PH26332A - A process for the preparation of (S)-ethyl-2-oxo-1-pyrrolidineacetamide - Google Patents
A process for the preparation of (S)-ethyl-2-oxo-1-pyrrolidineacetamide Download PDFInfo
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- PH26332A PH26332A PH39568A PH39568A PH26332A PH 26332 A PH26332 A PH 26332A PH 39568 A PH39568 A PH 39568A PH 39568 A PH39568 A PH 39568A PH 26332 A PH26332 A PH 26332A
- Authority
- PH
- Philippines
- Prior art keywords
- ethyl
- pyrrolidineacetamide
- oxo
- methylthio
- temperature
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 13
- ZDGXMOZHFUQHKZ-LURJTMIESA-N 2-[(3s)-3-ethyl-2-oxopyrrolidin-1-yl]acetamide Chemical compound CC[C@H]1CCN(CC(N)=O)C1=O ZDGXMOZHFUQHKZ-LURJTMIESA-N 0.000 title 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- GSYTVXOARWSQSV-BYPYZUCNSA-N L-methioninamide Chemical compound CSCC[C@H](N)C(N)=O GSYTVXOARWSQSV-BYPYZUCNSA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 4
- LBTUTDYXOOUODJ-UHFFFAOYSA-N 2-pyrrolidin-1-ylacetamide Chemical compound NC(=O)CN1CCCC1 LBTUTDYXOOUODJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- -1 (aminocarbonyl)-3- (methylthio)propyl Chemical group 0.000 claims description 2
- 206010001488 Aggression Diseases 0.000 claims description 2
- 206010021143 Hypoxia Diseases 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000016571 aggressive behavior Effects 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims description 2
- 230000001146 hypoxic effect Effects 0.000 claims description 2
- 230000000302 ischemic effect Effects 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 150000002816 nickel compounds Chemical class 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 229930195722 L-methionine Natural products 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PWCBMJHINDTXGV-WCCKRBBISA-N [(2s)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]azanium;chloride Chemical compound Cl.CSCC[C@H](N)C(N)=O PWCBMJHINDTXGV-WCCKRBBISA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960004452 methionine Drugs 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- HNNJFUDLLWOVKZ-VKHMYHEASA-N (2s)-2-aminobutanamide Chemical compound CC[C@H](N)C(N)=O HNNJFUDLLWOVKZ-VKHMYHEASA-N 0.000 description 1
- YAQLSKVCTLCIIE-UHFFFAOYSA-M 2-bromobutanoate Chemical compound CCC(Br)C([O-])=O YAQLSKVCTLCIIE-UHFFFAOYSA-M 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- HYTACLVSJIFYBY-UHFFFAOYSA-N azane;dichloromethane;methanol Chemical compound N.OC.ClCCl HYTACLVSJIFYBY-UHFFFAOYSA-N 0.000 description 1
- ZTZTWQPPCCBBML-UHFFFAOYSA-N azane;ethyl acetate;methanol Chemical compound N.OC.CCOC(C)=O ZTZTWQPPCCBBML-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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
- C07D207/27—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
1 : go .
SL | Ck Na oo A process for the preparation of (S)-a-ethyl-2- : : © oxo-l-pyrrolidineacetamide. }
Ce : The present invention relates to & new process for the preparation
Co of (S)-a-ethyl-2-oxo-1-pyrrolidineacetamide which has the formula }
Hh” NN { com,
H :
Co U.S. Patents No. 4,696,943 and No. 4,837,223 in the name of the
Applicant describe this compound, which has the absolute S configuration ° and state that it has particular therapeutic properties which completely
Le unexpectedly distinguish it from the racemic form. Thanks to its
B . . properties, the S enantiomer is more suitable than the racemic form for - ‘ . the treatment and prevention of hypoxic and ischemic type ‘aggressions of the central nervous system. | ; } : : The preparation of (5)-a-ethyl-2-oxo-1l-pyrrolidineacetamide 1s ’ described in the above mentioned U.S. Patents No. 4,696,943 and ‘No. : " . 4,837,223. According to these patents, the compound cannot be obtained i - directly from the racemic mixture by separation of the two enantiomers. .
