DK152654B - METHOD OF ANALOGUE FOR THE PREPARATION OF (DL) - OR (L) -5- (2-FUROYL) -, 5- (2-THENOYL) -, 5- (FUROYL) - OR 5- (3-THENOYL) -1,2- dihydro-3H-pyrrol-OE1,2-AAA-pyrrole-1-carboxylic acid - Google Patents

Description

DK 152654BDK 152654B

. 1. 1

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte (dl)- eller (1)-5-(2-furoyl)-, 5-(2-the-noyl)-, 5-(3-furoyl)- eller 5-(3-thenoyl)-l,2-dihydro-3H-pyrrol-[1,2-a]-pyrrol-1-carboxylsyrer med de almene formler: R 8 7 ' . ‘The present invention relates to an analogous process for the preparation of novel (dl) - or (1) -5- (2-furoyl) -, 5- (2-thienoyl) -, 5- (3-furoyl) - or 5 - (3-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylic acids of the general formulas: R 8 7 '. '

*^ΓΊΐ Jl. ]!· COOH I--- C—C°°S* ^ ΓΊΐ Jl. COOH I --- C - C °° S

5 hvori X er oxygen eller svovl, R er hydrogen eller en alkylgruppe med 1-4 carbonatomer, og er hydrogen, methyl, chlor eller brom, hvilken analogifremgangsmåde er ejendommelig ved det i kravets kendetegnende del anførte.Wherein X is oxygen or sulfur, R is hydrogen or an alkyl group of 1-4 carbon atoms, and is hydrogen, methyl, chlorine or bromine, which analogous process is characterized by the characterizing part of the claim.

10 De omhandlede forbindelser udøver antiinflammatorisk, analgetisk og antipyretisk virkning og er således nyttig ved behandlingen af inflammation, smerte og/eller pyrexi hos pattedyr som beskrevet nærmere i det følgende. De er også glatmuskelafslappelsesmidler, blodpladeaggregationsinhibitorer og fibrinolytiske midler. Forbindel-15 serne kan anvendes både profylaktisk og terapeutisk.The compounds of this invention exert anti-inflammatory, analgesic and antipyretic action and are thus useful in the treatment of inflammation, pain and / or pyrexia in mammals as described in more detail below. They are also smooth muscle relaxants, platelet aggregation inhibitors and fibrinolytic agents. The compounds can be used both prophylactically and therapeutically.

De hidtil ukendte forbindelser med formlerne (A1) og (B1) eksisterer som par af optiske isomere (eller enantiomorfe), dvs. en (dl) blanding. Den foreliggende opfindelse omfatter^imidlertid fremstil-20 ling af den 1-isomere forbindélse deraf, såvel som (dl) blandingerne deraf.The novel compounds of formulas (A1) and (B1) exist as pairs of optical isomers (or enantiomorphs), i.e. a (dl) mixture. The present invention, however, comprises the preparation of the 1-isomeric compound thereof, as well as (dl) the mixtures thereof.

**

De hidtil ukendte (dl) forbindelser ifølge den foreliggende opfindelse kan fremstilles ved hjælp af en fremgangsmåde, der kan illu-25 streres ved hjælp af følgende reaktionsskema:The novel (dl) compounds of the present invention can be prepared by a process which can be illustrated by the following reaction scheme:

2 DK 152654B2 DK 152654B

^COOCH, ^COOCH^ COOCH, ^ COOCH

Γ2 r = h (i CH + COOCH„ y ii _________Γ2 r = h (i CH + COOCH „y ii _________

I ΈΧ^ (HDI ΈΧ ^ (HD

CH„ 1 I V** , H2C'&2CH 1 I V **, H2 C & 2

OH (II)\V IOH (II) \ V I

OH w (I) C00CH3 r cooch3 ΤΧ/-η3 * iOH w (I) C00CH3 r cooch3 ΤΧ / -η3 * i

1 \ I1 \ I

CH X * 1 I 2 \ h2c-ch2 CH0 (V) \ I (iv)CH X * 1 I 2 \ h2c-ch2 CH0 (V) \ I (iv)

\ 1 \ OH\ 1 \ OH

^ j oso2ch3 >. i X_^COOCH3 Rv_ .C00CH3^ j oso2ch3>. in X_ ^ COOCH3 Rv_ .C00CH3

C00CH3 > NC00CH3> N

L i_IL i_I

I 2 ,VI, <VII) ih2cI 2, VI, <VII) ih2c

VV

COOH R _ COOHCOOH R _ COOH

VY 2 <— Y“jf ^n^VcoorVY 2 <- Y «jf ^ n ^ Vcoor

i_I f , i_Ii_I f, i_I

(IX) (VIII) V RX_ 1 i 2 r1—i*· ji ji i(IX) (VIII) V RX_ 1 i 2 r1 — i * · ji ji i

XN.-X^COORz --> \x^\C C00RXN.-X ^ COORz -> \ x ^ \ C C00R

/ i—r» ° lj * / (XI) til / (xii) 0 ^-‘ (A) ίχ) 3 DK 152654Β/ i-r »° lj * / (XI) to / (xii) 0 ^ - '(A) ίχ) 3 DK 152654Β

. R. R

ν.Λ ; -γ-,: - • Χ ;(Β) 1 2 hvori X, R og R har den ovenfor anførte betydning, og R er en lavere alkylgruppe med 1-4 carbonatomer, f.eks. methyl, ethyl, , isopropyl eller n-butyl.ν.Λ; (Β) 1 2 wherein X, R and R are as defined above and R is a lower alkyl group of 1-4 carbon atoms, e.g. methyl, ethyl, isopropyl or n-butyl.

