CH668066A5 - New alkyl 4-alkoxy-2-oxo-3 -pyrroline-1-acetate cpds. - Google Patents
New alkyl 4-alkoxy-2-oxo-3 -pyrroline-1-acetate cpds. Download PDFInfo
- Publication number
- CH668066A5 CH668066A5 CH1958/86A CH195886A CH668066A5 CH 668066 A5 CH668066 A5 CH 668066A5 CH 1958/86 A CH1958/86 A CH 1958/86A CH 195886 A CH195886 A CH 195886A CH 668066 A5 CH668066 A5 CH 668066A5
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- Prior art keywords
- alkyl
- alkoxy
- ester
- oxo
- pyrroline
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Classifications
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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
- C07D207/30—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
Alkyl 4-alkoxy-2-oxo-3-pyrroline-1 -acetates of formula (I) are new: (where R1 = Me or Et; R2 = 1-4C alkyl or benzyl.
Description
BESCHREIBUNG
Die 4-Alkoxy-3 -pyrrolin-2-on-1 -yl -essigsäurealkylester sind wertvolle Zwischenprodukte für die Herstellung des ce rebral wirksamen 4-Hydroxy-2-oxo -pyrrolidin- 1 -yl-acet- amids.
Zur Herstellung des Wirkstoffs sind zwar einige Verfahren bekannt, allen haftet jedoch der Nachteil der Unrentabilität, wegen schlechten Ausbeuten oder teuren Ausgangsprodukten, an.
Es stellte sich daher die Aufgabe, Verfahren zu entwikkeln, die diese Nachteile vermeiden.
Ein wesentlicher Teil der Aufgabe konnte gelöst werden mit dem vorliegenden Verfahren nach Patentanspruch 1, das erlaubt, ausgehend von 4-Halogen-3 -(C1 -C2)-alkoxy-2-Ebuten-säure -C1-C4-alkylester durch Umsetzung mit Glycin Cl-C4-alkyl- oder -benzylester oder dessen Hydrohalogenid in Gegenwart einer Base zum gewünschten 4-Alkoxy-3 -pyr rolin-2-on-1-yl-essigsäureester umzusetzen.
Der 4-Halogen-3 -(C1-C2)-alkoxy-2-E-buten -säure C,-C4-alkylester kann auf literaturbekannte Weise, z.B. nach Köhler, Dissertation Universität Bayreuth 1985, aus 4-Halogenacetessigester hergestellt werden.
Die Umsetzung wird zweckmässig in Gegenwart von schwachen anorganischen Basen oder tert. aliphatischen Aminen als Basen durchgeführt. Besonders bevorzugte Vertreter der schwachen anorganischen Basen sind z.B. Natriumacetat, Kaliumcarbonat oder Kaliumhydrogencarbonat.
Als geeigneter Vertreter eines tert. aliphatischen Amins kann Triethylamin verwendet werden.
Es ist ausserdem von Vorteil, die Reaktion in einem Lö sungsmittel durchzuführen. Zweckmässig werden dazu aprotische oder protische Lösungsmittel mit hoher Polarität verwendet.
Geeignete Vertreter sind z.B. Acetonitril, Propionitril, Butyronitril, Diethylenglycolmonomethylether, Diethylenglycoldimethylether, N,N'-Dimethylformamid oder N,N'-Dimethylacetamid.
Zweckmässig wird der Glycin-C1-C4-alkyl- oder -benzylester in einer Menge von 1 bis 4 Mol, vorzugsweise von 1,25 bis 2 Mol pro Mol Halogenalkoxybutensäureester eingesetzt.
Vielfach gelangt das Hydrohalogenid, vorzugsweise das Hydrochlorid des Glycinalkylesters zur Anwendung. Dann ist es zweckmässig, vor der Umsetzung mit dem Halogenalkoxybutensäureester durch Behandeln mit einer Base, wie z.B.
einem Trialkylamin, vorzugsweise Triethylamin, oder mit einem Alkalimethylat, wie Natriummethylat, das Glycinalkylesterhydrohalogenid in den freien Glycinalkylester überzuführen.
Die Reaktionstemperatur wählt man zweckmässig zwischen 60 und 120 C.
Sofern es die Siedetemperatur des Lösungsmittels zulässt (wie z.B. bei Acetonitril), kann bei Rückflusstemperatur gearbeitet werden.
Nach Beendigung der Reaktion wird auf übliche Weise, z.B. durch Extraktion und gegebenenfalls durch eine anschliessende Umkristallisation, das Produkt aufgearbeitet.
Mit diesen erfindungsgemässen Verfahren werden Ausbeuten erreicht, die in der Regel 80% übersteigen.
Die Gehalte der erhaltenen Produkte liegen üblicherweise höher als 95%.
