GB2028307A - Production of pyrrolidin-2-ones and 2-pyrrolin-2-ones - Google Patents

Production of pyrrolidin-2-ones and 2-pyrrolin-2-ones Download PDF

Info

Publication number
GB2028307A
GB2028307A GB7920275A GB7920275A GB2028307A GB 2028307 A GB2028307 A GB 2028307A GB 7920275 A GB7920275 A GB 7920275A GB 7920275 A GB7920275 A GB 7920275A GB 2028307 A GB2028307 A GB 2028307A
Authority
GB
United Kingdom
Prior art keywords
alkyl
aryl
substituted
pyrrolin
pyrrolidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB7920275A
Other versions
GB2028307B (en
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mundipharma AG
Original Assignee
Mundipharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mundipharma AG filed Critical Mundipharma AG
Publication of GB2028307A publication Critical patent/GB2028307A/en
Application granted granted Critical
Publication of GB2028307B publication Critical patent/GB2028307B/en
Expired legal-status Critical Current

Links

Classifications

    • 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
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)

Abstract

A method for the preparation of a substituted pyrrolidin-2-one by the hydrogenation of the corresponding 3- pyrrollin-2-one and a method for the preparation of substituted 3-pyrrolin-2- ones by the ring closure of corresponding N-aroylmethyl-acetamide. The ring closure is effected in basic media under nitrogen.