It has to be prepared by other methods, and these U.S. patents . 15 specifically describe two processes for the preparation of the compound. : . In the first process, (5)-a-ethyl-2-oxo-1-pyrrolidineacetic acid is . reacted successively with an alkyl haloformate, preferably ethyl chloroformate, and with ammonia. In the second process, an alkyl (5)-4- [(1-(aminocarbonyl)propyl]amino}butyrate or an (S)-N-[1- (aminocarbonyl)propyl]-4-halobutanamide is cyclized, the two compounds themselves being prepared from (S)-2-aminobutanamide.’
These two processes have in common the same disadvantage. Both * - require the preparation of a starting reactant which already has the correct stereochemical configuration. This starting reactant is obtained by resolution of the corresponding racemic compound, respectively racemic (%)-c-ethyl-2-oxo-1-pyrrolidineacetic acid in the case of the first
LL oe 1
Yi
Lo : 77 process and racemic (%)-2-amino-butanamide in the case of the second process. Prior separation of the enantiomer with the desired ’ ’ . configuration from the corresponding racemic compound necessarily causes, iE from the beginning, a loss of 502 of the raw material employed. Moreover, - 5 if it is taken into account that recovery of an optical isomer is rarely ] carried out in-a quantitative yield, the total loss of raw material incurred is much greater than 50% of the starting racemic compound. :
A process which would not have this disadvantage, while remaining relatively easy to carry out, would be extremely desirable.
The present invention thus provides a new process for the preparation of (S)-a-ethyl-2-oxo-l-pyrrolidineacetamide which does not have the disadvantage of the previous processes and which, as a consequence, is more economical. Moreover, this new process also offers the advantage of using a naturally occurring amino acid, L-methionine, or its readily accessible amide as the starting material. oo The process according.to the present invention for the preparation } of (S)-a-ethyl-2-oxo-l-pyrrolidineacetamide comprises hydrogenolysis of (S)-a-[2-(methylthio)ethyl]-2-oxo-1l-pyrrolidineacetamide by means of a ol desulphurizing reagent, in accordance with the equation - CL
Ao | CL
N .
LL co —~C ’ .-C —- ci,~CH, "7 4 : cH,5Ci, CH, [ 372 / CONH, : CONH,,. H ‘ H ) The desulphurization of (S)-a-(methylthio)ethyl]-2-oxo-1- } oo pyrrolidineacetamide is stereoselective. This reaction is generally carried out in water at a temperature between 50 en 100°C in the presence of a desulphurizing reagent such as NaBH, /NiCl, .6H,0 (R.B. BOAR et al.,
J.Chem.Soc., Perkin Trans.I (1973),654), Raney nickel W-2 or, preferably,
Raney nickel T-1 under normal or increased pressure (X. DOMINGUEZ et al.,
J.0rg.Chem.26, (1961),1625). _ :
The (S)-a-[2-(methylthio)ethyl}-2-oxo-1-pyrrolidineacetamide which is the starting compound in this process is a new compound. It can be 2 oo
A? prepared by one or other of the following two methods : : 1) reacting (S)-2-amino-4-(methylthio)butanamide hydrochloride with a 4- halobutyryl halide of the formula HalCH,CH,CH,COHal in which Hal is a halogen atom, preferably a chlorine atom, in accordance with the . equation - } oo NH. HCL EE UC : i aE
Ce Hal-CRCE, CH, COHal | . cuscH.cH,” AN Kod --¢
TTI / CONE CH,SCH, CH,” / \
EE CONH.,
This reaction is generally carried out in an inert solvent, for : - example dichloromethane, at a temperature of about 0°C in the presence of a catalyst, such as tetrabutylammonium bromide in the presence of powdered potassium hydroxide. 2) a) reacting first (S)-2-amino-4-(methylthio)butanamide with an alkyl 4-halobutyrate of the formula XCH,CH,CH,COOR, in wich X is a oo halogen atom and R is an alkyl radical having 1 to 4.carbon atoms, in accordance with the equation : . © NH, ’ C) 2 Ni . | ig | OR : _- c_- XCH,CH,CH,CO0R : _c oH, SCH.CH, / NU : ca scr, cH,” - NL oo Cone, Co [ i CONH., i ' # H
This reaction is generally carried out by heating for several hours at a temperature between 80 and 100°C in an inert solvent, such as toluene, in the presence of an acid acceptor such as a tertiary organic base, such as, for example, triethylamine. : b) then cyclizing the alkyl (S)-4-[[1-(aminocarbonyl)-3- - (methylthio)propyl]amino]-butyrate obtained in step a), in accordance with the equation a ’ 0) } 0
OR : Co Co . — ~ _ - .
