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NO871976L - 4-ALKOSY-3-PYRROLIN-2-ON-1-YL-ACETIC ACID AMIDES AND THE PREPARATION AND USE OF THEREOF. - Google Patents

4-ALKOSY-3-PYRROLIN-2-ON-1-YL-ACETIC ACID AMIDES AND THE PREPARATION AND USE OF THEREOF.

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Publication number
NO871976L
NO871976L NO871976A NO871976A NO871976L NO 871976 L NO871976 L NO 871976L NO 871976 A NO871976 A NO 871976A NO 871976 A NO871976 A NO 871976A NO 871976 L NO871976 L NO 871976L
Authority
NO
Norway
Prior art keywords
acetic acid
pyrrolin
alkyl
compounds according
preparation
Prior art date
Application number
NO871976A
Other languages
Norwegian (no)
Other versions
NO871976D0 (en
Inventor
Thomas Meul
John Mcgarrity
Original Assignee
Lonza Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lonza Ag filed Critical Lonza Ag
Publication of NO871976D0 publication Critical patent/NO871976D0/en
Publication of NO871976L publication Critical patent/NO871976L/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic 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
    • C07D207/18Heterocyclic 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
    • C07D207/22Heterocyclic 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
    • C07D207/24Oxygen or sulfur atoms
    • C07D207/262-Pyrrolidones
    • C07D207/2732-Pyrrolidones 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 other ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic 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
    • C07D207/30Heterocyclic 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
    • C07D207/34Heterocyclic 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
    • C07D207/36Oxygen or sulfur atoms
    • C07D207/382-Pyrrolones

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Electric Clocks (AREA)

Description

De nye forbindelser ifølge oppfinnelsen er verdifulle mellomprodukter ved fremstilling av det cerebralt virksomme 4-hydroksy-2-okso-pyrrolidin-l-yl-acetamid. The new compounds according to the invention are valuable intermediates in the production of the cerebrally active 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide.

Hittil er det kjent flere fremgangsmåter for å fremstille det ovenfornevnte virkestoff. Dårlige utbytter og dyre utgangs-produkter gjør imidlertid disse veier urentable (G. Pifferi, H. Pinza, Il Farmaco, Ed.Sc, 1977, 32, 602). To date, several methods have been known for producing the above-mentioned active substance. However, poor yields and expensive starting products make these routes unprofitable (G. Pifferi, H. Pinza, Il Farmaco, Ed.Sc, 1977, 32, 602).

Det besto derfor den oppgave å finne en vei som ikke er beheftet med disse ulemper. The task was therefore to find a way that is not affected by these disadvantages.

Ved oppfinnelsen av de nye 4-(Ci-C2)-alkoksy-3-pyrrolin-2-on-l-yl-eddiksyreamider ifølge krav 1, kunne denne oppgaven løses forbausende enkelt. With the invention of the new 4-(C1-C2)-Alkoxy-3-pyrrolin-2-on-1-yl-acetic acid amides according to claim 1, this task could be solved surprisingly simply.

De nye mellomprodukter, fortrinnsvis 4-metoksy-3-pyrrolin-3-on-l-yl-eddiksyreamidet, fremstilles etter en fremgangsmåte ifølge krav 2 ut fra 4-alkoksy-3-pyrrolin-2-on-l-yl-eddiksyre-Ci-C4-alkylestere ved omsetning av dem med ammoniak. The new intermediates, preferably the 4-methoxy-3-pyrrolin-3-on-l-yl-acetic acid amide, are prepared according to a method according to claim 2 from 4-methoxy-3-pyrrolin-2-on-l-yl-acetic acid Ci-C4 alkyl esters by reacting them with ammonia.

4-alkoksy-3-pyrrolin-2-on-l-yl-eddiksyre-Ci -C4-alkylesterene kan fremstilles på enkel måte ifølge Sveitsisk patentsøknad nr. 4119/85. 4-Alkoxy-3-pyrrolin-2-on-1-yl-acetic acid C 1 -C 4 alkyl esters can be prepared in a simple manner according to Swiss Patent Application No. 4119/85.

Hensiktsmessig oppløser man 4-alkoksy-3-pyrrolin-2-on-l-yl-eddiksyre-Ci-C4-alkylesteren i en alkohol som løsningsmiddel. Fortrinnsvis kommer lavere alifatiske alkoholer så som etanol eller metanol, særlig foretrukket metanol til anvendelse. It is expedient to dissolve the 4-Alkoxy-3-pyrrolin-2-on-1-yl-acetic acid C1-C4 alkyl ester in an alcohol as solvent. Preferably, lower aliphatic alcohols such as ethanol or methanol, particularly preferably methanol, are used.

