WO1990007499A1 - Process for the preparation of 3-carboalkoxypyrrolidones - Google Patents

Process for the preparation of 3-carboalkoxypyrrolidones Download PDF

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Publication number
WO1990007499A1
WO1990007499A1 PCT/US1989/005400 US8905400W WO9007499A1 WO 1990007499 A1 WO1990007499 A1 WO 1990007499A1 US 8905400 W US8905400 W US 8905400W WO 9007499 A1 WO9007499 A1 WO 9007499A1
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Prior art keywords
hydrogen
lower alkyl
proceεε
catalyεt
formula
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PCT/US1989/005400
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French (fr)
Inventor
Frank X. Woolard
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Ici Americas Inc.
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Publication of WO1990007499A1 publication Critical patent/WO1990007499A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention is related to the preparation of 3-carboalkoxypyrrolidones.
  • the primary method for synthesizing pyrrolidone ⁇ used the reduction of a nitro group to an amine to form the 1,2-bond of the pyrrolidone ring.
  • This method precludes the formation of a pyrrolidone ring in which the nitrogen atom is substituted with anything other than hydrogen.
  • To substitute the nitrogen after the ring has been formed involves forcing conditions and the problem that the 3-position of the ring is more reactive.
  • a process has been described (Japanese publication JP 46/24381; CA 75(23):140709m) that allows for the introduction of a variety of substituents on the nitrogen, but it also results in mixtures of two different ring systems.
  • the pyrrolidones that are formed must have the methylene group at the 3-po ⁇ ition oxidized to a carboxylic acid and the carboxylic acid at the 4-position reduced to an alkyl group, a difficult and time-consuming procedure.
  • the process of the present invention provides 3- carboalkoxypyrrolidones by the cyclization of a malonate, followed by reduction with hydrogen in the presence of a noble metal catalyst.
  • this invention is directed to a process for the manufacture of a compound having the formula
  • R is lower alkyl, lower haloalkyl, lower cycloalkyl, lower cycloalkylalkyl, benzyl, chlorobenzyl or the group
  • each of X and Y is independently hydrogen, halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkylsulfinyl, lower haloalkylsulfinyl, lower alkyl ⁇ uIfonyl, lower haloalkylsulfonyl, phenoxy, substituted phenoxy, pyridyloxy, or substituted pyridyloxy; R is hydrogen or lower alkyl, and R is hydrogen or lower alkyl; which process comprises a) reacting a compound having the formula
  • R, R 1 and R 2 are as defined above, with a moderate or a strong base, followed by acidification to give a pyrroliden-2-one of the formula
  • any strong or moderate base which will effect the desired result may be used in the pre ⁇ ent invention.
  • bases are selected from those in the range of pK 9-18 and which are not nucleophilic. Examples include sodium hydride, pyridine and substituted pyridines, tertiary amines such as triethylamine, and the salts of tertiary alcohols such as tert-butoxide.
  • the reaction is preferably run using an excess of the base. While the amount of exce ⁇ is a matter of choice, the reaction may conveniently be run at an excess of up to about 20% of base.
  • the selection of the acid and its amount for the acidification step in reaction a) is any acid and amount which is sufficient to effect spontaneous elimination of water from the intermediate to give the pyrroliden-2-one
  • a noble metal cataly ⁇ t may be chosen from those comprising gold, silver, platinum, iridium, rhodium, ruthenium or palladium chemically bound with other elements in the form of metal-containing compounds, such as salts and oxides.
  • the metal-containing compounds can also be pre ⁇ ent in the form of complexe ⁇ with common complexing agents, examples of which are triphenylpho ⁇ phine and carbon monoxide.
  • the noble metal catalysts are selected from those comprising platinum or palladium. Examples include palladium on carbon and platinum oxide. Platinum oxide is preferred.
  • the noble metal catalysts may be used singly or as mixtures.
  • the noble metal cataly ⁇ t is pre ⁇ ent in the reaction in a catalytic amount.
  • the quantity which will constitute a "catalytic amount” will be any quantity that serves to increase the rate of reaction, with larger quantities providing a greater, increase.
  • the quantity used in any particular application will be determined in large part by the individual needs of the manufacturing facility. Factors which enter into such a determination include the catalyst cost, recovery costs, desired reaction time, and sy ⁇ tem capacity. A ⁇ ide from these con ⁇ ideration ⁇ , the cataly ⁇ t quantity i ⁇ not a critical feature of the invention and can vary over a wide range.
