Патент USA US3093668код для вставки
United States Patent 0 1 r.‘ ICC Patented June 11, 1963 1 ylethyl iodide or alpha-iodopropiophenone) , l-oxo-l-phem ‘ yl-Z-butyl sulfate (same as 1-ethyl~2-oxo-2-phenylethyl 3,093,652 ALKYL I-(Z-ARYL-Z-0XOALKYL)-4-PHENYLPIPER sulfate), 2-oxo-2-phenylethyl methanesulfona-te, l-oxohl IDINE-4-CARBOXYLATES AND THEIR PREPA RATION phenyl-Z-propyl benzenesulfonate, 2-oxo-2-pl1enylethyl para-toluenesulfonate, or the like, with the bromides being preferred. The reaction is carried out generally by Bill Elpern, Walnut Creek, Calif, assignor to Sterling I Drug Inc., New York, N.Y., a corporation of Dela ware heating, at a temperature between about 50° C. and No Drawing. Filed Oct. 23, 1958, Ser. No. 769,059 6 Claims. (Cl. 260-2932) with the 2~(monocarbocyclic-aryl)-2-oxo-(lower-alkyl) 150° C‘., the lower-alkyl 4-phenylpiperidine-4-carboxylate 10 halide, preferably the bromide, in the presence or ab This invention relates to compositions of matter of the class of substituted piperidines and to their preparation. sence of a suitable solvent, but preferably in the presence of a solvent such as a lower-alkanoL. Illustrative of the reaction is the preparation of ethyl l-(2~oxo-2-phenyl ‘ The invention here resides in the concept of a com . position having a molecular structure in which a 2~(mono ethyl)~4-phenylpiperidine-4-carboxylate by heating ethyl carbocyclic-aryl)-2-oxo~(lower-alkyl) radical is attached 15 4-phenylpiperidine-4-carboxylate .with 2-oxo-2-phenyl to the nitrogen atom of the piperidine ring of lower-alkyl - ethyl bromide. This reaction is carried out preferably in re?uxing n-butanol with stirring in the presence of an alkaline agent such as sodium carbonate to neutralize the 4-phenylpiperidine-4~carboxylates and in a process for physically embodying such concept. hydrogen bromide formed by the reaction. The prod The physical embodiments of the concept are useful as intermediates in the preparation of compounds having 20 nets are isolated in free base form or in the form of pharmacological activity, in particular, analgesic activity. their acid-addition salts. - Speci?cally, they are useful in the preparation of the My lower-alkyl 1-[2-(monocarbocycliciaryl)-2-oxo corresponding lower-alkyl 1- [Z-(monocarbocyclic-aryl)-2 hydroxy-(lower-alkyl) ]-4-phenylpiperidine-4-carboxylates (lower-alkyl)]-4-phenylpiperidine-4-carboxylates are use gesic activity. same invention. ful in the free base'form or in the form of acid-addi which have been tested by standard pharmacological eval 25 tion salts, and ‘both forms are within the purview of the uation procedures in animals and found to possess anal invention, and in fact, are considered to be one and the in free base ‘form have the structural Formula I Since my compounds are useful as in termediates in the preparation of pharmacologically-ac Among the compounds of my invention are thosewhich tive compounds, the acids which can be used to prepare 30 the acid-addition salts arepreferably those which produce, 1 when combined with the freebase of the corresponding 1-‘[2-(monocarbocyclic-aryl)-2ehydroxy-(lower - alky1)] compounds, pharmacologically acceptable salts, that is, 35 salts whose anions are relatively innocuous to the animal organism in pharmacological doses of the salts, so that . the bene?cial physiological properties inherent in the free base are not vitiated by side effects ascribable to the I anions; in other words, the latter do not substantially affect the pharmacological properties inherent in the cat 40 ions. In practicing my invention, I found it convenient to employ the hydrochloride salts. However, other ap where R represents hydrogen, methyl or ethyl and Ar is a propriate pharmacologically