CS257300B2 - Production method of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide - Google Patents
Production method of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide Download PDFInfo
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- CS257300B2 CS257300B2 CS87617A CS61787A CS257300B2 CS 257300 B2 CS257300 B2 CS 257300B2 CS 87617 A CS87617 A CS 87617A CS 61787 A CS61787 A CS 61787A CS 257300 B2 CS257300 B2 CS 257300B2
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- CS
- Czechoslovakia
- Prior art keywords
- pyrrolidin
- hydroxy
- oxo
- acetic acid
- anhydrous
- Prior art date
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- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 230000009435 amidation Effects 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- ZZJLZWBHBUGCAZ-UHFFFAOYSA-N 2-(2,4-dioxopyrrolidin-1-yl)acetic acid Chemical compound OC(=O)CN1CC(=O)CC1=O ZZJLZWBHBUGCAZ-UHFFFAOYSA-N 0.000 claims 1
- BMOXYLBGPIDAAN-UHFFFAOYSA-N 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid Chemical compound OC1CN(CC(O)=O)C(=O)C1 BMOXYLBGPIDAAN-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 125000005907 alkyl ester group Chemical group 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- YDBONCLBTWFUPF-UHFFFAOYSA-N ethyl 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetate Chemical compound CCOC(=O)CN1CC(O)CC1=O YDBONCLBTWFUPF-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- FCPNSEAKHSMNCT-UHFFFAOYSA-N 2-(3-methoxy-5-oxo-2h-pyrrol-1-yl)acetic acid Chemical compound COC1=CC(=O)N(CC(O)=O)C1 FCPNSEAKHSMNCT-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- SZFQKAPNPSIRHD-UHFFFAOYSA-N ethyl 2-(2,4-dioxopyrrolidin-1-yl)acetate Chemical compound CCOC(=O)CN1CC(=O)CC1=O SZFQKAPNPSIRHD-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
Nový způsob výroby cerebrálně účinného 4-hydroxy-2-oxopyrrolidin-l-yl-acetamidu, který vychází z alkylesterů 4-alkoxy-3-pyrrolin-2-on-l-yl-octové kyseliny.A new method of producing cerebrally effective 4-Hydroxy-2-oxopyrrolidin-1-yl-acetamide, starting from 4-alkoxy-3-pyrrolin-2-on-1-yl-acetic alkyl esters acid.
Description
Vynález se týká nového způsobu výroby oerebrálně účinného 4-hydroxy-2-oxo-pyrrolidin-l-yl-acetamidu. Z publikace Pfifferiho a spol., II Farmaco, Ed. Sc., 1977, 32, 602 je známa pětistupňová příprava 4-hydroxy-2-oxo-pyrrolidin-l-yl-acetamidu. Vzhledem ke drahým výchozím látkám a celkovému výtěžku asi 33,8 % není však tento způsob rentabilní. Vznikl proto úkol nalézt jiný způsob, který nebude mít uvedené nedostatky.The present invention relates to a novel process for the preparation of an orally active 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide. From Pfifferi et al., II Farmaco, Ed. Sc., 1977, 32, 602, a five-step preparation of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide is known. However, due to expensive starting materials and an overall yield of about 33.8%, this process is not profitable. Therefore, the task was to find another way that would not have the shortcomings mentioned.
Úkol byl vyřešen postupem podle vynálezu. 4-(C^-Cj)-alkoxy-3-pyrrolin-2-on-l-yl-octová kyselina ve formě (C^-C^lalkylesteru, výhodně ethylester 4-raethoxy-3-pyrrolin-2-on-l-yl-octové kyseliny, se při tomto postupu podrobí působení kyselého bezvodého prostředí, vzniklý produkt se hydrogenuje a posléze amiduje amoniakem.The object was solved by the process according to the invention. 4- (C1-C4) -alkoxy-3-pyrrolin-2-one-1-yl-acetic acid in the form of (C1-C4) alkyl ester, preferably 4-methoxy-3-pyrrolin-2-one-1-ethyl ester -yl acetic acid is treated with an acidic anhydrous medium, the product is hydrogenated and then amidated with ammonia.
