CS257294B2 - Productionmethod of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamid - Google Patents
Productionmethod of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamid Download PDFInfo
- Publication number
- CS257294B2 CS257294B2 CS866880A CS688086A CS257294B2 CS 257294 B2 CS257294 B2 CS 257294B2 CS 866880 A CS866880 A CS 866880A CS 688086 A CS688086 A CS 688086A CS 257294 B2 CS257294 B2 CS 257294B2
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- Czechoslovakia
- Prior art keywords
- oxo
- pyrrolidin
- hydroxy
- alkyl
- acetic acid
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- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 4
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract 5
- 238000000034 method Methods 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- DWAWYEUJUWLESO-UHFFFAOYSA-N trichloromethylsilane Chemical compound [SiH3]C(Cl)(Cl)Cl DWAWYEUJUWLESO-UHFFFAOYSA-N 0.000 claims description 4
- 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 description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- 230000009435 amidation Effects 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 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
- -1 ammonia 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetic acid tert-butyl ester Chemical compound 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 2
- JLUFWMXJHAVVNN-UHFFFAOYSA-N methyltrichlorosilane Chemical compound C[Si](Cl)(Cl)Cl JLUFWMXJHAVVNN-UHFFFAOYSA-N 0.000 abstract 2
- 229910004373 HOAc Inorganic materials 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- 239000000047 product Substances 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- XTZSOEDDUBNWON-UHFFFAOYSA-N CCC(C(=O)O)N1CC(=CC1=O)OC Chemical compound CCC(C(=O)O)N1CC(=CC1=O)OC XTZSOEDDUBNWON-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 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
- LJSRSOQMKIBVRH-UHFFFAOYSA-N ethyl 2-(3-methoxy-5-oxo-2h-pyrrol-1-yl)acetate Chemical compound CCOC(=O)CN1CC(OC)=CC1=O LJSRSOQMKIBVRH-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D207/30—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Vynález se týká nového způsobu výroby cerebrálně účinného 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamidu. Z publikace Pifferiho a spol., II Farmaco, Ed.Sc., 1977, 32, 602 je známa pětistupňová syntéza 4-hydroxy-2-oxo-pyrrolidin-l-yl-acetamidu.The present invention relates to a novel process for the preparation of cerebrally active 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide. A five-step synthesis of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide is known from Pifferi et al., II Farmaco, Ed.Sc., 1977, 32, 602.
Vzhledem ke drahým výchozím látkám a celkovému výtěžku asi 33,8 % není však tento způsob rentabilní. Vznikl proto úkol nalézt způsob, který by neměl výše uvedené nevýhody.However, due to expensive starting materials and an overall yield of about 33.8%, this process is not profitable. The object is therefore to find a method which does not have the disadvantages mentioned above.
Úloha byla vyřešena způsobem podle vynálezu. Při tomto postupu se /C^-С^/-alkylester 4-/C^-C2/-alkoxy-3-pyrrolin-2-on~l-yl~octové kyseliny, výhodně etylester 4-methoxy-3-pyrrolin-2-on-l-yl-octové kyseliny, nechá reagovat s trichlormetylsilanem za přítomnosti jodidu alkalického kovu, výhodně jodidu sodného, vzniklý produkt se hydrogenuje a posléze amidu^e amoniakem.The object was solved by the method according to the invention. In this process, 4- (C 1 -C 2 ) -alkoxy-3-pyrrolin-2-one-1-yl-acetic acid (C 1 -C 6 ) -alkyl ester, preferably ethyl 4-methoxy-3-pyrroline- 2-on-1-yl-acetic acid is reacted with trichloromethylsilane in the presence of an alkali metal iodide, preferably sodium iodide, the resulting product is hydrogenated and then the amide is treated with ammonia.
Výhodně se postupuje tak, že se /C^C^Z-alkylester 4-/C1“C2/alkoxy-3-pyrrolin-2-on-l-yl-octové kyseliny, trichlormetylsilan a jodid alkalického kovu nechají reagovat v poměru 1:1:1 až 1:2:2, výhodně 1:1,2:1,2 až 1:1,6:1,6.Preferably, the procedure is such that / C ^ C ^ alkyl ester of Z-4 / C 1 'C 2 / alkoxy-3-pyrroline-2-one-l-yl-acetic acid, chlorotrimethylsilane, and alkali metal iodide are reacted in a ratio 1: 1: 1 to 1: 2: 2, preferably 1: 1.2: 1.2 to 1: 1.6: 1.6.
