raffike (Hive Addict)
01-25-03 22:31
No 401449
      Meperidine from benzyl cyanide  Bookmark   

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-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.

For those about to synth,we salute you
 
 
 
 
    Rhodium
(Chief Bee)
01-28-03 01:32
No 402006
      Synthesis of Meperidine (Part 1)
(Rated as: excellent)
 Bookmark   

Synthesis of Meperidine (Demorol)
Patent US2167351

(1) 1-methyl-4-phenyl-piperidine-4-carboxylic acid and the derivatives thereof

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 30-40C, 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 148C, in the form of  a colorless oil, under a pressure of 6 mmHg  it passes over at about 158C, After having  been allowed to cool the distillate solidifies completely to form a crystalline mass, Its solidification point is at 53C.; 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 190-200C,  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 299C,; 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 130C/15 mmHg and at 255-260C. under normal pressure, It is a thinly liquid colorless oil, the hydrochloride of  which, recrystallized from acetone, forms colorless crystals melting at 196-197C, 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 130C, 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 202C,  with decomposition,
Ethyl ester: base, a radiated crystalline mass,  melting at 30C, boiling at 147C/3mmHg; hydrochloride, colorless  crystalline powder, melting at 187-188C,
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 208-209C,
Beta-diethylaminoethylester: base, colorless oil  boiling at about 163C/1mmHg; dihydrochloride, colorless crystalline  powder, melting at 181-182C,
Amide: base, colorless crystals; hydrochloride  from alcohol, colorless crystals, melting at  235C.
Diethylamide: base, oil, boiling at 180-183C/4mmHg; hydrochloride,  crystallized from- ethyl acetate, melts at  180-182C.
Beta-diethylaminoethylamide: base,. boiling at  about 193C/1mmHg, Melting point about 57C.
Urea: base, colorless crystalline powder, melting at 225-227C, with decomposition.

(2) 1-benzyl-4-phenyl-piperidine-4-carboxylic acid and the derivatives thereof

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 180-190C/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 35-50C, 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  259-260C, 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 75-76C, 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 190-200C.

The 1-benzyl-4-phenyl-piperidine-4-carboxylic acid is a colorless crystalline powder of melting point 285-286C, 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 236C 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 73-74C.

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 133-134C. and is very readily soluble in water.
 
 
 
 
    Rhodium
(Chief Bee)
01-28-03 01:35
No 402008
      Synthesis of Meperidine (Part 2)
(Rated as: good read)
 Bookmark   

(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  40-50C. 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 182-185C/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 149-152C,  under normal pressure for the most part the  methyl-di(beta-oxypropyl)-amine boiling, at 102-103C/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 35-40C, 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 157C/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 200C 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 291C 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  160-163C/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 185-195C/6 mmHg  (mainly at 190C,), 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 202C, under a pressure of  3 mm, Recrystallized from cyclohexane it forms  colorless crystals, melting at 112-113C, Its  hydrochloride. Is a colorless crystalline powder,  readily soluble in water, It decomposes at 275-276C. While heating the nitrile with addition of  methyl-alcoholic potash lye for 6 hours at a temperature of 210-220C 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  185C/1.5 mmHg, Its hydrochloride, recrystallized from amylacetate, melts  at 185-187C, 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 232-234C. 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 96-97C, 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 140-150C, The  acid is a fine, colorless crystalline powder melting  at 220-221C, 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 179C.

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 203-204C.

(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 150C/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 303-304C, It may be readily recrystallized from water. The base of the nitrile forms colorless crystals melting at 99-100C, 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 358C, with decomposition. The ethyl ester has a melting point of 61-62C, its hydrochloride melts at 223C, with decomposition.