Når den ovennævnte fremgangsmåde gennemføres til fremstilling af 5 forbindelsen med formlen' (IV), hvori R er hydrogen, omsættes ækvi-molære mængder af ethanolamin (i) og dimethyl-l,3-acetonedicarboxy= „ lat (II) ved en temperatur fra ca. 0°C til omkring stuetemperatur for let at danne en opløsning af vinylaminen med formlen (III), som derpå, fortrinsvis in situ, behandles i et egnet inaktivt organisk 10 opløsningsmiddel under vandfri betingelser med 2-bromacetaldehyd eller 2-chloracetaldehyd ved en temperatur fra ca. 40°C til ca. 100°C i et tidsrum fra ca. 30 minutter til ca. 16 timer. Egnede opløsningsmidler for denne,reaktion er de aprotiske opløsningsmidler, såsom acetonitril, tetrahydrofuran, dimethoxyethan, chloroform, dichlor= 15 methan og lignende. Ved de foretrukne udførelsesformer gennemføres reaktionen i acetonitrilopløsning ved tilbagesvalingstemperatur i ca.When the above process is carried out to prepare the compound of formula '(IV) wherein R is hydrogen, equimolar amounts of ethanolamine (i) and dimethyl-1,3-acetonedicarboxy =' lat (II) are reacted at a temperature of ca. 0 ° C to about room temperature to readily form a solution of the vinylamine of formula (III) which is then, preferably in situ, treated in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at a temperature of ca. 40 ° C to approx. 100 ° C for a period of approx. 30 minutes to approx. 16 hours. Suitable solvents for this reaction are the aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloro = 15 methane and the like. In the preferred embodiments, the reaction is carried out in acetonitrile solution at reflux temperature for approx.

1 time. 2-brom-(chlor)-acetaldehydreagenserne er kendte forbindelser eller kan opnås ved pyrolyse af de tilsvarende diethylacetaler i nærværelse af oxalsyredihydrat.1 hour. The 2-bromo (chloro) acetaldehyde reagents are known compounds or can be obtained by pyrolysis of the corresponding diethyl acetals in the presence of oxalic acid dihydrate.

2020

Til fremstilling af forbindelserne med formlen (IV), hvori R er en fortrinsvis ligekædet lavere alkylgruppe med 1-4 carbonatomer, behandles en vandig blanding af ethanolamin (i) og dimethyl-1,3-acetone-dicarboxylat (II) med en forbindelse med formlen R^-C-CHgX, hvori X 25 er brom eller chlor, og R^ er en lavere alkylgruppe, fortrinsvis ligekædet med 1-4 carbonatomer, og især 1-bromacetone, l-brom-2-butanon, l-brom-2-pentanon og l-brom-2-hexanon ved en temperatur fra ca. 40°C til ca. 100°C i' et tidsrum fra ca. 30 minutter til ca. 16 timer. Ved den foretrukne udførelsesform gennemføres reaktionen ved 30To prepare the compounds of formula (IV) wherein R is a preferably straight chain lower alkyl group of 1-4 carbon atoms, an aqueous mixture of ethanolamine (i) and dimethyl-1,3-acetone dicarboxylate (II) is treated with a compound of the formula R 1 -C-CH 2 X wherein X 25 is bromine or chlorine and R 2 is a lower alkyl group, preferably straight chain 1-4 carbon atoms, and especially 1-bromoacetone, 1-bromo-2-butanone, 1-bromo 2-pentanone and 1-bromo-2-hexanone at a temperature of ca. 40 ° C to approx. 100 ° C for a period of approx. 30 minutes to approx. 16 hours. In the preferred embodiment, the reaction is carried out at 30

4 DK 152654B4 DK 152654B

en temperatur fra can -10°C til omkring stuetemperatur i fra 1 time •Z n til ca. 6 timer. R -C-C^X-reagenserne er kendte forbindelser.a temperature of can -10 ° C to about room temperature for from 1 hour • Z n to approx. 6 hours. The R-C-C3 X reagents are known compounds.

Forestring af forbindelse (IV) med methansulfonylchlorid i nærværelse "af en tertiær amin, dvs. triethylamin, pyridin og lignende, eventuelt 5 i nærværelse af et coopløsningsmiddel, såsom dichlormethan, ved en temperatur fra ca. -10°C til omkring stuetemperatur i ca. .10 minutter til ca. 2 timer, giver det tilsvarende mesylat med formlen (V), som omdannes til den tilsvarende N-(2-iodethyl)-pyrrol med formlen (VI) ved reaktion med natriumiodid i acetonitrilopløsning, ved tilbage-svalingstemperatur i fra ca. 1 til ca. 10 timer.Esterification of Compound (IV) with methanesulfonyl chloride in the presence of a tertiary amine, i.e. triethylamine, pyridine and the like, optionally in the presence of a co-solvent such as dichloromethane, at a temperature of about -10 ° C to about room temperature for about .10 minutes to about 2 hours, gives the corresponding mesylate of formula (V) which is converted to the corresponding N- (2-iodoethyl) pyrrole of formula (VI) by reaction with sodium iodide in acetonitrile solution at reflux temperature for from about 1 to about 10 hours.