Description

SPECIFICATION Production of pyrrolidin-2-ones and 3-pyrrolin-2-ones This invention relates to a process for the production of pyrrnlidin-2-ones, and to a process for the production of intermediates useful in this process.
Pyrrolidin-2-ones of the formula, (I):
and the corresponding pyrrolidines of the formula (ill):
in which R1 represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or aroyl; R3 represents hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R4 represents aryl, substituted aryl, alkyl or substituted alkyl; R5 represents hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; and R5 represents hydrogen, alkyl or substituted alkyl, include many known compounds exhibiting interesting CNS activity (Archivum Immunologiae et Therapiae Experimentalis 1975,23,733-751). Many of the compounds of Formula I above exhibit prostaglandin-like activity as described in German Offenlegungsschrift No.
2,527,989.
The pyrrolidin-2-ones (I) have generally been prepared by ring closure of the corresponding 4aminobutyric acid or ester of the formula (III):
and 4-halogeno-butyramide, by reaction of lactones with amines, or hydrolysis of 2-imino-pyrrolidines as described in British Patent No. 1,350,582 and U.S. Patent No. 4,012,495.
These methods of producing compounds of Formula I and II are limited as to efficiency, type of substituents in the various positions and difficulty of producing pure stereo- and optically active isomers.
The present invention therefore provides a process for the preparation of 3-4-cis-su bstituted, optionally optically active, pyrrolidine-2-ones of Formula I, namely:
or after isomerization
by hydrogenation of 3-pyrrolin-2-ones of the formula (V):
in R1, R3, R4, R5 and R5 are as defined above, using the appropriate catalyst, optionally optically active (Angew. Chem. 83, 956 (1971) or a built-in assymmetric centre of C-S of V, during hydrogenation.
One of the major difficulties in the production of the pyrrolidin-2-ones (I) by hydrogenation of the 3.pyrrolin-2-ones (V) is the difficulty of producing 3-pyrrolin-2-ones (V).
The present invention, therefore, further provides a general method of preparing compounds of Formula V, by ring closure of an N-aroylmethyl acetamide of the formula (IV):
to form the corresponding compound of Formula V. This ring closure is accomplished according to the invention under basic conditions, for example in t-butanol with potassium t-butoxide as base under nitrogen followed by acidification with a mineral acid such as HCI and dilution with water, or by ring closure of the corresponding phosphonium bromide (Xill) oftheformula:
the ring closure being effected in basic medium to the corresponding compound of Formula V above.
The following definitions of terms are used herein: Aroyl = Aryl-CO Acyl = Alkyl (minus 1 C)-CO Aryl = phenyl, pyridyl, furyl, thienyl, N-alkyl- or N-aryl-pyrrolyl, and the corresponding benzo derivatives, i.e. naphtyl, quinolyl, etc.
Alkyl = C1 to C16 hydrocarbons Substituents (up to 5 same of mixed) = alkyl, haloalkyl (e.g. F3C), alkyl, N-dialkyl (same and different), S-alkyl, halogen, O-benzyl, N-dibenzyl N-alkyl/ benzyl, S-benzyl, O-aryl, S-aryl, N-diaryl, N-alkyl/benzyl/aryl, OH, NH2, SH (the last three are protected during the basic ring closure) Certain 3-pyrrolin-2-ones (V) are claimed in U.S. Patent No. 3,272,842 and are prepared according to the following sequence:
However R5 and R51 exclude hydrogen and R4 is always S-CH2- (S = substituent). This ring closure of IV with R4 = aryl or substituted aryl and R5 and/or R5 = hydrogen according to the examples of u.S. Patent No.
3,272,842 either does not proceed or yields yellow compounds (probably dimers), which is the result of the difference in substituents i.e. the cited methods were not applicable to our compounds.
3-Pyrrolin-2-ones (V) have been produced (G. Stork and R. Matthews, Chemical Communications 1970, 445-6) in accordance with the following reaction sequence:
However, the use of dicyclohexylcarbodiimide (DCC) for the condensation of the aminoketone derivative (VI) with the unstable phosphonoacetic acid (VII) is unsuitable for large scale syntheses. In addition, the price of DCC is quite high, and the N,N'-dicyclohexylurea is a byproduct which is difficult to remove and makes the process even more uneconomic.
A similar ring closure reaction (T.W. Guntert et al, Helv. Chim. Acta 60, 334-9 (1977)) has been proposed as follows:
however, this process requires repeated chromatographic separation for the isolation of the 3-pyrrolin-2-one (V) with R4 = 17B-steroidyl in 10% yield so that this process too is unsuitable for large scale synthesis, whereas they were unable to prepare the parent bromo compound of IX (corresponding to our XII).
In accordance with the present invention, direct ring closure of compounds of Formula IV can be effective, even for the synthesis of substituted 3-pyrrolin-2-ones (V) most conveniently where the substituents R1 and R3 of (IV) fulfil the following two criteria: (1 ) either R1 H, i.e. R1 = alkyl, substituted alkyl; aryl, substituted alkyl, acyl or aroyl, or (2) if R1 = H, then R3 is a group which stablizes anions at C-3 and is stable to bases, i.e.