  • the process may successfully be run over a wide range of temperatures.
  • the operating temperature may range from about 10°C to about 40°C.
  • the proce ⁇ does not have a critical operating pre ⁇ ure, but i ⁇ operable over a wide pre ⁇ ure range, subject only to con ⁇ ideration ⁇ of time, economy, proce ⁇ s convenience and materials of construction. It i ⁇ mo ⁇ t convenient, however, to conduct the reaction a) at approximately atmospheric pre ⁇ ure. It i ⁇ mo ⁇ t convenient to conduct the reaction b) at a pressure of from about 0 to about 60 p ⁇ ig, preferably from about 5 to about 60 p ⁇ ig, and more preferably of about 35-55 p ⁇ ig.
  • solvents can be used in the practice of the present invention.
  • Any inert solvent can be used, including, but not limited to the following: aliphatic compound ⁇ , for example hexane or octane; aromatic compound ⁇ , for example benzene, toluene, xylene or me ⁇ itylene; chlorinated aliphatic or aromatic compound ⁇ , for example methylene chloride, ethylene dichloride or chlorobenzene; ethers, for example 1,2-dimethoxyethane, diethyl ether, tetrahydrofuran (THF) or 1,4-dioxane; alcohols, for example isopropanol or ethylene glycol; ketone ⁇ , for example acetone, methyl ethyl ketone or methyl i ⁇ obutyl ketone; amides, for example N,N-dimethylformamide or N-methyl- pyrrolidinone; nitriles, for example acetonitrile or
  • the 3-carboalkoxypyrrolidone ⁇ produced by the reaction of the invention can be recovered from the reaction mixture by any conventional technique.
  • lower alkyl refers to an alkyl group, straight or branched, of one to six carbon atoms.
  • lower cycloalkyl refers to a cycloalkyl group of three to seven carbon atoms.
  • lower cycloalkylalkyl refer ⁇ to a lower alkyl group ⁇ ubstituted with a lower cycloalkyl group, the total number of carbon atoms being from four to eight.
  • lower alkoxy refers to an alkoxy group, straight or branched, of one to six carbon atoms.
  • lower alkylsulfinyl refer ⁇ to an alkyl ⁇ ulfinyl group, ⁇ traight or branched, of one to six carbon atom ⁇ .
  • lower alkyl ⁇ ulfonyl refers to an alkyl ⁇ ulfonyl group, ⁇ traight or branched, of one to six carbon atoms.
  • lower haloalkyl refers to a lower alkyl group, a lower alkoxy group, a lower alkyl ⁇ ulfinyl group, and a lower alkyl ⁇ ulfonyl group, respectively, substituted by one or more halogen atom ⁇ .
  • halogen i ⁇ preferably fluoro.
  • substituted phenoxy and substituted pyridyloxy refer to a phenoxy group and a pyridyloxy group, re ⁇ pectively, ⁇ ub ⁇ tituted at one to five of the carbon atom ⁇ with group ⁇ ⁇ uch as halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy.
  • ⁇ uch halogen i ⁇ conveniently ⁇ elected from bromo, chloro or fluoro.
  • X and Y are ⁇ elected from hydrogen, halogen, C j . ⁇ alkyl, trifluoromethyl, trifluoromethyl- ⁇ ulfinyl, and trifluoromethyl ⁇ ulfonyl.
  • X bromo, chloro, C j . ⁇ alkyl, and trifluoromethyl are preferred, and trifluormethyl i ⁇ more preferred.
  • Y hydrogen and C ⁇ alkyl are preferred, and hydrogen i ⁇ more preferred.
  • R hydrogen and C j . ⁇ alkyl are preferred, and hydrogen, methyl and ethyl are more preferred.
  • R hydrogen and C j . ⁇ alkyl are preferred, and methyl i ⁇ more preferred.
  • the ⁇ tarting malonate of formula II is prepared by the acylation of a ketone of formula IV with an alkyl malonyl chloride of formula V, in the presence of a base ⁇ uch a ⁇ pyridine and at a preferred temperature range of from about 5°C to about 10°C. •NH—CH 2 —C—CH 2 —R (IV)
  • the ketone of formula IV i ⁇ prepared by the reaction of the corre ⁇ ponding alcohol (VI) with a reagent that will form a carbamate.