Efter reaktion af iodethylforbindelser med formlen (VI) med natrium= 1 - hydrid i et egnet inaktivt organisk opløsningsmiddel, såsom dimethyl= formamid,fås dimethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1,7-di= 15 carboxylat og de 6-alkylsubstituerede derivater deraf (VII). Denne ringslutning gennemføres under en inaktiv atmosfære, dvs. under en argon eller en nitrogenatmosfære ved temperaturer af størrelsesordenen fra ca. 15°C til ca. 40°C i et tidsrum fra ca. 15 minutter til ca. 4 timer. De bedste resultater opnås ved at gennemføre reaktionenAfter reaction of iodoethyl compounds of formula (VI) with sodium = 1 - hydride in a suitable inert organic solvent such as dimethyl = formamide, dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1 is obtained. 7-di = 15 carboxylate and the 6-alkyl substituted derivatives thereof (VII). This ring closure is carried out under an inactive atmosphere, i.e. under an argon or nitrogen atmosphere at temperatures of the order of ca. 15 ° C to approx. 40 ° C for a period of approx. 15 minutes to approx. 4 hours. The best results are obtained by conducting the reaction

2D2D

ved stuetemperatur i ca. 3 minutter, når R er hydrogen.at room temperature for approx. 3 minutes when R is hydrogen.

. Forbindelserne med formlen (VII) kan alternativt fremstilles ved direkte ringslutning af mesylatet (V) med natriumhydrid i dimethylform= amidopløsning ved en temperatur fra ca. -10°C til omkring stuetem-25 ( peratur fra ca. 30 minutter til ca. 2 timer.. Alternatively, the compounds of formula (VII) may be prepared by direct cyclization of the mesylate (V) with sodium hydride in dimethyl form = amide solution at a temperature of ca. -10 ° C to about room temperature-25 (temperature from about 30 minutes to about 2 hours).

Basisk hydrolyse af en forbindelse med formlen (VII) med et alkali= metalhydroxid eller alkalimetalcarbonat, f.eks. natriumhydroxid, na= triumcarbonat, kaliumcarbonat og lignende i en vandig lavere alifa-30 tisk alkohol, f.eks. methanol eller ethanol ved en temperatur mellem stuetemperatur og tilbagesvalingstemperaturen i fra ca. 4 til ca.Basic hydrolysis of a compound of formula (VII) with an alkali metal hydroxide or alkali metal carbonate, e.g. sodium hydroxide, sodium carbonate, potassium carbonate and the like in an aqueous lower aliphatic alcohol, e.g. methanol or ethanol at a temperature between room temperature and the reflux temperature for from ca. 4 to approx.

24 timer, giver den tilsvarende fri disyre med formlen (VIII), dvs.24 hours, the corresponding free diacid of formula (VIII), i.e.

1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrol-1,7-dicarboxylsyre og 6-alkyl-derivaterne deraf. Hydrolysen gennemføres fortrinsvis under anvendel-. 35 se af vandig methanolisk kaliumhydroxid ved tilbagesvalingstempera-turen i ca. 10 timer.The 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and the 6-alkyl derivatives thereof. The hydrolysis is preferably carried out during use. 35 aqueous methanolic potassium hydroxide at reflux temperature for approx. 10 hours.

Carboxylsyregruppen i C-l-stillingen i forbindelsen (VIII) forestres derpå selektivt ved behandling med en lavere alifatisk alkohol, f.eks.The carboxylic acid group at the C-1 position of the compound (VIII) is then selectively esterified by treatment with a lower aliphatic alcohol, e.g.

5 DK 152654 BDK 152654 B

methanol, ethanol, isopropanol, n-butanol og lignende,i nærværelse af hydrogenchlorid til fremstilling af den tilsvarende alkyl-l,2-di= hydro-3H-pyrrolo[1,2-a]-pyrrol-l-carboxylat-7-carboxylsyre med formlen (IX). Reaktionen gennemføres ved en temperatur fra ca. 0°C til 5 ca. 50°C, i fra ca. 1 til ca. 4 timer.methanol, ethanol, isopropanol, n-butanol and the like, in the presence of hydrogen chloride to prepare the corresponding alkyl-1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7- carboxylic acid of formula (IX). The reaction is carried out at a temperature of approx. 0 ° C to 5 approx. 50 ° C, for approx. 1 to approx. 4 hours.