CH,SCH,CH, NL CH, SCH, CH, ~~ NL
CONH,, - . CONH } 2 +B H
This cyclization is generally carried out in an inert solvent, such as for example toluene or xylene, by heating at a temperature between 100 and 130°C for several hours in the presence of a : catalyst, such as 2-hydroxypyridine. } (S)-2-Amino-4-(methylthio)butanamide, as the free base, can be . prepared from L-methionine according to the method of E. SANDRIN and R.A.
BOISSONNAS, Helv.Chim.Acta,46,(1963),1637-1669.
M.P.: 50-51°C. (a)? = -27.7° (c¢ = 2, dimethylformamide). . (S)-2-Amino-4-(methylthio)butanamide hydrochloride, which is a known . compound, can be prepared from the base according to the process - described by A. EBERLE et al., Helv.Chim.Acta,61,(1978),2360-74. M.P.:.212-215°C. [a)2’ = 426.4° (c = 1, dimethylformamide).
The following example is given for the purpose of illustrating the 15. invention.
Co In this example, the optical purity of the final product was : oo verified by calorimetric determination of the differential enthalpies (C.
FOUQUEY and J. JACQUES, Tetrahedron,23,(1967),4009-19).
I. Preparation of the starting (S)-a-[2-(methylthio)ethyl]-2-oxo-1- pyrrolidineacetamide. 1) From a 4-halobutyryl halide. . 84 g of anhydrous sodium sulphate are added to a suspension of 92.25 g (0.5 mole) of (S)-2-amino-4-(methylthio)butanamide in 600 ml of dichloromethane at room temperature. The mixture is then cooled to 0°C and 115 g of ground potassium hydroxide and 8.1 g
Co to - | 77 . /
So 2633: (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of . ‘ dichloromethane are added in succession. A solution : containing 77.5 g (0.55 mole) of 4-chlorobutyryl chloride in 100 ml of dichloromethane is added dropwise at the same temperature, and ‘5 with vigorous stirring. During the addition, the reaction medium is diluted by simultaneous introduction of 550 ml of i ‘ dichloromethane. After stirring at 0°C for two hours, 29 g of ground potassium hydroxide are added to the mixture. After four and a half hours'reaction, a further 29 g of ground potassium hydroxide are added and stirring is continued for one hour at 0°C. :
The reaction mixture is then filtered over Hyflocel and the filtrate is evaporated under reduced pressure. The residue is purified by chromatography over silica (eluent: mixture of ‘ dichloromethane-methanol-ammonia 95.5:4.5:0.2 v/v/v). 66 g of (S)- o-[2-(methylthio)ethyl]-2-oxo-1-pyrrolidineacetamide are obtained in the form of a white powder. [@)2’ = - 39.1° (¢ = 1, methanol).
Yield:611.
Analysis for CoH, (N,0,8 in I: oo calc. : C 50.00 H 7.41 N 12.96 found : 50.15 7.80 12.94 . 2) From an alkyl &4-halobutyrate. Co a) Ethyl (S)-4-[[1-(aminocarbonyl)-3-(methylthio)propyl]- . se amino }butyrate. ’ : : 10.57 ml (76 mmoles) of triethylamine are added to a suspension of 10 g (68 mmoles) of (§)-2-amino-4-(methylthio)butanamide in . 100 ml of toluene. The mixture is heated to 80-85°C, with vigorous stirring, and 13.26 g (68 mmoles) of ethyl 4° oo bromobutyrate are added dropwise. This temperature is maintained . for 8 hours. The solvent is then evaporated off under reduced pressure and the residue is taken up in 100 ml of Pp . dichloromethane. The mixture is heated under reflux for 30 minutes and filtered hot. The filtrate is evaporated to dryness and the residue obtained is purified by chromatography over } silica (eluent: mixture of ethyl acetate-methanol-ammonia 10:0.1:0.1 v/v/v). 6.2 g of ethyl (S)-4-[[l-(aminocarbonyl)-3- : : (methylthio)propylJamino]butyrate are thus obtained. [212 -14.1° (c = 1, methanol). Yield: 35.