  • Thi ⁇ can be accompli ⁇ hed with a variety of alkyl chloroformate ⁇ or anhydride ⁇ and i ⁇ preferably conducted with di-t-butyldicarbonate.
  • the reaction can be conducted without ⁇ olvent, at between 80°C and 100°C.
  • the resulting carbamate is then oxidized to the ketone under basic to neutral condition ⁇ u ⁇ ing either aqueous sodium hypochlorite or pyridine dichromate in refluxing methylene chloride.
  • the ketone is treated with anhydrous HC1 gas to give the hydrochloride of the ketone (IV).
  • the alcohol of formula VI i ⁇ known ⁇ ee, e.g. U.S. Patent 4,723,986) or, in tho ⁇ e cases where it may not be known, can be synthesized by procedures known in the art.
  • the ⁇ e example ⁇ are offered ⁇ trictly for purpo ⁇ e ⁇ of illu ⁇ tration, and are not intended to either limit or to define the invention.
  • the ⁇ uspen ⁇ ion was then diluted with 400 mL of ether to precipitate the inorganic salts and wa ⁇ filtered through diatomaceou ⁇ earth. Removal of the ⁇ olvent ⁇ under reduced pre ⁇ sure provided a dark oil that was flash chromatographed on silica gel with ether as eluent. The resulting tan oil was taken up in 400 mL of ether and rapidly stirred, and the ⁇ olution wa ⁇ ⁇ aturated at room temperature with anhydrou ⁇ HC1 gas.
  • EXAMPLE 3 This example illustrates the preparation of l-(3- trifluoromethyl)phenyl-3-carboethoxy-4-ethyl- ⁇ - pyrroliden-2-one.
  • a suspen ⁇ ion of sodium hydride (4.28 g, 0.178 mol) and freshly distilled (from Na/benzophenone) THF (50 L) was stirred, and a solution of crude ethyl N-(3-trifluoro ⁇ methyl)-phenyl-N-(2-oxo)butylmalonate monoamide (43.31 g) in 140 mL of THF was added dropwise at ⁇ uch a rate that the evolution of hydrogen wa ⁇ controlled (ca. 20 min.).
  • EXAMPLE 4 Thi ⁇ example illu ⁇ trate ⁇ the preparation of l-(3- trifluoromethyl)phenyl-3-carboethoxy-4-ethyl-2-pyrrolidone.
  • platinum oxide 250 mg
  • l-(3-trifluoromethyl)phenyl-3-carboethoxy-4- ethyl- ⁇ 3, ⁇ *-pyrroliden-2-one 32.55 g, 99.4 mmol
  • the bottle wa ⁇ placed on a Parr apparatus and evacuated/flushed with hydrogen three times.
  • the hydrogen pre ⁇ ure wa ⁇ adjusted to 50 psi and the flask wa ⁇ ⁇ haken.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The process of the present invention provides 3-carboalkoxypyrrolidones by the cyclization of a malonate, followed by reduction with hydrogen in the presence of a noble metal catalyst. The products are useful as intermediates for pesticides.

Description

PROCESS FOR THE PREPARATION OF 3-CARBOALKOXYPYRROLIDONES
BACKGROUND OF THE INVENTION The present invention is related to the preparation of 3-carboalkoxypyrrolidones.
The compounds to be synthesized, 3-carboalkoxy- pyrrolidoneε of the formula
Figure imgf000003_0001
are useful as intermediates in the preparation of certain pesticides, and more particularly of certain herbicides.
Prior to the present invention, the primary method for synthesizing pyrrolidoneε used the reduction of a nitro group to an amine to form the 1,2-bond of the pyrrolidone ring. This method precludes the formation of a pyrrolidone ring in which the nitrogen atom is substituted with anything other than hydrogen. To substitute the nitrogen after the ring has been formed involves forcing conditions and the problem that the 3-position of the ring is more reactive. A process has been described (Japanese publication JP 46/24381; CA 75(23):140709m) that allows for the introduction of a variety of substituents on the nitrogen, but it also results in mixtures of two different ring systems. In addition, to be useful as herbicide intermediates, the pyrrolidones that are formed must have the methylene group at the 3-poεition oxidized to a carboxylic acid and the carboxylic acid at the 4-position reduced to an alkyl group, a difficult and time-consuming procedure. SUMMARY OF THE INVENTION The process of the present invention provides 3- carboalkoxypyrrolidones by the cyclization of a malonate, followed by reduction with hydrogen in the presence of a noble metal catalyst.