Decarboxylering af de monoforestrede.forbindelser (IX) til de tilsvarende forbindelser med formlen (X), de vigtigste mellemprodukter ved fremgangsmåden til opnåelse af forbindelserne ifølge den fore-10 liggende opfindelse,opnås ved at opvarme (IX) ved en forhøjet temperatur af størrelsesordenen fra ca. 230°C til ca. 280°C i et tidsrum, som er tilstrækkeligt til at få reaktionen til at forløbe til „ ende. Reaktionsforløbet kan følges ved omfanget af carbondioxidudvikling og tyndtlagskromatografisk analyse, idet decarboxyleringen almindeligvis er forløbet til ende i løbet af ca. 45 til ca. 90 minutter. Reaktionsproduktet, nemlig alkyl-1,2-dihydro-3H-pyrrolo-[l,2-a]pyrrol-l-carboxylat og 6-alkylderivaterne deraf (X),kan renses n ved hjælp af kromatografiske metoder. Alternativt og specielt til decarboxyleringen af små portioner af forbindelse (IX) kan reaktions- nn produktet (X) destilleres direkte fra reaktionsbeholderen. Kondensation af en forbindelse (X) med et amid med formlerne CON(CH^)~ 25 - »HF1 eller Γ~ί ^X'/^CON(CH3)2 ^x^ hvori X og R^ har de ovenfor anførte betydninger, giver de tilsvaren-30 de alkyl-5-substitueret-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carb= oxylater med formlerne henholdsvis (XI) eller (XII).Decarboxylation of the mono-esterified compounds (IX) to the corresponding compounds of formula (X), the main intermediates of the process for obtaining the compounds of the present invention, is obtained by heating (IX) at an elevated temperature of the order of ca. 230 ° C to approx. 280 ° C for a time sufficient to allow the reaction to proceed. The course of the reaction can be followed by the extent of carbon dioxide evolution and thin-layer chromatographic analysis, the decarboxylation usually being completed over approx. 45 to approx. 90 minutes. The reaction product, namely alkyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate and the 6-alkyl derivatives thereof (X), can be purified n by chromatographic methods. Alternatively and especially for the decarboxylation of small portions of compound (IX), the reaction and product (X) can be distilled directly from the reaction vessel. Condensation of a compound (X) with an amide of the formulas CON (CH2) ~ 25 - HF1 or Γ ~ ί ^ X '/ ^ CON (CH3) 2 ^ x ^ wherein X and R ^ have the above meanings, gives the corresponding alkyl-5-substituted-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylates of formulas respectively (XI) or (XII).

Denne reaktion gennemføres i et inaktivt organisk aprotisk opløsningsmiddel og i nærværelse af phosphoroxychlorid ved tilbagesvalingstem-35 peratur i tidsrum fra ca. 1 til ca. 72 timer under en inaktiv atmosfære efterfulgt af yderligere tilbagesvaling i nærværelse af natrium= acetat i fra ca. 2 til ca. 10 timer. I stedet for phosphoroxychlorid kan der alternativt anvendes andre syrechlorider, såsom phosgen eller oxalylchlorid.This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature for a period of about 1 to approx. 72 hours under an inactive atmosphere followed by further reflux in the presence of sodium = acetate for from ca. 2 to approx. 10 hours. Alternatively, instead of phosphorus oxychloride, other acid chlorides such as phosgene or oxalyl chloride may be used.

4040

e DK152654Be DK152654B

Ved de foretrukne udførelsesformer gennemføres denne kondensation ved at sætte en opløsning af forbindelse (X) i et egnet opløsningsmiddel til en forud tilbagesvalet blanding af 1,1-2 molærækvivalenter'af både det ønskede amin og phosphoroxychlorid i det samme opløsnings-5 middel, tilbagesvale den således opnåede reaktionsblanding i fra ca. 2 til ca. 30 timer under en argonatmosfære og derpå hertil sætte fra ca. 3 til ca. 10 molærækvivalenter natriumacetat, efterfulgt af en yderligere tilbagesvalingsperiode fra ca. 4 til ca. 6 timer.In the preferred embodiments, this condensation is carried out by adding a solution of compound (X) in a suitable solvent to a pre-refluxed mixture of 1.1-2 molar equivalents of both the desired amine and phosphorus oxychloride in the same solvent, refluxing the reaction mixture thus obtained in from ca. 2 to approx. 30 hours under an argon atmosphere and thereafter set from approx. 3 to approx. 10 molar equivalents of sodium acetate, followed by a further reflux period of approx. 4 to approx. 6 hours.

10 Passende opløsningsmidler til denne reaktion er de halogenerede hydro= carboner, såsom dichlormethan, 1,2-dichlorethan, chloroform, carbon= tetrachlorid og lignende, dimethoxyethan og tetrahydrofuran. Det foretrukne opløsningsmiddel er 1,2-dichlorethan.Suitable solvents for this reaction are the halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like, dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