Reakce se výhodně provádí v acetonitrilu jako rozpouštědle. Reakční teplota leží v oblasti teploty varu rozpouštědla.The reaction is preferably carried out in acetonitrile as a solvent. The reaction temperature lies in the boiling range of the solvent.
Po reakční době od asi 1 do 5 hodin a běžném zpracování, např. a popřípadě čištění produktu, např. překrystalováním, je možno získat příslušný /C1-C4/-alkylester 2,4-dioxo-pyrrolidin-1-yl-octové kyseliny.After a reaction time of about 1-5 hours and the usual processing, e.g., and optionally purifying the product, e.g., by recrystallization, is obtained respective / C 1 -C 4 / alkyl esters of 2,4-dioxo-pyrrolidin-1-yl-acetic acid acid.
Převedení /C^-C^Z-alkylesteru 2,4-dioxo-pyrrolidin-l-yl-octové kyseliny, zvláště etylesteru, na konečný 4-hydroxy-2-oxo-pyrrolidin-l-yl-acetamid redukcí natriumborohydridem a následující amidací amoniakem je v literatuře popsáno /G. Pifferi, M. Pinza, II. Farmaco, Ed.Sc., 1977, 32, 602/.Conversion of 2,4-dioxo-pyrrolidin-1-yl-acetic acid, C1-C12-alkyl ester, especially ethyl ester, to the final 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide by reduction with sodium borohydride and subsequent amidation ammonia is described in the literature / G. Pifferi, M. Pinza, II. Farmaco, Ed.Sc., 1977, 32, 602 /.
4-hydroxy-2-oxo-pyrrolidin~l-yl-acetamid je tak možno získat jako čistý bílý produkt v dobrém výtěžku.Thus, 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide can be obtained as a pure white product in good yield.
Příklad a/ Výroba etylesteru 2,4-dioxo-pyrrolidin-2-on-l-yl-octové kyselinyExample a / Preparation of 2,4-dioxo-pyrrolidin-2-one-1-yl-acetic acid ethyl ester
2,0 g /10 mmol/ etylesteru 4-methoxy-3-pyrrolin-2-on-l-yl-octové kyseliny a 2,1 g /14 mmol/ jodidu sodného se rozpustí ve 20,0 ml acetonitrilu. Pak se přidá 1,6 g /14 mmol/ trichlormetylsilanu. Nažloutlý zakalený reakční roztok se pak zahřívá 4 hodiny к varu. Pak se nechá zchladnout na teplotu místnosti a rozpouštědlo se odpaří při vakuu vodní vývěvy. Zbytek se rozmíchá v 50,0 ml metylenchloridu a přidá se к němu roztok 1,0 g hydrogenuhliČitanu sodného v 5 ml ledové vody. Vodná fáze se třikrát extrahuje 50,0 ml metylenchloridu. Spojené organické fáze se suší síranem sodný, odpaří a suší ve vysokém vakuu.2.0 g (10 mmol) of 4-methoxy-3-pyrrolin-2-one-1-yl-acetic acid ethyl ester and 2.1 g (14 mmol) of sodium iodide are dissolved in 20.0 ml of acetonitrile. 1.6 g (14 mmol) of trichloromethylsilane are then added. The yellowish turbid reaction solution was then heated to reflux for 4 hours. It is then allowed to cool to room temperature and the solvent is evaporated off under a water pump vacuum. The residue is stirred in 50.0 ml of methylene chloride and treated with a solution of 1.0 g of sodium bicarbonate in 5 ml of ice water. The aqueous phase is extracted three times with 50.0 ml of methylene chloride. The combined organic phases were dried over sodium sulfate, evaporated and dried under high vacuum.
Získá se 1,9 g oranžově zbarvené hmoty, která pomalu krystaluje.1.9 g of an orange-colored mass are obtained, which crystallizes slowly.
Překrystalovaný produkt /toluen:petrolether 1:1/ taje při 92 až 93 °C.The recrystallized product (toluene: petroleum ether 1: 1) melts at 92-93 ° C.