aryl, substituted aryl, carbonyl, etc., but not alkyl or hydrogen.
For the production of compounds of Formula V by ring closure in the case where R1 = hydrogen and R3 = hydrogen, alkyl, or substituted alkyl it has been found best to proceed in accordance with the following reaction sequence. Thus, where R4 = aryl substituted aryl, R5 = hydrogen, alkyl or substituted alkyl and P5 = hydrogen, alkyl or substituted alkyl it is possible to react 2-amino-acetophenone (Xl) of the formula:
with a 2-bromo-acyl chloride or bromide to form the corresponding bromo compound (XII) of the formula:
in almost quantitative yield.Unlike the chloro compound 4, the bromo compound XII reacts between room temperature and 50"C with triphenylphosphine, e.g. in benzene or chlorobenzene solution, without decomposition, to form the corresponding phosphonium bromide (XIII) of the formula:
which is sufficiently soluble in alcohols and water for the ring closure reaction to the corresponding compound of Formula V above, e.g. with 2N NaOH solution.
Thus, in accordance with this method, the starting aminoketones (XI) wherein R4 = aryl, substituted aryl, alkyl or substituted alkyl, R5 = hydrogen, alkyl or substituted alkyl, and R5 = hydrogen or alkyl, are generally readily available compounds which can be acylated in practically quantitative yield in weakly basic media, e.g. sodium bicarbonate in an aqueous-ether mixture, with 2-bromoacyl chlorides or bromides to the corresponding N-(2-bromoacyl)-aminoketone (XII) wherein R3 = hydrogen, aryl, substituted aryl, alkyl or substituted alkyl.
The ketones of Formula XII as indicated above react at room temperature with triphenylphosphine, e.g. in benzene solution, to form the corresponding phosphonium bromide XIII which precipitates and can be collected by simple filtration. The solution of XIII in alcohol (preferably methanol) or water, and treatment with more than one equivalent of base (preferable 2N NaOH solution) at room temperature quickly forms the desired 3-pyrrolin-2-one (V) and triphenylphosphine oxide in practically quantitative yield which precipitates from the solution. After dilution with water and evaporation of the alcohol, the mixture is collected and separated by extraction, e.g. with methylene chloride which removes the triphenylphosphine oxide.
The 3-pyrrolin-2-one (V) produced by any of the reactions described above, can easiiy be hydrogenated with, e.g. Pd/C, Pt, or chiral rhodium complexes as catalyst in alcohol (preferably methanol) solution to the CNS active substituted pyrrolidine-2-ones (I-cis). This reaction sequence has the advantage that derivatives are obtained in which R3 and R4 are produced exclusively as cis subsitutuents. The 1This compounds may be converted to the corresponding I-trans compounds by base or acid treatment.
The pyrrolidone-2-ones (I) can be hydrolyzed by strong acid or base treatment to the corresponding 4-amino-butyric acid derivatives Ill accompanied by partial isomerization of the R3 substituent resulting in a diastereoisomeric mixture which can be isolated as salts (e.g. HCI or sodium and magnesium etc.) or as free amino acids. The hydrolysis with R1 = alkyl is incomplete due to the formation of an equilibrium between I and Ill which can be separated by extraction.
An additional advantage of the present invention is that reduction of the new-pyrrolidin-2-ones (I) e.g. with B2H6 or LiAl H4 results in the formation of new pyrrolidines (Il-cis (R3 and R4 cis) or ll-trans (R3 and R4 tanS) ) depending upon the starting material.
The reduction of the C=C double bond in V is easily accomplished with hydrogen and about 5% to 15% of about 10% palladium on charcoal as catalyst. Asymmetric hydrogenation is obtained by chiral rhodium catalysts (e.g. J. Am. Chem. Soc. 1977, 99, 5946-52). Filtration and evaporation ofthe solvent, preferably methanol, directly yields the desired lactams l-cis in quantitative yield. In the case where R1 = benzyl in Formula V the 1This with R1 = hydrogen can be obtained due to hydrogenolysis, i.e. the N-benzyl group has the function of a protecting group in the case where R3 = hydrogen, alkyl, or substituted alkyl.
Hydrolysis of I in refluxing concentrated (15-35%) mineral acids (e.g. HCI) followed by evaporation leads directly to the formation of the corresponding 4-amino-butyric acid hydrochlorides of Formula III in case of HCI. With sulphuric acid, the sulphates may be removed with barium hydroxide solution to obtain the free amino acids of Formula Ill which may be converted to a desired carbonic acid salt (e.g. magnesium) orto an ammonium salt with a therapeutically acceptable acid. On the other hand, hydrolysis with base leads to the corresponding carbonic acid salts (e.g. sodium, potassium).
