US3065237A - Process for preparing pyrrolidinones - Google Patents

Process for preparing pyrrolidinones Download PDF

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US3065237A
US3065237A US3065237DA US3065237A US 3065237 A US3065237 A US 3065237A US 3065237D A US3065237D A US 3065237DA US 3065237 A US3065237 A US 3065237A
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pyrrolidinone
trimethyl
hydroxy
piperidinone
carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4

Definitions

  • This invention deals with a method for the preparation of specifiopyrrolidinones and piperidinones.
  • the compounds that are prepared by the present invention may be represented by the formula Thesecompounds are produced by the hydrogenolysis of compounds having the formula
  • R represents a hydrogen atom, an alkyl group of one to eighteen carbon atoms, an aryl group of up to ten carbon atoms, an aralkyl group of up to eighteen carbon atoms, an alkarylalkyl group of up to thirty carbon atoms, an alkoxyalkyl group of three to twentyfour carbon atoms, a hydroxyalkyl group of two to twelve carbon atoms, and an alkylaminoalkyl group of three to eighteen carbon atoms provided that the amino group is a secondary or tertiary structure, that is non-primary.
  • Alkyl in the above definition, is to be construed to include cycloalkyl and alkylcycloalkyl Within the range of carbon atoms previously set forth.
  • Typical R representations are methyl, ethyl, butyl, octyl, decyl, dodecyl, octadecyl, cyclopentyl, cyclohexyl, butylcyclohexyl, octylcyclohexyl, butylcyclohexylethyl, phenyl, naphthyl, benzyl, phenylethyl, phenylbutyl, phenyldodecyl, methylphenyl, ethylphenyl, butylphenyl, octylphenyl, nonylphenyl, decylphenyl, hexadecyiphenyl, octadecylphenyl, methylbenzyl, ethylbenzyl, butylhenzyl,
  • octylbenzyl dodecylbenzyl, butylphenylbutyl, octylphenylethyl, dioctylphenylethyl, dodecylphenyloctyl, methoxymethoxypropyl, methoxyhexyl, methoxydecyl, methoxyoctadecyl, ethoxyethyl, ethoxybutyl, ethoxyoctyl, ethoxydodecyl, propoxyethyl, propoxybutyl, propoxyheptyl, propoxytetradecyl, ⁇ butoxyethyl, butoxybutyl, butoxyoctyl, butoxydodecyl, butoxyoctadecyl, pentoXyethyl, pentoxybutyl, pentoxydecyl, hexoxyethyl, hexoxyhe
  • N-dimethylaminoethyl N,N,-dipropylaminopropyl, N,N-
  • R represents hydrocarbon groups of one to ten carbon atoms, preferably alkyl, arylalkyl, cycloalkyl, aryl, and alkaryl.
  • R may typically represent methyl, butyl, octyl, benzyl, phenylbutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, butyl phenyl groups, and the like.
  • R stands for a hydroxyl group, an alkoxyl group of one to four carbon atoms, such as methoxyl, ethoxyl, isopropoxyl, or butoxyl, or an alkylamino group in which the alkyl portion contains one to twelve carbon atoms, such as methyl, ethyl, hexyl, octyl, decyl, and dodecyl.
  • D is a divalentchain containing two to .three carbon atoms.
  • the carbon atoms in the D chain may have their remaining valences satisfied by hydrogen. atoms, by alkyl groups whose total carbon atom content is no greater than 18, or by combinations of hydrogen atoms and alkyl groups.
  • D contains two carbon atoms, there are fourvalences to be satisfied by hydrogen atoms, alkyl groups, or combinations thereof. For instance, there may be four hydrogen atoms, four alkyl groups, three hydrogen atoms and one alkyl group, two hydrogen atoms and two alkyl groups, or one hydrogen atom and three alkyl groups.
  • D contains three carbon atoms
  • the alkyl substituents on the carbon atoms of the D chain may have any possible spatial configurations, such as normal, iso, tertiary, and the like. These alkyl substituents may also be straight chained or cyclic. Typical of the alkyl substituents that may be used to satisfy the remaining valences of the carbon atoms in the D chain include methyl, ethyl, propyl, butyl, cyclopentyl, heXyl, cyclohexyl, octyl, decyl, dodecyl, tridecyl, tetradecyl, and octadecyl groups.
  • Illustrative of the compounds that may be employed as reactants in the present invention include 1,4,5 -trimethyl-5 -hydroxy-Z-pyrrolidinone,
  • the present invention involves the hydrogenolysis of specific pyrrolidinones and piperidinones. This method is carried out in the presence of a catalyst.
  • a catalyst Suitable as catalysts are Raney nickel, Raney cobalt, cobalt with ammonia, nickel with ammonia, cobalt-copper, nickel-cobalt, palladium, platinum, rubidium, ruthenium, and the like.
  • the catalyst may be employed in any convenient particle size. Generally, the smaller particle sizes produce the higher yields.
  • the catalyst may be deposited on a carrier material in order to extend and activate it. Suitable for use as a carrier are activated alumina, activated clays, silica gel, charcoal, asbestos, pumice, and the like.
