Some opoid faq told that meperidine is prepared from cyanide.Searched the hive but nothing,but i found and interesting patent that describes whole procedure.
Piperidine compounds and a process of preparing themPatent US2167351 (http://l2.espacenet.com/dips/viewer?PN=US2167351&CY=gb&LG=en&DB=EPD)
Here's a cutout from abstract:
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80 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 or methyl-di(beta-chloroethyl)-amine (prepared from di-ethanol-methylamine by means of thionyl chloride),117 parts of benzyl cyanide and 600 parts of toluene.The reaction sets in at once at room 5 temperature. The temperature of the mixture is maintained between 30° C.and 40° C.; when self-heating of the mixture no longer occurs a further portion of the sodium amide is introduced dur-ing the reaction of which always a large quantity 10 of heat is liberated and gaseous ammonia escapes. 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 precipates 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 20 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 millimetres 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 millimetres 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° C. to 222° C.The nitrite may best be saponified with methyl alcoholic potash while heating to 190° C-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-carboxyIic 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 @ 130C under a pressure of 15 mm and @ 255-260 under normal pressure.It is a thinly liquid colorless oil, the hydrochloride of which, rccrystallized from acetone, forms colorless crystals melting at 196° C.-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 hydrochlorlde of the. acid chloride in alcohols and amines for instance the following derivatives are obtained in a good yield:
Methyl ester: hydrochlorlde, 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. under a pressure of 3 mm.; hydrochlorlde, colorless crystalline powder, melting at 187° C.-1880 C.
Butyl ester; hydrochlorlde, crystallized from ethyl acetete In colorless crystals melting at 161" C.-162" C.
Benzyl-ester: hydrochlorlde, from water colorless crystals containing crystal water, melting at 172° C.-173" C.
Phenyl ester: hydrochloride from isopropyl alcohol, thin colorless needles, melting at 208° C-209° c.
Beta-diethylaminoethylester; base, colorless oil boiling at about 163° C. under a pressure of 1 mm.; dihydrochloride, colorless crystalline powder, melting at 181° C.-182' C.
Amide: base, colorless crystals; hydro chloride from alcohol, colorless crystals, melting at 235° C.
Diethylamide: base, oil, boiling at 180" C.-183" C. under a pressure of 4 mm.; hydrochloride, crystallized from- ethyl acetate, melts at 180° C.-1828 C.
Beta-diethylaminoethylamide: base, boiling at about 193° c. under a pressure of 1 mm. Malting point about 57" C.
Urea: base, colorless crystalline powder, melting at 225° C.-227" C. with decomposition.
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That intermediate 1-methyl-4-phenyl-piperidine-4-carboxylic acid is a watched compound but this method doesn't seem to be very popular so there should be no problem acquiring chemicals
EDIT:Found that this amine is also a chemical weapon of some sort but should be no problem when handled carefully.
Synthesis of Meperidine (Demorol)Patent US2167351 (http://l2.espacenet.com/dips/viewer?PN=US2167351&CY=gb&LG=en&DB=EPD)
(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.
(3) 1-methyl- 4 -(para-methoxy-phenyl)- Piperidine-4-carboxylic acid nitrile
Methyl-di(beta-bromoethyl)-amine can be produced. from methyl-di(beta-oxyethyl)-amine hydrobromide by treatment with hydrogen bro- mide at an elevated temperature; after the salt has been dissolved in water, the base is set free by means of caustic soda solution, while well cooling, and introduced into toluene, The toluene solution, dried over potassium carbonate and containing 123 parts of methyl-di(beta-bromoethyl)-amine in 500 parts of toluene is mixed with 73 parts of 4-methoxybenzyl cyanide, 42 parts of pulverized sodium amide in portions of about 5g, are then gradually added while stirring and cooling, the temperature thus being kept at between 40-50°C. The mixture is then slowly heated to boiling and boiled in a reflux apparatus until. the separation of ammonia has ceased, It is then worked up as described in Example 1, The nitrile boils at 182-185°C/5mmHg, being an almost colorless oil which rapidly and completely solidifies, The yield is not quite as-good as in the case of using, under the same conditions of treatment, 78 parts of methyl-di-(beta-chlorethyl)-amine instead of the above named 123 parts of methyl-di(beta-bromoethyl)-amine (63% of the theoretical yield).