Deretter mettes løsningen normalt i en autoklav hensiktsmessig med gassformig ammoniak ved temperaturer rundt 0°C. The solution is then normally saturated in an autoclave appropriately with gaseous ammonia at temperatures around 0°C.

Ved reaksjonstemperaturer mellom 40 og 70° C er reaksjonen som regel avsluttet etter 5 til 10 timer. At reaction temperatures between 40 and 70° C, the reaction is usually finished after 5 to 10 hours.

Opparbeidingen kan foretas på enkel måte ved fordampning av løsningsmiddelet og eventuelt ved en etterfølgende rensning ved omkrystallisering. The processing can be carried out in a simple way by evaporation of the solvent and possibly by a subsequent purification by recrystallization.

Etter denne fremgangsmåten er det mulig å oppnå nesten kvantitative utbytter og ytterst rene produkter. Following this procedure, it is possible to obtain almost quantitative yields and extremely pure products.

Ifølge krav 4 kan de nye forbindelser ifølge oppfinnelsen med fordel anvendes som mellomprodukter ved fremstilling av det cerebralt virksomme 4-hydroksy-pyrrolin-2-on-l-yl-acetamid. According to claim 4, the new compounds according to the invention can advantageously be used as intermediates in the production of the cerebrally active 4-hydroxy-pyrrolin-2-on-1-yl-acetamide.

For dette omsettes hensiktsmessig det tilsvarende mellomprodukt i et vannfritt surt medium i et første trinn og omsettes så med et alkaliborhydrid til sluttproduktet. For this, the corresponding intermediate product is suitably reacted in an anhydrous acidic medium in a first step and then reacted with an alkali borohydride to the final product.

Som vannfritt medium anvendes hensiktsmessig hydrogenklorid eller hydrogenbromid oppløst i en Ci -C-» -karboksylsyre. Hydrogen chloride or hydrogen bromide dissolved in a C 1 -C 2 -carboxylic acid is suitably used as an anhydrous medium.

Særlig foretrukket er det å anvende hydrogenbromid i eddiksyre. It is particularly preferred to use hydrogen bromide in acetic acid.

I forhold til 1 mol anvendt alkoksypyrrolinonylacetamid anvendes hydrogenklorid hhv. hydrogenbromid i mengder på hensiktsmessig 1 til 2 mol. In relation to 1 mol of alkoxypyrrolinyl acetamide used, hydrogen chloride is used or hydrogen bromide in amounts of suitably 1 to 2 mol.

Reaksjonstemperaturen beveger seg hensiktsmessig mellom 40 og 50° C. The reaction temperature is suitably between 40 and 50° C.

Det midlertidige dannede hydrohalogenid av 2,4-dioksy-pyrrolin-l-yl-acetamid omsettes som regel direkte med et alkaliborhydrid, fortrinnsvis med natriumborhydrid. Dette reaksjons-trinnet utføres hensiktsmessig i dimetylformamid som løsnings-middel ved temperaturer fra 0 til 40°C, hensiktsmessig fra 20 til 30 °C. The temporarily formed hydrohalide of 2,4-dioxy-pyrrolin-1-yl-acetamide is usually reacted directly with an alkali borohydride, preferably with sodium borohydride. This reaction step is suitably carried out in dimethylformamide as solvent at temperatures from 0 to 40°C, suitably from 20 to 30°C.

Opparbeidingen kan utføres på vanlig måte ved f.eks. surgjøring av reaksjonsblandingen, ekstrahering av produktet og eventuelt ved etterfølgende omkrystallisering. Processing can be carried out in the usual way by e.g. acidification of the reaction mixture, extraction of the product and possibly by subsequent recrystallization.

På denne måten lykkes det å få et sluttprodukt i gode utbytter og med høy kvalitet. In this way, it is possible to obtain a final product in good yields and of high quality.