/ 15 Repræsentative eksempler på N,N-dimethylamiderne, der kan anvendes, er: N, N-dimethylthiophen-2-carboxamid, N,N-dimethylf uran-2-carboxamid, N, N-dimethyl-3-methylthiophen-2-carboxamid, 20 N, N-dimethyl-4-methylthiophen-2-carboxamid, N,N-dimethyl-5-methylthiophen-2-carboxamid, N,N-dimethyl-4-chlorthiophen-2-carboxamid,· N,N-dimethyl-5-chlorthiophen-2~carboxamid, • N,N-dimethyl-3-bromthiophen-2-carboxamid, 25 N,N-dimethyl-5-bromthiophen-2-carboxamid, ζ ·, N,N-dimethyl-3-methylfuran-2-carboxamid, N,N-dimethyl-4-methylfuran-2-carboxamid, N,N-dimethyl-4-chlorfuran-2-carboxamid, N,N-dimethyl-3-chlorfuran-2-carboxamid, on N,N-dimethyl-4-bromf uran-2-carboxamid, N,N-dimethyl-5-bromfuran-2-carboxamid, N,N-dimethylthiophen-3-carboxamid og , .Representative examples of the N, N-dimethylamides that can be used are: N, N-dimethylthiophene-2-carboxamide, N, N-dimethylfuran-2-carboxamide, N, N-dimethyl-3-methylthiophene-2 carboxamide, N, N-dimethyl-4-methylthiophene-2-carboxamide, N, N-dimethyl-5-methylthiophene-2-carboxamide, N, N-dimethyl-4-chlorothiophene-2-carboxamide, · N, N- dimethyl-5-chlorothiophene-2-carboxamide, N, N-dimethyl-3-bromothiophene-2-carboxamide, N, N-dimethyl-5-bromothiophene-2-carboxamide, ζ ·, N, N-dimethyl-3 -methylfuran-2-carboxamide, N, N-dimethyl-4-methylfuran-2-carboxamide, N, N-dimethyl-4-chlorofuran-2-carboxamide, N, N-dimethyl-3-chlorofuran-2-carboxamide, one N, N-dimethyl-4-bromofuran-2-carboxamide, N, N-dimethyl-5-bromfuran-2-carboxamide, N, N-dimethylthiophene-3-carboxamide and,.

N,N-dimethylf uran-3-carboxamid.N, N-dimethylfuran-3-carboxamide.

3535

Disse amider kan fremstilles på sædvanlig måde ud fra de tilsvarende thiophen- eller furan-2-(3)-carboxylsyrer, dvs. ved omdannelse til syrechloriderne.efterfulgt af behandling med dimethylamin.These amides can be prepared in the usual manner from the corresponding thiophene or furan 2- (3) carboxylic acids, i.e. upon conversion to the acid chlorides, followed by treatment with dimethylamine.

Ved alkalisk hydrolyse-af alkylestergruppen i en forbindelse med formlerne (XI) eller (XII) fås de tilsvarende fri syrer henholdsvis med 40 formlerne (A) eller (B). Hydrolysen gennemføres på sædvanlig måde medBy alkaline hydrolysis of the alkyl ester group in a compound of formulas (XI) or (XII), the corresponding free acids are obtained by formulas (A) or (B), respectively. The hydrolysis is carried out in the usual manner

7 DK 152654 B7 DK 152654 B

et alkalimetalhydroxid eller alkalimetalcarbonat, f.eks. natrium= hydroxid, kaliumhydroxid, natriumcarhonat, kaliumcarbonat og lignende i en vandig lavere alifatisk alkohol, f.eks. methanol, ethanol og lignende ved en temperatur fra omkring stuetemperatur til tilbage-5 svalingstemperaturen i fra ca. 30 minutter til ca. 4 timer under en inaktiv atmosfære. Ved de foretrukne udførelsesformer gennemføres denne hydrolyse med vandig methanolisk kaliumhydroxid ved tilbagesvalingstemperatur i ca. 2 timer.an alkali metal hydroxide or alkali metal carbonate, e.g. sodium = hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like in an aqueous lower aliphatic alcohol, e.g. methanol, ethanol, and the like at a temperature of about room temperature to the reflux temperature of from ca. 30 minutes to approx. 4 hours under an inactive atmosphere. In the preferred embodiments, this hydrolysis is carried out with aqueous methanolic potassium hydroxide at reflux temperature for approx. 2 hours.

10 Forbindelserne med formlerne (A) og (B) kan spaltes i overensstemmelse med i teknikken kendte metoder til opnåelse af de tilsvarende enkelte isomere deraf. Forbindelsen med formlen (A), hvori R og begge er hydrogen, og X er svovl kan således f.eks. udsættes for en yderligere behandling i overensstemmelse med følgende diagram: 15 __* __ ....... ..... .The compounds of formulas (A) and (B) can be cleaved according to methods known in the art to obtain the corresponding single isomers thereof. Thus, the compound of formula (A) wherein R and both are hydrogen and X is sulfur can e.g. is subjected to further treatment in accordance with the following diagram: 15 __ * __ ....... ......

Ux^^yc°°* V' ' ·.'— - · , . ; (A1) ·. · .Spalding, ^ .Λ: ’/ _ - *. . . . ** ·, ’ ,‘f ' ^ % ·,·,· . ~~ * * *,.·..·.·**.* ·"·* ·· .....Ux ^^ yc °° * V '' · .'— - · ,. ; (A1) ·. · .Spalding, ^ .Λ: '/ _ - *. . . . ** ·, ',' f '^% ·, ·, ·. ~~ * * *,. · .. ·. · **. * · "· * ·· .....

• : . . ·. . i ..· ' . · - . „· - . . ... . . ^ · ’· .·,*· . .' p · . . . ‘ , 1 V. " 1 . · * .· i ’ z- · ’·· ,. . · : · ' · ·. ' ...•:. . ·. . i .. · '. · -. „· -. . .... . ^ · '·. ·, * ·. . ' p ·. . . ', 1 V. "1. · *. · I' z- · '··,. ·: ·' · ·. '...