i aa? . . . oe? . i . This intermediate compound is used as such without further purification for carrying out the final cyclization. b) 0.6 g (2.29 mmoles) of the crude product obtained in a) and 21.3 . mg - (0.225 mmole) of 2-hydroxypyridine are mixed in 1.15 ml of p-
Le 5 xylene. The mixture is heated at 130°C under nitrogen for 4 and
Bn a half hours. It is then cooled and stirred for 30 minutes at room temperature. The precipitate which forms is filtered off and recrystallized from ethyl acetate. 0.18 g of (S)-a-{2- methylthio)-ethyl]-2-oxo-1-pyrrolidineacetamide are obtained. (2? = -36.5° (¢ = 1, methanol). Yield: 362.
Analysis for CoH, gN,0,5 in 2: calc.: C 50.00 H 7.41 N 12.96 . found: 49.88 7.49 12.68 . 1I. Preparation of (S)-a-ethyl-2-oxo-l1-pyrrolidineacetamide. 50 g of Raney nickel T-1 (X.A. DOMINGUEZ et al., J.Org.Chem.26, } (1961),1625), 386 ml of water and 7 g (0.0324 mole) of (S)-a-[2- } (methylthio)ethyl]-2-oxo-1-pyrrolidineacetamide are introduced successively into a one litre three-necked round-bottomed flask. The
Co mixture is heated to 75°C and stirred at this temperature for one ’ hour. It is filtered and the water is evaporated off under reduced pressure. The residue (5.3 g) is recrystallized from 60 ml of ethyl acetate. 3.87 g of (S)-a-ethyl-2-oxo-1-pyrrolidineacetamide are - obtained. M.P.: 112-115°C. (@12’ = -90° (c = 1, acetone).
Yield: 69%. Co
Analysis for Celi ,N,0, in 2: . calc.: C 56.45 H 8.29 N 16.46 : found: 56.30 8.42 16.18 .
Claims (1)
- Pe »7”’ 1. ‘A process for the preparation of (S)-a-ethyl-2-0x0-1- i oo oo - pyrrolidineacetamide, which comprises the steps of (1) reacting” - . (S)-2-amino-4-(methylthio)butanamide with a 4-halobutyryl halide i ‘of the formula HalCH CH, CH COHal, in which Hil is a halogen atom, Co ’ + in an inert solvent, at a temperature of about 0°C, i “and (2) subjecting the thus obtained (S)-a-[2-(methylthio)ethyl]- : '2-oxo0-1-pyrrolidineacetamide to hydrogenolysis by means of a "nickel compound as desulphurizing reagent, in water and at a Cd "temperature between 50 and 100°C. : oo i : : : o b: 2. A process for the preparation of (8)-a-ethyl-2-oxo-1- oo Cd pyrrolidineacetamide, which comprises the ‘steps of (1). reacting (S)-2-amino-4-(methylthio)butanamide with an alkyl 4-halobutyrate of the formula XCH, CH CH COOR, in which'X represents a halogen . atom and R an alkyl radical having 1 to 4 carbon atoms, at a temperature between 80 and 100°C, in an inert solvent and in the presence of an acid acceptor, to form an alkyl (S)-4-[[1- - a (aminocarbonyl)-3- (methylthio)propyl)amino]-butjrate, which is } then cyclized in an inert solvent by heating at a temperature SEER ~ between 100 and 130°C and (2) subjecting the thus obtained (S)-«- (2-methylthio)ethyl]-2-oxo-1-pyrrolidineacetamide to hydrogenolysis by means of a nickel compound as desulphurizing : ‘reagent, in water and.at a temperature between 50 and 100°C. . B i } i . A3. A process according to claim 1 or 2, wherein the desulphurizing : : reagent is Raney nickel T-1. BE oo . . . i4. A process according to claim 1 or 2, wherein the desulphurizing J reagent is NaBH, /NiCl,.6H 0. | } . . oo :- 5. A process according to claim 1 or 2, wherein the desulphirizing © mesgent ds Ramey mickelW-2.6... (S)-a- [2- (methylthio)ethyl]-2-oxo-1-pyrrolidineacetamide. . . ” ? E : - : . . .