acceptable salts within the monocarbocyclic-aryl radical having six ring-carbon atoms. The term “lower-alkylff asused herein, means alkyl scope of the invention are those derived from mineral acids such as hydrobromic acid, hydriodic acid, nitric radicals having from one to six carbon atoms, inclusive, 45 acid, phosphoric acid, and sulfuric acid; and organic acids ,and is illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, n-amyl, n~hexyl, and the like. The term “monocarbocyclic-aryl,” as used herein, means ,aryl radicals having six ring-carbon atoms or, in other such as acetic acid, citric acid, tartaric acid, lactic acid, methanesultonic acid, ethanesulfonic acid, quinic acid, and the like, giving the hydrobromide, hydriodide, nitrate, phosphate, sulfate, acetate, citrate, tartrate, lactate, meth words, aryl radicals of the benzene series, and is illustrated 50 anesulfonate, ethanesulfonate and quinate, respectively. by the unsubstituted phenyl radical and phenyl radicals > The acid-addition salts are prepared either by dissolving bearing low-molecular Weight substituents, preferably one the free base in aqueous solution containing the appro to three, illustrated bynitro, amino, (lower-alkyl) amino, ‘(lower-alkanoyl) amino, lower-alkyl, lower-alkoxy, benz priate acid and isolating the salt by evaporating the solu yloxy, lower-alkylmercapto, ‘lower-alkylsulfonyl, halo, 55 solvent, in which case the salt separates directly or can ‘and the like. Furthermore, these substituents can be in be obtained by concentration of the solution. Although pharmacologically acceptable salts are pre ferred, all acid-addition salts are within the scope of my ‘any of the available positions of the phenyl nucleus, and "where more than one substituen-t, they can be the same or different and they can be in any of the various posi tion, or by reacting the free base and acid in an organic invention. All acid-addition salts are useful as sources tion combinations relative to each other. The (lower 60 of the free base form even if the particular salt per se ,alkyDamino,‘ (lower-alkanoyl)amino; lower-alkyl, lower- . is not desired as the ?nal product, as for example when ,alkoxy, lower-alkylmercapto and lower~alkylsulfonyl sub the salt is formed only for purposes of puri?cation or .stituents each has preferably from one to six carbon atoms identi?cation. ‘which can be arranged as straight or branched chains.‘ ' The compounds of my invention are used either in free The lower-alkyl l-[v(monocarbocyclic-aryl) -'2-oxo 65 base form or in the form of their acid-addition salts, pref (lower-alkyl)]~4-phenylpiperidine-4-carboxylates are pre erably the former,‘ when converted into the correspond pared by ‘reacting a lower-alkyl _4-phenylpiperidine»'4~ “carboxylate with a 2-(monocarbocyclic-aryl)72-oxo-(low ing lower-alkyl 1- [2-(monocarbocyclic-aryl)-2-hydroxy (lower-alkyD] - 4-phenylpiperidine-4-carboxylates. The -er-alky1) ester of a strong inorganicgor an organic sul ‘conversion is carried out by reacting my compounds with fonic acid. Suitable esters are illustrated by 2-oxo-V2 70 a reducing agent effective to reduce keto groups to hy iphenylethyl bromide, .2-oxo-2-phehylethyl chloride, l-oxo r droxy groups. The reduction can be carried out both by chemical methods and by catalytic hydrogenation. 