LV13631B - Manufacturing method of n-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone - Google Patents

Manufacturing method of n-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone Download PDF

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LV13631B
LV13631B LV060046A LV060046A LV13631B LV 13631 B LV13631 B LV 13631B LV 060046 A LV060046 A LV 060046A LV 060046 A LV060046 A LV 060046A LV 13631 B LV13631 B LV 13631B
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pyrrolidinone
phenyl
organic solvent
suitable organic
haloacetic
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LV060046A
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Latvian (lv)
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Grigorijs Veinbergs
Maksims Vorona
Antons Lebedevs
Aleksandrs Cernobrovijs
Ivars Kalvins
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Olainfarm As
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Priority to LV060046A priority Critical patent/LV13631B/en
Priority to PCT/EP2007/052428 priority patent/WO2007104781A2/en
Priority to EA200801977A priority patent/EA015420B1/en
Publication of LV13631B publication Critical patent/LV13631B/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
    • C07D207/263—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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for the preparation of R-enantiomer of N-carbamoylmethyl-4-phenyl-2-pyrrolidinone by the N-alkylation of 4(R)-phenyl-2-pyrrolidinone with haloacetic acid ester and the following conversion of intermediate N-alkoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone into target product by the treatment with ammonia.

Description

LV 13631 b.
Manufacturing method of N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidinone
Background of the invention.
The invention relates to the methods of preparation of new N-carbamoyImethyl-4-phenyl-2-5 pyrrolidinone derivative, more particularly, to the preparation of N-carbamoylmethyI-4(i?)~ phenyl-2-pyrrolidinone (i?-phenotropil) which according to our special investigation represents biologically active part of a known racemic phenotoropil molecule, which significantly exceeds pharmacological properties of racemic phenotropil itself and especially its S-enantiomeric counterpart. 10 Therefore the elaboration of the manufacturing method for this substance opens way to its introduction in medicine as a new effective pharmaceutical aģent.
Description of the prior art
Several methods of the preparation of racemic N-carbamoylmethyl-4-phenyl-2-pyrrolidinone 15 are documehted in literature. They are based on the alkylation of racemic 4-phenyl-2-pyrrolidinone with chloro or bromoacetic acid esters and on the following ammonolysis of intermediate N-alkoxycarbonylmethyl-4-phenyl-2-pyrrolidinone with ammonia in gaseous or in water solution form [1-6]. 20 Summary of the invention
An object of present invention is to provide a process for the production of optically pure R-enantiomer of N-carbamoylmethyl-4-phenyl-2-pyrrolidinone with commercial advantages in a simple and easy manner. After extensive investigations we discovered, that TTphenotropil 5 can be produced from easily available optically active 4(7?)-phenyl-2-pyrrolidinone (1) as 25 starting material, which could be obtained by various Chemical and enzymatic methods [7-14], according to the Scheme 1.
The substitution of amide proton in 4(7?)-phenyl-2-pyrrolidinone (1) with mētai ion or trimethylsilyl group facilitates the N-alkylation of pyrrolidinone intermediate 2 with haloacetic acid esters 3. Thus obtained N-alkoxycarbonylmethyl-4(7?)-phenyl-2-pyrrolidinone (4) was 30 converted into target N-carbamoylmethyl-4(/?)-phenyl-2-pyrrolidinone (5) by the treatment with ammonia.