DETAILED DESCRIPTION OF THE INVENTION More particularly, this invention is directed to a process for the manufacture of a compound having the formula
Figure imgf000004_0001
wherein,
R is lower alkyl, lower haloalkyl, lower cycloalkyl, lower cycloalkylalkyl, benzyl, chlorobenzyl or the group
Figure imgf000004_0002
in which each of X and Y is independently hydrogen, halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkylsulfinyl, lower haloalkylsulfinyl, lower alkylεuIfonyl, lower haloalkylsulfonyl, phenoxy, substituted phenoxy, pyridyloxy, or substituted pyridyloxy; R is hydrogen or lower alkyl, and R is hydrogen or lower alkyl; which process comprises a) reacting a compound having the formula
Figure imgf000005_0001
wherein R, R1 and R2 are as defined above, with a moderate or a strong base, followed by acidification to give a pyrroliden-2-one of the formula
Figure imgf000005_0002
and, b) reducing the compound of formula III with hydrogen gas in the presence of a noble metal catalyεt to produce a compound of formula I.
Any strong or moderate base which will effect the desired result may be used in the preεent invention. Such bases are selected from those in the range of pK 9-18 and which are not nucleophilic. Examples include sodium hydride, pyridine and substituted pyridines, tertiary amines such as triethylamine, and the salts of tertiary alcohols such as tert-butoxide. For maximum efficiency, the reaction is preferably run using an excess of the base. While the amount of exceεε is a matter of choice, the reaction may conveniently be run at an excess of up to about 20% of base.
The selection of the acid and its amount for the acidification step in reaction a) is any acid and amount which is sufficient to effect spontaneous elimination of water from the intermediate to give the pyrroliden-2-one
(III).
A noble metal catalyεt may be chosen from those comprising gold, silver, platinum, iridium, rhodium, ruthenium or palladium chemically bound with other elements in the form of metal-containing compounds, such as salts and oxides. The metal-containing compounds can also be preεent in the form of complexeε with common complexing agents, examples of which are triphenylphoεphine and carbon monoxide. Advantageously, the noble metal catalysts are selected from those comprising platinum or palladium. Examples include palladium on carbon and platinum oxide. Platinum oxide is preferred. The noble metal catalysts may be used singly or as mixtures.
The noble metal catalyεt is preεent in the reaction in a catalytic amount. The quantity which will constitute a "catalytic amount" will be any quantity that serves to increase the rate of reaction, with larger quantities providing a greater, increase. The quantity used in any particular application will be determined in large part by the individual needs of the manufacturing facility. Factors which enter into such a determination include the catalyst cost, recovery costs, desired reaction time, and syεtem capacity. Aεide from these conεiderationε, the catalyεt quantity iε not a critical feature of the invention and can vary over a wide range. It will be moεt convenient to uεe an amount of catalyεt which compriεes from about 0.01 to about 20.0 mole percent, preferably from about 0.1 to about 10.0 mole percent based on the pyrroliden-2-one of formula III.
The process may successfully be run over a wide range of temperatures. The operating temperature may range from about 10°C to about 40°C. The proceεε does not have a critical operating preεεure, but iε operable over a wide preεεure range, subject only to conεiderationε of time, economy, proceεs convenience and materials of construction. It iε moεt convenient, however, to conduct the reaction a) at approximately atmospheric preεεure. It iε moεt convenient to conduct the reaction b) at a pressure of from about 0 to about 60 pεig, preferably from about 5 to about 60 pεig, and more preferably of about 35-55 pεig.
A variety of solvents can be used in the practice of the present invention. Any inert solvent can be used, including, but not limited to the following: aliphatic compoundε, for example hexane or octane; aromatic compoundε, for example benzene, toluene, xylene or meεitylene; chlorinated aliphatic or aromatic compoundε, for example methylene chloride, ethylene dichloride or chlorobenzene; ethers, for example 1,2-dimethoxyethane, diethyl ether, tetrahydrofuran (THF) or 1,4-dioxane; alcohols, for example isopropanol or ethylene glycol; ketoneε, for example acetone, methyl ethyl ketone or methyl iεobutyl ketone; amides, for example N,N-dimethylformamide or N-methyl- pyrrolidinone; nitriles, for example acetonitrile or butyronitrile; and carboxylic acids and their esters, for example acetic, propionic or butyric acid or ethyl acetate.