  • Room temperatures and somewhat above, such as 30 C. and above, may be employed when a noble metal is used as the catalyst.
  • temperatures in the range of about 75 to 250 C. are employed with about to 200 C. preferred.
  • An inert, volatile, organic solvent may be desirable, such as hydrocarbons, alcohols, ethers,-
  • the lower alkanols such as methanol or ethanol, are particularly suited for this use.
  • an activating acid such as acetic or hydrochloric may be employed.
  • pressures in the range of atmospheric to 10 atmospheres may be employed.
  • pressures in the range of 10 to 1000 atmospheres or more are used.
  • a preferred way of consummating the instant reaction is to introduce the pyrrolidinone or piperidinone reactant along with a catalyst of the type described heretofore into a pressure retention reac tion vessel and add hydrogen until a certain desired pressure is reached.
  • the reaction vessel or at least the reaction ingredients may be preferably agitated such as by stirring or rotating until a precalculated drop in pressure is observed. This significant drop in pressure indicates that an equivalent amount of hydrogen has reacted.
  • the corresponding 5-a1koxyl and 6-alkoxyl reactants may be derived from their hydroxy counterparts by reaction with an alkanol in the presence of alkali and the S-amino and 6-amino reactants may be obtained from their hydroxyl counterparts by heating with an amine.
  • the product is ob- Example 1 .peridinone from 1-(2-phenylethyl)-6-hydroxy-3,3,6-trimethyl-Z-piperidinone and I-(Z-hydroxypropyl)-5,5,-dimethyl-Z-piperidinone from 1-(2-hydroxypropyl)-5,5-dimethyl-6-hydroxy-2-piperidinone.
  • Example 2 3,5 dimethyl 3 neopentyl-S-hydroxy-2-pyrrolidinone (100 parts), ethanol (60 parts), and Raney nickel (3,5 parts) absorb hydrogen at 140 C. and 1500 p.s.i.g. to give on filtration and evaporation of solvent 3,5-dimethyl-3-neopentyl-Z-pyrrolidinone (93 parts) having a melting point of 80 to 995 C. and a nitrogen content of 7.53% (theoretical for C H NO7.65%). The yield is quantitative. Since the methyl groups in this compound can be either cis or trans to one another, the wide melting point range indicates that a mixture of the two possible racemates is obtained.
  • Example 3 6-hydroxy-5,5-dimethyl-Z-piperidinone parts) and Water (50 parts) and Raney nickel (1 part) are charged to the hydrogenation reactor and heated at 140 to Example 4 2,2dimethyl-4-oxopentanonitrile (71 parts) is added to 0.2 N sodium hydroxide solution (60 parts by volume). The mixture is stirred at to 45 C. for 16 hours. The mixture is transferred to a hydrogenation reaction vessel and Raney nickel (7.5 parts) is added. The mixture is pressurized with hydrogen at 2000 p.s.i.g. during three hours at 100 to 140 C. The reactor is vented, the reaction mixture is filtered and the low boiling materials are removed by stripping under reduced pressure.
  • first crop (54 parts), meltingpoint 89 to 91 C., and second crop (75 parts) represent a yield of 86% of theflproduct, 3,3,5-trimethyl-2- pyrrolidinone.
  • Example 5 To 0.6 N sodium hydroxide (41 parts) is added 3- methyl-4-oxopentanonitrile (56 parts) over a period of minutes. A 17 C. rise in temperature is observed. Sodium hydroxide (1 part) is added after the exothermic reaction has subsided and the reaction mixture is stirred overnight at room temperature. The entire reaction mix ture, methanol (10 parts by volume) and Raney nickel (8 parts), is charged to a hydrogenationreactor and hydrogenated at 2000 p.s.i.g. of hydrogen and 140 C. The theoretical amount ofhydrogen is absorbed. The reactor is vented, catalyst is removed by filtration and the filtrate is distilled. The product has a boiling point of 88 to 92 C. (0.05 mm.
  • Example 6 5-methoxy-3,3,5-trimethyl-2-pyrrolidinone (50 parts), methanol (50 parts by volume), and Raney nickel (2 parts) are charged to a hydrogenation autoclave and pressurized at 1500 p.s.i.g. The tempertaure is held at 120 to 150 C. during the two hours which are required for hydrogenation to proceed to completion as judged by cessation of the fall of pressure. The mixture is cooled, vented, and filtered. The filtrate is stripped of methanol and the residue (which crystallizes on cooling) is recrystallized from heptane to give the product, 3,3,5- trimethyl-2-pyrrolidinone in 92% yield.
  • 4,5-dimethyl-2-pyrrolidinone is made from 5-butoxy-4,5-dimethyl-2-pyrro1idinone;
  • 5,5- dimethyl-Z-piperidinone is made from 6-ethoxy-5,5-dimethyI-Z-piperidinone;
  • S-ethyl-5-butyl-2-piperidinone is made from 6-methoxy-5-ethyl-5-butyl-2-piperidinone;
  • 3,5 dihexyl 3 methyl 2 pyrrolidinone is prepared from 5-propoxy-3,S-dihexyl-Z-methyl-2-pyrrolidinone.