Scheme 1. HNa
Me3SiCI or \Me3SiNHSiMe3 /
Ph 'N H 1
Ph* _ HalCH2COOR t>0—
N
X 2 ►
NH3 -►
Ph
I >=o L CONH2 X=Na, K, Me3Si; Hal=CI, Br; R=Me, Et 5
Detailed description of the invention
According to the invention a process for the preparation of optically pure N-carbamoylmethyl-4(7?)-phenyl-2-pyrrolidinone (5) is provided by: 10 1. The substitution of hydrogen in the amide group of enantiomeric 4(7?)-phenyl-2-pyrrolidinone (1), with mētai ion or trialkylsilyl group in a suitable organic solvent; preferred reaction conditions for this reaction include: a) representation of mētai ion with sodium and potassium atoms; b) representation of trialkylsilyl group with trimethylsilyl group; 15 c) the introduction of mētai ion into i?-pyrrolidinone 1 by the reaction of latter with bases such as sodium hydride or potassium hydroxide in temperature range between 20^130°C in a suitable organic solvent; d) N-trimethylsilylation of 4(i?)-phenyl-2-pyrrolidinone (1) with chlorotrimethylsilane or hexamethyldisilazane in temperature range betvveen 40-^150¾ in a suitable organic solvent; 20 e) organic solvents: hydrocarbons such as hexane, benzene, toluene; halogenated hydrocarbons such as chloroform, methylene chloride; esters such as ethyl acetate; ethers such as l,4-dioxane are employed for reaction purposes. 2. The N-alkylation of N-metallated or N-silylated intermediates 2 with haloacetic acid ester 3, wherein Hal is chlorine or bromine and R is methyl or ethyl, in a suitable organic solvent; 25 LV 13631 preferred reaction conditions for this reaction include: a) N-alkylation of N-metallated pyrrolidinone 2 with haloacetic acid ester 3 in temperature range between 120^180°C in a suitable organic solvent; b) N-alkylation of N-silylated pyrrolidinone 2 with haloacetic acid esters 3 in 5 temperature range between 120-^-180°C in the presence of catalytic amounts of bromotrimethylsilane or trimethylsilyl trifluoromethanesulfonate; c) organic solvents: hydrocarbons represented, but not restricted by such as toluene; ethers represented, but not restricted by such as l,4-dioxane are employed for reaction purposes. 10 3. The carbamoylation of N-alkoxycarbonylmethyl-4(7?)-aryl-2-pyrrolidinone (4) with ammonia in a suitable solvent; preferred reaction conditions for this reaction include: a) the usage of aqueous ammonia; b) the usage of gaseous ammonia in suitable organic solvent; 15 c) solvents employed for reaction purposes are represented, but not restricted by such as alcohols, for example, methanol, ethanol, propanol; halogenated hydrocarbons such as chloroform, methylene chloride; esters such as ethyl acetate. 20 The foIlowing examples are illustrating but not restricting the present invention.
Example 1
The solution of 4(i?)-phenyl-2-pyrrolidinone (345 mg, 2.14 mM) in l,4-dioxane (30 ml) was added to the suspension of sodium hydride (56 mg, 2.35 mM) in l,4-dioxane (30 ml). The 25 mixture was heated at 80^-90°C during 30 min and then cooled to the room temperature. Ethyl bromoacetate ( 393 mg, 2.37 mM) was added to the reaction mixture, which was heated at 110+120°C for 6 hours and than concentrated under reduced pressure The residue was purified by column chromatography with ethylacetate-hexane mixture 1:1 giving N-ethoxycarbonylmethyl-4(7?)-phenyl-2-pyrrolidinone (338 mg, 64%). [cx]d20= +4.6° (c=3, 30 MeOH). ’H NMR (CDC13), δ: 1.28 (3H, t, CH2CH3); 2.59 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.64 (1H, quintet, 4-CH); 3.83 (1H, t, 5-CH2); 4.11 (2H, s, NCH2CO); 4.20 (2H, q. CH2CH3); 7.20-7.39 (5H, m, C6H5).
Example 2.
The solution of N-ethoxycarbonylmethyl-4(i?)-phenyl-2-pyrrolidinone (250 mg, 1.01 mM) in methanol (30 ml) was saturated with gaseous ammonia for 5 hours. Reaction mixture was concentrated under reduced pressure and residue was purified by column chromatography with 5 ethylacetate-hexane mixture 1:1 giving N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidinone (187 mg, 85%). M.p. 107.5-108°C. [a]D20= +8.5° (c=3, MeOH). lU NMR (CDC13), 5: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and br.s, NH2); 7.20-7.40 (5H, m, C6H5). 10
Example 3
By substituting of ethyl bromoacetate in example 1 by the methyl bromoacetate, there is obtained N-methoxycarbonylmethyl-4(R)-4-phenyl-2-pyrrolidinone. ’HNMR (CDC13), δ: 2.58 (1H, d, d, 3-CH2); 2.88 (1H, d, d, 3-CH2); 3.53 (1H, t, 5-CH2); 3.64 (1H, quintet, 4-CH); 3.65 15 (3H, s, CH3); 3.83 (1H, t, 5-CH2); 4.10 (2H, s, NCH2CO); 7.20-7.41 (5H, m, C6H5).