The 3-carboalkoxypyrrolidoneε produced by the reaction of the invention can be recovered from the reaction mixture by any conventional technique.
As used in this specification and the attached claims:
The term "lower alkyl" refers to an alkyl group, straight or branched, of one to six carbon atoms. The term "lower cycloalkyl" refers to a cycloalkyl group of three to seven carbon atoms.
The term "lower cycloalkylalkyl" referε to a lower alkyl group εubstituted with a lower cycloalkyl group, the total number of carbon atoms being from four to eight. The term "lower alkoxy" refers to an alkoxy group, straight or branched, of one to six carbon atoms.
The term "lower alkylsulfinyl" referε to an alkylεulfinyl group, εtraight or branched, of one to six carbon atomε. The term "lower alkylεulfonyl" refers to an alkylεulfonyl group, εtraight or branched, of one to six carbon atoms. The termε "lower haloalkyl", "lower haloalkoxy", "lower haloalkylεulfinyl" and "lower haloalkylεulfonyl" refer to a lower alkyl group, a lower alkoxy group, a lower alkylεulfinyl group, and a lower alkylεulfonyl group, respectively, substituted by one or more halogen atomε. Such halogen iε preferably fluoro.
The termε "substituted phenoxy" and "subεtituted pyridyloxy" refer to a phenoxy group and a pyridyloxy group, reεpectively, εubεtituted at one to five of the carbon atomε with groupε εuch as halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy.
Where any of the εubεtituentε R, X and Y iε or compriεeε halogen, εuch halogen iε conveniently εelected from bromo, chloro or fluoro. Within the εcope of the above deεcription, certain embodimentε are preferred.
In R, the phenyl group εubεtituted with X and Y iε preferred.
Conveniently, X and Y are εelected from hydrogen, halogen, Cj.ή alkyl, trifluoromethyl, trifluoromethyl- εulfinyl, and trifluoromethylεulfonyl. In X, bromo, chloro, Cj.ή alkyl, and trifluoromethyl are preferred, and trifluormethyl iε more preferred. In Y, hydrogen and C^ alkyl are preferred, and hydrogen iε more preferred. In R , hydrogen and Cj.^ alkyl are preferred, and hydrogen, methyl and ethyl are more preferred.
In R , hydrogen and Cj.ή alkyl are preferred, and methyl iε more preferred.
The εtarting malonate of formula II is prepared by the acylation of a ketone of formula IV with an alkyl malonyl chloride of formula V, in the presence of a base εuch aε pyridine and at a preferred temperature range of from about 5°C to about 10°C. •NH—CH2—C—CH2—R (IV)
Figure imgf000009_0001
The ketone of formula IV iε prepared by the reaction of the correεponding alcohol (VI) with a reagent that will form a carbamate. Thiε can be accompliεhed with a variety of alkyl chloroformateε or anhydrideε and iε preferably conducted with di-t-butyldicarbonate. The reaction can be conducted without εolvent, at between 80°C and 100°C. The resulting carbamate is then oxidized to the ketone under basic to neutral conditionε uεing either aqueous sodium hypochlorite or pyridine dichromate in refluxing methylene chloride. The ketone is treated with anhydrous HC1 gas to give the hydrochloride of the ketone (IV).
OH R— H—CH2—C IH—CH2— ΕC2 (VI)
The alcohol of formula VI iε known (εee, e.g. U.S. Patent 4,723,986) or, in thoεe cases where it may not be known, can be synthesized by procedures known in the art. The procesε of the preεent invention iε further illuεtrated by the following exampleε. Theεe exampleε are offered εtrictly for purpoεeε of illuεtration, and are not intended to either limit or to define the invention.
EXAMPLE 1
Thiε example illustrateε the preparation of N-(2- oxo)butyl-3-aminobenzotrifluoride hydrochloride.