  • Example 7 1 benzyl 5 benzylamino 3,3,5 trimethyl 2 pyrrolidinone parts), methanol parts), and Raney cobalt (10 parts) are shaken in a rocking autoclave under a hydrogen pressure of 1500 p.s.i.g. at 150 C. until no further pressure drop is observed. The mixture is cooled, vented and filtered. The solvent and benzylamine which is formed in the process are removed under reduced pressure. The product, 1-benzyl-3,3,S-trimethyl- 2-pyrrolidinone, has a boiling point of to C. (3 mm. absolute pressure).
  • 1,3 dimethyl 3,5 dihexyl 5 methyl which comprises hydrogenolysis of a compound having the formula in which R is a member of the group consisting of hydrogen, alkyl of one to eighteen carbon atoms, aryl of up to ten carbon atoms, aralkyl of up to eighteen carbon atoms, alkarylalkyl of up to thirty carbon atoms, alkoxyalkyl of three to twenty-four carbon atoms, hydroxyalkyl of two to twelve carbon atoms, and alkylamino- 'alkyl of three to eighteen carbon atoms in which the amino group is non-primary in structure, R is a member from the group consisting of alkyl, arylalkyl, cycloalkyl, aryl, and alkaryl of up to ten carbon atoms, R is a member of the group consisting of hydroxyl, alkoxyl of one to four carbon atoms, and alkylamino in which the alkyl portion
  • a hydrogenolysis catalyst which is a member from the class consisting of Raney nickel, Raney cobalt, cobalt with ammonia, nickel with ammonia, cobalt-copper, nickel-cobalt, palladium, platinum, rubidium, and ruthenium.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

ethyl,
decyl,
.butyl, heptadecoxyethyl,
United States Patent *Gfiiee 3,065,237 Patented Nov. 20, 1962 3,065,237 PROCESS FDR PREPARING PYRROLIDENONES AND PIPEREDHNONES BY HYDROGENDLYSIS Newman M. Bortnick, Oreiand, and Marian F. Fegley,
Mont Clare, Pa assignors to Rohm &:Haas Company, Philadelphia, Pa., a corporation of Delaware No Drawing. Filed st. 13, 1959, Ser. No. 846,0e9 10 Claims, (Cl.,260293.2)
This invention deals With a method for the preparation of specifiopyrrolidinones and piperidinones.
The compounds that are prepared by the present invention may be represented by the formula Thesecompounds are produced by the hydrogenolysis of compounds having the formula The symbol R represents a hydrogen atom, an alkyl group of one to eighteen carbon atoms, an aryl group of up to ten carbon atoms, an aralkyl group of up to eighteen carbon atoms, an alkarylalkyl group of up to thirty carbon atoms, an alkoxyalkyl group of three to twentyfour carbon atoms, a hydroxyalkyl group of two to twelve carbon atoms, and an alkylaminoalkyl group of three to eighteen carbon atoms provided that the amino group is a secondary or tertiary structure, that is non-primary. Alkyl, in the above definition, is to be construed to include cycloalkyl and alkylcycloalkyl Within the range of carbon atoms previously set forth.
Typical R representations are methyl, ethyl, butyl, octyl, decyl, dodecyl, octadecyl, cyclopentyl, cyclohexyl, butylcyclohexyl, octylcyclohexyl, butylcyclohexylethyl, phenyl, naphthyl, benzyl, phenylethyl, phenylbutyl, phenyldodecyl, methylphenyl, ethylphenyl, butylphenyl, octylphenyl, nonylphenyl, decylphenyl, hexadecyiphenyl, octadecylphenyl, methylbenzyl, ethylbenzyl, butylhenzyl,
. octylbenzyl, dodecylbenzyl, butylphenylbutyl, octylphenylethyl, dioctylphenylethyl, dodecylphenyloctyl, methoxymethoxypropyl, methoxyhexyl, methoxydecyl, methoxyoctadecyl, ethoxyethyl, ethoxybutyl, ethoxyoctyl, ethoxydodecyl, propoxyethyl, propoxybutyl, propoxyheptyl, propoxytetradecyl, \butoxyethyl, butoxybutyl, butoxyoctyl, butoxydodecyl, butoxyoctadecyl, pentoXyethyl, pentoxybutyl, pentoxydecyl, hexoxyethyl, hexoxyhexyl, hexoxydodecyl, hexoxyoctadecyl, heptoxyethyl, heptoxyoctyl, octoxyethyl, octoxybutyl, octoxyoctyl, octoxydodecyl, nonoxypropyl, nonoxyheptyl, nonoxytridecoxyethyl, decoxyoctyl, undecoxybutyl, dodecoxypropyl, dodecoxydecyl, dodeoxydodecyl, tridecoxyethyl, tetradecoxypropyl, pentadecoxypentyl, hexadecoxyoctadecoxyethyl, octadecoxyhexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, .hydroxyoctyl, hydroxydecyl, hydroxydodecyl, ethylaminoethyl, propylaminoethyl, butylaminopropyl, octylaminohexyl, hexylarninoctyl, heptylaminopentyl, octylaminooctyl, nonylaminoethyl, ethylaminononyl, decylarninopropyl, propylarninododecyl, dodecylaminoethyl, dodecylaminopropyl, dodecylaminobutyl, dodecylaminohexyl, N-methyl-N-ethylaminoethyl, N-propyl-N-ethylaminoethyl, N-butyl-N-pentylaminoethyl, N- octyl-N-hexylaminobutyl, N-decyl-N-butylaminobutyl, N,
N-dimethylaminoethyl, N,N,-dipropylaminopropyl, N,N-
dicyclohexylaminobutyl, morpholinopropyl and pyrrolidinoethyl.