Výhodně se postupuje následujícím způsobem:Preferably, the following procedure is performed:
Kyselé médium se výhodně připraví zaváděním plynného chlorovodíku nebo plynného bromovodiku do C^-C^-karboxylové kyseliny, která je popřípadě bezvodá.The acidic medium is preferably prepared by introducing hydrogen chloride or hydrogen bromide gas into a C 1 -C 4 -carboxylic acid, which is optionally anhydrous.
Výhodnou C^-C^-karboxylovou kyselinou je kyselina octová. Zvláště výhodně se používá plynný chlorovodík v kyselině octové. Reakční teplota se volí mezi 0 a 50 °C.A preferred C 1 -C 4 -carboxylic acid is acetic acid. Hydrogen chloride gas in acetic acid is particularly preferably used. The reaction temperature is chosen between 0 and 50 ° C.
Po uplynutí reakční doby od 5 do 10 hodin se může reakční směs zpracovat obvyklým způsobem, například odpařením rozpouštědla a popřípadě krystalizací.After a reaction time of from 5 to 10 hours, the reaction mixture may be worked up in the usual manner, for example by evaporation of the solvent and optionally crystallization.
Převedení (C^-C^)-alkylesteru 2,4-dioxo-pyrrolidin-l-yl-octové kyseliny, zvláště ethylesteru, na konečný produkt 4-hydroxy-2-oxo-pyrrolidin-l-yl-acetamid redukcí natriumborohydridem a následující amidací amoniakem je v literatuře popsáno (G. Pifferi, M. Pinza, .11 Farmaco, Ed. Sc., 1977, 32, 602). 4-hydroxy-2-oxo-pyrrolidin-l-yl-acetamid se tak získá jako čistě bílý produkt v dobrém výtěžku.Conversion of 2,4-dioxo-pyrrolidin-1-yl-acetic acid (C 1 -C 4) -alkyl ester, especially ethyl ester, to the final product 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide by reduction with sodium borohydride and following amidation with ammonia is described in the literature (G. Pifferi, M. Pinza, 11 Farmaco, Ed. Sc., 1977, 32, 602). Thus, 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide is obtained as a pure white product in good yield.
PříkladExample
a) Výroba ethylesteru 2,4-dioxo-pyrrolidin-l-yl-octové kyseliny(a) Preparation of 2,4-dioxo-pyrrolidin-1-yl-acetic acid ethyl ester
10,0 g ethylesteru 4-methoxy-3-pyrrolidin-2-on-l-yl-octové kyseliny (obsah podle plynové chromatografie: 80 %) se rozpustí v 50,0 ml kyseliny octové a při 35 až 40 °C se 9 hodin za míchání sytí plynným chlorovodíkem. Nakonec se kyselina octová odpaří na rotační odparce za vakua pří teplotě lázně 60 °C. Zbytek se vyjme do 50,0 ml toluenu a ještě jednou odpaří. Získá se 12,4 g surového produktu, který krystaluje v chladničce.Dissolve 10.0 g of 4-methoxy-3-pyrrolidin-2-one-1-yl-acetic acid ethyl ester (content by gas chromatography: 80%) in 50.0 ml of acetic acid and it is saturated with hydrogen chloride gas while stirring. Finally, the acetic acid is evaporated on a rotary evaporator under vacuum at a bath temperature of 60 ° C. The residue is taken up in 50.0 ml of toluene and evaporated again. 12.4 g of crude product are obtained, which crystallizes in a refrigerator.