A mixture of N-(2-hydroxy)butyl-3-aminobenzotri- fluoride (106.86 g, 0.458 mol) and di-t-butyl dicarbonate (110.0 g, 0.504 mol), under N , was heated on a steam bath with occaεional swirling. After 10 hours, gas evolution had ceaεed. The crude product waε then combined with ether (300 mL), washed with water (3 x 250 mL) and with saturated NaCl solution (1 x 250 mL), and dried over Na2SOή, after which the solvent was removed in vacuo to give N-(2-hydroxy)butyl- N-t-butoxycarbonyl-3-aminobenzotrifluoride (152.73 g, 100%) as a thick colorless oil.
A suspension of pyridinium dichromate (86.14 g, 0.229 mol), methylene chloride (200 mL), trifluoroacetic acid (7.70 g, 4.53 mL, 0.067 mol) and pyridine (4.75 g, 4.86 mL, 0.060 mol) was stirred and heated to a gentle reflux. N-(2-hydroxy)butyl-N-t-butoxycarbonyl-3-aminobenzotri- fluoride (51.0 g, 0.153 mol) in 100 mL of methylene chloride was added dropwise over one hour. When the addition was complete, the refluxing was continued for another 8 hours. The heating waε then diεcontinued and the εtirring waε continued overnight at room temperature. The εuspenεion was then diluted with 400 mL of ether to precipitate the inorganic salts and waε filtered through diatomaceouε earth. Removal of the εolventε under reduced preεsure provided a dark oil that was flash chromatographed on silica gel with ether as eluent. The resulting tan oil was taken up in 400 mL of ether and rapidly stirred, and the εolution waε εaturated at room temperature with anhydrouε HC1 gas. After stirring overnight, the precipitated product waε iεolated by vacuum filtration to yield 30.61 g (75%) of N-(2-oxo)butyl- 3-aminobenzotrifluoride hydrochloride as a white powder, .p. 113°C dec, the εtructure of which waε confirmed by NMR, IR and MS.
EXAMPLE 2
Thiε example illuεtrateε the preparation of ethyl N- (3-trifluoromethyl)phenyl-N-(2-oxo)butylmalonate monoamide. A mixture of N-(2-oxo)butyl-3-aminobenzotri-fluoride hydrochloride (30.61 g, 0.114 mol), benzene (200 mL) and pyridine (20.61 mL, 20.16 g, 0.255 mol) waε εtirred, placed in an ice bath and cooled to 5°C. Ethyl malonyl chloride (27.10 g, 0.180 mol) in 40 mL of benzene was then added at εuch a rate that the temperature did not rise above 10°C. When the addition waε complete, the εuεpension waε poured into 200 mL of water and the layerε were separated. The organic phase was washed with water (3 x 150 mL), with 3% aq. HC1 (1 x 150 mL) and with sat. NaCl solution (1 x 150 mL), and was dried over MgSOή. The solvent was removed under reduced presεure to provide crude ethyl N-(3- trifluoromethyl)phenyl-N-(2-oxo)butylmalonate monoamide (43.31 g, 110%).
EXAMPLE 3 This example illustrates the preparation of l-(3- trifluoromethyl)phenyl-3-carboethoxy-4-ethyl-Δ - pyrroliden-2-one. A suspenεion of sodium hydride (4.28 g, 0.178 mol) and freshly distilled (from Na/benzophenone) THF (50 L) was stirred, and a solution of crude ethyl N-(3-trifluoro¬ methyl)-phenyl-N-(2-oxo)butylmalonate monoamide (43.31 g) in 140 mL of THF was added dropwise at εuch a rate that the evolution of hydrogen waε controlled (ca. 20 min.). When the addition waε complete, the εtirring was continued for an additional 0.5 hour and then cone. HC1 (100 mL) was added dropwise. Water (250 mL) was added, and the crude product waε iεolated by vacuum filtration. Recryεtallization from a minimum volume of methanol gave l-(3-trifluoromethyl)phenyl- 3-carboethoxy-4-ethyl-Δ3'*-pyrroliden-2-one (32.55 g, 87% based on εtarting amount of aminoketone hydrochloride in Example 2) aε thick, colorless prisms, m.p. 120-126°C, the structure of which was confirmed by NMR, IR and MS.