Example 4
By substituting of ethyl bromoacetate in example 1 by the ethyl chloroacetate, there is obtained N-ethoxycarbonylmethyI-4(i?)-4-phenyl-2-pyrrolidinone. 20
Example 5. 4(7?)-Phenyl-2-pyrrolidinone (345 mg, 2.14 mM) and potassium hydroxide (123 mg, 2.20 mM) in benzene-dimethylsulfoxide mixture (1:1) (100 ml) was heated under reflux for 8 hours. Reaction was accompanied by the elimination of water by azeotropic distillation. Ethyl 25 bromoacetate (290 mg, 2.37 mM) was added and the reaction mixture was heated at 110-5-120°C for 6 hours and than concentrated under reduced pressure. Residue was purified by column chromatography with ethylacetate-hexane mixture 1:1 giving N-ethoxycarbonylmethyl-4(7?)-phenyl-2-pyrrolidinone. 30 Example 6. 4(7?)-Phenyl-2-pyrrolidinone (345 mg, 2.14 mM) and chlorotrimethylsilane (0.28 ml, 2.20 mM) in dichloromethane (30 ml) was heated under reflux for 3 hours. Reaction mixture was concentrated under reduced pressure and toluene (30 ml) and ethyl bromoacetate ( 393 mg, 2.37 mM) was added to the residue. Obtained solution was heated at 100—110°C for 6 hours 35 and then concentrated under reduced pressure. Residue was purified by column LV 13631 7 chromatography with ethylacetate-hexane mixture 1:1 giving N-ethoxycarbony 1 methyl-4(R)-phenyl-2-pyrrolidinone.
Example 7. 5 4(i?)-Phenyl-2-pyrrolidinone (345 mg, 2.14 mM) and hexamethyldisilazane (0.47 ml, 2.20 mM) in toluene (30 ml) in the presence of the catalytic amount of conc. sulfuric acid (10 mg) was heated under reflux for 3 hours. Reaction mixture was concentrated under reduced pressure and methyl bromoacetate ( 363 mg, 2.37 mM), bromotrimethylsilane (30 mg) and toluene (30 ml) were added to the residue. Obtained mixture was heated at 100M10°C for 6 10 hours and then concentrated under reduced pressure. Residue was purified by column chromatography with ethylacetate-hexane mixture 1:1 giving N-methoxycarbonylmethyl-4(R)-4-phenyl-2 -pyrrol idinone.
Example 8. 15 By substituting of bromotrimethylsilane (as the catalyst of N-alkylation) in example 7 by the trimethylsilyl trifluoromethanesulfonate, there is obtained N-methoxycarbonylmethyl-4(R)-4-phenyl-2-pyrrolidinone.
Example 9. 20 By substituting of gaseous ammonia in example 2 by the 25% aqueous ammonium, there is obtained N-carbamoylmethyl-4(7?)-4-phenyl-2-pyrrolidinone.
