01-25-03 22:31
No 401449
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 them
Patent US2167351
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-carboxyli
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-carboxyli
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-carboxyli
EDIT:Found that this amine is also a chemical weapon of some sort but should be no problem when handled carefully.
For those about to synth,we salute you
(Chief Bee)
01-28-03 01:32
No 402006
(Rated as: excellent)
Synthesis of Meperidine (Demorol)
Patent US2167351
(1) 1-methyl-4-phenyl-piperidine-4-carboxyli
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 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-carboxyli
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-carboxyli
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-carboxyli
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-carboxyli
For 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-carboxyli
The 1-benzyl-4-phenyl-piperidine-4-carboxyli
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-carboxyli
(Chief Bee)
01-28-03 01:35
No 402008
(Rated as: good read)
(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-ca
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-car
(5) 1-methyl-3,5-di-methoxymethyl-4-phenylpi
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)-
(6) 1-methyl-4-(naphthyl-alpha)-piperidine-4
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
(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
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-carbo
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
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-carbo