Reduction of the carbonyl in lactams of Formula I with, e.g., lithium aluminium hydride or boron hydride results in the formation of the corresponding pyrrolidines of Formula II which may be converted to an ammonium salt with a therapeutically acceptable acid.
The following examples are given to illustrate further the invention.
EXAMPLE 1 3,4-Diphenyl-3-pyrrolin-2-one (Va) A solution of 12.6 g (50 mmoles) of 2-phenylacetamido-acetophenone in 200 ml of t-butanol is added to a refluxing solution of potassium t-butoxide prepared from 6.5 g of potassium (166 mmoles) and 200 ml of t-butanol under nitrogen. After 40 min of refluxing the solution is cooled to 400C and acidified with 2N HCI (about 120 ml) to pH 6 to 5. The formed suspension is poured into 31 of ice water. The precipitate is collected and washed with water. After drying 9.85 g (84.1%) of Va with mp 183-90"C are obtained. Extraction of the water with chloroform gave additional 1.3 g (11.1%) of Va. A recrystallized sample from benzene showed mp 177-9 C.The following compounds of structure V were prepared analogously: 3-Phenyl-4-(4'-ch lorophenyl )-3-pyrrolin-2-one (Vb), mp 204-10"C 3-(2'-Carboxyphenyl)-4-phenyl-3-pyrrolin-2-one (Vc), mp 238-41"C 3-Phenyl-4-(4'-fluorophenyl)-3-pyrrolin-2-one (Vd), mp 200-2"C 3-(4'-Fluorophenyl)-4-phenyl-3-pyrrolin-2-one (Ve), mp 199-209"C 3-Phenyl-4-(4'-methylphenyl)-3-pyrrol in-2-one (Vf), mp 210-20"C 3-Phenyl-4-(4'-trifluoromethylphenyl)-3-pyrrolin-2-one (Vg), mp 195-8"C 3-(2'-Fluorophenyl)-4-(4'-trifluoromethylphenyl)-3 pyrrolin-2-one (Vh), mp 165-6 C 1,3,5-Trimethyl-4-phenyl-3-pyrrolin-2-one (Vi), mp 79-81"C 1-Benzyl-4-(4'-trifluormethylphenyl)-3-pyrwlin-2-one (Vk), gum 1 -Benzyl-3-methyl-4-(4'-trifluoromethylphenyl)-3- pyrrolin-2-one (VI), 1 ,5-Dimethyl-3,4-diphenyl-3-pyrrolin-2-one (Vm), mp 95-103 C 1,5-Dimethyl-4-phenyl-3-pyrrolin-2- one (vn), mp 130-5 C 1 -Methyl-3-phenyl-4-(4'-methylphenyl)-3-pyrrolin-2-one (Vo), mp 123-4 C 3-Phenyl-4-(4'-methoxyphenyl)-3-pyrrolin-2-one (Vp), mp 179-81 C 3-Phenyl-4-(3',4' -dimethoxyphenyl )-3-pyrrolin-2-one (Vq, mp 202-4"C 3-(4'Fluorophenyl)-4-(4'-trifluoromethylphenyl)-3 pyrrolin-2-one (Vu), mp 212-3"C EXAMPLE2 cis-3,4-Diphenyl-pyrrolidin-2-one lcis-laJ A solution of 9.00 g of 3,4-diphenyl-3-pyrrolin-2-one (Va) in 200 ml of methanol and 0.90 g of 10% palladium on charcoal are placed into a 500 ml hydrogenation flask and hydrogenated for 16 hr at room temperature. The catalyst is fiitered off and the methanol evaporated in vacuo.Crystallization from benzene-petroieum ether/1 :1 gave crystals with mp 154-5"C. The following compounds were prepared analogously: 3-Phenyl-4-(4'-fl uorophenyl )-pyrrolidin-2-ones (cis-ld), mp 198-200"C 3-(4'-Fluorophenyl)-4-phenyl-pyrrolidin-2-one (cis-le), mp 167-8 C 3-Phenyl-4-(4'-methyl phenyl )-pyrrolidin-2-one (cis-lf), mp 190-1"C 3-Phenyl-4-(4'-trifluoromethylphenyl )-pyrrol idin-2-one (cis-lg), mp 149-51"C 3-(2'-Fluorophenyl)-4-(4'-trifluoromethylphenyl) pyrrolidin-2-one (cis-lh), mp 154-6 C I ,3,5-Trimethyl-4-phenyl-pyrrolidin-2-one (cis-li). gum 4-(4'-Trifluoromethylphenyl)-pyrrolidin-2-one (lK), mp 121-22"C 3-Methyl-4-(4'-trifl uoromethyl phenyl )-pyrrol idin-2-one (cis-lD, 1,5 Dimethyl-4-phenyl-pyrrolidine-2-one (In), gum 1-Methyl-3-phenyl-4-(4'-methylphenyl)-pyrrolidin-2-one (cis-lo), mp 113-4"C 3-Phenyl-4-(4'-methoxyphenyl)-pyrrolidin-2-one (cis-lp), mp 156-9"C 3-Phenyl-4-(3',4'-dimethoxyphenyl)-pyrrnlidine-2-one (cis-lq), mp 144-6"C 3-(4'Fluorophenyl)-4-(4'-trifluoromethylphenyl) pyrrolidin-2-one (cis-lu), mp 203-4"C EXAMPLE3 1,5-Dimethyl-4{4'-nitrophenyl)-pyrrolidin-2-one) (Ir) 4.32 of In are gradually added to 30 ml of fuming nitric acid at to 0 C. After 1 hr at -100C the solution was poured into 300 ml of water. Extraction with ethyl acetate and washing with bicarbonate solution and water gave after evaporation of the solvent 4.89 g (91.6%) of Ir. Crystallization from acetone-etherll :3 gave crystals with mp 94-5"C.
EXAMPLE4 1, 5-Dimeth yI-4-(4'-chlorophenyl)-p yrrolldin-2-one (It) A solution of 4.89 g (20.9 mmoles) of Ir in 50 ml of methanol and 0.49 g of 10% palladium on charcoal are placed into a 250 ml hydrogenation flask and hydrogenated at room temperature for 30 hr. The catalyst is filtered off and the methanol evaporated in vacuo. The resulting 1,5-dimethyl-4-(4'-aminophenyl)-pyrrolidin- 2-one (Is), isolated in 100% yield, is dissolved in 12 ml of 18% hydrochloric acid in a 250 ml beaker and dropwise treated with 5.23 ml of 4N sodium nitrite solution at 0-50C. After 5 min at 0 C the excess nitrite was destroyed with urea.After 10 min at 0-5"C the diazonium solution was added dropwise to a freshly prepared solution of CuCI (20.9 mmoles) in 8 ml of 37% hydrochloric acid at OOC. A brown precipitate forms immediately which is warmed to 60"C for 1 hr. Extraction with chloroform and washing with water gave 4.30 g of crude reaction product after evaporation. After filtration through 130 g of silica gel 3.80 g (81%) of It were recovered as a gum.