EXAMPLE 4 Thiε example illuεtrateε the preparation of l-(3- trifluoromethyl)phenyl-3-carboethoxy-4-ethyl-2-pyrrolidone. To a hydrogenation bottle waε added platinum oxide (250 mg) and l-(3-trifluoromethyl)phenyl-3-carboethoxy-4- ethyl-Δ3,<*-pyrroliden-2-one (32.55 g, 99.4 mmol) in 150 mL of ethyl acetate. The bottle waε placed on a Parr apparatus and evacuated/flushed with hydrogen three times. The hydrogen preεεure waε adjusted to 50 psi and the flask waε εhaken. Periodically, aε the hydrogen waε conεumed the preεεure waε readjusted to 50 psi. When hydrogen uptake ceased, the catalyεt waε removed by vacuum filtration through a pad of diatomaceouε earth and the ethyl acetate waε removed under reduced preεεure to give l-(3- trifluoromethyl)phenyl-3-carboethoxy-4-ethyl-2-pyrrolidone (32.70 g, 100%) aε a very pale yellow oil, the εtructure of which waε confirmed by'NMR, IR and MS.
Although the preεent invention has been described in some detail by way of example for purposes of clarity and understanding, it will be apparent that other arrangements and equivalents are possible and may be employed without departing from the spirit and scope of the invention.
Therefore, the description and illustrations εhould not be conεtrued aε limiting the εcope of the invention, which iε delineated by the appended claimε.

Claims

WHAT IS CLAIMED IS:
1. A proceεε for the manufacture of a compound having the formula
Figure imgf000013_0001
wherein,
R is lower alkyl, lower haloalkyl, lower cycloalkyl, lower cycloalkylalkyl, benzyl, chlorobenzyl or the group
Figure imgf000013_0002
in which each of X and Y is independently hydrogen, halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkylεulfinyl, lower haloalkylsulfinyl, lower alkylsulfonyl, lower haloalkylεulfonyl, phenoxy, εubεtituted phenoxy, pyridyloxy, or εubεtituted pyridyloxy; R is hydrogen or lower alkyl; and R is hydrogen or lower alkyl; which proceεε compriεeε a) reacting a compound having the formula
Figure imgf000013_0003
wherein R, 1 and 2 are aε defined above, with a moderate or a εtrong baεe, followed by acidification to give a pyrroliden-2-one of the formula
Figure imgf000014_0001
and, b) reducing the compound of formula III with hydrogen gaε in the presence of a noble metal catalyεt to produce a compound of formula I.
2. A proceεε according to Claim 1 wherein εaid noble metal catalyεt compriεeε platinum or palladium.
3. A process according to Claim 2 wherein εaid noble metal catalyεt iε platinum oxide or palladium on carbon.
4. A procesε according to Claim 1 wherein εaid noble metal catalyεt iε preεent in an amount of from about 0.01 to about 20.0 mole percent.
5. A proceεs according to Claim 1 wherein said noble metal catalyεt iε preεent in an amount of from about 0.1 to about 10.0 mole percent.
6. A procesε according to Claim 1 wherein εaid baεe iε not nucleophilic and has a pK in the range of 9-18.
7. A procesε according to Claim 6 wherein εaid baεe iε sodium hydride.
8. A proceεε according to Claim 1 wherein R is the group —- -^X
- P T'
Y , R is hydrogen or lower alkyl
2 of 1 to 4 carbon atoms, and R iε hydrogen or lower alkyl of 1 to 4 carbon atomε.
9. A proceεε according to Claim 8 wherein each of X and Y is independently hydrogen, bromo, chloro, lower alkyl of 1 to 4 carbon'atomε, trifluoromethyl, trifluoromethyl-εulfinyl or trifluoromethylsulfonyl.
10. A procesε according to Claim 9 wherein X iε trifluoromethyl and Y iε hydrogen.
11. A proceεε according to Claim 10 wherein R iε
2 hydrogen, methyl or ethyl and R iε methyl.
PCT/US1989/005400 1988-12-27 1989-11-29 Process for the preparation of 3-carboalkoxypyrrolidones WO1990007499A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2028307A (en) * 1978-06-12 1980-03-05 Mundipharma Ag Production of pyrrolidin-2-ones and 2-pyrrolin-2-ones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2028307A (en) * 1978-06-12 1980-03-05 Mundipharma Ag Production of pyrrolidin-2-ones and 2-pyrrolin-2-ones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Organic Chemistry, Vol. 31, No. 8, 12 August 1966 (Easton, US) R.D. DILLARD et al.: "Acetylenic Amines. XIII. Syntheses of 3-Carboxy-3- Pyrrolin-2-Ones", pages 2580-2584 see the whole article *

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