The symbol R represents hydrocarbon groups of one to ten carbon atoms, preferably alkyl, arylalkyl, cycloalkyl, aryl, and alkaryl. R may typically represent methyl, butyl, octyl, benzyl, phenylbutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, butyl phenyl groups, and the like.
The symbol R stands for a hydroxyl group, an alkoxyl group of one to four carbon atoms, such as methoxyl, ethoxyl, isopropoxyl, or butoxyl, or an alkylamino group in which the alkyl portion contains one to twelve carbon atoms, such as methyl, ethyl, hexyl, octyl, decyl, and dodecyl.
D is a divalentchain containing two to .three carbon atoms. The carbon atoms in the D chain may have their remaining valences satisfied by hydrogen. atoms, by alkyl groups whose total carbon atom content is no greater than 18, or by combinations of hydrogen atoms and alkyl groups. When D contains two carbon atoms, there are fourvalences to be satisfied by hydrogen atoms, alkyl groups, or combinations thereof. For instance, there may be four hydrogen atoms, four alkyl groups, three hydrogen atoms and one alkyl group, two hydrogen atoms and two alkyl groups, or one hydrogen atom and three alkyl groups. When D contains three carbon atoms, there are six valences to be satisfied by hydrogen atoms, alkyl groups, or combinations thereof and these valences may be satisfied in a way analogous to the manner described above when D contains two carbon atoms. It is also possible for the above-mentioned alkyl substituents to be joined together to form carbocyclic rings in conjunction with the D chain.
The alkyl substituents on the carbon atoms of the D chain may have any possible spatial configurations, such as normal, iso, tertiary, and the like. These alkyl substituents may also be straight chained or cyclic. Typical of the alkyl substituents that may be used to satisfy the remaining valences of the carbon atoms in the D chain include methyl, ethyl, propyl, butyl, cyclopentyl, heXyl, cyclohexyl, octyl, decyl, dodecyl, tridecyl, tetradecyl, and octadecyl groups.
Illustrative of the compounds that may be employed as reactants in the present invention include 1,4,5 -trimethyl-5 -hydroxy-Z-pyrrolidinone,
1, 3,5-trirnethyl-3- 2,2-dimetl1ylpropyl -5-methoXy-2- pyrrolidinone,
1,3-dimethyl-3,S-dihexyl-S-rnethyl-amino-Z-pyrrolidinone,
7 a-hydroxyl -methyl-3, 3-pentamethylene-2, 3,3 a,4, 5, 6,7,
7a-octahydroindol-Z-one,
1ethyl-3,3,5-trimethyl-5 Z-ethylhexoxy) -2-pyrrolidinone,
1ethyl-3-methyl-3,S-dipropyl-5-hydroxy-Z-pyrrolidinone,
3-butoxy-2-ethyl-3 ,7a-dimethyll ,3,3a,4,5,6,7,7a-octahydroisoindoll-one,
1 2-ph enylethyl) 3,3,5-trimethyl-S-hydroxy-Z-pyrrolidinone,
1- Z-dirnethylaminoethyl -3 ,3,5-trimethyl-5- Z-dimethylaminoethyl amino) -2-pyrrolidinone,
1 Z-methylarninopropyl) -3, 3 ,5 rtrimethyl-5 -hydroxy;2-
pyrrolidinone,
3, 3 ,5 -trimethyl-5 -hydroxy-2-pyrrolidinone,
3 ,5-dimethyl-3 -neop entyl-5-hydroxy-2-pyrro1idinone,
1- Z-methyl-Z-propylaminopropyl) -3 ,5-dihexyl-3-methyl- S-methoxy-2 pyrrolidinone,
7a-methoxy- 1 3 dimethylaminopropyl -3 ,3-pentamethylene-2,3 3 a,4,5,6,7,7a-octahydroindol-2-one,
l- 4-diethylaminophenyl) -3, 3,5 -trimethyl-5 -hydroxy-2- pyrrolidinone,
3 ,5 -dihexyl-3-r nethyl-5 -methoxy-2-pyrrolidinone,
1- 4-dimethylaminophenyl -3,3,S-trimethyl-S-hydroxyl-pyrrolidinone,
