US patent 3080366
1-(w,w-Diphenylalkyl)-4-amino-4-piperidine-carboxamides and Derivatives ThereofNote: The compounds of the present invention are useful because of their valuable pharmacological properties. Specifically, they induce a morphine-like analgesic effect of long duration but lack toxic side reactions which seriously limit the applicability of morphine.General Reaction Scheme:
To prepare the compounds of the present invention, an N-benzylated 3-pyrrolidone or 4-piperidone is treated with a source of cyanide ion and a secondary amine. The resultant alpha-aminonitrile is hydrolyzed to the carbamyl derivative and the amide is debenzylated by catalytic hydrogenolysis; the side chain is introduced by condensation with a substituted w,w-diphenylalkyl halide. Typically, the cyano groups of some derivatives can be converted by hydrolysis to the corresponding carbamyl compounds. The salts of the derivatives are produced in the usual manner. Example 1: 1-(3,3-diphenyl-3-cyanopropyl)-4-piperidino-4-piperidinecarboxamideTo a stirred solution of 130 parts of potassium cyanide and 243 parts piperidine HCl in 800 parts of water and 320 parts of ethanol is added slowly 378 parts of N-benzyl-4-piperidone. The resultant mixture is stirred at RT for 24 hours; a precipitate is apparent after one hour. The reaction mixture is filtered and the solid material thus obtained is recrystallized from 1200 parts of diisopropyl ether.
The 1-benzyl-4-cyano-4-(N-piperidino) piperidine prepared this way melts at 104-106*C. A mixture of 141 parts of 1-benzyl-4-cyano-4-piperidinopiperidine and 400 parts of 90% sulfuric acid is heated at about 100*C for 10 minutes; heating is discontinued and the mixture is stirred for about one hour. The resultant mixture is poured onto 1500 parts of ice water, and the solution thus obtained is rendered alkaline with ammonium hydroxide; an oil forms. The aqueous layer is decanted from the oil and 800 parts of acetone is added.
The resultant solid material is removed by filtration and dried in air to give 1-benzyl-4-piperidino-4-piperidinecarboxamide, MP: 138-140*C.A mixture of 215 parts of 1-benzyl-4-cyano-4-piperidinopiperidinecarboxamide, 40 parts of 10% Pd/C, 1200 parts isopropyl alcohol, 1000 parts of water and 157 parts of HCl is subjected to treatment with H2 at atmospheric pressure at 40*C. After the stoichiometric quantity of H2 is taken up, the reaction is filtered and the filtrate is evaporated to dryness. The residue is taken up in a mixture of 80 parts acetone and 80 parts benzene, and the resultant solution is evaporated to dryness.
The residue is triturated with 200 parts of methanol, and the resultant mixture is filtered, to give 4-piperidino-4-piperinecarboxamide di-HCl; MP: 299-301*C. with decomposition . To a solution of 200 parts of the hydrochloride in 300 parts water is added 150 parts of a 44% aqueous solution of sodium hydroxide solution, and the resultant mixture is stirred for a short time. The suspension which results is filtered and the solid material thus obtained is extracted with toluene in a soxhlet extractor overnight. The resultant toluene solution is reduced in volume until a precipitate forms.
The solid material thus obtained is removed by filtration to give 4-piperidino-4-piperidinecarboxamide; MP: 119-120*C.A mixture of 84 parts of 3,3-diphenyl-3-cyanopropyl bromide, 41 parts of 4-piperidino-4-piperidinecarboxamide, 64 parts of sodium carbonate, a small amount of potassium iodide and 1200 parts of anhydrous toluene is stirred, and heated under reflux for 48 hours. At the end of this time the reaction mixture is allowed to cool to RT and 500 parts of water is added.
The resultant precipitate is filtered and triturated with 320 parts of acetone, to give 1-(3,3-diphenyl-3-cyanopropyl)-4-piperidino-4-piperidinecarboxamide; MP: 149-150*C.Salts of said compound can be obtained by mixing a solution of the free amine with appropriate compound. In the case of salts with compounds such benzyl chloride or methyl iodide, refluxing under inert solvent is always desirable. Dihydrochloride ; MP: 286.5-289.0*C (decomp.)
Dihydrobromide; MP: 313.0-317.0*C
Methiodide; MP: 231.6-235.8*C
Ditartrate; MP: 86-110*C (decomp.)
Benzyl Chloride; MP: 253.5-254.5*C Example 2:1-(3,3-diphenyl-3-carbamylpropyl)-4-piperidino-4-piperidinecarboxamideA mixture of 35 parts of 1-(3,3-diphenyl-3-cyanopropyl)-4-piperidino-4-piperidinecarboxamide and 600 parts 90% sulfuric acid are heated at 100*C for 3 hours. The resultant mixture is allowed to cool to about 50*C and then poured into excess of ice-cold ammonium hydroxide. The precipitate which forms is filtered off and then taken up in chloroform. The chloroform solution is extracted with water; the organic layer is dried over anhydrous potassium carbonate, and evaporated to dryness.