EKSEMPELEXAMPLE

Fremstilling av 4- metoksy- 3- pyrrolin- 2- on- l- yl- acetamid Preparation of 4-methoxy-3-pyrroline-2-on-1-yl-acetamide

25,0 g (0,10 mol) 4-metoksy-3-pyrrolin-2-on-l-yl-eddiksyre-etylester med et innhold ifølge GC på 78,7% ble oppløst i 300 ml metanol og mettet med gassformid NH3ved 0°C. Reaksjonsblandingen ble rørt i en autoklav i 5 timer ved 60°C. Etter inndamping av reaksjonsløsningen ble resten omkrystallisert varmt fra metanol. 25.0 g (0.10 mol) of 4-methoxy-3-pyrrolin-2-on-1-yl-acetic acid ethyl ester with a content according to GC of 78.7% was dissolved in 300 ml of methanol and saturated with gas formamide NH3 at 0°C. The reaction mixture was stirred in an autoclave for 5 hours at 60°C. After evaporation of the reaction solution, the residue was recrystallized hot from methanol.

Man fikk 16,6 g (=97,5% av teoretisk utbytte) tynnskikt-kromatografisk rent produkt med et smeltepunkt på 184 til 186°C. 16.6 g (=97.5% of theoretical yield) of thin-layer chromatographically pure product with a melting point of 184 to 186°C was obtained.

NMR (DMSO-de , 300 MHz):NMR (DMSO-de, 300 MHz):

7,4 (br. s, 1H), 7,06 (br. s, 1H), 5,16 (s, 1H), 3,97 (s, 2H), 3,85 (s, 2H), 3,68 (s, 3H). 7.4 (br. s, 1H), 7.06 (br. s, 1H), 5.16 (s, 1H), 3.97 (s, 2H), 3.85 (s, 2H), 3 .68 (p, 3H).

Fremstilling av 4- hydroksy- pyrrolidin- 2- on- l- yl- acetamid Preparation of 4-hydroxy-pyrrolidin-2-on-1-yl-acetamide

10,0 g (0,0058 mol) 4-metoksy-3-pyrrolin-2-on-l-yl-acetamid ble oppløst i 117 ml eddiksyre og blandet med 14,4 g (0,0058 mol) av en 33 %-ig løsning av hydrogenbromid i eddiksyre. Man lot reaksjonsløsningen røre i 5 timer ved 40°C. Under røringen falt en hvit felling ut som ble frafiltrert, vasket med 50 ml metylen-klorid og tørket. Fellingen ble satt porsjonsvis under nitrogen ved romtemperatur til en løsning av 2,6 g (0,069 mol) natriumborhydrid i 130 ml dimetylformamid. Så ble reaksjonsløsningen surgjort med konsentrert saltsyre og inndampet med rotasjonsfor-damper. Resten ble utkokt med isopropanol, deretter filtrert, filtratet inndampet på nytt og resten utkrystallisert to ganger varmet fra metanol. 10.0 g (0.0058 mol) of 4-methoxy-3-pyrrolin-2-one-l-yl-acetamide was dissolved in 117 ml of acetic acid and mixed with 14.4 g (0.0058 mol) of a 33% -ig solution of hydrogen bromide in acetic acid. The reaction solution was allowed to stir for 5 hours at 40°C. During stirring, a white precipitate fell out which was filtered off, washed with 50 ml of methylene chloride and dried. The precipitate was added portionwise under nitrogen at room temperature to a solution of 2.6 g (0.069 mol) of sodium borohydride in 130 ml of dimethylformamide. The reaction solution was then acidified with concentrated hydrochloric acid and evaporated with a rotary evaporator. The residue was boiled off with isopropanol, then filtered, the filtrate evaporated again and the residue recrystallized twice heated from methanol.

Man fikk 5,0 g (= 54,5% av teoretisk utbytte) hvitt, krystallinsk produkt med et smeltepunkt på 167 til 168°C. 5.0 g (= 54.5% of theoretical yield) of white, crystalline product with a melting point of 167 to 168°C were obtained.