1-benzyl-3,3 ,5 -trimethyl- -hydroxy-2-pyrrolidinone,
1-p-tolyl-3 ,3,5-trimethyl-5-hydroxy-Z-pyrrolidinone,
1, 3,3,5 -tetrarnethyl-5 -methylamino-2-pyrrolidinone,
1-( 3-dimethylaminopropyl -3 ,5 -dimethyl-3-neopentyl-5 hydroxy-Z-pyrrolidinone,
1- 3-methoxypropyl) -3, 3,5 -trimethyl-5 -hydroxy-2-pyrrolidinone,
1-(2-hydroxyethy1) -3 ,3 ,5 -trimethyl-5 Z-hydroxyethylamino) -2-pyrrolidinone,
1-( Z-hydroxypropyl -3,3,5-trimethyl-5- (Z-hydroxypropylamino) -2-pyrrolidinone,
1- 3-hydroxypropyl -3 ,5 -dimethyl-3-ethyl-5 B-hydroxypropylamino -2-pyrro1idinone,
1- 2-hydroxyethyl) 3,5 -di- 2methylpropyl -3-methyl-5- Z-hydroxyethylarnino) -2-pyrrolidinone,
7a- 2- 2-hydroxyethylamino ethylamino] -3 ,3 ,6-trimethyl-2,3, 3a,4,5,6,7,7a-octahydroindol-Z-one,
- 1- Z-diethylaminoethyl -3 ,3,5-trimethyl-5- Z-diethylaminoethylamino) -2-pyrrolidinone,
1- (Z-methylaminoethyl -3,5-dimethyl-3-heXyl-5-hydroxy- 2-pyrrolidinone,
1- (2-butylaminopropyl -3 ,3,S-trimethyl-S-hydroxy-Z- pyrrolidinone,
spiro{3,3-dimethylbicyclo(2.2.1)heptane-2,3'-[5'-methyl- 5 -methoxy-2'-pyrrolidinone] 1-butyl-3,3 ,S-trimethyl-S-butylamino-2-pyrro1idinone,
1-dodecyl-3 3,5 -trimethyl-5 -hydroxy-2pyrrolidinone,
1-phenyl-3,3,5-trimethyl-5-methoxy-2-pyrrolidinone,
1-butyl-3 ,5 -dibutyl-3-methyl-5 -butylamino-2-pyrrolidinone,
1-benzyl-3,5-dibutyl-3-methyl-5-benzylamino-2-pyrrolidinone,
1,4,6-trimethyl-6-methylamino-2-piperidinone,
1,3 ,6-trimethyl-3- (2,2-dimethylpropyl -6-hydroxy-2-piperidinone,
1,3-dimethyl-3,6-dihexyl-6-methylamino-2-piperidinone,
l-ethyl-3,3,6-trimethyl-6-ethylamino-Z-piperidinone,
methyl-3,6-dipropyl-6-hydroxy-2-piperidinone,
1-( 2-phenylethyl -3 ,3,6-trimethyl-6-hydroXy-2-piperidinone,
1- Z-dimethylaminoethyl -3,3,6-trimethyl-6-hydroxy-2- piperidinone,
3,3 ,6-trimethyl-6-hydroXy-2-piperidinone,
1- 6-diethylaminohexyl) -3 ,3,6-trimethyl-6-methoxy-2- piperidinone,
1- Z-butylaminoethyI) -3,6-dimethyl-3-neopentyl-6-hydroxy-Z-pip eridinone,
3,6-dihexyl-3-methyl-6-hydroxy-2-piperidinone,
1- (Z-diethylaminophenyl) -3,3,6-trimethyl-6-methoxy-2- piperidinone,
1- 3-diethylamino-4-methylphenyl) -4,6-dihexyl-4-methyl- 6-ethoxy-2-pip eridinone,
5,5-dimethyl-6-methoxy-2-piperidinone,
l-benzyl-S ,5 ,6-trimethyl-6-benzylamino-2-piperidinone,
1-p-tolyl-3,3 ,6-trimethyl-6-hydroXy-2-piperidinone,
1 ,5 ,5 -trimethyl-6-methylamino-Z-piperidinone,
1-( 3-dimethylaminopropyl) -4,6-dimethyl-4-neopentyl-6- methoxy-Z-piperidinone,
1-( 3-methoxypropyl) -4,4,6-trimethyl-6- 3-methoxypropylamino -2-piperidinone,
1- 2-hydroxyethyl -5 ,5 ,6-trimethyl-6- (2-hydroxyethylamino) -2-piperidinone,
1-( Z-hydroxypropyl -5, 5-dimethyl-6-hydroxy-2-piperidinone,
5 ,5 -dimethyl-4-ethyl-6-hydroxy-2-piperidinone,
1- (2-hydroxyethyl) -3 ,6-di- Z-methylpropyl) -3-methyl-6- methoxy-Z-piperidinone,
1- 2-diethylaminoethyl -5 ,5 -dimethyl-6-hydroxy-2-piperidinone,
1- 2-methylaminoethyl) 3 ,4-dimethyl-3 -hexyl-6-hydroxy- Z-piperidinone,
5 ,5-dimethy1-6-hydroxy-2-piperidinone,
spiro{3,3-dimethylbicyclo-(2.2.1)heptane2,3-[6'-methyl-6-hydroxy-2'-piperidinone] A 1-butyl-3,4,4-trimethyl-6-hydroxy-2-piperidinone, 1-dodecyl-3,5,5-trimethyl-6-butylamino-Z-piperidinone, 1-phenyl-3 ,5 ,5 -trimethyl-6-hydroxy-2-piperidinone, 1-butyl-3 ,5 -dibutyl-6-methyl-6-methoxy-2-piperidinone, and 1-benzyl-3,6-dibutyl-S-methyl-6-hydroXy-2-piperidinone.