1-phenyl-2~propyl iodide (same as 1-methyl-2-oxo42-phen 3,093,652 3 4 . Suitable chemical reducing agents include lithium alumi num hydride, lithium borohydride, sodium and ethanol, aluminum isopropoxide, etc. Catalysts suitable when . EXAMPLE 2 Ethyl 1 - (1-Ox0-1-Phenyl-2-Pr0pyl)-4-Phenylpiperidine 4-Carboxylate catalytic hydrogenation is employed include Raney nickel, platinum oxide, copper-chromium oxide, and other cata lysts generally effective to catalyze hydrogenation of keto A mixture containing 27.0 g. of ethyl 4-phenylpiperidine 4-carboxy1ate hydrochloride, 21.3 g. of l-oxo-l-phenyl-Z groups to hydroxy groups. The preferred reductive pro propyl bromide (alpha-bromopropiophenone), 150 cc. of dry n-butanol and 210 g. of anhydrous sodium carbonate cedure in practicing my invention comprised the catalytic was re?uxed with stirring for about twenty-three hours. hydrogenation of my intermediate keto compounds in lower-alkanol, e.g., n-butanol, solution using Raney nickel 10 To the hot reaction mixture was added about 100 cc. of methanol and the mixture was ?ltered while hot to re as the catalyst. Illustrative of this procedure is the re move the sodium bromide formed by the reaction. The action of ethyl 1-[l~(3,4~dibenzyloxyphenyl)-l-oxo-2 ?ltrate was allowed to cool and the crystalline product that separated was collected and recrystallized several the presence of Raney nickel to produce ethyl 1-[l-(3,4 15 times from absolute ethanol, several times from n-butanol and once from 2-propanol. There was thus obtained dihydroxyphenyl) - 1 - hydroxy-Z-butyl]~4-phenylpiperi about 5 g. of ethyl 1-(l-oxo-l-phenyl-Z-propyl)-4-phenyl dine-4-carboxylate, which can be isolated in free base piperidine-4- carboxylate, M. P. 123.3—125.1° C. (corr.). form or in the form of its acid-addition salt. butyl]-4-phenylpiperidine-4-carboxylate with hydrogen under pressure at a temperature about 50 to 100° C. in Analysis.-—Calcd. for C23H27NO3I C, 75.59; H, 7.45; The lower-alkyl 1 - [2~(monocarbocyclic-aryl)-2-hy droxy - (lower-alkyl)]-4-phenylpiperidine-4-carboxylates 20 O, 13.13. Found: C, 75.76; H, 7.17; O, 12.95. addition salts, as discussed hereinabove for the correspond 4-carboxylate is ‘obtained as its hydrochloric acid-addition salt by treating its solution in ether with gaseous hydrogen are useful in the free base form or in the form of acid ing intermediate lower-alkyl 1-[2- (monocarbocyclic-aryl) 2-oxo- (lower-alkyl) ]-4-phenylpiperidine-4-carboxylates. Ethyl 1-( l-oxo~l-phenyl-2-propyl) ~4-phenylpiperidine chloride and collecting the precipitated hydrochloride. Other representative lower-alkyl 1-[2-(monocarbocy Another aspect of my invention resides in ethyl 1-[1 25 clic-aryl) - 2-oxo-(lower-alkyl) ]-4-phenylpiperidine-4-car (3,4 - dihydroxyphenyl) - 1-hydroxy-2-butyl]-4-phenylpl boxylates that can be prepared according to the procedure peridine-4-carboxylate and its acid-addition salts, said described in Example 1 using the corresponding lower salts embracing those disclosed hereinabove for my inter alkyl 4-phenylpiperidine-4-carboxylate and appropriate 1 mediate lower-alkyl 1-[2-(monocarbocyclic-aryl)~2-oxo (lower-alkyl) ]-4-phenylpiperidine-4-carboxylates. The molecular structures of the compounds of my in vention are established by their mode of synthesis and corroborated by the correspondence of calculated and [2-(monocarbocyclic-aryl)-2-oxo-(lower-alkyl)] ester of 30 a strong inorganic acid or an organic sulfonic acid are the following compounds of Examples 3-15. These com pounds can be isolated in their free base form or in the form of their acid-addition salts, preferably their hydro found values for the elementary analyses for representa chlorides. tive examples. 