A - (1) ~syreisomer^_i.d) -amphetaminsalt . * f ·. 1 Φ .· ··.'. · ·· ' ·A - (1) ~ acid isomer (_i.d) -amphetamine salt. * f ·. 1 ·. · ··. '. · ·· '·

A -U) -:syreisoraeass I .· . · · · IA-U) -: syreisoraeass I. ·. · · · I

* . * · - s i v ...*. * · - s i v ...

’.Blanding aå V h ^ “ syreisomexr (d) -amphetaminsalt ) 8Mixture of VH₂ (acid odometer (d) -amphetamine salt) 8

DK 152654BDK 152654B

En mere detaljeret beskrivelse af denne fremgangsmåde findes i det efterfølgende eksempel 10 B-l.A more detailed description of this method can be found in the following Example 10B-1.

(l)-syreisomere og (d)-syreisomere af forbindelserne med formlerne (A) og (B) kan alternativt opnås ved at anvende den kendte teknik 5 med højtryksvæskekromatografi (HPLC) på a-phenethyldiastereoisomere estre af forbindelserne med formlerne (A) og (B) efterfulgt af syre-spaltning. Forbindelserne med formlen (A), hvori R og R begge er hydrogen, og X er svovl, kan således f.eks. underkastes en yderligere behandling i overensstemmelse med følgende diagram: 10 v/· ; ·'.· : · ·.· C00n ^ -'—"-” · '·- _ ^ ^ . -adskilligel --- ' · - "'· - ' trin.;:" 'Γ .'' • ‘ ' nU . ·. . · v . c . ·; - C (A^*)-(1)-syréisomer-(l)'-a-^phenethylester--") .Alternatively, (l) acid isomers and (d) acid isomers of the compounds of formulas (A) and (B) can be obtained by applying the prior art high pressure liquid chromatography (HPLC) technique to α-phenethyl diastereoisomeric esters of the compounds of formulas (A) and (B) followed by acid cleavage. Thus, the compounds of formula (A) wherein R and R are both hydrogen and X are sulfur can be e.g. is subjected to further treatment according to the following diagram: 10 v / ·; · '. ·: · ·. · C00n ^ -'— "-” ·' · - _ ^ ^. Separator --- '· - "' · - 'step.;:"' Γ. '' • ' 'nU. ·... v. c. ·; - C (A ^ *) - (1) -accharomer- (l)' - a- ^ phenethyl ester-- ").

Blanding af < . 1. - - CMixture of <. 1. - - C

'. · / (A1) - (d) - syreisomer^-(l) -cr-phena-thylester- -Λ ... . · ·! . separering under - ' r **..·'- _ · anvendelse af . · . _ '*·. · ' ' . ' - · ttøjtryksvæskekromatografi (A^)·- (lj - sy r ejjsomer^O^'. · / (A1) - (d) - Acidomer ^ - (l) -cr-phena-thylester- -Λ .... · ·! . separation under - 'r ** .. ·' - _ · use of. ·. _ '* ·. · ''. Cloth Pressure Liquid Chromatography (A ^) · - (L

(A^-Cd) -syreisomer-(1)-phenethylester - J(A 1 -Cd) acid isomer (1) -phenethyl ester - J

1 v - . , 4/ .1 v -. , 4 /.

(A )-{!)-syreisomgr·r- ' (A ) - (d) - syreisomer-_ 9(A) - {!) - Acid environment · (A) - (d) - Acidomer-_ 9

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En mere detaljeret beskrivelse af denne fremgangsmåde findes i det efterfølgende eksempel 10 B-2.A more detailed description of this method can be found in the following Example 10 B-2.

De fri syrer med formlerne (A) og (B) kan omdannes til andre alkyl-estere med fra 1 til 12 carbonatomer ved hjælp af sædvanlige metoder, 5 f.eks. ved behandling med (a) alkoholen, som svarer til den ønskede ester i nærværelse af en stærk mineralsyre, (b) en etherisk diazoal= kan eller (c) det ønskede alkyliodid i nærværelse af lithiumcarbonat.The free acids of formulas (A) and (B) can be converted to other alkyl esters having from 1 to 12 carbon atoms by conventional methods, e.g. by treatment with (a) the alcohol corresponding to the desired ester in the presence of a strong mineral acid, (b) an ethereal diazoal can or (c) the desired alkyl iodide in the presence of lithium carbonate.

(1)-syreisomere kan omdannes til deres alkylestere ved hjælp af de ovennævnte fremgangsmåder fra (b) og (c).(1) acid isomers can be converted to their alkyl esters by the aforementioned methods of (b) and (c).

10 .10.