The present invention involves the hydrogenolysis of specific pyrrolidinones and piperidinones. This method is carried out in the presence of a catalyst. Suitable as catalysts are Raney nickel, Raney cobalt, cobalt with ammonia, nickel with ammonia, cobalt-copper, nickel-cobalt, palladium, platinum, rubidium, ruthenium, and the like. The catalyst may be employed in any convenient particle size. Generally, the smaller particle sizes produce the higher yields. If desired, the catalyst may be deposited on a carrier material in order to extend and activate it. Suitable for use as a carrier are activated alumina, activated clays, silica gel, charcoal, asbestos, pumice, and the like. Room temperatures and somewhat above, such as 30 C. and above, may be employed when a noble metal is used as the catalyst. When the other materials are employed as catalysts, temperatures in the range of about 75 to 250 C. are employed with about to 200 C. preferred. An inert, volatile, organic solvent may be desirable, such as hydrocarbons, alcohols, ethers,-
and the like. The lower alkanols, such as methanol or ethanol, are particularly suited for this use. When the noble metals are used as catalysts, a small amount of an activating acid, such as acetic or hydrochloric may be employed.
When a noble metal is employed as the catalyst, pressures in the range of atmospheric to 10 atmospheres may be employed. When the other listed substances are used as catalysts, pressures in the range of 10 to 1000 atmospheres or more are used. A preferred way of consummating the instant reaction is to introduce the pyrrolidinone or piperidinone reactant along with a catalyst of the type described heretofore into a pressure retention reac tion vessel and add hydrogen until a certain desired pressure is reached. The reaction vessel or at least the reaction ingredients may be preferably agitated such as by stirring or rotating until a precalculated drop in pressure is observed. This significant drop in pressure indicates that an equivalent amount of hydrogen has reacted. This precalculated pressure drop indicating that an equivalent amount of hydrogen has reacted is readily calculable by known methods. Therefore, an indication of reaction completion may be readily calculated and observed. The actual time for total reaction will, of course, vary depend ing, more or less, upon reaction conditions and the individual reactants employed.
The piperidinone and pyrrolidinone reactants employed in the present process may be obtained by cyclization of 'yand .a-oxonitriles. It is possible to start with 'yand 6 oxonitriles and, by cyclization and hydration employing aqueous amines, obtain the corresponding 5-hydroXy-2= pyrrolidinone and 6-hydroxy-2-piperidinone reactants; The corresponding 5-a1koxyl and 6-alkoxyl reactants may be derived from their hydroxy counterparts by reaction with an alkanol in the presence of alkali and the S-amino and 6-amino reactants may be obtained from their hydroxyl counterparts by heating with an amine. Hydrogenolysis of any of these leads to the corresponding 2-pyrrolidinones and Z-piperidinones as described heretofore. Thus, it is possible to go from the y-oxonitriles and 6- oxonitriles to the Z-pyrrolidinones and Z-piperidinones in a rather continuous way without the necessity of separating or purifying the S-hydroxy-Z-pyrrolidinones or 6-hydroxy-2-piperidinones. It is, of course, generally desirable, from the viewpoint of yields, to employ as reactants the specific pyrrolidinones and piperidinones discussed heretofore. The products obtained have known utilities.
At the conclusion of the reaction, the product is ob- Example 1 .peridinone from 1-(2-phenylethyl)-6-hydroxy-3,3,6-trimethyl-Z-piperidinone and I-(Z-hydroxypropyl)-5,5,-dimethyl-Z-piperidinone from 1-(2-hydroxypropyl)-5,5-dimethyl-6-hydroxy-2-piperidinone.
Example 2 3,5 dimethyl 3 neopentyl-S-hydroxy-2-pyrrolidinone (100 parts), ethanol (60 parts), and Raney nickel (3,5 parts) absorb hydrogen at 140 C. and 1500 p.s.i.g. to give on filtration and evaporation of solvent 3,5-dimethyl-3-neopentyl-Z-pyrrolidinone (93 parts) having a melting point of 80 to 995 C. and a nitrogen content of 7.53% (theoretical for C H NO7.65%). The yield is quantitative. Since the methyl groups in this compound can be either cis or trans to one another, the wide melting point range indicates that a mixture of the two possible racemates is obtained.
In like manner, are prepared 1-(2-methylaminoethyl) 3,5-dimethyl-3-hexyl-2-pyrrolidinone from 1-(2-methylaminoethyl) 3,5 dimethyl-3-hexyl-5-hydroxy-2-pyrro1idinone and spiro{3,3-dimethy1bicyclo(2.2.l)heptane-2,3 [5-methyl-2'-pyrrolidinonel} from spir{3,3-diemthylbicyclo (2.2.1 heptane-2,3, -methyl-5-hydroxy-2-pyrro1idinone1}.