MNR /CDC13/ delta = 4,25 /s, 2Н/; 4,23 /q, J « 7,1 Hz, 2Н/; 4,03 /t, J = 1,0 Hz, 2Н/;MNR / CDC1 3 / delta = 4.25 / s 2Н /; 4.23 (q, J = 7.1 Hz, 2H); 4.03 (t, J = 1.0 Hz, 2H);
3,11 /Š,s, 2Н/; 1,30 /t, J = 7,1 Hz, ЗН/.3.11 (b, s, 2 N); 1.30 (t, J = 7.1 Hz, ZN).
b/ Výroba etylesteru 4-hydroxy-2-oxo-pyrrolidin-l-yl-octové kyselinyb) Preparation of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetic acid ethyl ester
К 8,8 g /47,5 mmol/ etylesteru 2,4-dioxo.pyrrolidin-l-yl-octové kyseliny ve 200 ml dimethoxyetanu se při 0 °C přidá 0,54 g /14,5 mmol/ natriumborohydridu. Směs se míchá jednu hodinu při teplotě místnosti. Po ochlazení na 0 °C se přidá přebytek koncentrované kyseliny chlorovodíkové a anorganický zbytek se odfiltruje.To 8.8 g (47.5 mmol) of 2,4-dioxo-pyrrolidin-1-yl-acetic acid ethyl ester in 200 ml of dimethoxyethane at 0 ° C was added 0.54 g (14.5 mmol) of sodium borohydride. The mixture was stirred at room temperature for one hour. After cooling to 0 ° C, excess concentrated hydrochloric acid was added and the inorganic residue was filtered off.
Filtrát se odpaří do sucha. Zbytek se vyjme do chloroformu, suší se síranem sodným a znovu se odpaří dosucha za vakua.The filtrate was evaporated to dryness. The residue is taken up in chloroform, dried over sodium sulfate and evaporated again to dryness under vacuum.
Získá se 8,8 g produktu ve formě oleje.8.8 g of product are obtained in the form of an oil.
Po konečné destilaci při 180 °C /1.10^ Pa se získá 5,3 g /60 %/ bezbarvého oleje.After final distillation at 180 ° C (5.3 mm Hg) 5.3 g (60%) of a colorless oil are obtained.
IR /film/ 3 400 cm1 /ОН/, 1 740 cm1 /С=О/, 1 680 cm1 /С=0/, 1 200 cm”1.IR / film / 3400 cm 1 / ОН /, 1740 cm 1 / С = О /, 1680 cm 1 / С = 0 /, 1 200 cm ” 1 .
с/ Výroba 4-hydroxy-2-oxo-pyrrolidin-l-yl-acetamiduProduction of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide
13,7 g /73 mmol/ etylesteru 4-hydroxy-2-oxo-pyrrolidin-l-yl-octové kyseliny se rozpustí v 500 ml metanolu a nasytí se při 0 °C amoniakem. Pak se udržuje po dobu 1 hodiny při teplotě místnosti. Odpařením rozpouštědla za vakua se získá pevný zbytek, který se krystaluje z matanolu.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 kept at room temperature for 1 hour. Evaporation of the solvent in vacuo 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.7.17 g (62%) of the product are obtained in the form of a white powder, m.p. Mp 165-168 ° C.
IR /nujel/ 3 400 cm“1, 3 300 cm”1 /ОН a NH/, 1 660 cm1 /С=О/. ’IR / nujel / 3400 cm "1, 3300 cm" 1 / ОН and NH /, 1660 cm 1 / С = О /. '
Claims (3)
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 (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH412685A CH664957A5 (en) | 1985-09-24 | 1985-09-24 | 4-Hydroxy-2-oxo-1-pyrrolidinyl-acetamide prodn. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS688086A2 CS688086A2 (en) | 1987-09-17 |
| CS257294B2 true CS257294B2 (en) | 1988-04-15 |
Family
ID=4270309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS866880A CS257294B2 (en) | 1985-09-24 | 1986-09-24 | Productionmethod of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamid |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS6272661A (en) |
| CH (1) | CH664957A5 (en) |
| CS (1) | CS257294B2 (en) |
| SU (1) | SU1482525A3 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9309749D0 (en) * | 1993-05-12 | 1993-06-23 | Boots Co Plc | Therapeutic agents |
-
1985
- 1985-09-24 CH CH412685A patent/CH664957A5/en not_active IP Right Cessation
-
1986
- 1986-09-19 JP JP22177186A patent/JPS6272661A/en active Pending
- 1986-09-23 SU SU864028166A patent/SU1482525A3/en active
- 1986-09-24 CS CS866880A patent/CS257294B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SU1482525A3 (en) | 1989-05-23 |
| CS688086A2 (en) | 1987-09-17 |
| CH664957A5 (en) | 1988-04-15 |
| JPS6272661A (en) | 1987-04-03 |
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