EXAMPLE 5 4-Amino-2-phenyl-3-{4'-trifluoromethylphenyl)-butyric acid hydrochloride {Ilig-HCI) 9.15 g of cis-lg are suspended in 300 ml of 25% HCI solution in a 500 ml flask and refluxed for 13 hr. Dilution with 300 ml of water and evaporation in vacuoto dryness gave a crystalline white residue which was suspended in ether overnight to remove any lactam. Filtration and washing with ether gave 9.65 g (89.4%) of Ilig-HClwith mp 182-3 C Analysis calc. for C17H17ClF3NO2-0.S H2O (368.8) found C 55.84% H 4.96% N 3.79% calc.C 55.37% H 4.85% N 3.80% The following acid hydrochlorides were prepared analogously: 4-Amino-2,3-diphenyl-butyric acid - HCI (Illa-HCI, mp 210-22 C 4-Amino-3-(4'-fluorophenyl)-2-phenyl-butyric acid - HCI (Illd-HCI), mp 190-5 C 4-Amino-2-(4'-fluorophenyl)-3-phenyl-butyric acid - HCI (Ille-HCI), mp 170-5 C 4-Amino-3-(4'-methylphenyl)-2-phenyl-butyric acid - HCI (Illf-HCI), m p 210-6OC 4-Amino-2-(2'-fluorophenyl)-3-(4'-trifluoromethylphenyl)- butyric acid - HCI (Ilih-HCI), mp 182-5 C 4Amino-2-(4'-fl uorophenyl )-3-(4'-trif luoromethylphenyl)- butyric acid-HCI (llIu-HCI), mp 200-3 C 4-Amino-3-(4'-trifluoromethylphenyl)-butyric acid - HCI (flIk-HCI), mp 175-77 C 4-Amino-2-methyl-3-(4'-trifluoroemthylphenyl)-butyric acid - HCI (IIII-HCI) 4-Methylamino-4-methyl-3-phenyl-butyric acid - HCI (llIn-HCI), m p 165-75 C 4-Amino-3-(4'-methoxyphenyl-2-phenyl-butyric acid - HCI (Illp-HCI), mp 190-210 C 4-Amino-3-(3',4'-dimethoxyphenyl)-2-phenyl-butyric acid - HCI (Iliq-HCI), mp. 230-3 C.
EXAMPLE 6 3,4Diphenyl-pyrrolidine (lla) A solution of 1.185 g of cis-3,4-diphenyl-pyrrolidin-2-one (la) in 30 ml of tetrahydrofuran (THF) is added slowly to a suspension of 0.950 g of lithium aluminium hydride (LAH) and refluxed for 7 hr. After cooling 5 ml of ethyl acetate are added to destroy the excess of LAH and 7 ml of water to form hydroxides. The suspension is filtered and washed with THF. The THF is removed in vacuo and the residue taken up into chloroform and extracted twice with 50 ml of 2N sulphuric acid. The water phase is treated with 2N NaOH solution until alkaline and extracted with chloroform. Crystallization of the residue from methylene chloride gave crystals with mp 169-72 C. 0.05 ml of 37% HCI solution is added to a solution of 0.100 g of lea dissolved in 3 ml of methanol.Evaporation and suspension in ether gave 0.111 g of IIa-HClwith mp 74-84 C.
EXAMPLE 7 N-[64'-Trifluoromethylbenzoyl)methyl7-2-bromoactamide FXlik) A solution of 51.1 6g (0.609 mole) of sodium bicarbonate in 550 ml of water is added under nitrogen at 0 to 10"C to a two phase solution of 48.5 g (0.203 mole) of 2-amino-4'-trifluoromethylacetophenone hydrochloride (Xlk) in 250 ml of water and 250 ml of ether. A second solution of 18.41 ml (0.223 mole) of bromoacetyl chloride in 200 ml of dry ether is added at 0 to 5 C within 15 min to the above stirred suspension. The initially thick suspension becomes thinner. After 2 hr of stirring ethyl acetate is added until a clear two phase solution is obtained. The water is separated and the ethyl acetate-ether solution washed with water until neutral. Evaporation in vacuo gave 62.3 g (95%) of Xllk. A recrystallized sample had a methoxy point of 201-11"C.
EXAMPLE 8 N-f4'- Trifluoromethylbenzoyl)methyl]-2-(triphenyl-phosphonium bromide)-acetamide (X/llk) 70.5 g (0.269 mole) oftriphenylphosphine are added to a suspension of 62.36 g (0.192 mole) of Xlikin 600 ml of benzene. After 4 days of stirring at room temperature the solid is collected and suspended in 250 ml of acetone for 3 hr. Filtration gave 77.66 g (69%) of Xllk with mp 250-1 C.
EXAMPLE 9 464'-TrifluoromethylphenylJ-3-pyrrolin-2-one (Vk) 72.5 ml of 2N NaOH solution are slowly added under nitrogen to a solution of 77.6 g (0.132 mole) of Xlilkin 780 ml of methanol to keep the temperature below 40"C. After 1 hr of stirring 15 ml of 2N HCI solution are added to reach a pH of about 6.5. The methanol is partially evaporated in vacuo and after the addition of 200 ml of water removed completely. The precipitate is collected and washed with water. After drying the residue, weighing 67.25 g, is suspended in 200 ml of methylene chloride for 2 hr. Filtration gave 27.3 g (91%) of Vkwith mp. 208-20"C (decomposition).
EXAMPLE 10 4-(4- Trffluoromethylphenyl)-pyrrolldin-2-one (1K) A solution of 27.2 g (0.12 mole) of Vk in 500 ml of methanol (partially suspended) is hydrogenated for 10 hr with 4.1 g of 10% Pd on charcoal as catalyst. Filtration and evaporation in vacuo gave 27.5 g (100%) of Ik.A recrystallized (acetone-ether/1 :2) sample has mp 121-2"C.
Analysis (CH1oF3NO): calc. C 57.64% H 4.40% N 6.11% found C 57.65% H 4.38% N 6.35% EXAMPLE 11 4-Amino-3-(4' -trifluoromethylphenyl)-butyric acid - hcl IIllk-HCII 11.45 g (50 mmoles) of 1k are refluxed for 15 hr in 100 ml of 25% HCI solution. After dilution with water and extraction with ether the water phase was evaporated in vacuo. The residue is suspended in little ether and collected: 13.45 g (95%) of Ilik-HCl with mp 175-7"C.
Analysis (C11H13CIF3NO2): calc. C 46.57% H 4.62% N 4.94% found C 46.44% H 4.67% N 5.06%