Saltderivaterne af forbindelserne med formlerne (A) og (B) og (1)— syreisomere deraf fremstilles ved at behandle disse fri syrer med en passende mængde af en farmaceutisk acceptabel base. Eksempler på farmaceutisk acceptable baser er natriumhydroxid, kaliumhydroxid, lithium= 15 hydroxid, ammoniumhydroxid, calciumhydroxid, magnesiumhydroxid, ferro= hydroxid, zinkhydroxid, kobberhydroxid, manganhydroxid, aluminiumhy= ' droxid, ferrihydroxid, manganhydroxid, isopropylamin, trimethylamin, diethylamin, triethylamin, tripropylamin, ethanolamin,.2-dimethylamino= ethanol, 2-diethylaminoethanol, tromethamin, lysin, arginin, histidin, 20 kaffein, procain, hydrabamin, cholin, betain, ethylendiamin, glucos-amin, methylglucamin, theobromin, puriner, piperazin, piperidin, N-ethylpiperidin, polyaminharpikser og lignende. Reaktionen gennemføres i vand alene eller i kombination med et inaktivt med vand blandbart organisk opløsningsmiddel ved en temperatur fra ca. 0°C til ca. 100°C, » \ _·?* fortrinsvis ved stuetemperatur. Typiske inaktive med vand blandbare organiske opløsningsmidler omfatter methanol, ethanol, isopropanol, butanol, acetone, dioxan eller tetrahydrpfuran. Det molære forhold af forbindelser med formlerne (A) eller (B) eller {i) -syreisomere deraf til base, der anvendes, vælgeé, så der tilvejebringes det til det ^ pågældende salt ønskede forhold. Til fremstilling for eksempel af calciumsaltene eller magnesiumsaltene af forbindelserne med formlerne (A) eller (B) eller (1)-syreisomere deraf, kan det fri syreudgangsmateriale behandles med mindst et halvt molærækvivalent farmaceutisk acceptabel base til dannelse af et neutralt salt. Når aluminiumsaltene 35 af forbindelserne med formlerne CA) eller (B) eller (1)-syreisomere. deraf fremstilles, anvendes mindst en tredjedel molærækvivalent af den farmaceutisk acceptable base, hvis der ønskes et neutralt saltprodukt.The salt derivatives of the compounds of formulas (A) and (B) and (1) - acid isomers thereof are prepared by treating these free acids with an appropriate amount of a pharmaceutically acceptable base. Examples of pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide, ferric hydroxide, ferric hydroxide, ferric hydroxide, ferric hydroxide. ethanolamine, .2-dimethylamino = ethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethyl piperidine, polyamine resins and the like. The reaction is carried out in water alone or in combination with an inert water-miscible organic solvent at a temperature of approx. 0 ° C to approx. 100 ° C, preferably at room temperature. Typical inert water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrpfuran. The molar ratio of compounds of formulas (A) or (B) or {i) acid isomers thereof to the base used is selected to provide the ratio desired for the salt concerned. For example, to prepare the calcium salts or magnesium salts of the compounds of formulas (A) or (B) or (1) acid isomers thereof, the free acid starting material may be treated with at least half a molar equivalent of pharmaceutically acceptable base to form a neutral salt. When the aluminum salts of the compounds of formulas CA) or (B) or (1) acid isomers. thereof, at least one-third molar equivalent of the pharmaceutically acceptable base is used if a neutral salt product is desired.

Ved den foretrukne metode kan calciumsaltene og magnesiumsaltene af LU iIn the preferred method, the calcium salts and the magnesium salts of LU can

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forbindelserne med formlerne (A) og (B) og (1)-syreisomere deraf fremstilles ved at behandle de tilsvarende natrium- eller kaliumsalte deraf med mindst et halvt molærækvivalent af henholdsvis calciumchlo= rid eller magnesiumchlorid i en vandig opløsning alene eller i kombi-g nation med et inaktivt med vand blandbart organisk opløsningsmiddel ved en temperatur fra ca. 20°C til ca. 100°C. Aluminiumsaltene af forbindelserne deraf kan fortrinsvis fremstilles ved at behandle de tilsvarende fri syrer med mindst en tredjedel molærækvivalent aluminium= alkoxid, såsom aluminiumtriethoxid, aluminiumtripropoxid og lignende 2ø i et hydrocarbonopløsningsmiddel, såsom benzen, xylen, cyklohexan og lignende ved en temperatur fra ca. 20°C til ca. 115oc. Lignende metoder kan anvendes til at fremstille salte af uorganiske baser, som ikke er' tilstrækkeligt opløselige til let at reagere.the compounds of formulas (A) and (B) and (1) acid isomers thereof are prepared by treating the corresponding sodium or potassium salts thereof with at least half a molar equivalent of calcium chloride or magnesium chloride, respectively, in an aqueous solution alone or in combination nation with an inert water-miscible organic solvent at a temperature of ca. 20 ° C to approx. 100 ° C. The aluminum salts of the compounds thereof can preferably be prepared by treating the corresponding free acids with at least one third molar equivalent of aluminum = alkoxide such as aluminum triethoxide, aluminum tripropoxide and the like 2o in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like at a temperature of about 20 ° C to approx. 115oc. Similar methods can be used to prepare salts of inorganic bases which are not sufficiently soluble to readily react.

