Original Jaansen Fentanyl Patent

piglet · Thu Sep 29, 2005 9:05 pm

Below is the english translation of Belgium patent 3,164,600, the original patent for fentanyl synthesis. As you can see, it relies on the chemist already having access to N-(-piperidyl)propionanilide....

Description of GB992732

PATENT SPECIFICATION

XTn TD A1W7T-KT/A - MT IrC"4; 1JE e 1 Date of Applicatlon and filing Complete Specifica No. 38269/62.

Application made In United States of America (N( Complete Specification Published: May 19, 1965.

H 0oso3' Crown Copyright 1965.

Ution: Oct. 9, 1962.

ation: Oct. 9, 1962.

o. 144,059) on Oct. 10, 1961.

Index at aeptance:-C2 C (1D, 1F1A2, IF1B, 1F10C4, 1F1C5, 1F1D3, 1Q2, 1Q6C, 1Q8A, 1Q9A, 1Q9F1, 1Q9F2, 1QllD, 1QllG, 2A3, 2A5, 2A13, 2A14, 2B3A4, 2B3B, 2B3G1, 2B3G8, 2B3G9, 2B22, 2B40D, 2B40E, 2B40G, 2B40H1, 2B40H3, 2B40J2, 2B40J3, 2B40M, 2B42D, 2B42E, 2B42G, 2B42H1, 2B42H3, 2B42J2, 2B42J3, 2B42M, 2B43D1, 2B43D3, 2B43D4, 2B43E, 2B43G1, 2B45D1, 2B45D3, 2B45D4, 2B45E, 2B45G1, 2B48D1, 2B48D3,2B48D4, 2B48E, 2B48G1, 2BS8G3, 2B51D1, 2B51D3, 2B51D4, 2B51E, 2B51G1, 2R16,2T18) Int. CI.:-C 07 d COMPLETE SPECIFICATION

1-Arylalkyl4- (N-Arylalkanamido)Piperidines and related compounds and method for their preparation We, N.V. RESEARCH LABORATORIUM DR.

C. JANSSEN, a Belgian Body Corporate, of 30 Turnmhoutsebaan, Beerse, Belgium, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement:The present invention relates to a novel group of N - aralkyl - 4 - piperidyl - Narylalkanamides. More particularly, it relates to compounds of the general formula:

FRt Art-AIk-NJi O? and the pharmaceutically equivalent, non-toxic salts thereof, wherein Ar represents cyclohexyl, phenyl, halophenyl, methoxyphenyl, aminophenyl, nitrophenyl, pyridyl, furyl, or thienyl; Alk represents ethylene or propylene; R represents lower alkyl, lower alkoxy, dimethylamino, cyclopropyl, 1-pyrrolidinyl, morpholino or 1piperidyl; R' represents hydrogen, methyl or methoxy and R"' represents hydrogen or a lower alkyl radical.

The halophenyl radicals referred to above indude fluorophenyl, chlorophenyl, bromophenyl and iodophenyl. The lower alkyl and lower alkoxy radicals referred to contain less than 7 carbon atoms; typical examples are methyl, [Price 4s. 6d.] ethyl, propyl, butyl, methoxy, ethoxy, propoxy and butoxy.

The organic bases of this invention form pharmaceutically acceptable salts with a variety of inorganic and strong organic acids including sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic and ascorbic. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride and bromide, phenethyl bromide, naphthylmethyl chloride, dimethylsulfate, diethylsulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The compounds to which this invention relates are useful because of their valuable pharmacological properties. In particular, they are potent analgesics and appetite inhibitors.

They are also mydriatic and cholinergic in their action.

The compounds of this invention can be advantageously prepared by the condensation of a compound of the structural formula Ar-Alk-halogen with an appropriately selected compound of 60 the formula 992,732 N-C-R wherein Ar, Alk, R, Rt and RW' are defined as above. The reaction can be carried in an inert solvent such as an aromatic hydrocarbon, (e.g.

benzene, toluene), a lower alkanol (e.g.

butanol), or a lower alkanone (e.g. 4-methyl2-pentanone). The reaction can be accelerated by use of elevated temperatures.

The intermediate piperidines described above can be conveniently prepared by the 10 following series of reactions.

N-benzylpiperidone is reacted with an arylamine to give an intermediate Schiff base of the formula:

C12-N N--<Yt1 -I RI 15 Representative bases of this in Table I.

type are listed TABLE I

RI bp.