Claims (14)

1. A method of producing a pyrrolidin-2-one of the formula:
in which R' represents hydrogen, alkyl, substitted alkyl, aryl, substituted aryl, acyl or aroyl; R3 represents hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R4 represents aryl, substituted aryl, alkyl or substituted alkyl, R5 represents hydrogen, alkyl, substituted alkyl, aryl or substituted aryl and R5 represents hydrogen, alkyl or substituted alkyl, which comprises subjecting a 3-pyrrolin-2-one of the formula
in which R1, R3, R4, R5 and R5 are as defined above, to hydrogenation.
2. A method as claimed in Claim 1 in which the hydrogenation is effected using a catalyst to form the 3,4-cis isomer of said pyrrolidin-2-one.
3. A method as claimed in claim 2 in which the catalyst is palladium-carbon, platinum, or rhodium.
4. A method as claimed in Claim 3 in which the catalyst is used in the form of an optically active complex to product the optically active isomer of the cis-pyrrolidin-2-one.
5. A method as claimed in claim 3 or claim 4 in which the cis-isomer is converted to the corresponding trans isomer by acid or base treatment.
6. A process as claimed in claim 1 substantially as herein described with reference to the Examples.
7. A pyrrolidin-2-one when produced by a process as claimed.
8. A method of producing a 3-pyrrolin-2-one of the formula:
in which R' represent hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or aroyl; R3 represents hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R4 represents aryl or substituted aryl; R5 represents hydrogen, alkyl, substituted alkyl, aryl or substituted aryl and B5, represents hydrogen, alkyl or substituted alkyl, one of the substituents R5 and B5, being hydrogen, which comprises subjecting a compound of the formula:
in which R1, R3, R4, R5 and R5, are as defined above to ring closure under basic conditions.
9. A method as claimed in claim 8 in which the ring closure is effected with potassium t-butoxide in t-butanol.
10. A method as claimed in claim 8 or claim 9 in which after the said ring closure, the reaction medium is acidified and diluted with water.
11. A method as claimed in claim 8 substantially as herein described with reference to any of the Examples.
12. A method of producing a 3-pyrrolin-2-one of claim 8, which comprises subjecting a phosphonium bromide of the formula:
in which R1, R3, R4, R5 and R5 are as defined above, to ring closure in basic medium.
15. A medium as claimed in claim 12 substantially as herein described with reference to any of the Examples.
14. A 3-pyrrolin-2-one when prepared by a process as claimed in any of claims 8 to 13.
GB7920275A 1978-06-12 1979-06-11 Production of pyrrolidin-2-ones and 3-pyrrolin-2-ones Expired GB2028307B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US91468278A 1978-06-12 1978-06-12
US1249679A 1979-02-15 1979-02-15