Beispiel 4-Methoxy-3-pyrrolin-2-on -I-yl-essigsäurenzet¯ylestel aus 4-Chlor-3 -methoxy-buten-2-E-säuremetAlylester
Eine Suspension von 6,5 g (0,052 Mol) Glycinmethylester-hydrochlorid in 30 ml Acetonitril wurde mit einer Lösung von 5,3 g Triethylamin in 10 ml Acetonitril versetzt.
Man erhitzte zum Rückfluss und gab 2,1 g wasserfreies Natriumacetat hinzu. Anschliessend wurde innerhalb von 30 Minuten eine Lösung von 4,4 g (0,025 Mol) 4-Chlor-3-methoxy-buten -2-E-säuremethylester (Gehalt (GC): 95,2%) und 20 ml Acetonitril zugetropft. Man liess unter Rückfluss 4,5 Stunden nachrühren. Dann wurde die Reaktionslösung auf 0 "C abgekühlt, vom ausgefallenen Feststoff abfiltriert und das Filtrat am Rotationsverdampfer eingeengt. Der Rückstand wurde in 100 ml Eiswasser aufgenommen, mit 6,0 g 32%iger Salzsäure angesäuert und fünfmal mit je 100 ml Methylenchlorid extrahiert. Die organische Lösung wurde über Na2SO4 getrocknet und eingedampft. Der Rückstand wurde in 30 ml Tetrachlorkohlenstoff umkristallisiert. Man erhielt 4,0 g weisses, kristallines Produkt vom Schmelzpunkt: 105 bis 107 C (GC-Gehalt: 96%). Ausbeute: 81,5%.
DESCRIPTION
The 4-alkoxy-3-pyrrolin-2-one-1-yl -acetic acid alkyl esters are valuable intermediates for the production of the ce-rebral active 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide.
Some methods are known for the preparation of the active ingredient, but all have the disadvantage of unprofitability because of poor yields or expensive starting materials.
The task was therefore to develop methods that avoid these disadvantages.
An essential part of the object could be achieved with the present method according to claim 1, which allows starting from 4-halo-3 - (C1-C2) alkoxy-2-ebutene acid C1-C4-alkyl ester by reaction with glycine Cl-C4-alkyl or benzyl ester or its hydrohalide in the presence of a base to convert the desired 4-alkoxy-3-pyrrolin-2-one-1-yl-acetic acid ester.
The 4-halo-3 - (C1-C2) alkoxy-2-E-butenoic acid C 1 -C 4 -alkyl ester can be prepared in a manner known from the literature, e.g. according to Köhler, dissertation University of Bayreuth 1985, from 4-haloacetoacetic ester.
The reaction is conveniently carried out in the presence of weak inorganic bases or tert. aliphatic amines carried out as bases. Particularly preferred representatives of the weak inorganic bases are e.g. Sodium acetate, potassium carbonate or potassium hydrogen carbonate.
As a suitable representative of a tert. aliphatic amine, triethylamine can be used.
It is also advantageous to carry out the reaction in a solvent. Aprotic or protic solvents with high polarity are expediently used for this purpose.
Suitable representatives are e.g. Acetonitrile, propionitrile, butyronitrile, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, N, N'-dimethylformamide or N, N'-dimethylacetamide.
The glycine-C1-C4-alkyl or benzyl ester is expediently used in an amount of 1 to 4 moles, preferably 1.25 to 2 moles, per mole of haloalkoxybutonic acid ester.
The hydrohalide, preferably the hydrochloride of the glycine alkyl ester, is often used. Then it is convenient to treat with the haloalkoxybutenic acid ester by treating with a base such as e.g.
a trialkylamine, preferably triethylamine, or with an alkali methylate, such as sodium methylate, to convert the glycinalkyl ester hydrohalide into the free glycinalkyl ester.
The reaction temperature is appropriately chosen between 60 and 120 C.
If the boiling point of the solvent allows it (e.g. acetonitrile), you can work at the reflux temperature.
After the reaction has ended, the product is worked up by extraction and optionally by subsequent recrystallization.
With these methods according to the invention, yields are achieved which generally exceed 80%.
The contents of the products obtained are usually higher than 95%.
Example 4-methoxy-3-pyrrolin-2-one -I-yl-acetic acid zentyl from 4-chloro-3-methoxy-buten-2-E-acidic acid methyl ester
A suspension of 6.5 g (0.052 mol) of glycine methyl ester hydrochloride in 30 ml of acetonitrile was mixed with a solution of 5.3 g of triethylamine in 10 ml of acetonitrile.
The mixture was heated to reflux and 2.1 g of anhydrous sodium acetate were added. A solution of 4.4 g (0.025 mol) of 4-chloro-3-methoxybutene-2-E-acidic acid methyl ester (content (GC): 95.2%) and 20 ml of acetonitrile was then added dropwise within 30 minutes. The mixture was allowed to stir under reflux for 4.5 hours. The reaction solution was then cooled to 0 ° C., the precipitated solid was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was taken up in 100 ml of ice water, acidified with 6.0 g of 32% hydrochloric acid and extracted five times with 100 ml of methylene chloride organic solution was dried over Na2SO4 and evaporated. The residue was recrystallized from 30 ml of carbon tetrachloride. 4.0 g of white, crystalline product of melting point: 105 to 107 C (GC content: 96%) were obtained. Yield: 81.5% .