References I. VIDAL®, Russian medicīnai drugs, «Acrpa<l>apMCepBHc» Publisher, 2005, p. E-967. 25 2. J. L’ Itatalien, US 4144246 (1979). 3. M. Glozman et al., Khim.-Pharm. J., 1980,14, Nr 11, 43-48. 4. E. Kramarova et al., SU1265191 (1986). 5. E. Kramarova et al, SU 1265192 (1986). 6. I. Basova et al, SU 1432051 (1986). 30 7. R. D. Allan et al, Tetrahedron, 1990, 46, No7, 2511-2524. 8. N. Langlois et. al. Tetrahedron, 1996, 52, No 48,15117-15126. 9. R. E. Zelle, Synthesīs, 1991, 1023. 10. M. Soborcinska et al, Pol. J. Chem., 1979, 53, 435-446. II. A. F. Wildervanck, et al, US 6051734, 2000. 35 12. R. Chenevret, M. Desjardins, Can. J. Chem., 1994, 72, 2312-2317. 13. R. V. Muralidhar, R. R. Chirumamilla et al., Med. Fac. Landbouww. Univ, Gēni, 2001, 66, Nr 3a, 227-232. 14. W. Levadoux et al, D. US 5483765 (1998). LV 13631 9.
We claim: 1. A process for the preparation of N-carbamoylmethyl-4(7?)-phenyl-2-pyrrolidinone (I) from 4(iž)-phenyl-2-pyrrolidinone 5
o
L conh2; (I) which includes following steps: (1) the substitution of hydrogen in the amide group of 4(JR)-phenyl-2-pyrrolidinone with 10 mētai ion or trialkylsilyl group in a suitable organic solvent; (2) the N-alkylation of N-metallated or N-silylated 4(i?)-phenyl-2-pyrrolidinone with haloacetic acid esters in a suitable organic solvent; (3) the carbamoylation of N-alkoxycarbonyhnethyl-4(A)-phenyl-2-pyrrolidinone with ammonia in a suitable organic solvent. 15 2. A process according to claim 1 wherein in step (1) sodium ion is introduced vvith sodium hydride in a suitable organic solvent. 3. A process according to claim 1 vvherein in step (1) potassium ion is introduced vvith potassium hydroxide in a suitable organic solvent. 4. A process according to claim 1 vvherein in step (1) trialkylsilyl group is represented vvith 20 trimethylsilyl group. 5. A process according to claim 1 vvherein in step (1) trimethylsilyl group is introduced vvith chlorotrimethyl silane in a suitable organic solvent. 6. A process according to claim 1 vvherein in step (1) trimethylsilyl gruop is introduced by hexamethyldisilazane in a suitable organic solvent. 25 7. A process according to claim 1 vvherein in step (2) haloacetic acid ester is represented vvith bromoacetic acid ester. 8. A process according to claim 1 vvherein in step (2) haloacetic acid ester is represented vvith chloroacetic acid ester. 9. A process according to claim 1 vvherein in step (2) haloacetic acid ester is represented vvith methyl ester. 10. A process according to claim 1 vvherein in step (2) haloacetic acid ester is represented vvith ethyl ester. 30 11. A process according to claim 1 vvherein in step (2) the N-alkylation of N-trimethylsi]yl substituted 4(/?)-phenyl-2-pyrroIidinone with haloacetic acid esters is catalized by bromotrimethylsilane. 12. A process according to claim 1 wherein in step (2) the N-alkylation of N-trimethylsilyl 5 substituted 4 (7?) -ph en y 1 -2-pyrro 1 idinone with haloacetic acid esters is catalized by trimethylsilyl trifluoromethanesulfonate. 13. A process according to claim 1 wherein in steps (1) and (2) organic solvent used for reactions is selected from group consisting of hexane, benzene, toluene, chloroform, dichloromethane, dichloroethane. ethyl acetate, methyl acetate, diethyl ether, 1,4- 10 dioxane, dimethylsulfoxide and mixtures of them. 14. A process according to claim 1 wherein in step (3) the carbamoylation of N- alkoxycarbonylmethyl-4(i?)-phenyl-2-pyrrolidinone is realized in aqueous ammonia or its mixture with a suitable organic solvent.. 15. A process according to claim 1 wherein in step (3) the carbamoylation of N- 15 alkoxycarbonylmethyl-4(7?)-phenyl-2-pyrrolidinone is realized in a suitable organic solvent by its saturation with gaseous ammonia. 16. A process according to claim 1 vvherein in step (3) the organic solvent used for reactions is selected from group consisting of methanol, ethanol, propanol; chloroform, dichloromethane; ethyl acetate and l,4-dioxane. 20