Publications (2)

Publication Number Publication Date
GB2028307A true GB2028307A (en) 1980-03-05
GB2028307B GB2028307B (en) 1983-01-19

Family

ID=26683628

Family Applications (1)

Application Number Title Priority Date Filing Date
GB7920275A Expired GB2028307B (en) 1978-06-12 1979-06-11 Production of pyrrolidin-2-ones and 3-pyrrolin-2-ones

Country Status (19)

Country Link
AR (1) AR222997A1 (en)
AT (1) ATA386679A (en)
AU (1) AU529479B2 (en)
CA (1) CA1108628A (en)
CH (1) CH650772A5 (en)
DE (3) DE2954237C2 (en)
DK (1) DK157847C (en)
ES (1) ES481315A1 (en)
FI (1) FI70209C (en)
FR (1) FR2434151A1 (en)
GB (1) GB2028307B (en)
GR (1) GR68438B (en)
IL (1) IL57266A (en)
IT (1) IT1116891B (en)
NL (1) NL7904584A (en)
NO (1) NO791943L (en)
NZ (1) NZ190705A (en)
PT (1) PT69716A (en)
SE (1) SE431644B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990007499A1 (en) * 1988-12-27 1990-07-12 Ici Americas Inc. Process for the preparation of 3-carboalkoxypyrrolidones
US4943640A (en) * 1983-10-14 1990-07-24 The Dow Chemical Company Preparation of 5-(1-alkyl-carbonyloxy)alkylpyrrolidin-2-one
US5021587A (en) * 1990-01-24 1991-06-04 Petrolite Corporation Synthesis of N,3,4-trisubstituted-3-azoline-2-ones

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3272842A (en) * 1965-06-25 1966-09-13 Lilly Co Eli Novel pyrrolinones
GB1350582A (en) * 1970-07-24 1974-04-18 Ucb Sa Cerivatives of 2-pyrrolidinone
DE2413935A1 (en) * 1974-03-20 1975-10-16 Schering Ag 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4943640A (en) * 1983-10-14 1990-07-24 The Dow Chemical Company Preparation of 5-(1-alkyl-carbonyloxy)alkylpyrrolidin-2-one
WO1990007499A1 (en) * 1988-12-27 1990-07-12 Ici Americas Inc. Process for the preparation of 3-carboalkoxypyrrolidones
US5021587A (en) * 1990-01-24 1991-06-04 Petrolite Corporation Synthesis of N,3,4-trisubstituted-3-azoline-2-ones