H 170 C. at 0.5 mm Hg o.CH3- 176- 185 C. at 0.5 mm Hg m.CH3- 190- 1960 C. at 0.6 mm Hg p.CH3- 180- 190 C. at 0.5 mm Hg m.CH3O- 180- 190 C. at 0.1 mm Hg p.CH30- 200 - 210 C. at 0.2 mm Hg The Schiff base is then reduced to the corres- hydride or alkyl lithium to give a compound ponding diamine with lithium aluminium of the formula:

(3J-CH2-NO8 NH-- Jn Representative compounds of this type, corresponding to the are listed in Table 2.

, compounds listed in Table 1, TABLE 2 base or salt H H base base m. CHs2 HC1 base m. CH2O2 HCi p.CH.O base p. CH30 2 HC1 -n.C4H9 2 HC mp.

84.8- 860 C.

103- 103.8 C.

254 - 256.5 C.

95.8- 96.8 C.

230 - 235 C.

- 66 C.

252 - 265 C. (dec.) 230.4 - 232 C.

H 992,732 The resultant compound is reacted with an appropriate anhydride to give the corresponding amide. with an appropriate alkyl chloroformate to give the corresponding urethane or with phosgene to give a carbamyl chloride which is further reacted with a secondary amine to give a urea derivative. The intermediates produced can be represented by the following general formula:

RI1 N-C-R wherein R, R' and R' are defined as above.

Typical compounds of this type are listed in Table 3.

TABLE 3

R R' H H , -CH3 -C2Hn --n. CaH7 base or salt base base HC1 mp 107- 109.2 C.

74 - 76 C.

230 - 231 0 C.

-GIl3, 255 - 258.40 C.

231 - 233 C.

178- 185 C.

99.8- 101 0 C.

92 - 95.5 C.

115- 116 C.

104- 106 C.

- 73.4 C. (dec.) 73.8- 74.40 C.

73.5 -74.5 C.

111 - 112 C.

oil oil oil 210 - 2200 C.

H --n. C4H9 -1 -OC2H5 -Cl -N(CH.)2 -NJ _#D::

o. CH3m. CH3m.CH3p. CH3m.CH3Om.CH3O, -C2H5 --CH3 HC1 HC1 HC1 base base base base base base base base base base base HCI p.CH30p.CH30-C2H5 -C2115 -C2I-15 Hcl - 100' C. (dec.) Subsequent debenzylation by hydrogenation Specific examples of this type of compound, 5 over palladium-on-charcoal gives the compound corresponding to the compounds listed in of the formula: Table 3, are given in Table 4.

1I H pi TABLE 4

R -CH3 -C2.H5 -n.C3H7 base or salt base base base mp.

129 - 130 C.

83 - 85 C.

93.4 - 95.8 C.

-OC2H5 -N(CH3)2 -NJ -CD -4cih -C2H5 -CH3 --CH3 -C2H5 -CaH5 -n.C4H9 238 - 239 0 C.

225 - 227 C.

242 - 246 C.

110.6 - 113 C.

266 - 267 C.

101 - 103 C.

254 - 256.5 0 C.

oil oil oil 176 - 177 C.

- 112.8 C.

oil oil oil The following Examples illustrate the invention. In these Examples quantities are indicated in parts by weight, temperatures in degrees centigrade ( C), and pressure in millimeters of mercury (mm.).

EXAMPLE 1.

A mixture of 5.2 parts 8-cyclohexylethyl bromide, 5.9 parts N-(-piperidyl)propionanilide, 10 parts of sodium carbonate, 0.05 part potassium iodide in 200 parts 4-methyl-2pentatone is stirred and refluxed for 36 hours.

After cooling, 200 parts of water are added with stirring. The organic layer is separated, dried, filtered and evaporated. The oily residue is dissolved in 280 parts diisopropyl ether, then hydrogen chloride gas is introduced into the mixture. The precipitated hydrochloride is filtered off and recrystallized from 40 parts acetone to yield N - [1 - (P/ - cyclohexylethyl)H H , HCI o. CHIl3m. CH3m. CH3p.CH3m. CH3O m. CH30p.CH30 H Ha HC1 base HC1 base HIC1 base base base HC1 base base base base 992,732 Substitution of N - (4 - piperidyl)propionotoluidide for the N-substituted amide of paragraph 1 yields N - [1 - (US - phenylethyl) - 4piperidyl] - p - propionotoluidide, melting at about 136--138 C.

Substitution of N - (4 - piperidyl)butyranilide for the amide of paragraph 1 yields N - [1 - (13 - phenylethyl) - 4 - piperidyl] butyranilide, melting at about 90-91 C.