The residue is washed with diisopropyl ether, and dried in air to give
1-(3,3-diphenyl-3-carbamylpropyl)-4-piperidino-4-piperidinecarboxamide; MP: 215-218*C.Example 3:A solution of phenylmagnesium bromide is prepared from 6 parts of Mg and 40 parts of bromobenzene in 160 parts of ether and refluxed for 2 hours. A solution of 29 parts of beta- chloropropiophenone in 400 parts of anhydrous ether is added portionwise and the mixture is decomposed by the addition of 10% ammonium chloride solution while the temp is maintained below 10*C. The ether solution is decanted, washed with water and dried and the solvent is evaporated.
The residue solidified on standing. It is dissolved in a mixture of petroleum ether and acetone and the solvent is evaporated to give
3,3-diphenyl-3-hydroxypropyl chloride melting at about 77.4-78.6*C.
Substitution of 69 parts of 3,3-diphenyl-3-hydroxypropyl chloride for the 3,3-diphenyl-3-cyanopropyl bromide of Example 1 gives, by the procedure therein detailed,
1-(3,3-diphenyl-3-hydroxypropyl)-4-piperidino-4-piperidinecarboxamide; MP: 188-190*C. A mixture of 4.5 parts of 1-(3,3-diphenyl-3-hydroxypropyl)-4-piperidino-4-piperidinecarboxamide, 20 parts of acetic anhydride, and 80 parts of anhydrous benzene is stirred and refluxed for 3.5 hours. The solvent is evaporated and the residue is dissolved in 100 parts of water. After the aqueous solution is neutralized with potassium carbonate, it is extracted with ether. The ether solution is separated and dried over anhydrous potassium carbonate.
Introduction of HCl in the dried solution precipitates the HCl salt which is recrystallized twice from a mix of 2-propanol and acetone and water to give
1-(3,3-diphenyl-3-acetoxypropyl)-4-piperidino-4-piperidinecarboxamide dihydrochloride; MP: 260-260.6*CExample 4:1-(3,3-diphenylpropyl)-4-piperidino-4-piperidinecarboxamideSubstitution of 77 parts of 3,3-diphenylpropyl bromide for the 3,3-diphenyl-3-cyanopropyl bromide of Example 1 gives, by procedure therein detailed, 1-(3,3-diphenylpropyl)-4-piperidino-4-piperidinecarboxamide; MP: 131-132*C.Example 5:1-(3,3-diphenyl-3-cyanopropyl)-4-morpholino-4-piperidinecarboxamideSubstitution of 248 parts of pyrrolidine HCl the for piperidine HCl of Example 1 gives, by the same procedure, successively:
1-benzyl-4-cyano-4-morpholinopiperidine; MP: 117-118*C
1-benzyl-4-morpholino-4-piperidinecarboxamide; MP: 150-151*C
4-morpholino-4-piperidinecarboxamide; MP: 183-187*C
1-(3,3-diphenyl-3-cyanopropyl)-4-morpholino-4-piperidinocarboxamide; MP: 203-204*C
Example 6:1-(3,3-diphenyl-3-cyanopropyl)-4-(1-pyrrolidinyl)-4-piperidinecarboxamideSubstitution of 212 parts of pyrrolidine HCl for the piperidine HCl in Example 1 give, by the same procedure, successively:
1-benzyl-4-cyano-4-(1-pyrrolidinyl)-piperidine; MP: 87-88*C.
1-benzyl-4-(1-pyrrolidinyl)-4-piperidinecarboxamide; MP: 124-127*C.
4-(1-pyrrolidinyl)-4-piperidinecarboxamide; MP: 141-142*C.
1-(3,3-diphenyl-3-cyanopropyl)-4-(1-pyrrolidinyl)-4-piperidinecarboxamide; MP:159-160*C
Example 7:1-(3,3-diphenyl-3-cyanopropyl)-4-hexamethylenimino-4-piperidinecarboxamideTo a cooled solution of 37.9 parts of N-benzyl-4-piperidone there is added a solution of 40.6 parts of sodium bisulfite and 80 parts water. The mix is cooled and stirred vigorously for 30 minutes before 24 parts of hexamethyleneimine is added portionwise. Stirring is continued for 15 hours at RT before 13 parts of potassium cyanide is added and the resultant mix is stirred for 2 hours at RT and then 1 hour at 50-60*C. 100 parts of water is added to the mix and the aqueous solution is extracted twice with 1120 parts of ether and once with 600 parts of chloroform.
The combined organic layers are dried over potassium carbonate and HCl gas is introduced to precipitate
1-benzyl-4-cyano-4-hexamethyliminopiperidine HCl; MP: 139-149*C.
Substitution of 1-benzyl-4-cyano-4-hexamethyliminopiperidine HCl for the 1-benzyl-4-cyano-4-piperidinopiperidine of Example 1, by the same procedure, gives successively:
1-benzyl-4-hexamethylimino-4-piperidinecarboxamide; MP: 110-111*C.
4-hexamethylimino-4-piperidinecarboxamide; MP: 111-118*C
1-(3,3-diphenyl-3-cyanopropyl)-4-hexamethylimino-4-piperidinecarboxamide dihydrochloride; MP: 289-291.2*CIn this case the dihydrochloride of the final product is obtained by passing HCl gas through an ether solution of the free base. The crude HCl is purified by recrystallization from water.