Megatherium (Newbee)
01-07-03 01:53
No 395965
      Chalenge: piritramide synthesis  Bookmark

I found this molecule, and I started wondering about it.  What would be the dose?  There must be chemical literature about the synthesis.  Now, the problem is: finding it. 
(Hive Addict)
01-07-03 01:59
No 395968
      Deutsch?  Bookmark   

as is already obvious, aurelius doesn't speak german.  So, why the interest in this drug? 
(Chief Bee)
01-07-03 02:11
No 395974
      Piritramide dosage  Bookmark   

Plugging it into Google gave a lot of hits, at it can be read that the usual dosage is 7,5-22,5 mg i.v. (given at a rate of 10 mg/min), that it has a morphine equivalency of 0.7, fast acting (5 min), and is strongly sedating and analgesic, while having low emetic activity.

The Merck Index references Patent US3080366 and Patent BE606850 for its synthesis.
01-07-03 02:25
No 395977
      Well, thanks Rhodium.  Bookmark   

Well, thanks Rhodium.  You 've won the golden cup wink.  In 18 minutes, wow, ... congrats, this must be a record.

Aurelius, I also am not German ... but I do an attempt to understand it.  I brought the subject up, because this compound was not already covered by The Hive.  It 's just an academic interest.  And it can't hurt to read about analgesics, can it? LOL
(Chief Bee)
01-07-03 02:47
No 395987
      No match  Bookmark   

Not a record for me simply performing a web-search and consulting my personal references, that has been done by me a lot faster before, when I haven't been doing other things at the same time. But for formatting a posted writeup and uploading it to my page, I believe my personal record is in Post 212052 (Rhodium: "Personal record", Novel Discourse) wink
01-08-03 23:50
No 396499
      I tried several times, but that like to that...  Bookmark   

I tried several times, but that like to that belgian patent doesn't work ... that damned patent office always says: 'Database not accessible' ...frownfrownfrown

Someone, please help ...
01-09-03 02:22
No 396525
      Hmm ... this is probably the reason: ...  Bookmark   

Hmm ... this is probably the reason:

Damn frown
(Hive Addict)
01-10-03 22:54
No 397030
      US patent 3080366  Bookmark   

US patent 3080366

1-(w,w-Diphenylalkyl)-4-amino-4-piperidine-carboxamides and Derivatives Thereof

Note:  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:


To 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:


A 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*C

Example 4:


Substitution 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:


Substitution 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:


Substitution 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:


To 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*C

In 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.
(Hive Addict)
01-10-03 22:55
No 397031
      finishing the patent  Bookmark   

Example 8:

1-(3,3-diphenyl-3-cyanopropyl)-4-dimethylamino-4-piperidinecarboxamide Dihydrochloride

Substitution of 184 parts of dimethylamine HCl for the piperidine HCl of Example 1 give, by the same procedure, successively:
1-benzyl-4-cyano-4-dimethylaminopiperidine; MP: 107-109*C
1-benzyl-4-dimethylamino-4-piperidinecarboxamide: MP: 122-124*C
4-dimethylamino-4-piperidinecarboxamide; MP: 118-121*C
1-(3,3-diphenyl-3-cyanopropyl)-4-dimethylamino-4-piperidinecarboxamide; MP: not given

the last-named compound is taken up in ether, and the resultant solution is saturated with HCl gas.  The precipitate is filtered off and recrystallized using isopropyl alcohol to give the HCl.

1-(3,3-diphenyl-3-cyanopropyl)-4-dimethylamino-4-piperidinecarboxamide; MP: 270-271*C (decomp.)

Example 9:


Substitution of 247 parts of diethylamine HCl for the piperidine HCl in Example 1 gives, by the same procedure, successively the Ethyl analogues of the products for each step in Example 8.

Example 10:


Substitution of 365 parts of dibutylamine HCl for the piperidine HCl in Example 1 gives, by the same procedure, successively the dibutyl analogues of the products for each step in Example 8.

Example 11:


A mix of 6.6 parts of 4,4-diphenyl-4-cyanobutyl bromide, 8.4 parts of 4-piperidino-4-piperidinecarboxamide, and 0.1 part of potassium iodide in 120 parts of toluene is heated in a sealed tube for 100 hours at 110*C. The cooled mix is filtered and the filtrate is diluted with 480 parts of ether.  The precipitated is filtered from the solvent and dried to give
1-(4,4-diphenyl-4-cyanobutyl)-4-piperidino-4-piperidinecarboxamide: MP: 187-188*C

Example 12:


Substitution of 96 parts of 6,6-diphenyl-6-cyanohexyl bromide for the 3,3-diphenyl-3-cyanopropyl bromide in Example 1 gives, by the same procedure, 1-(6,6-diphenyl-6-cyanohexyl)-4-piperidino-piperidinecarboxamide.