(4) 1,3,5-trimethyl-4-phenyl-piperidine-4-carboxylic acid nitrile
By causing propylene oxide to react with an aqueous solution of methylamine there is obtained, besides a small amount of methyl-(beta- oxypropyl)-amine which boils at 149-152°C, under normal pressure for the most part the methyl-di(beta-oxypropyl)-amine boiling, at 102-103°C/7mmHg, it is a colorless liquid which, having been caused to react with thionyl chloride, yields the hydrochloride of the methyl-di(beta-chloropropyl)-amine. It is dissolved in water and the base is set free by the reaction with caustic soda solution while well cooling, It is then introduced into toluene, the solution of toluene separated is dried over sodium carbonate. For the future reaction a solution containing 184 parts of methyl-di(beta-chloropropyl)-amine in 500 parts of toluene, is used.
After the addition of 117 parts of benzyl cyanide 84 parts of pulverized potassium amide are introduced at a temperature between 35-40°C, while stirring and suitably cooling, The mixture is then gradually heated to boiling and boiled for 2 hours in a reflux apparatus. It is worked up as described in Example 1, The 1,3,5-trimethyl-4-phenylpiperidine-4-carboxylic acid nitrile thus obtained boils at about 157°C/6mmHg, It is a feebly yellowish oil, The yield amounts to 90 parts. The saponification of the nitrile to form the carboxylic acid, for instance with the aid of methylalcoholic caustic potash solution by heating to 200°C takes place not as readily and more slowly than in the case of the nitrile of Example 1. The 1,3,5-trimethyl-4-phenylpiperidine-4-carboxylic acid thus obtained crystallizes from water in the form of thin white needles which melt at 291°C with decomposition.
(5) 1-methyl-3,5-di-methoxymethyl-4-phenylpiperidine-4-carboxylic acid nitrile
By causing the methyl-(beta-gamma-epoxy- propyl)-ether (epimethyline) to react with an aqueous solution of methyl-amine there is obtained the methyl-di(gamma-methoxy-beta-oxypropyl)-amine, being a colorless liquid, boiling at 160-163°C/13mmHg, the hydrochloride of which is, by the aid of thionyl chloride, transformed into methyl-di(gamma-methoxy-beta-chloropropyl)-amine, which as a base constitutes a feebly brownish oil, 119 parts of methyl-di(gamma-methoxy-beta-chloropropyl)-amine, 58 parts of benzyl cyanide and 300 parts of toluene are worked up together with 42 parts of sodium amide as described in Example 1, There are obtained 32 parts of nitrile boiling at 185-195°C/6 mmHg (mainly at 190°C,), being a yellowish oil.
(6) 1-methyl-4-(naphthyl-alpha)-piperidine-4-carboxylic acid and the derivatives thereof
By treating, under the same conditions as described in Example 1, 167 parts of alpha-me-naphthylcyanide (naphthyl-alpha-acetic acid nitrile) and 156 parts of methyl-di(beta-chloroethyl)-amine in 500 parts of toluene together with 84 parts of sodium amide there are obtained 50%, of the theoretical yield of 1-methyl-4-(naphthyl-alpha)-piperidine-4-carboxylic acid nitrile, boiling at about 202°C, under a pressure of 3 mm, Recrystallized from cyclohexane it forms colorless crystals, melting at 112-113°C, Its hydrochloride. Is a colorless crystalline powder, readily soluble in water, It decomposes at 275-276°C. While heating the nitrile with addition of methyl-alcoholic potash lye for 6 hours at a temperature of 210-220°C under normal pressure, the nitrile saponifies, The free acid can not be separated by neutralization from the aqueous solution of the potassium salt obtained. The hydrochloride of the acid is a colorless crystalline powder, readily soluble in water and in alcohol. The ethyl ester obtained by boiling the hydrochloride with alcohol containing hydrochloric acid, forms a feebly yellowish syrup which distils at about 185°C/1.5 mmHg, Its hydrochloride, recrystallized from amylacetate, melts at 185-187°C, with decomposition; it forms a. colorless crystalline powder, which is readily soluble in water and in alcohol.