Example 3 6-hydroxy-5,5-dimethyl-Z-piperidinone parts) and Water (50 parts) and Raney nickel (1 part) are charged to the hydrogenation reactor and heated at 140 to Example 4 2,2dimethyl-4-oxopentanonitrile (71 parts) is added to 0.2 N sodium hydroxide solution (60 parts by volume). The mixture is stirred at to 45 C. for 16 hours. The mixture is transferred to a hydrogenation reaction vessel and Raney nickel (7.5 parts) is added. The mixture is pressurized with hydrogen at 2000 p.s.i.g. during three hours at 100 to 140 C. The reactor is vented, the reaction mixture is filtered and the low boiling materials are removed by stripping under reduced pressure. The
residue is dissolved in benzene and filtered to remove inorganic salts. The combined first crop (54 parts), meltingpoint 89 to 91 C., and second crop (75 parts) represent a yield of 86% of theflproduct, 3,3,5-trimethyl-2- pyrrolidinone.
Example 5 To 0.6 N sodium hydroxide (41 parts) is added 3- methyl-4-oxopentanonitrile (56 parts) over a period of minutes. A 17 C. rise in temperature is observed. Sodium hydroxide (1 part) is added after the exothermic reaction has subsided and the reaction mixture is stirred overnight at room temperature. The entire reaction mix ture, methanol (10 parts by volume) and Raney nickel (8 parts), is charged to a hydrogenationreactor and hydrogenated at 2000 p.s.i.g. of hydrogen and 140 C. The theoretical amount ofhydrogen is absorbed. The reactor is vented, catalyst is removed by filtration and the filtrate is distilled. The product has a boiling point of 88 to 92 C. (0.05 mm. absolute pressure), and n value of 1.4701, and is obtained in 63% yield. The product contains 12.10% nitrogen (theoretical for The procedures of Examples 4 and 5 are very useful methods applicable to a wide variety of hydroxylactarns and their parent 7- and fi-ketonitriles. Thus, fiollowing the procedure of Example 4, 1-(2-oxocyclohexyl)-cyclohexanecarbonitrile gives 3,3-pentamethylene-2,3,3a,4,5,6,7, 7a octahydroindol-Z-one, 2-acetylcylohexanecarbonitrile gives 3 methyl-1,3,3a,4,5,6,7,7a-octahydro-l-isoindolone, 4-methyl-5-oxohexanonitrile gives 5,6-dimethyl-2-piperidinone, 4-oxopentanonitrile gives S-methyl-Z-pyrrolidinone, Z-oxo ct,ot 4-trimethylcyclohexaneacetonitrile gives 3,3,6 trimethyl 2,3,3a,4,5,6,7,7a-0ctahydro'2-indolone, and 1,3,3-trimethyl-5-oxycyclohexanecarbonitrile gives 6-aza-7-oxo-1,3,3-trimethylbicyclo( 3 .2. 1 octane.
Example 6 5-methoxy-3,3,5-trimethyl-2-pyrrolidinone (50 parts), methanol (50 parts by volume), and Raney nickel (2 parts) are charged to a hydrogenation autoclave and pressurized at 1500 p.s.i.g. The tempertaure is held at 120 to 150 C. during the two hours which are required for hydrogenation to proceed to completion as judged by cessation of the fall of pressure. The mixture is cooled, vented, and filtered. The filtrate is stripped of methanol and the residue (which crystallizes on cooling) is recrystallized from heptane to give the product, 3,3,5- trimethyl-2-pyrrolidinone in 92% yield.
In a similar manner, 4,5-dimethyl-2-pyrrolidinone is made from 5-butoxy-4,5-dimethyl-2-pyrro1idinone; 5,5- dimethyl-Z-piperidinone is made from 6-ethoxy-5,5-dimethyI-Z-piperidinone; S-ethyl-5-butyl-2-piperidinone is made from 6-methoxy-5-ethyl-5-butyl-2-piperidinone; and 3,5 dihexyl 3 methyl 2 pyrrolidinone is prepared from 5-propoxy-3,S-dihexyl-Z-methyl-2-pyrrolidinone.
Example 7 1 benzyl 5 benzylamino 3,3,5 trimethyl 2 pyrrolidinone parts), methanol parts), and Raney cobalt (10 parts) are shaken in a rocking autoclave under a hydrogen pressure of 1500 p.s.i.g. at 150 C. until no further pressure drop is observed. The mixture is cooled, vented and filtered. The solvent and benzylamine which is formed in the process are removed under reduced pressure. The product, 1-benzyl-3,3,S-trimethyl- 2-pyrrolidinone, has a boiling point of to C. (3 mm. absolute pressure). The same product is formed when 5 hydroxy 3,3,5 trimethyl 1 benzyl 2 pyrrolidinone is hydrogenated in aqueous medium in the presence of Raney nickel. In a similar fashion, S-methylamino-1,3,3,5-tetramethyl-2-pyrrolidinone gives 1,33,5- tetramethyl-Z-pyrrolidinone.