Claims (11)

1-LV 13631 IZGUDROJUMA FORMULA 1. N-Karbamoilmetil-4(i?)-fenil-2-pirolidinona 5N-Carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone 1 O L conh2 iegūšanas metode no 4(7?)-fenil-2-pirolidinona, kas atšķiras ar to, ka pirmajā stadijā (a) 4(i?)-fenil-2-pirolidinona amīda grupas ūdeņraža atomu aizvieto ar metāla jonu vai trialkilsililgrupu piemērotā organiskajā šķīdinātājā, un iegūto N-metalēto vai N-sililēto 10 4(2?)-fenil-2-pirolidinonu tālāk stadijā (b) N-alkilē ar halogēnetiķskābes esteri piemērotā organiskajā šķīdinātājā, un iegūto N-alkoksimetil-4(J?)-fenil-2-pirolidinonu stadijā (c) karbamoilē ar amonjaku piemērotā organiskajā šķīdinātājā.A method for obtaining OL conh2 from 4 (7?) -Phenyl-2-pyrrolidinone, characterized in that in the first step (a) 4 (i) -phenyl-2-pyrrolidinone amide hydrogen atom is replaced by a metal ion or trialkylsilyl group in a suitable in the organic solvent and the resulting N-metallized or N-silylated 10 4 (2?) -phenyl-2-pyrrolidinone in step (b) N-alkyl with a haloacetic acid ester in a suitable organic solvent and the resulting N-alkoxymethyl-4 (J?) -phenyl-2-pyrrolidinone in step (c) of carbamoyl with ammonia in a suitable organic solvent. 2. Process pēc p. 1., kas atšķiras ar to, ka stadijā (a) nātrija jonu ievada ar nātrija hidrīda palīdzību piemērotā organiskajā šķīdinātājā.2. Process after p. Characterized in that, in step (a), sodium ion is administered via sodium hydride in a suitable organic solvent. 3. Process pēc p. 1., kas atšķiras ar to, ka stadijā (a) kālija jonu ievada ar kālija hidroksīda palīdzību piemērotā organiskajā šķīdinātājā.3. Process after p. Characterized in that, in step (a), potassium ion is administered by means of potassium hydroxide in a suitable organic solvent. 4. Process pēc p. 1., kas atšķiras ar to, ka stadijā (a) trialkilsililgrupa ir pārstāvēta ar trimetilsililgrupu.4. Process after p. 1. wherein, in step (a), the trialkylsilyl group is represented by a trimethylsilyl group. 5. Process pēc p. 1., kas atšķiras ar to, ka stadijā (a) trimetilsililgrupu ievada ar 20 trimetilhlorsilānu palīdzību piemērotā organiskajā šķīdinātājā.5. Process after p. Characterized in that, in step (a), trimethylsilyl is introduced via trimethylchlorosilane in a suitable organic solvent. 6. Process pēc p. 1., kas atšķiras ar to, ka stadijā (a) trimetilsililgrupu ievada ar heksametildisilazāna palīdzību piemērotā organiskajā šķīdinātājā.6. Process after p. Characterized in that, in step (a), trimethylsilyl is administered via hexamethyldisilazane in a suitable organic solvent. 7. Process pēc p. 1., kas atšķiras ar to, ka stadijā (a) kā halogēnetiķskābes esteri lieto brometiķskābes esteri.7. Process after p. 1. wherein, in step (a), the haloacetic acid ester is a bromoacetic acid ester. 8. Process pēc p. 1., kas atšķiras ar to, ka stadijā (b) kā halogēnetiķskābes esteri lieto hloretiķskābes esteri.8. Process after p. Characterized in that, in step (b), chloroacetic acid esters are used as haloacetic esters. 