35 EXAMPLE 3 The following examples will further illustrate the in vention without, however, limiting it thereto. Ethyl 1-(2-oxo-2-phenylethyl)-4-phenylpiperidine-4_car boxylate is obtained following the procedure described in EXAMPLE 1 Example 1 using ethyl 4-phenylpiperidine-4-carboxylate Lower-A lkyl 1- [2—(M0nocarb0cyclic-Aryl) -2-0x0- (Low and 2-oxo-2-phenylethyl bromide (alpha-bromoacetophe er-Alkyl)1-4-Phenylpiperidine-4-Carb0xylates 40 none). The preparation of these compounds is illustrated by EXAMPLE 4 the following preparation of ethyl 1-[1-(3,4-dibenzyloxy Methyl 1 ~ (2-oxo-2-phenylethyl)-4-phenylpiperidine-4 phenyl) - l-oxo-2-butyl] -4-phenylpip eridine-4-carb oxylate. A mixture containing 11.6 g. of ethyl 4-phenylpiperi 45 carboxylate is obtained following the procedure described in Example 1 using methyl 4-phenylpiperidine-4-carboxyl dine-4-carboxylate, 22 g. of l-(3,4-dibenzyloxyphenyl)-1 ate and 2-oxo-2-phenylethyl chloride (alpha-chloroaceto oxo-2-butyl bromide (alpha-bromo-3,4-dibenzyloxybutyr phenone). ophenone), 100 cc. of dry n-butanol and 10 g. of anhy EXAMPLE 5 drous sodium carbonate was re?uxed with stirring for about twenty-four hours. The reaction mixture was al 50 n-Propyl 1 - [1 - (4-ethoxypheny1)-l-oxo-2-propyl1-4 lowed to cool to room temperature and the precipitated phenylpiperidine-4-carboxylate is obtained following the sodium bromide was ?ltered off. The ?ltrate was distilled in vacuo to remove the solvent, thereby leaving a solid material which was crystallized from acetone-absolute procedure described in Example 1 using n-propyl 4-phenyl ethanol to yield 24.3 g. of the product, ethyl Lil-(3,4 55 piperidine-4~carboxylate and 1-(4-ethoxyphenyl)-l-oxo-2 propyl bromide ( alpha-bromo-4-ethoxypropiophenone). EXAMPLE 6 dibenzyloxyphenyl) - 1-oxo-2-butyl]-4-phenylpiperidine 4-carboxylate, M.P. 118.1-120.1° C. (corr.). n-Butyl 1-[ 1-(3,4-dimethoxyphenyl)-1-oxo-2=butyl]-4 Analysisr-Cakd. for C38H41NO5: C, 77.12; H, 6.99; O, 13.52. Found: C, 76.82; H, 6.77; O, 13.68. Ethyl 1 - [1-(3,4-dibenzyloxyphenyl)-1-oxo-2-butyl]-4 60 phenylpiperidine-4‘carboxylate is obtained following the procedure described in Example 1 using n-butyl 4-phenyl piperidine-4Jcarboxylate and 1-(3,4-dimethoxyphenyl)-1 phenylpiperidine-4-carboxylate is obtained as its hydro oxo-2-butyl bromide (alpha-bromo-3,4-dimethoxybutyro chloric acid-addition salt by treating its solution in ether phenone). with gaseous hydrogen chloride and collecting the pre EXAMPLE 7 cipitated salt. Similarly, use of hydrobromic acid, sul famic acid or ethanesulfonic acid in place of hydrochloric 65 n-Hexyl 1-[2-(4-isopropylphenyD-Z-oxoethyl]-4-phenyl acid results in the formation of the corresponding hydro piperidine-4-carboxylate is obtained following the proce bromide, sulfamate or ethanesulfonate salt, respectively. dure described in Example 1 using n-‘hexyl 4-phenylpiper Any other acid-addition salt can be prepared in a similar idine-4-carboxylate and 2-(4-isopropylphenyl)-2-oxoethyl manner using the desired acid. bromide. The above-described preparation of ethyl 1-[l-(3,4-di 70 EXAMPLE 8' benzyloxyphenyl) - 1 - oxo-2-butyl]-4-phenylpiperidine 4-carboxylate also can be carried out by using in place of 1-(3,4-dibenzyloxyphenyl)-1-oxo-2-butyl bromide oth er esters such as 1-(3,4-dibenzyloxyphenyl)-1-oxo-2-butyl chloride or 1-(3,4-dibenzyloxyphenyl)-1-oxo-2-butyl para toluenesulfonate. Ethyl 1 - [1 - (4-nitrophenyl)-1-oxo-2-propyl]-4-phenyl piperidine-4-carboxylate is obtained following the proce dure described in Example 1 using ethyl 4-phenylpiperi dine-4-carboxylate and 1-(4-nitrophenyl)-1-oxo-2~propyl 75 bromide. 3,093,652 5 EXAMPLE 9' . , collected, washed with ether and dissolved in a minimum ; quantity of Z-propanol (about 3Q cc.). To this solution Ethyl 1-[ 1'-(4-aminophenyl)ll-oxo-i-propyll -4-phenyl was added about 300 cc. of ethyl acetate and the resulting solutionwas treated gradually with ether until a perma piperidine-4-oarboxylate is obtained following the proce dure described in Example 1 using ethyl 4~phenylpiperi dine-4—carboxylate and 1-(4aamin'ophenyl)-l-oxo-Z-propyl bromide. Alternatively, this compound is obtained by re nently cloudy solution resulted. The precipitate which separated was collected, triturated with dry ether and col lected by ?ltering. There was thus obtained 5.5g. of acting the corresponding nitrophenyl compound of Exam ple 8 with a reducing agent effective to reduce nitro groups to amino groups, e.g., iron and hydrochloric acid.