Similarly, 1,3 dimethyl 3,5 dihexyl 5 methylwhich comprises hydrogenolysis of a compound having the formula in which R is a member of the group consisting of hydrogen, alkyl of one to eighteen carbon atoms, aryl of up to ten carbon atoms, aralkyl of up to eighteen carbon atoms, alkarylalkyl of up to thirty carbon atoms, alkoxyalkyl of three to twenty-four carbon atoms, hydroxyalkyl of two to twelve carbon atoms, and alkylamino- 'alkyl of three to eighteen carbon atoms in which the amino group is non-primary in structure, R is a member from the group consisting of alkyl, arylalkyl, cycloalkyl, aryl, and alkaryl of up to ten carbon atoms, R is a member of the group consisting of hydroxyl, alkoxyl of one to four carbon atoms, and alkylamino in which the alkyl portion contains one to twelve carbon atoms, and D is an alkylene chain containing two to three carbon atoms between the carbon atoms to which said D is attached, the remaining valences of said two to three carbon atoms of said D are satisfied by members of the group consisting of hydrogen atoms, alkyl groups having a total carbon atom content of up to eighteen and combinations of said hydrogen atoms and said alkyl groups, by reaction with substantially one equivalent of hydrogen at a temperature of at least about 30 C. in the presence of a hydrogenolysis catalyst which is a member from the class consisting of Raney nickel, Raney cobalt, cobalt with ammonia, nickel with ammonia, cobalt-copper, nickel-cobalt, palladium, platinum, rubidium, and ruthenium.
2. A method according to claim 1 in which D is a divalent chain containing two carbon atoms.
3. A method according to claim 1 in which D is a divalent chain containing three carbon atoms.
4. A method according to claim 1 in which the hydrogenolysis agent is a noble metal and the reaction is conducted at a pressure of from atmospheric to ten atmospheres.
5. A method according to claim 1 in which the reaction is conducted at a temperature of to 250 C. and at a pressure of at least 10 atmospheres.
6. A method according to claim 1 in which the reaction is conducted in the range of to 200 C. and at 10 to 1000 atmospheres of pressure.
7. A method according to claim 4 in which the reaction is conducted in the presence of an activating acid for a noble metal hydrogenolysis agent which is a member from the class consisting of acetic acid and hydrochloric acid.
8. A method according to claim 1 in which the reaction is conducted in the presence of an inert volatile organic solvent.
9. A method according to claim 1 in which the hydrogenolysis agent is Raney nickel.
10. A method according to claim 1 in which the hydrogenolysis agent is Raney cobalt.
References Cited in the file of this patent UNITED STATES PATENTS 2,845,431 Lutz et a1 July 29, 1958 FOREIGN PATENTS 1,068,821 France Feb. 10, 1954

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3332938A (en) * 1965-05-11 1967-07-25 Gen Aniline & Film Corp Alkylated lactams and process of preparation
US4211711A (en) * 1977-08-06 1980-07-08 Dynamit Nobel Aktiengesellschaft Method of preparing phthalide
EP0270093A2 (en) * 1986-12-03 1988-06-08 Tanabe Seiyaku Co., Ltd. Lactam derivatives, processes for the preparation thereof, pharmaceutical compositions comprising the same, and the use of such derivatives for the manufacture of a medicament having valuable therapeutic properties
US6066666A (en) * 1995-06-05 2000-05-23 Washington University Anticonvulsant and anxiolytic lactam and thiolactam derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1068821A (en) * 1951-10-05 1954-07-01 Hoffmann La Roche Process for the preparation of piperidiones
US2845431A (en) * 1952-04-22 1958-07-29 Hoffmann La Roche Alkyl-piperidiones and process for the manufacture thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1068821A (en) * 1951-10-05 1954-07-01 Hoffmann La Roche Process for the preparation of piperidiones
US2845431A (en) * 1952-04-22 1958-07-29 Hoffmann La Roche Alkyl-piperidiones and process for the manufacture thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3332938A (en) * 1965-05-11 1967-07-25 Gen Aniline & Film Corp Alkylated lactams and process of preparation
US4211711A (en) * 1977-08-06 1980-07-08 Dynamit Nobel Aktiengesellschaft Method of preparing phthalide
EP0270093A2 (en) * 1986-12-03 1988-06-08 Tanabe Seiyaku Co., Ltd. Lactam derivatives, processes for the preparation thereof, pharmaceutical compositions comprising the same, and the use of such derivatives for the manufacture of a medicament having valuable therapeutic properties
FR2607809A1 (en) * 1986-12-03 1988-06-10 Tanabe Seiyaku Co LACTAM DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
EP0270093A3 (en) * 1986-12-03 1989-12-27 Tanabe Seiyaku Co., Ltd. Lactam derivatives, processes for the preparation thereof, pharmaceutical compositions comprising the same, and the use of such derivatives for the manufacture of a medicament having valuable therapeutic properties
US6066666A (en) * 1995-06-05 2000-05-23 Washington University Anticonvulsant and anxiolytic lactam and thiolactam derivatives

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