methyl-B-carbomethoxy-4-hydroxypiperidine which comprises dissolving the piperidone in a solvent selected from the group consisting of aromatic hydrocarbons and saturated aliphatic hydrocarbons, and hydrogenating the piperidone in the solvent solution in the presence of at least about one part of Raney nickel catalyst for each four parts of the piperidone, said hydrogenation being effected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

3. A process for hydrogenating Nmethyl-3 carbethoxyi-piperidone to N-methyl 3 carbethoxy-4-hydroxypiperidine which comprises dissolving the piperidone in a solvent selected from the group consisting of aromatic hydrocarbons and saturated aliphatic hydrocarbons, and hydrogenating the piperidone in the solvent solution in the presence of at least about one part of Raney nickel catalyst for each four parts of the piperidone, said hydrogenation being effected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

4. The process of claim 2 wherein the hydrocarbon solvent is benzene.

5. The process of claim 2 wherein the hydrocarbon solvent is toluene.

6. The process of claim 2 wherein the hydrocarbon solvent is xylene.

7. A process for converting N-methyl-3-carbomethoxy-d-piperidone to N-methyl-3-carbomethoxy-e-hydroxypiperidine which comprises admixing an alkali metal enolate salt of the piperidone with a mixture of an aqueous solution of at least a stoichiometrically equivalent weight of an alkali metal bicarbonate and a solvent selected from the group consisting of aromatic hydrocarbons and saturated aliphatic hydrocarbons, completely dissolving the alkali metal enolate salt of the piperidone in the mixture thus liberating the free piperidone from the salt, sop-- arating the hydrocarbon solvent and the free piperidone which has become dissolved therein from the mixture, ,and then hydrogenating the piperidone in the hydrocarbon solvent in the presence of at least about one part of Raney nickel catalyst for each four parts of the piperidone, said hydrogenation being effected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

8. The process of claim 7 wherein the hydrocarbon solvent is benzene.

9. The process of claim 7 wherein the hydrocarbon solvent is toluene.

10. The process of claim '7 wherein the hydrocarbon solvent is xylene.

11. A process for converting N-Inethyl-3-carbomethoxyl-piperidone to N-methyl-3-carbomethoxyi-hydroxypiperidine which comprises adding an alkali metal enolate salt of the piperidone to an aqueous solution of an alkali metal bicarbonate containing an amount of bicarbonate at least stoichiometrically equivalent to the amount of piperidone salt, mixing the piperidone salt with the aqueous solution until the salt is completely dissolved at which time the free piperidone will have been liberated from the salt, extracting the free piperidone from the aqueous mixture with a solvent selected from the group consisting of aromatic hydrocarbons and saturated aliphatic hydrocarbons, and hydrogenating the piperidone in the hydrocarbon solvent in the presence of at least about one part of Baney nickel catalyst for each four parts of the piperidone, said hydrogenation being effected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

12. The process of claim 11 wherein the hydrocarbon solvent is benzene.

13. The process of claim 11 wherein the hydrocarbon solvent is toluene.

14. The process of claim 11 wherein the hydrocarbon solvent is xylene.

15. The process of claim 2 wherein the hydrogenation is carried out at about room temperature and under a hydrogen pressure of about two to about five atmospheres.

16. The process of claim 7 wherein the hydrogenation is carried out at about room temperature and under a hydrogen pressure of about two to about five atmospheres.

17. The process of claim 11 wherein the hydrogenation is carried out at about room temperature and under a hydrogen pressure of about two to about five atmospheres.

18. The process of claim 2 wherein the hydrogenation is carried out in the presence of at 19 least about one part of Raney nickel catalyst for each two parts of piperidone.

19. The process of claim '7 wherein the hydrogenation is carried out in the presence of at least about one part of Fancy nickel catalyst for each two parts of piperidone.

20. The process of claim 11 wherein the hydrogenation is carried out in the presence of at least about one part of Raney nickel catalyst for each two parts of piperidone.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 1,695,666 Schirmacher et a1. Dec. 18, 1928 1,980,638 Scheuing et a1. Nov. 13, 1934 2,018,680 Lazier Oct. 29, 1935 2,477,842 Wenner Aug. 2, 1949 FOREIGN PATENTS Number Country Date 485,139 Germany Oct. 31, 1929 520,201 Great Britain Apr. 17, 1940 OTHER REFERENCES

Claims (1)

1. A PROCESS FOR HYDROGENATING AN N-ALKYL-3CARBALKOXY-4-PIPERIDONE TO AN N-ALKYL-3-CARBALKOXY-4-HYDROXYPIPERIDINE WHICH COMPRISES DISSOLVING AN N-ALKYL-3-CARBALKOXY-4-PIPERIDONE IN A SOLVENT SELECTED FROM THE GROUP CONSISTING OF AROMATIC HYDROCARBONS AND SATURATED ALIPHATIC HYDROCARBONS, AND HYDROGENATING THE PIPERIDONE IN THE SOLVENT SOLUTION IN THE PRESENCE OF AT LEAST ABOUT ONE PART OF RANEY NICKEL CATALYST FOR EACH FOUR PARTS OF THE PIPERIDONE, SAID HYDROGENATION BEING EFFECTED AT ABOUT ROOM TEMPERATURE AND UNDER A HYDROGEN PRESSURE OF FROM ABOUT 2 TO ABOUT 20 ATMOSPHERES.