Substitution of,8 _ (m - methoxyphenyl)ethyl chloride of paragraph 1 yields N - { 1[13 - (m - anisyl)ethyl] - 4 - piperidyl propionanilide.

4-piperidyl] propionanilide hydrochloride, melting at about 204-206oC. This compound has the structural formula /"'%_cH.,cH.-NO"X Ho 0- CH2CH2 - -INCCH2CH3 HCI EXAMPLE 2.

To the stirred solution of 5 parts of N-(4pipe.ridyl)propionanilide, 6.85 parts sodium carbonate, 0.05 part potassium iodide in 120 parts hexone is added portionwise a solution of 3.8 parts 1?-phenylethyl chloride in 24 parts 4-methyl-2-pentanone. The mixture is stirred and refluxed for 27 hours. The reaction mixture is filtered while hot, and the filtrate is evaporated. The oily residue is dissolved in 160 parts diisopropyl ether and the solution is filtered several times until clear, then concentrated to a volume of about 70 parts. The residue is then cooled for about 2 hours at temperatures near 0 C. to yield N-[l-(fphenylethyl) - 4 - piperidyl]propionanilide, melting at about 83-84 GC.

Substitution of 1 - (p - fluorophenyl)ethyl bromide for the chloride of the above procedure yields N - 1 - [L8 - (p - fluorophenyl)ethyl] - 4 - piperidyl}propionanilide, melting at about 104-105 C.

Substitution of 13 - (p - iodophenyl)ethyl chloride yields N _ 1 - [FI - (p - iodophenyl)ethyl]-4-piperidyl}propionanilide.

Substitution of P-(m-bromophenyl)ethyl bromide for the halogen of paragraph 1 yields N - J 1 - [jS - (m - bromophenyl)ethyl] - 4piperidy,-propionanilide, when reflux time is increased from 36 to 48 hours.

Substitution of 13 - (p - chlorophenyl)ethyl chloride for the chloride of paragraph 1 of this example yields N-/ l-[1i-(p-chlorophenyl)ethyl] - 4 - piperidyl propionanilide, melting at about 73-74 C.

Substitution of 18-(p-methoxyphenyl)ethyl chloride for the chloride of paragraph 1 of this example yields N - { 1 - [1 - (p - anisyl)ethyl] - 4 - piperidyl}propionanilide, melting at about 97-98 C.

Substitution of 1t - (p - nitrobenzyl)ethyl chloride for the chloride of paragraph 1 in this example yields N - 1 - [p - (p - nitrophenyl)ethyl] - 4 - piperidyl [propionanilide, melting at about 114-119 C., when reflux time is reduced from 36 to 24 hours.

Substitution of P-(2-thienyl)ethyl chloride for the phenylethyl chloride of the above procedure yields N -J 1 - [1i - (2 - thienyl)ethyl}4-piperidyl tpropionanilide, melting at about 62---63 C.

EXAMPLE 3.

To a stirred mixture of 5.66 parts N-(4piperidyl) - o - propionotoluidide, 7.3 parts sodium carbonate, 0.05 part potassium iodide and 120 parts 4 - methyl 2 - pentanone is added portionwise a solution of 4.1 parts 2phenyl - 1 - chloroethane in 16 parts 4methyl-2-pentanone. The mixture is stirred and refluxed for 36 hours. While hot, the reaction mixture is filtered and the filtrate evaporated. After dissolving the residue in 200 parts diisopropyl ether, the solution is filtered 80 several times until clear. The filtrate is diluted with 320 parts of diisopropyl ether and hydrogen chloride gas is introduced into the solution.

The precipitated hydrochloride is filtered off and stirred in 56 parts of acetone. The acetone 85 solution is filtered yielding a residue of N[1 - (13 - phenylethyl) - 4 - piperidyl] - opropionotoluidide hydrochloride, melting at about 194-196 C.

Substitution of the appropriate amides for 90 the N - (4 - piperidyl) - o - propionotoluidide in the above example yields:

N - [1 - (1 - phenylethyl) - 4 - piperidyl]m - propionotoluidide hydrochloride, melting at about 210-218 C. 95 N - [1 - (13 - phenylethyl) - 4 - piperidyl]m-acetotoluidide hydrochloride, melting at about 235.5-241,0C.

N - [1 - (l/ - phenylethyl) _ 4 - piperidyl]butyranilide hydrochloride, melting at about 100 210-2110C. Reflux time is increased to 80 hours.

