Synthesis of Meperidine (Demorol)Patent US2167351
(1) 1-methyl-4-phenyl-piperidine-4-carboxylic acid and the derivatives thereof80 parts of finely pulverised sodium amide are added in portions each of about 1/5 of the entire quantity, while stirring and cooling in a suitable manner, to a mixture of 156 parts of di(beta-chloroethyl)-methylamine (prepared from diethanolmethylamine by means of thionyl chloride), 117 parts of benzyl cyanide and 600 parts of toluene, The reaction sets in at once at room temperature, The temperature of the mixture is maintained between 30-40°C, when self- heating of the mixture no longer occurs a further portion of the sodium amide is introduced during the reaction of which always a large quantity of heat is liberated and gaseous ammonia escapes.
Caution! Di(beta-chloroethyl)-methylamine is a vesicant "war gas", also called "nitrogen mustard". The original "Mustard gas" is the same molecule, but with a Sulfur atom instead of the N-CH3 functionality.The mixture is then slowly heated to the boiling of the toluene and kept boiling for one hour under reflux, After the mixture has been allowed to cool the sodium chloride which precipitates is separated by extraction with water, The solution of toluene is then extracted with dilute hydrochloric acid,. From the hydrochloric acid extract the basic substance is separated in the form of an oil by means of caustic soda solution and is introduced into ether, The ethereal solution is dried with the aid of potassium carbonate and then distilled, Under a pressure of 4,5 mmHg the 1-methyl-4-phenyl-piperidine-4-carboxylic acid nitrile passes over at a temperature of about 148°C, in the form of a colorless oil, under a pressure of 6 mmHg it passes over at about 158°C, After having been allowed to cool the distillate solidifies completely to form a crystalline mass, Its solidification point is at 53°C.; the yield amounts to about 135 parts, that is about 2/3 of the theoretical yield.
When recrystallized from isopropyl alcohol the hydrochloride of the nitrile forms colorless crystals, readily soluble in water and melting at 221-222° C, The nitrile may best be saponified with methyl alcoholic potash while heating to 190-200°C, with application of pressure. After the methyl alcohol has evaporated the salt is introduced into water and, by the addition of dilute mineral acid until the alkaline reaction to phenolphthalein has just disappeared, the amphoteric 1-methyl-4-phenyl-piperidine-4-carboxylic acid is precipitated while hot in the form of a colorless, coarsely crystalline powder. When dried on the water bath the acid still contains 1 mol of crystal water which is lost only at a raised temperature; The acid melts at 299°C,; it may well be recrystallized from water; the solution has a neutral reaction to litmus, The acid is readily soluble in caustic soda solution and in. dilute hydrochloric acid and to a somewhat smaller extent in sodium carbonate solution. It may be precipitated from an alkaline solution by means of carbon dioxide.
When heated to above its melting point the acid gradually gives off carbon dioxide and is, transformed into 1-methyl-4-phenyl-piperidine, boiling at 130°C/15 mmHg and at 255-260°C. under normal pressure, It is a thinly liquid colorless oil, the hydrochloride of which, recrystallized from acetone, forms colorless crystals melting at 196-197°C, which are readily soluble in water.
The hydrochloride of 1-methyl-4-phenyl-piperidine-4-carboxylic acid chloride, in the form of a colorless crystalline powder which slowly decomposes when heated over 130°C, may readily be obtained from the acid by dissolving the latter in thionyl chloride and distilling the excess. By dissolving the hydrochloride of the acid chloride in alcohols and amines for instance the following derivatives are obtained in, a good yield:
Methyl ester: hydrochloride, crystallized from acetone, colorless crystals, melting at 202°C, with decomposition,
Ethyl ester: base, a radiated crystalline mass, melting at 30°C, boiling at 147°C/3mmHg; hydrochloride, colorless crystalline powder, melting at 187-188°C,
Butyl ester: hydrochloride, crystallized from ethyl acetate in colorless crystals melting at 161-162° C.