- . CL Lo L Lo oo Cn { oo gue = : : Oo eh® \co : 2) . : 57’ . . . . : 7 Tr ! : : ) J- .“ ot » oo 2637 RE : ! - i. Cor. Sumo : -- - oo. comme oo) RE CL . . © ABSTRACT : i A process for the preparation of (S)-a-ethyl-2-oxo-1- k : pyrrolidineacetamide. - : oo } } This compound is prepared by hydrogenolysis of (S)-c-[2- co - (methylthio)ethyl]-2-oxo-1-pyrrolidineacetamide in the presence of a } desulphurizing reagent such as NaBH, /NiCl,.6H,0, Raney nickel W-2 or, ] ’ preferably, Raney nickel T-1. (S)-e-ethyl-2-oxo-1-pyrrolidineacetamide is a ; useful in the treatment and prevention of hypoxic and ischemic type So aggressions of the central nervous system. © . : : : oo 1- . . . . : . L ! ] . } ee BE SL . . : ¢
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888827389A GB8827389D0 (en) | 1988-11-23 | 1988-11-23 | Process for preparation of(s)alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PH26332A true PH26332A (en) | 1992-04-29 |
Family
ID=10647345
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH39568A PH26332A (en) | 1988-11-23 | 1989-11-23 | A process for the preparation of (S)-ethyl-2-oxo-1-pyrrolidineacetamide |
Country Status (17)
| Country | Link |
|---|---|
| KR (1) | KR0157610B1 (en) |
| CN (1) | CN1020604C (en) |
| AT (1) | AT392781B (en) |
| BG (1) | BG51041A3 (en) |
| CY (1) | CY1672A (en) |
| ES (1) | ES2023532A6 (en) |
| FI (1) | FI91961C (en) |
| GB (2) | GB8827389D0 (en) |
| GR (1) | GR1000719B (en) |
| HK (1) | HK102492A (en) |
| HU (1) | HU204508B (en) |
| NO (1) | NO173823C (en) |
| PH (1) | PH26332A (en) |
| PL (1) | PL161781B1 (en) |
| PT (1) | PT92365B (en) |
| RU (1) | RU1797607C (en) |
| SG (1) | SG89392G (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9319732D0 (en) | 1993-09-24 | 1993-11-10 | Ucb Sa | Use of (s)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide for the treatment of anxiety |
| US6107492A (en) * | 1998-05-08 | 2000-08-22 | Ucb, S.A. | Process for the preparation of levetiracetam |
| ES2287039T3 (en) | 1999-12-01 | 2007-12-16 | Ucb, S.A. | A PIRROLIDINACETAMIDE DERIVATIVE FOR THE TREATMENT OF CHRONIC OR NEUROPATHIC PAIN. |
| GB0004297D0 (en) | 2000-02-23 | 2000-04-12 | Ucb Sa | 2-oxo-1 pyrrolidine derivatives process for preparing them and their uses |
| US7132552B2 (en) * | 2003-02-03 | 2006-11-07 | Teva Pharmaceutical Industries, Ltd. | Process for producing levetiracetam |
| ES2214147B1 (en) * | 2003-02-28 | 2005-10-01 | Farma-Lepori S.A. | PROCEDURE FOR OBTAINING AN ANTIEPILEPTIC AGENT. |
| PL1667967T3 (en) | 2003-09-24 | 2012-11-30 | Ucb Pharma Sa | Process for preparing 2-oxo-1-pyrrolidine derivatives |
| CA2488325C (en) | 2004-11-22 | 2010-08-24 | Apotex Pharmachem Inc. | Improved process for the preparation of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide and (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
| AU2006254336B9 (en) | 2005-06-01 | 2013-02-28 | Ucb Pharma, S.A. | 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system |
| US8338621B2 (en) | 2005-12-21 | 2012-12-25 | Ucb S.A. | Process for the preparation of 2-oxo-1-pyrrolidine derivatives |