N - [1 - (fl - phenylethyl) _ 4 - piperidyl]p-propionanisidide hydrochloride, melting at about 210-211.5oC. 105 By substituting 1t-(2-furyl)ethyl chloride for the 2-phenyl-1-chloroethane of paragraph 1 in this example and repeating the procedure of this example, there is obtained:

N _1- Ol - [,f -(2- furyl)ethyl] - 4 piperidyl}-o-propionotoluidide hydrochloride, melting at about 232.5-233.5oC.

By substituting 4-butyl-4-piperidyl-propionanilide for the amide of paragraph 1; of this example, there is obtained in the same manner: 115 N - [1 - (13 - phenyl)ethyl - 4 - butyl - 4piperidyl]propionanilide hydrochloride, melting at about 168 169.8 0C.

992,732 EXAMPLE 4.

A mixture of 3.5 parts P-phenylethyl chloride, 6 parts N - (4 - piperidyl) - N phenyl - N',N1 - dimethylurea hydrochloride, 0.05 part potassium iodide in 160 parts hexane is stirred, then refluxed for 45 hours. After cooling, the reaction mixture is filtered, the filtrate is evaporated. The residue is dissolved in 160 parts of diisopropyl ether and filtered.

Upon evaporation of the filtrate, solid N-[1(/l - phenylethyl) - 4 - piperidyl] - N - phenylN1,Nl-dimethylurea is precipitated, which, upon recrystallization from diisopropyl ether, melts at about 115-116 0C.

EXAMPLE 5.

A mixture of 4.3 parts 2-phenyl-1-bromopropane, 10 parts N-(4-piperidyl)propionanilide, 0.05 part potassium iodide in 80 parts of toluene is refluxed at 150 for 65 hours. After addition of 150 parts of water, the organic layer is separated and washed with water, dried, filtered and evaporated. The residue is dissolved in 200 parts diisopropyl ether and dry hydrogen chloride gas passed into the solution. The precipitated hydrochloride is filtered off and recrystallized from 20 parts isopropanol to yield N - [1 - ( 8 - methyl - /phenyl)ethyl - 4 - piperidyl]propionanilide hydrochloride, melting at about 226-229.6 GC.

This compound has the formula:

CjH3 H <I. CH-CH2-NiZX9ccH l, cH-CH2 - Ng-N-C-2CHS HCI Substitution of 1 - phenyl - 2 - bromopropane for the bromide of the above example and following the same procedure yields N[1 - (a - methyl - J - phenyl)ethyl - 4 piperidyl]propionanilide hydrochloride, melting at about 272.8-273.6 C.

EXAMPLE 6.

A mixture of 6 parts 4-vinyl-pyridine, 3.1 parts N - (4 - piperidyl)propionanilide, and parts butanol is stirred and refluxed for hours. The residue remaining after evaporation of the solvent is dissolved in xylene and evaporated again. The oily residue is dissolved in diisopropyl ether. After cooling the solution at about - 15 C., N - { 1 - [/ - (4 - pyridyl)ethyl] - 4 - piperidyl}propionanilide, melting at about 123-125 C. is obtained.

EXAMPLE 7.

To a stirred mixture of 4.2 parts N-(4piperidyl)-m-acetanisidide, 6.4 parts sodium carbonate, 0.05 part potassium iodide, and 120 parts 4-methyl-2-pentanone, a solution of 4.9 parts 18-phenylethyl chloride in 24 parts hexanone is added portionwise. After mixing, the mixture is refluxed for 39 hours. After cooling the reaction mixture is refluxed for 39 hours. After cooling the reaction mixture, parts of water are added. The aqueous layer is separated and extracted once more with toluene. The combined organic layers are dried over magnesium sulfate, filtered, and the filtrate evaporated. The oily residue is dissolved in 32 parts diisopropyl ether and filtered until clear. After cooling to about -15 C., N - [1 - (fl - phenylethyl) - 4 - piperidyl]m-acetanisidide, melting at about 94.5-96 C.

is obtained.

Substitution of the appropriate amide or amide hydrochloride for the N-(4-piperidyl)acetanisidide of the above example yields:

Ethyl N - [1 - (G - phenyl) ethyl - 4 piperidyl] - N - phenylcarbamate, melting at about 110-110.8 CG, when the reflux time is increased to 60 hours.

Methyl - N - [1 - OS - phenyl)ethyl - 4piperidyl] -N-phenylcarbamate.

Butyl - N - [1 - (f - phenyl)ethyl - 4piperidyl] -N-phenylcarbamate.

N - [1 - (S - Phenylethyl) - 4 - piperidyllacetanilide, melting at about 96-97 C.

N - [1 - (1 - Phenylethyl) - 4- piperidyllN - phenyl - N',N' - tetramethyleneurea, melting at about 133-134 C.