Benzyl ester: hydrochloride, from water colorless crystals containing crystal water, melting at 172-173° C,
Phenyl ester: hydrochloride from isopropyl alcohol, thin colorless needles, melting at 208-209°C,
Beta-diethylaminoethylester: base, colorless oil boiling at about 163°C/1mmHg; dihydrochloride, colorless crystalline powder, melting at 181-182°C,
Amide: base, colorless crystals; hydrochloride from alcohol, colorless crystals, melting at 235°C.
Diethylamide: base, oil, boiling at 180-183°C/4mmHg; hydrochloride, crystallized from- ethyl acetate, melts at 180-182°C.
Beta-diethylaminoethylamide: base,. boiling at about 193°C/1mmHg, Melting point about 57°C.
Urea: base, colorless crystalline powder, melting at 225-227°C, with decomposition.
(2) 1-benzyl-4-phenyl-piperidine-4-carboxylic acid and the derivatives thereofFor the manufacture of the required benzyl-di(betachloroethyl)-amine diethanolamine is caused to react with benzyl chloride so as to form diethanolbenzylamine, a viscous liquid boiling between 180-190°C/4-5mmHg. By the reaction of the diethanolbenzylamine with an excess of thionyl chloride the two hydroxyl groups are substituted by chlorine, The base is set free, while cooling, with the aid of caustic soda solution, introduced into ether and dried with the aid of potassium carbonate, The ether is distilled finally under reduced pressure, The base remains in the form of an oil of feebly brownish color. 80 parts of finely pulverized sodium amide are gradually added, while stirring and cooling with ice, to 117 parts of benzyl cyanide, 232 parts of N,N-di(beta-chloroethyl)-benzylamine and 600 parts of toluene, During the introduction of the amide the temperature is kept between 35-50°C, The mixture is then gradually heated to boiling and boiled for one hour under reflux.
After the mixture has. been cooled dilute hydrochloric acid is added and the whole is shaken until the acid reaction to congo remains. There is obtained a thick crystalline magma which is filtered by suction on a wide filter and pressed, The product, the 1-benzyl-4-phenyl-piperidine-4-carboxylic acid nitrile hydrochloride, is then recrystallized from methyl alcohol. It is obtained therefrom in the form of colorless needles in a yield of about 180 parts; it melts at 259-260°C, even when further recrystallized from water, 30 parts of boiling water dissolve 1 part of the salt. The free 1-benzyl-4-phenyl-piperidine-4-carboxylic acid nitrile is precipitated from the hot aqueous solution of the hydrochloride by sodium carbonate; it melts at 75-76°C, It may best be saponified to form the acid by means of a methyl alcoholic caustic, soda lye with application of pressure at a temperature of between 190-200°C.
The 1-benzyl-4-phenyl-piperidine-4-carboxylic acid is a colorless crystalline powder of melting point 285-286°C, which is readily soluble in dilute hydrochloric acid and soluble to a small. extent in an excess of dilute acetic acid and in ammonia, The hydrochloride of the acid chloride may readily be produced by dissolving the acid in thionyl chloride and evaporating the excess. It is a colorless crystalline powder, With ethyl alcohol it yields the ethyl ester hydrochloride; this crystallizes in the form of needles from alcohol, which crystals melt at 236°C with decomposition. The product is soluble to a small extent in water and to a rather large extent in hot water, The base which is precipitated from the aqueous solution of the hydrochloride by sodium carbonate is a colorless crystalline powder melting at 73-74°C.
By the reaction of benzyl cyanide with di(beta-chloroethyl)-amine in a solution of toluene with sodium amide the 4-phenyl-piperidine-4-carboxylic acid is obtained only in a very small yield, For the manufacture of 4-phenyl-piperidine-4-carboxylic acid and the derivatives the parent material may be the hydrochlorides of the 1-benzyl-4-phenyl-piperidine-4-carboxylic acid or the derivatives thereof, These starting materials are shaken in an alcoholic solution together with palladium and hydrogen by which operation the benzyl radical is readily eliminated while hydrogen is incorporated. Thus from the above named hydrochloride of 1-benzyl-4-phenyl-piperidine-4-carboxylic acid ethyl ester there is obtained for example the hydrochloride of 4-phenyl-piperidine-4-carboxylic acid ethyl ester in the form of a colorless crystalline powder which when recrystallized from ethyl acetate melts at 133-134°C. and is very readily soluble in water.