(7) 1,4-bis-phenyl-piperidine-4-carboxylic acid and the derivatives thereof
218 parts of di(beta-chloroethyl)-aniline and 117 parts of benzyl cyanide diluted with 500 parts of toluene are caused to react with 80 parts of pulverulent sodium amide in the same way as described in Example 2, The hydrochloride of the 1,4-bis-phenyl-piperidine-4-carboxylic acid nitrile precipitated by the subsequent treatment with dilute hydrochloric acid is obtained in a pure state after filtering it with suction arid washing it with methyl alcohol (2/3 of the theoretical yield), It forms a colorless crystalline powder melting at 232-234°C. When heated with the aid of water a hydrolytic decomposition occurs for the most part, while an insoluble base separates. The base, separated from the hot aqueous solution with the aid of ammonia, rapidly solidifies; it melts at 96-97°C, even when recrystallized from methyl alcohol from which it is obtained in the form of thick, colorless needles.
The nitrile may best be saponified to the acid with the aid of sulfuric acid of 70% strength, at a temperature of 140-150°C, The acid is a fine, colorless crystalline powder melting at 220-221°C, and being completely insoluble in water. The hydrochloride of the acid chloride, obtained from the acid in suspension of benzene with phosphorous pentachloride, is a colorless crystalline powder; being caused to react with beta-diethylaminoethanol it yields the hydrochloride of the 1,4-bis-phenyl-piperidine-4-carboxylic acid beta-diethylaminoethylester which is a colorless crystalline powder, fairly readily soluble in water and melting at 179°C.
With the aid of 1-amino-2-diethylaminoethane there may be obtained the 1,4-bis-phenyl-piperidine-4-carboxylic acid-beta-diethylaminoethylamide, The free base is oily; with addition of water it constitutes a crystalline hydrate. The monohydrochloride is a colorless crystalline powder melting at 203-204°C.
(8) 1-cyclohexyl-4-phenyl-piperidine-4-carboxylic acid and the derivatives thereof
NN-di-(beta-oxyethyl)-N-cyclohexylamine is obtained by causing cyclohexylamine to react with 2 mols of ethylene-chlorohydrine and caustic soda solution, It boils at about 150°C/3mmHg and is a colorless and almost odorless oil which, with the aid of thionyl chloride, yields the hydrochloride of the NN-di-(beta-chloroethyl)-cyclohexylamine, being a colorless crystalline powder which, dissolved in water with the aid of caustic soda solution yields the free oily base which is eliminated, and isolated in the usual manner, 224 parts of the NN-di(beta-chloroethyl)-cyclohexylamine thus obtained, 117 parts of benzylcyanide and 500 parts of toluene are caused to react with 117 parts of pulverulent sodium amide in the way as described in Example 2. After shaking the whole with dilute hydrochloric acid a crystalline magma is obtained which is filtered with suction, washed with ether, pressed out and recrystallized from methyl alcohol, The hydrochloride of the 1-cyclohexyl-4-phenyl-piperidine-4-carboxylic acid nitrile is thereby obtained in a pure form (61% yield).
Colorless crystals, decomposition point 303-304°C, It may be readily recrystallized from water. The base of the nitrile forms colorless crystals melting at 99-100°C, It is readily soluble in alcohol, ether, benzine, acetone and may be recrystallized from methyl alcohol.
The free 1-cyclohexyl-4-phenyl-piperidine-4-carboxylic acid obtained by saponification of the nitrile in the usual manner is a colorless crystalline powder, melting at about 358°C, with decomposition. The ethyl ester has a melting point of 61-62°C, its hydrochloride melts at 223°C, with decomposition.