b) Výroba ethylesteru 4-hydroxy-2-oxo-pyrrolidin-l-yl-octové kyselinyb) Preparation of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetic acid ethyl ester
12,2 g výše získaného surového produktu se rozpustí v 50,0 ml acetonitrilu a při teplotě místnosti se přidá k suspenzi 1,6 g natriumborohydridu v 50,0 ml acetonitrilu. Reakční teplota přitom stoupne na 35 až 40 °C. Při této teplotě se reakční roztok míchá jednu hodinu. Pak se okyselí koncentrovanou kyselinou chlorovodíkovou na hodnotu pH asi 5. Rozpouštědlo se odstraní na rotační odparce, zbytek se zředí 25 ml ledové vody a extrahuje se methylenchloridem. Po vysušení methylenchloridového roztoku síranem sodným a odpaření rozpouštědla zůstane12.2 g of the crude product obtained above are dissolved in 50.0 ml of acetonitrile and added at room temperature to a suspension of 1.6 g of sodium borohydride in 50.0 ml of acetonitrile. The reaction temperature rises to 35 to 40 ° C. The reaction solution was stirred at this temperature for one hour. It is then acidified with concentrated hydrochloric acid to a pH of about 5. The solvent is removed by rotary evaporation, the residue is diluted with 25 ml of ice-water and extracted with methylene chloride. After drying the methylene chloride solution with sodium sulfate and evaporating the solvent, it remains
9,5 g surového produktu, který podle HPLC obsahuje 51,5 % připravované sloučeniny, což odpovídá výtěžku 66,1'% vztaženo: na výchozí ethylester 4-methoxy-3-pyrrolin-2-on-l-yl-octové kyseliny.9.5 g of crude product which, according to HPLC, contained 51.5% of the compound to be prepared, corresponding to a yield of 66.1% based on 4-methoxy-3-pyrrolin-2-on-1-yl-acetic acid starting ethyl ester.
Chromatograflckou filtraci na silikagelu za použití kyseliny octové jako elučního činidla se získá produkt, který podle HPLC obsahuje více než 96 % připravované sloučeniny.Chromatography on silica gel using acetic acid as the eluent gave a product which contained more than 96% of the title compound as determined by HPLC.
c) Výroba 4-hydroxy-2-oxo-pyrrolidin-l-yl-acetamiduc) Preparation of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide
13,7 g (73 mmol) ethylesteru 4-hydroxy-2-oxo-pyrrolidin-l-yl-octové kyseliny se rozpustí v 500 ml methanolu a nasytí při 0 °C amoniakem. Pak se udržuje po dobu jedné hodiny při teplotě místnosti. Odpařením rozpouštědla za vakua se získá pevný zbytek, který se krystaluje z methánolu.13.7 g (73 mmol) of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetic acid ethyl ester are dissolved in 500 ml of methanol and saturated at 0 ° C with ammonia. It is then maintained at room temperature for one hour. Evaporation of the solvent under vacuum gave a solid residue which was crystallized from methanol.
Získá se 7,17 g (62 %) produktu ve formě bílého prášku. T.t. 165 až 168 °C. XR (nujol) 3 400 cm-1, 3 300 cm-1, 3 250 cm-1 (OH a NH) , 1 660 cm-1 (C=0).7.17 g (62%) of the product are obtained in the form of a white powder. Mp 165-168 ° C. XR (nujol) 3400 cm -1 , 3300 cm -1 , 3250 cm -1 (OH and NH), 1660 cm -1 (C = O).
PŘEDMĚT VYNÁLEZUSUBJECT OF THE INVENTION
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS87617A CS257300B2 (en) | 1986-05-20 | 1987-01-30 | Production method of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH202386A CH666481A5 (en) | 1986-05-20 | 1986-05-20 | 4-Hydroxy-2-oxo-1-pyrrolidinyl-acetamide prodn. |
| CS866880A CS257294B2 (en) | 1985-09-24 | 1986-09-24 | Productionmethod of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamid |
| CS87617A CS257300B2 (en) | 1986-05-20 | 1987-01-30 | Production method of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS61787A2 CS61787A2 (en) | 1987-09-17 |
| CS257300B2 true CS257300B2 (en) | 1988-04-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS87617A CS257300B2 (en) | 1986-05-20 | 1987-01-30 | Production method of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS257300B2 (en) |
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1987
- 1987-01-30 CS CS87617A patent/CS257300B2/en unknown
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| Publication number | Publication date |
|---|---|
| CS61787A2 (en) | 1987-09-17 |
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