Claims (7)

1. Forbindelser karakterisert ved at de er 4-alkoksy-3-pyrrolin-2-on-l-yl-eddiksyreamider med formel 1. Connections characterized by that they are 4-Alkoxy-3-pyrrolin-2-on-l-yl-acetic acid amides of the formula hvori Ri betyr (Ci-C2 )-alkyl.wherein R 1 means (C 1 -C 2 )-alkyl. 2. Fremgangsmåte ved fremstilling av forbindelser ifølge krav 1, karakterisert ved at man omsetter 4-alkoksy-3-pyrrolin-2-on-l-yl-eddiksyre-Ci -C4-alkylestere med formel 2. Process for the preparation of compounds according to claim 1, characterized by reacting 4-Alkoxy-3-pyrrolin-2-on-1-yl-acetic acid C 1 -C 4 alkyl esters with the formula hvori Ri betyr Ci-C2 -alkyl og R2 Ci-C4 -alkyl eller -benzyl med ammoniakk.wherein R 1 means C 1 -C 2 -alkyl and R 2 C 1 -C 4 -alkyl or -benzyl with ammonia. 3. Fremgangsmåte ifølge krav 2, karakterisert ved at omsetningen foretas med alkoholer som løsningsmidler.3. Method according to claim 2, characterized by the fact that the turnover is carried out with alcohols as solvents. 4. Fremgangsmåte ifølge krav 2 og 3, karakterisert ved at omsetningen foretas ved temperaturer mellom 40 og 70° C.4. Method according to claims 2 and 3, characterized by the turnover being carried out at temperatures between 40 and 70° C. 5. Anvendelse av forbindelser ifølge krav 1 ved fremstilling av 4-hydroksy-pyrrolidin-2-on-l-yl-acetamid ved omsetning derav i surt vannfritt medium og videreoverføring av det dannede mellomprodukt med et alkaliborhydrid til sluttproduktet .5. Use of compounds according to claim 1 in the production of 4-hydroxy-pyrrolidin-2-on-1-yl-acetamide by reaction thereof in an acidic anhydrous medium and further transfer of the intermediate product formed with an alkali borohydride to the final product. 6. Anvendelse av forbindelsene ifølge krav 1 ifølge krav 5 ved vannfri omsetning med hydrogenbromid eller hydrogenklorid i en Ci-C4 -karboksylsyre og videre overføring av det dannede mellomprodukt med natriumborhydrid i sluttproduktet.6. Use of the compounds according to claim 1 according to claim 5 by anhydrous reaction with hydrogen bromide or hydrogen chloride in a Ci-C4 carboxylic acid and further transfer of the formed intermediate with sodium borohydride in the final product. 7. Anvendelse av forbindelsene ifølge krav 1 ifølge krav 5 og 6, ved vannfri omsetning med hydrogenbromid i eddiksyre og videre overføring av det tilsvarende mellomprodukt med natriumborhydrid i sluttproduktet.7. Use of the compounds according to claim 1 according to claims 5 and 6, by anhydrous reaction with hydrogen bromide in acetic acid and further transfer of the corresponding intermediate product with sodium borohydride in the final product.
NO871976A 1986-05-14 1987-05-13 4-ALKOSY-3-PYRROLIN-2-ON-1-YL-ACETIC ACID AMIDES AND THE PREPARATION AND USE OF THEREOF. NO871976L (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH1959/86A CH668067A5 (en) 1986-05-14 1986-05-14 4-ALKOXY-3-pyrroline-2-ON-1-YL-ESSIGSAEUREAMIDE, PRODUCTION AND USE THEREOF.

Publications (2)

Publication Number Publication Date
NO871976D0 NO871976D0 (en) 1987-05-13
NO871976L true NO871976L (en) 1987-11-16

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Family Applications (1)

Application Number Title Priority Date Filing Date
NO871976A NO871976L (en) 1986-05-14 1987-05-13 4-ALKOSY-3-PYRROLIN-2-ON-1-YL-ACETIC ACID AMIDES AND THE PREPARATION AND USE OF THEREOF.

Country Status (7)

Country Link
EP (1) EP0249018A1 (en)
JP (1) JPS62273950A (en)
CH (1) CH668067A5 (en)
DK (1) DK243887A (en)
HU (1) HUT44234A (en)
IL (1) IL82467A0 (en)
NO (1) NO871976L (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH680293A5 (en) * 1990-06-26 1992-07-31 Lonza Ag

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR211398Q (en) * 1975-08-13 1977-12-15 Isf Spa A PROCEDURE FOR PREPARING (-PIRROLIN -2- ON -1- IL) -ACILAMIDE DERIVATIVES

Also Published As

Publication number Publication date
JPS62273950A (en) 1987-11-28
DK243887D0 (en) 1987-05-13
NO871976D0 (en) 1987-05-13
DK243887A (en) 1987-11-15
CH668067A5 (en) 1988-11-30
EP0249018A1 (en) 1987-12-16
IL82467A0 (en) 1987-11-30
HUT44234A (en) 1988-02-29

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