N - [1 - (O - Phenylethyl) - 4 - piperidyl]N - phenyl - N,N1 - pentamethyleneurea, melting at about 114.5-116 C.

N - [1 - (,O - Phenylethyl) - 4 - piperidyl]N - phenyl - N1,N' - (3 - oxapentamethylene)urea, melting at about 99-1001 C.

Substitution of (tS-cyclohexyl)ethyl bromide for the chloride of paragraph 1 of this example and N - (4 - piperidyl) - N - phenylcyclopropanecarboxamide hydrochloride for the amide yields N _ [1 - (fl _ cyclohexylethyl) 4 - piperidyl] - N - phenylcyclopropanecarboxamide, melting at about 102-40.5 C.

Substitution of the 13-cyclohexylethyl bromide and N - (4 - piperidyl) - N - phenylNSN - tetramethyleneurea hydrochloride for, respectively, the phenylethyl chloride and amide of paragraph 1 yields N - [1 - (3cyclohexylethyl) - 4 - piperidyll - N - phenylNlN1 - tetramethyleneurea, melting at about 106-1080C.

EXAMPLE 8.

Preparation of oxalic acid salts is accomplished by adding portionwise to a stirred mixture of 7.8 parts N - (4 - piperidyl) mpropionanisidide, 9.5 parts sodium carbonate, 110 0.05 part potassium iodide and 120 parts 4methyl-2-pentanone a solution of 5.27 parts t&-phenylethyl chloride in 16 parts 4-methyl-2pentanone. After stirring, the solution is refluxed for 36 hours, and then filtered while 115 hot. After evaporation of the filtrate, the residue is dissolved in 240 parts diisopropyl ether, and the solution is filtered several times until clear. The filtrate is evaporated in vG'cuo, 992,732 92,72 7 and the residue dissolved in 1'50 parts isopropanol. Next, a solution of 3.8 parts oxalic acid dihydrate in 16 parts isopropanol is added.

After filtration, the sticky precipitate is recrystallized from 120 parts of isopropanol and cooled to room temperature yielding N-[l(phenyl)ethyl - 4 - piperidyl] - m propionanisidide oxalate, melting at about 178.4-179.2 C.

EXAMPLE 9.

A mixture of 2.8 parts P-phenylethyl chloride, 5 parts N - (4 - piperidyl) - N phenylcyclopropanecarboxamide hydrochloride, 5.7 parts sodium carbonate, 0.05 part potassium iodide, and 176 parts 4 - methyl - 2pentanone is stirred and refluxed for 40 hours.

After cooling, the reaction mixture is filtered, then the filtrate evaporated. After dissolving the residue in 56 parts diisopropyl ether and cooling at room temperature N - [1 - (flphenylethyl) - 4 - piperidyll - N - phenylcyclopropanecarboxamide is obtained, melting at about 1:19.5--120.4 C.

EXAMPLE 10.

A solution of 4 parts N - 1 - [l -(pnitro)phenyl] - ethyl - 4 - piperidyl propionanilide in 40 parts methanol is reduced by catalytic hydrogenation at room temperature and normal pressure in the presence of 0.1 part of Adams catalyst. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off, and the filtrate is evaporated. The residue is dissolved in 25 parts of hot diisopropyl ether.

After cooling the solution, a precipitate is obtained which is filtered off and dried to yield N - { 1 - [I - (p - amino)phenyl] ethyl - 4piperidyl -propionanilide, melting at about 150--151oC.

EXAMPLE 11.

The free base which remains upon evaporation of the solvent from an aqueous, alkaline benzene solution of 8.5 parts of ethyl N-(4'piperidyl)-N-phenylcarbamate hydrochloride is extracted with 24 parts butanol 3 times, and the organic layer dried. After addition of 3.1 parts 2-vinyl-pyridine in 88 parts butanol and stirring, the mixture is refluxed for 24 hours.

The solvent is evaporated, and the residue dissolved in 32 parts isopropanol. Storage at room temperature of this solution, after addition of 5.5 parts oxalic acid dihydrate in 8 parts isopropanol, yields 11.2 parts of the crude oxalate, which can be crystallized from 25 parts water. After cooling, the oxalate of the unreacted phenylcarbamate derivative is precipitated. After filtration, the mother liquor is made alkaline with 10% sodium hydroxide and extracted with toluene. The organic layer is dried, filtered and evaporated. Crystallization from 16 parts diisopropyl ether yields ethyl N - J 1 - [3 - (2 - pyridyl)ethyl] - 4piperidyl} - N - phenylcarbamate, melting at about 82-83.2 C.