Also Published As

Publication number Publication date
IL57266A (en) 1982-12-31
DE2923553C2 (en) 1988-06-01
FR2434151B3 (en) 1982-04-30
IT7949373A0 (en) 1979-06-11
CH650772A5 (en) 1985-08-15
FI791866A (en) 1979-12-13
DE2923553A1 (en) 1979-12-20
GR68438B (en) 1981-12-30
CA1108628A (en) 1981-09-08
AU4767079A (en) 1979-12-20
SE7905079L (en) 1979-12-13
IL57266A0 (en) 1979-09-30
DK241779A (en) 1979-12-13
GB2028307B (en) 1983-01-19
FI70209C (en) 1986-09-15
DK157847C (en) 1990-09-17
NL7904584A (en) 1979-12-14
AR222997A1 (en) 1981-07-15
NZ190705A (en) 1981-10-19
SE431644B (en) 1984-02-20
FR2434151A1 (en) 1980-03-21
DK157847B (en) 1990-02-26
DE2954236C2 (en) 1988-10-06
DE2954237C2 (en) 1989-09-21
PT69716A (en) 1979-07-01
ES481315A1 (en) 1980-08-16
IT1116891B (en) 1986-02-10
ATA386679A (en) 1983-12-15
AU529479B2 (en) 1983-06-09
FI70209B (en) 1986-02-28
NO791943L (en) 1979-12-13

Similar Documents

Publication Publication Date Title
AU592379B2 (en) Preparation of substituted and disubstituted pyridine - 2,3- dicarboxylate esters
US4118417A (en) Process for resolving cis-1-substituted phenyl-1,2-cyclopropanedicarboxylic acids
LU84070A1 (en) PHENYLCYCLOBUTYL DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION
CZ4994A3 (en) Pyrrolidine derivatives, process of their preparation and medicaments in which said derivatives are comprised
KR101159870B1 (en) Process for preparing 2-oxo-1-pyrrolidine derivatives by intramolecular allylation
JP2995704B2 (en) Method for producing optically active 1H-3-aminopyrrolidine compound
EP0385043A1 (en) New derivatives of 4-substituted piperazines
US6110947A (en) Pyrrolidinyl hydroxamic acid compounds and their production process
BG65657B1 (en) Process for preparing amlodipine benzenesulphonate
US4443616A (en) Production of 3-pyrrolin-2-ones
GB2028307A (en) Production of pyrrolidin-2-ones and 2-pyrrolin-2-ones
JPH02306947A (en) Preparation of chiral bata-amino acid
JPH0610192B2 (en) Bi-2H-pyrrole-dione compound
SU882409A3 (en) Method of preparing halogen-substituted mercaptoacylamino acids
US6156908A (en) Procedure for the manufacture of 3-amino-2-oxo-pyrrolidines, new intermediates and their use
CH653996A5 (en) TRYPTAMINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF.
EP0778827B1 (en) Process for producing a beta-amino alcohol
CA1117951A (en) Benzenesulfonamide derivatives and processes for their manufacture
US3038007A (en) Process for the preparation of dl-threonine
US2757177A (en) Basic derivatives of substituted cycloalkanecarboxylic acids and methods of preparing same
KR100228328B1 (en) Process for preparing (2r)-methyl-4,4,4-trifluorobutyl amine or addition salt thereof with acid
SU633478A3 (en) Method of obtaining 1,4-dioxy quinoxaline-2-carboxamide derivatives or salts thereof
Fujisaki et al. Synthesis of N-[2-(1-Piperidinyl) ethyl] benzamides
CA1075713A (en) Process for the preparation of 5-amino-2-propargyloxy-n-n-butylbenzamide
HU202481B (en) Process for producing n-phenyl-n-(methoxyacetyl)-dl-alanine methyl ester derivatives

Legal Events

Date Code Title Description
PCNP Patent ceased through non-payment of renewal fee