| WO2009050735A1 (en) * | 2007-10-15 | 2009-04-23 | Lupin Limited | A novel polymorph of levetiracetam and a process for its preparation |
| EP2147911A1 (en) | 2008-07-24 | 2010-01-27 | ZaCh System S.p.A. | Process for the preparation of levetiracetam |
| US7939676B2 (en) | 2009-09-17 | 2011-05-10 | Zach System S.P.A. | Process for the preparation of levetiracetam |
| KR102461134B1 (en) | 2014-01-21 | 2022-10-28 | 얀센 파마슈티카 엔.브이. | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
| UA121965C2 (en) | 2014-01-21 | 2020-08-25 | Янссен Фармацевтика Нв | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1309692A (en) * | 1970-02-13 | 1973-03-14 | Ucb Sa | N-substituted lactams |
| GB8412358D0 (en) * | 1984-05-15 | 1984-06-20 | Ucb Sa | Pharmaceutical composition |
| GB8412357D0 (en) * | 1984-05-15 | 1984-06-20 | Ucb Sa | Pharmaceutical composition |
-
1988
- 1988-11-23 GB GB888827389A patent/GB8827389D0/en active Pending
-
1989
- 1989-11-20 BG BG090398A patent/BG51041A3/en unknown
- 1989-11-20 GR GR890100769A patent/GR1000719B/en not_active IP Right Cessation
- 1989-11-21 PT PT92365A patent/PT92365B/en not_active IP Right Cessation
- 1989-11-21 GB GB8926244A patent/GB2225322B/en not_active Expired - Lifetime
- 1989-11-22 CN CN89108764A patent/CN1020604C/en not_active Expired - Fee Related
- 1989-11-22 AT AT2666/89A patent/AT392781B/en not_active IP Right Cessation
- 1989-11-22 RU SU4742434A patent/RU1797607C/en active
- 1989-11-22 NO NO894649A patent/NO173823C/en unknown
- 1989-11-22 HU HU896132A patent/HU204508B/en not_active IP Right Cessation
- 1989-11-22 ES ES8903978A patent/ES2023532A6/en not_active Expired - Lifetime
- 1989-11-22 FI FI895562A patent/FI91961C/en active IP Right Grant
- 1989-11-22 PL PL89282413A patent/PL161781B1/en unknown
- 1989-11-23 PH PH39568A patent/PH26332A/en unknown
- 1989-11-23 KR KR1019890017038A patent/KR0157610B1/en not_active IP Right Cessation
-
1992
- 1992-09-05 SG SG893/92A patent/SG89392G/en unknown
- 1992-12-17 HK HK1024/92A patent/HK102492A/en not_active IP Right Cessation
-
1993
- 1993-05-14 CY CY1672A patent/CY1672A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO894649L (en) | 1990-05-25 |
| GR1000719B (en) | 1992-11-23 |
| GB8926244D0 (en) | 1990-01-10 |
| PT92365B (en) | 1995-07-18 |
| BG51041A3 (en) | 1993-01-15 |
| GB8827389D0 (en) | 1988-12-29 |
| RU1797607C (en) | 1993-02-23 |
| NO173823B (en) | 1993-11-01 |
| KR900007797A (en) | 1990-06-02 |
| HK102492A (en) | 1992-12-24 |
| NO173823C (en) | 1994-02-09 |
| AT392781B (en) | 1991-06-10 |
| ATA266689A (en) | 1990-11-15 |
| NO894649D0 (en) | 1989-11-22 |
| GR890100769A (en) | 1990-12-31 |
| CN1042904A (en) | 1990-06-13 |
| HU204508B (en) | 1992-01-28 |
| ES2023532A6 (en) | 1992-01-16 |
| FI91961C (en) | 1994-09-12 |
| PL161781B1 (en) | 1993-07-30 |
| GB2225322A (en) | 1990-05-30 |
| CY1672A (en) | 1993-05-14 |
| GB2225322B (en) | 1992-03-25 |
| FI91961B (en) | 1994-05-31 |
| SG89392G (en) | 1992-12-04 |
| PT92365A (en) | 1990-05-31 |
| KR0157610B1 (en) | 1998-11-16 |
| HU896132D0 (en) | 1990-02-28 |
| HUT53072A (en) | 1990-09-28 |
| CN1020604C (en) | 1993-05-12 |
| FI895562A0 (en) | 1989-11-22 |
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