Claims (4)
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1958/86A CH668066A5 (en) | 1986-05-14 | 1986-05-14 | New alkyl 4-alkoxy-2-oxo-3 -pyrroline-1-acetate cpds. |
HU863310A HU195773B (en) | 1985-09-24 | 1986-08-01 | Process for preparing alkyl esters of 4-alkoxy-3-pyrrolin-2-on-1-yl-acetic acid |
IE216186A IE59030B1 (en) | 1985-09-24 | 1986-08-11 | 4-alkoxy-3-pyrrolin-2-on-1-ylacetic acid alkyl esters and process for the preparation thereof |
CS76790A CS274704B2 (en) | 1986-05-14 | 1986-08-14 | Method of 4-alkoxy-3-pyrroline-2-on-1-yl acetic acid's alkyl esters production |
IL8679947A IL79947A (en) | 1985-09-24 | 1986-09-04 | 4-alkoxy-3-pyrrolin-2-on-1-yl acetic acid esters and process for their preparation |
JP61221770A JPH0742269B2 (en) | 1985-09-24 | 1986-09-19 | 4-Alkoxy-3-pyrrolin-2-one-1-yl-acetic acid alkyl ester and process for producing the same |
EP86112951A EP0216324B1 (en) | 1985-09-24 | 1986-09-19 | 4-alkoxy-3-pyrrolin-2-one-1-yl-acetic acid alkyl and benzyl esters and their preparation |
AT86112951T ATE58527T1 (en) | 1985-09-24 | 1986-09-19 | 4-ALKOXY-3-PYRROLINE-2-ON-1-YL-ACETIC ACID REALKYLB. -BENZYLESTER AND THEIR PRODUCTION. |
DE8686112951T DE3675722D1 (en) | 1985-09-24 | 1986-09-19 | 4-ALKOXY-3-PYRROLIN-2-ON-1-YL-ACETIC ACID ALKYL- OR -BENZYLESTER AND THEIR PRODUCTION. |
ES8602068A ES2001695A6 (en) | 1985-09-24 | 1986-09-22 | 4-Alkoxy-3-pyrrolin-2-one-1-yl-acetic acid alkyl and benzyl esters and their preparation. |
DK453486A DK453486A (en) | 1985-09-24 | 1986-09-23 | 4-ALCOXY-3-PYRROLIN-2-ON-1-YL-ACETIC ACID ALKYL ESTERS AND THEIR PREPARATION |
NO86863791A NO171848C (en) | 1985-09-24 | 1986-09-23 | PREPARATION OF 4-ALCOXY-3-PYRROLIN-2-ON-1-YL-ACETIC ACYLIC ACYL ESTERS |
CA000519007A CA1271769A (en) | 1985-09-24 | 1986-09-24 | 4-alkoxy-3-pyrrolin-2-on-1-yl acetic acid alkyl esters and their production |
US06/931,849 US4780545A (en) | 1985-09-24 | 1986-11-18 | Production of 4-alkoxy-3-pyrrolin-2-on-1-yl acetic acid alkyl esters |
SU874203443A SU1486057A3 (en) | 1986-05-14 | 1987-10-12 | Method of producing c4-alkyl esters of 4-alkoxy-3-pyrroline-2-on-1-yl acetic acid |
US07/147,275 US4880940A (en) | 1985-09-24 | 1988-07-22 | 4-alkoxy-3-pyrrolin-2-on-1-yl acetic acid alkyl esters |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1958/86A CH668066A5 (en) | 1986-05-14 | 1986-05-14 | New alkyl 4-alkoxy-2-oxo-3 -pyrroline-1-acetate cpds. |
Publications (1)
Publication Number | Publication Date |
---|---|
CH668066A5 true CH668066A5 (en) | 1988-11-30 |
Family
ID=4222573
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH1958/86A CH668066A5 (en) | 1985-09-24 | 1986-05-14 | New alkyl 4-alkoxy-2-oxo-3 -pyrroline-1-acetate cpds. |
Country Status (3)
Country | Link |
---|---|
CH (1) | CH668066A5 (en) |
CS (1) | CS274704B2 (en) |
SU (1) | SU1486057A3 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
-
1986
- 1986-05-14 CH CH1958/86A patent/CH668066A5/en not_active IP Right Cessation
- 1986-08-14 CS CS76790A patent/CS274704B2/en unknown
-
1987
- 1987-10-12 SU SU874203443A patent/SU1486057A3/en active
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
US5371237A (en) * | 1990-06-26 | 1994-12-06 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
Also Published As
Publication number | Publication date |
---|---|
SU1486057A3 (en) | 1989-06-07 |
CS76790A2 (en) | 1990-11-14 |
CS274704B2 (en) | 1991-09-15 |
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