‘ - ‘i > EXAMPLE 10 . ethyl 1-[1-(3,4 - dihydroxyp'henyD-1-hydroxy-2-butyl]-4 phenylpiperidine-4-carboxylate in the form of its hydro 10 chloride, M.P. 103-1165” C. (corn) with decomposition. Analysis.—Calcd. for C24H31NO5J-ICI: C, 63.04; H, ‘ 7.17;‘ Cl, 7.88. Found: C, 63.73; H, 7.31; CI, 7.97. . Isopropyl 1-[2 .- (3-n-butylaminbphenyD-Zaoxoethyl]-4— Following the above procedure using hydrobromic acid, phenylpiperidine-4~carboxy1ate is obtained following the sulfamic acid or ethanesulfonic acid in place of hydrogen proceduredescribed in ‘Example 1 using isopropyl 4-phen ylpiperidine-4dc-arboxylate and 2-(3-n-butylaminophenyl) 15 chloride results in the formation of the corresponding hydrobromide, sulfamate- or ethanesulfonate, respectively. 2Joxoethyl bromide. Pharmacological evaluation of ethyl l-[1-(3,4-dihy EXAMPLE 11 droxyphenyD-l-hydroxy - 2 -1butyl] -4-phenylpiperidine-4 Ethyl 1-[1-(4-acetylaminopheny1)-1 - oxo - 2-propyl]-4a carboxylate hydrochloride in (aqueous solution adminis phenylpiperidine-4dcarboxylate is obtained following the 20 tered intraperitoneally by the Rat Thermal Stimulus Meth procedure described in Example 1 using ethyl 4-phenyl od of Bass and Vander Brook [1. Am. Pharm. Assoc, Sci. piperidine-4carboxylate and l-(4~acetylaminophenyl)-1 Ed., 41, 569-570 (1952)] has shown that this compound oxo-2-propyl bromide. Alternatively, this product is ob is approximately one-third as active an analgesic as meper tained by reacting the corresponding aminophenyl com idine hydrochloride. pound of Example 9 with an 'acetylating agent, e.g., acetic 25 Following the above procedure described in Example anhydride. 16 using in place of ethyl 1-[1-(3,4-dibenzyloxyphenyl)-1 EXAMPLE 12 oxo-2dbutyl]-4-phenylpiperidine-4-carboxylate the 1-[2 (monocarbocyclic-aryl)-2-oxo-(lower-alkyl)] compounds Ethyl 1- [ 1-(Z-methylmercaptophenyl)-1~oxo-2-butyl]-4 of Examples 3-15, the corresponding l-[2~(monocarbo phenylpiperidine-4-carboxylate is obtained following the procedure described in Example 1 using ethyl 4-phenyl 30 cyclicaaryl)-2-hydroxy-(lower~a1kyl)] compounds are ob tained. For example, use of the products of Examples 2, 3, 5 and 9 results in the formation of ethyl l-(l-hydroxy-l piperidine-4-oarboxylate and l-(2~methylmercaptophenyl) l-oxo-Z-butyl bromide. EXAMPLE 13> Ethyl 1 [ 1-(4-n-butylsulfonylphenyD-l-oxo-2-propyl] -4 35 phenylpiperidine-4~carboxylate is obtained following the procedure described in Example 1 using ethyl 4-phenyl be isolated in their free ‘base form or in the form of their l-oxo-Z-propyl bromide. piperidine-4-carboxylate is obtained following the proce dure described in Example 1 using ethyl 4-phenylpiperi dine-4-carboxylate and 2-(3,4-diehlorophenyl)~2-oxoethyl bromide. 40 clic~ary1) -2-hydroxy- (lower~alkyl) ]-4-phenylpiperidine~4 [formulation can be prepared using conventional excip ients, and the powder can be compounded in capsule form. These preparations can be administered orally or, EXAMPLE 15 Ethyl 1-[1-(2-chloro-4-ethoxyphenyl)-l-oxo-Z-propyl] in the case of aqueous preparations, intramuscularly or 4-phenylpiperidine-4Jcarboxylate is obtained following the procedure described in Example 1 using ethyl 4-phenyl intravenously. I claim: 1. A composition of matter selected from the group piperidine-4-carboxyl-ate and l-(2-chloro-4-ethoxyphenyl) 1-oxo-2—propyl bromide. (Lower-Alkyl) ]~4-Phenylpiperidine-4-Carb0xylates acid-addition