9. Process pēc p. 1., kas atšķiras ar to, ka stadijā (b) kā halogēnetiķskābes esteri lieto to metilesteri.9. Process after p. 1. wherein, in step (b), methyl esters are used as haloacetic esters. 10. Process pēc p. L, kas atšķiras ar to, ka stadijā (b) kā halogēnetiķskābes esteri lieto to 30 etilesteri.10. Process after p. L, characterized in that, in step (b), the ethyl ester is used as the haloacetic ester. 11. Process pēc p, 1., kas atšķiras ar to, ka stadijā (b) N-sililētā 4(i?)-fenil-2-pirolidinona N-alkilēšanu ar halogēnetiķskābes esteri katalīzē ar bromtrimetilsilānu; Process pēc p. 1kas atšķiras ar to, ka stadijā (b) N-siiilētā 4(7?)-feniI-2-pirolidinona N-alkilēšanu ar halogēnetiķskābes esteri katalizē ar trifluormetānsulfoskābes trimetilsililesteri; Process pēc p. 1., kas atšķiras ar to, ka stadijā (a) un stadijā (b) lieto organisko šķīdinātāju, kas ir izvēlēts no grupas, kas sastāv no heksāna, benzola, toluola, hloroforma, dihlormetāna, dihloretāna, etilacetāta, metilacetāta, dietilētera, 1,4-dioksāna, dimetilsulfoksīda un/vai to maisījumiem. Process pēc p. 1., kas atšķiras ar to, ka stadijā (c) N-alkoksimetil-4(7?)-fenil-2- pirolidinona karbamoilēšanu veic ar amonjaka ūdens šķīdumu vai arī ar tā maisījumu ar piemērotu organisko šķīdinātāju. Process pēc p. 1., kas atšķiras ar to, ka stadijā (c) N-alkoksimetil-4(7?)-fenil-2- pirolidinona karbamoilēšanu veic ar amonjaku, kas izšķīdināts piemērotā organiskajā šķīdinātājā. Process pēc p. 1., kas atšķiras ar to, stadijā (c) pielietotais organiskais šķīdinātājs, ir izvēlēts no grupas, kas sastāv no metanola, etanola, propanola, dihlormetāna, etilacetāta un 1,4-dioksāna.Process according to claim 1, characterized in that in step (b) the N-alkylation of N-silylated 4 (i) -phenyl-2-pyrrolidinone with haloacetic acid is catalyzed by bromtrimethylsilane; Process after p. Characterized in that the N-alkylation of N-silylated 4 (7?) - phenyl-2-pyrrolidinone with haloacetic acid in step (b) is catalyzed by trifluoromethanesulfonic acid trimethylsilyl ester; Process after p. 1. An organic solvent selected from the group consisting of hexane, benzene, toluene, chloroform, dichloromethane, dichloroethane, ethyl acetate, methyl acetate, diethyl ether, and the like in step (a) and step (b). , 4-dioxane, dimethylsulfoxide and / or mixtures thereof. Process after p. Characterized in that in step (c) the carbamylation of N-alkoxymethyl-4 (7?) -Phenyl-2-pyrrolidinone is carried out with an aqueous ammonia solution or a mixture thereof with a suitable organic solvent. Process after p. Characterized in that in step (c) the carbamylation of N-alkoxymethyl-4 (7?) -Phenyl-2-pyrrolidinone is carried out with ammonia dissolved in a suitable organic solvent. Process after p. 1. An organic solvent used in step (c) is selected from the group consisting of methanol, ethanol, propanol, dichloromethane, ethyl acetate and 1,4-dioxane.
LV060046A 2006-03-16 2006-03-16 Manufacturing method of n-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone LV13631B (en)

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US4144246A (en) * 1976-11-15 1979-03-13 Parke, Davis & Company Pyrrolidineacetic acid esters
SU797219A1 (en) * 1979-05-08 1995-07-25 Ленинградский государственный педагогический институт им.А.И.Герцена N-carbamoylmethyl-4-phenyl-2-pyrrolidone possessing hypotensive activity
SU1265192A1 (en) * 1984-06-27 1986-10-23 2-Ой Московский Ордена Ленина Государственный Медицинский Институт Им.Н.И.Пирогова Method of producing 4-phenylpyrrolidon-2-acetic-1-acid amide

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