Example 13:

1-(3,3-diphenyl-3-cyanopropyl)-3-piperidino-3-pyrrolidinecarboxamide dihydrochloride

Substitution of 350 parts of 1-benzyl-3-pyrrolidinone for  1-benzyl-4-piperidone in the Example 1 gives, by the same procedure, successively:
1-benzyl-3-cyano-3-piperidinopyrrolidine; BP: 135*C/0.3mmHg
1-benzyl-3-piperidino-3-pyrrolidinecarboxamide; MP: 85-86*C
3-piperidino-3-pyrrolidinecarboxamide; MP: 155-157*C
The last -named compound is taken up in ether and the resultant solution is gassed with anhydrous HCl.  The precipitate is filtered from solution and recrystallized from a mix of methanol and acetone to give
1-(3,3-diphenyl-3-cyanopropyl)-3-piperidino-3-pyrrolidinecarboxamide dihydrochloride; MP :257-267*C (decomp.)

Example 14:


To a cooled solution of 101.5 parts of 1-benzyl-3-methyl-4-piperidine in 215 parts of 15% HCl is added a solution of 50 parts of sodium cyanide in 130 parts water.  The mix is stirred overnight at RT before it is alkalized with ammonium hydroxide solution and extracted with 2 portions of benzene.  The solvent is evaporated from the dried organic layer and the residue is dissolved in 800 parts of diisopropyl ether and HCl is passed through the solution. The resulting precipitate is filtered off and recrystallized from butanone to give
1-benzyl-3-methyl-4-hydroxy-4-cyanopiperidine HCl; MP : 171-173*C

A mix of 57 parts of this Hydrochloride , 55.5 parts of piperidine, and 132 parts of methanol is stirred and refluxed for 16 hours.  The solvent is evaporated from the reaction.  The residue is dissolved in 300 parts water and extracted twice with benzene.  The benzene layer is washed twice with 50 parts water and dried over potassium carbonate.  The solvent is evaporated and the residue dissolved in 560 parts of diisopropyl ether.  HCl is passed through the ether and the precipitate is filtered off.  The hydrochloride is stirred in 160 parts of acetone at 45*C to give 1-benzyl-3-methyl-4-cyano-4-piperidinopiperidine dihydrochloride; MP: 145-163*C.

Substituting an equivalent quantity of 1-benzyl-3-methyl-4-cyano-4-piperidinopiperidine dihydrochloride for the 1-benzyl-4-cyano-4-piperidinopiperidine of Example 1 gives, by the same procedure, successively:
1-benzyl-3-methyl-4-piperidino-4-piperidinecarboxamide; MP: 136-137*C
3-methyl-4-piperidino-4-piperidinecarboxamide; MP: 144-145*C
1-(3,3-diphenyl-3-cyanopropyl)-3-methyl-4-piperodino-4-piperidinecarboxamide; MP: 177-178*C

Example 15:

A mix of 8 parts of NaNH2 and 42 parts of 4-fluorodiphenylacetonitrile in 320 parts of anhydrous benzene is refluxed for 2.5 hours.  The mix is cooled to 0*C and 90 parts ethylene bromide are added.  The mix is slowly warmed to room temp.  When the exothermic reaction has subsided, the mix is refluxed for 3.5 hours.  The mix is then cooled and decomposed by the addition of water.  The benzene layer is separated, washed with water, dried with K2CO3 and the solvent is evaporated.  The residue is recrystallized form 20propanol to give
3-phenyl-3-(4-fluorophenyl)-3-cyanopropyl bromide; MP: 40-41*C

If equivalent amounts of diphenylacetonitrile are substituted for the fluoro compound above, the following are obtained by the same procedure, successively:
  These oils obtained need no further purification to proceed to the next step.
3-phenyl-3-(4-chlorophenyl)-3-cyanopropyl bromide
3-phenyl-3-(4-methoxyphenyl)- 3-cyanopropyl bromide
3-phenyl-3-(bromophenyl)- 3-cyanopropyl bromide

Example 16:

A mix of 40 parts of 3-phenyl-3-(4-methoxyphenyl)- 3-cyanopropyl bromide, 25 parts of 4-piperidino-4-piperidinecarboxamide, 50 parts sodium carbonate and 0.1 part potassium iodide in 480 parts of 4-methyl-2-pentanone is stirred and refluxed for 86 hours.  The cooled reaction mix is filtered and the solvent is evaporated from the filtrate. The residue is recrystallized from a mix of benzene and ether to give
1-[3-phenyl-3-(4-methoxyphenyl)-3-cyanopropyl]-4-piperidino-4-piperidinecarboxamide; MP: 178.6-179.4*C

[red] Using the properly substituted halides from Example 14 and using them in Example 15 in proper molar equivalents will yield the following:

1-[-3-phenyl-(4-chlorophenyl)-3-cyanopropyl] -4-piperidino-4-piperidinecarboxamide; MP: 148-150*C
1-[-3-phenyl-(4-fluorophenyl)-3-cyanopropyl] -4-piperidino-4-piperidinecarboxamide; MP: 121-122*C
1-[-3-phenyl-(4-bromophenyl)-3-cyanopropyl] -4-piperidino-4-piperidinecarboxamide; MP: not given.