salts, preferably the hydroehlorides. The above-described l-owenalkyl I-[Z-(monocarbocy earboxylates can be formulated in the same manner as meperidine, e.g., in aqueous or aqueous-ethanol menstru 45 urn, or in solid form, e.ig., tablet or powder. The tablet . EXAMPLE 16 Lower-Alkyl 1 - [2- (Monocarbocyclic-A ryl ) -2-Hydroxy (4~aminophenyl)-l-hydroxy-Z-propyl] - 4 - phenylpiperi dine-4-carboxylate, respectively. These compounds can piperidine-4acarboxylate and 1-(4-n-butylsulfonylphenyl) EXAMPLE l4 Ethyl 1-[2-(3,4 - dichlorophenyl)-2-oxoethyl]-4-phenyl phenyl-Z-propyl)-4-phenylpiperidine-4-carboxylate, ethyl 1-(2-hydroxy - 2 - phenylethyl)~4-phenylpiperidine-4-car boxylate, n-propyl 1-[1-(4-ethoxyphenyl)-l-hydroxy-Z propyl]~4-phenylpiperidine-4-carboxylate and ethyl 1-[1 consisting of lower-alkyl 1-[2-(monocarbocyc1ic-aryD-2 oxo- (lower-alkyl) ]-4-phenylpiperidine—4carboxyl-ates hav 55 ing the formula The preparation of these compounds is illustrated by the following preparation of ethyl 1-[1-(3,4-dihydroxy p‘henyl)-l-hydroxy-Z-butyl]-4 - phenylpiperidine-4-carbox 60 ylate. A mixture containing 11.3 g. of ethyl 1-[1-(3,4~di || 0 $135 0—-0-(lower-alky1) 0\ (lléa CH: OH: H: benzyloxyphenyl) - 1 - oxo-Z-buty-l]-4-phenylpiperidine-4 carboxylate, Raney nickel catalyst and enough dry n butanol to bring the total volume to 90‘ cc. was hydro 65 genated under pressure. The reaction time was about ninety minutes and the temperature was kept between 70 where R represents a member selected from the group and 80° C., with the initial hydrogen pressure being about consisting of hydrogen, methyl 1and ethyl, C6H5 represents 680 lbs/sq. inch and the ?nal pressure being about 580 1=bs./ sq. inch. “The reaction mixture was then ?ltered to 70 phenyl and Ar represents a monocarbocyclic-aryl radical selected from the group consisting of unsubstituted-phenyl remove the catalyst and the ?ltrate was concentrated in and phenyl having from one to three substituents selected vacuo to yield the viscous oily product, ethyl 1-[1-(3,4 dihydroxyphenyl) - 1 - oxo-2-butyl]-4-phenylpiperidine-4 from the group consisting of nitro, amino, (lower-IatlkyD amino, (lowerdalleanoyDam-ino, lower<a1kyl, lowerdalkoxy, carboxylate. This was dissolved in about 400 cc. of dry ether and the resulting solution was treated with gaseous 75 benzyloxy, lower-alkylmercapto, lower~alkylsulfonyl and halo; and acid-addition salts thereof. hydrogen chloride. The precipitate which separated was 3,093,652 7 8 2. Ethyl 1- (l-oxo-l-phenyl-Z-propyl)-4-phenylpiperi 2,846,437 Elpern _______________ __ Aug. 5, 1958 dine-4-carboxylate. 3. Ethyl 1-[l-(3,4-dibenzyloxyphenyl)-l-oxo-2-butyl] 4-phenylpiperidine-4-oarboxy1ate. 2,858,316 Morren ______________ __ Oct. 28, 1958 2,962,501 Cutler at ‘al ___________ .._ Nov. 29, 1960 FOREIGN PATENTS 4. The process of preparing ethyl 1-[1-(3,4-dihydroxy-' phenyD-l-hydroxy - 2 - butyl]- 4 -phenylpiperidine-4-car boxylate which comprises catalytically hydrogenating ethyl 1-[1-(3,4 -dibenzyloxyphenyl) - 1 - 0xo-2-butyl1-4 phenylpiperidine-4-carboxylate. 546,982 Belgium _____________ __ Apr. 30, 1956 OTHER REFERENCES Braenden et 1211.: Bull. World Health Org., vol. 13, pp. (1955). 5. Ethyl l-[1-(3,4-dihydroxyphenyl)-1-hydroxy-2-'bu- 10 956-962 Gaylor: Reduction With Complex Metal Hydrides, pp. tyl] -4-phenylpiperidine-4-carb oxyl ate. 100-1 (1956). ‘6. Ethyl 1- [ 1-( 3,4-dihydroxyphenyl) -1-hydroxy-2-bu Perrine et ‘21.: J. Org. Chem., vol. 21, pp. 125—126 tyl]-4-phenylpiperidine-4-carboxylate hydrochloride. (1956). References Cited in the ?le of this patent UNITED STATES PATENTS 2,776,293 Levy et a1. ____________ .... Ian. 1, 1957 Janssen et ral.: Acta Physiol. et Phlarmacol. Neerland 15 vol. 7, pages 373402 (1958).