-*-5 Produkterne, som indeholder disse forbindelser^er således nyttige ved behandlingen og elimineringen af inflammation, såsom betændelsestilstande i det muskulære skeletsystem, skeletled og andre væv, f.eks. ved behandlingen af betændelsestilstande, såsom rheumatisme, konkus-sion, laceration, arthritis, benbrud, posttraumatiske tilstande og 20 gigt. I de tilfælde, hvor de ovennævnte tilstande omfatter smerte og pyrexi i forbindelse med inflammation, er de foreliggende forbindelser nyttige til at lindre disse tilstande, såvel som inflammationen. -·Thus, the products containing these compounds are useful in the treatment and elimination of inflammation, such as inflammatory conditions in the muscular skeletal system, skeletal joints and other tissues, e.g. in the treatment of inflammatory conditions such as rheumatism, concussion, laceration, arthritis, fractures, post-traumatic conditions and arthritis. In the cases where the above conditions include pain and pyrexia in connection with inflammation, the present compounds are useful in alleviating these conditions, as well as the inflammation. - ·

Den foretrukne administrationsmåde i forbindelse med de ovenfor be-25 skrevne tilstande er den orale, idet der anvendes en passende daglig dosismængde, der kan justeres i overensstemmelse med lidelsens karak-.ter og omfang. En daglig dosis fra 25 mg til 500 mg af den aktive forbindelse med formlerne (A) eller (B) eller (1)-syreisomere deraf, og de farmaceutiske acceptable ikke-toksiske estere og salte deraf an-^ vendes. De fleste lidelser reagerer på en behandling, som omfatter en dosismængde af størrelsesordenen 0,5 mg til 6 mg pr. kg legemsvægt pr. dag./The preferred mode of administration for the conditions described above is the oral one, using an appropriate daily dose amount that can be adjusted according to the nature and extent of the disorder. A daily dose of 25 mg to 500 mg of the active compound of formulas (A) or (B) or (1) acid isomers thereof, and the pharmaceutically acceptable non-toxic esters and salts thereof are used. Most disorders respond to a treatment comprising a dose amount of the order of 0.5 mg to 6 mg per day. kg body weight per day./

De farmaceutisk acceptable forbindelser med formlerne (A') og (B1) 2g og (l)-syreisomerer deraf er som beskrevet ovenfor også uterin-glatmuskelafslap pelsesmidler og er sålédes nyttige som midler til at opretholde graviditet hos gravide kvinder og drægtige pattedyr til gavn for moder . og/eller foster, indtil afsluttelse af graviditeten fra et medicinsk synspunkt findes gunstigt eller mere gunstigt for moderen og/eller fosteret.The pharmaceutically acceptable compounds of formulas (A ') and (B1) 2g and (1) acid isomers thereof, as described above, are also uterine smooth muscle relaxants and are thus useful as agents for maintaining pregnancy in pregnant women and pregnant mammals for the benefit of mother. and / or fetus until termination of pregnancy from a medical point of view is found favorable or more favorable to the mother and / or the fetus.

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A. Prøve for analgetisk (vridningsmodvirkende) virkning på mus.A. Test for analgesic (anti-torsional) effect on mice.

Protokol: Materiale, der skal afprøves, administreres oralt ved indgivelse i en vandig bære på tidspunkt 0 til 18-20 g han Swiss-Webster-mus. 20 minutter, senere injiceres 0,25 ml af en 0,02% opløsning af plie= 5 nylquinon intraperitonealt. Denne opløsning frembringer vridning. Dyrene observeres derpå i de næste 10 minutter med hensyn til vridning.Protocol: Material to be tested is orally administered by administration to an aqueous carrier at time 0 to 18-20 g male Swiss-Webster mice. 20 minutes later, 0.25 ml of a 0.02% solution of pie = 5 nylquinone is injected intraperitoneally. This solution produces distortion. The animals are then observed for the next 10 minutes for twisting.

Slutpunkt: Det samlede antal mus, som vrider sig·, og det gennemsnitlige antal vridninger pr. mus.End point: The total number of mice twisting · and the average number of twists per minute. mouse.

10 Under anvendelse af den ovennævnte protokol bestemmes det, at 5-(2-thenoyl)-l,2-dihydro~3H-pyrrolo[l,2-a]pyrrol-l-carboxylsyre har en analgetisk virkning på omkring 350 gange aspirins, og (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre 15 har en analgetisk virkning på 670 gange aspirins.Using the above protocol, it is determined that 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect of about 350 times aspirin. and (1) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect of 670 times aspirin.

Der blev desuden bestemt følgende virkningsstyrker: 5-(5-methyl-2-thenoyl)-l,2-dihydro-3H-pyrrol[1,2-a]- 80 20 pyrrol-1-carboxylsyre, 5-(3-furoyl)-l,2-dihydro-3H-pyrrol[l,2-a]pyrrol-l-carboxylsyre ca. 45 5-(2-thenoyl)-6-methy 1-1,2-dihydro-3H-pyrrol[1,2-a]- ca. 20.0 pyrro1-1-carboxylsyre, 5-(4-chlor-2-thenoyl).-l,2-dihydro-3H-pyrrol [1,2-a]- ca. 130 25 pyrrol-1-carboxylsyre, 5-(3-thenoyl)-l,2-dihydro-3H-pyrrol[l,2-a]pyrrol-l-carboxylsyre. . 160 B. Test for antiinflammatorisk virkning under anvendelse af Carrageenin- gg induceret poteinflammation i rotte. ..In addition, the following potency was determined: 5- (5-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] 80 pyrrole-1-carboxylic acid, 5- (3-furoyl) ) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylic acid ca. 5- (2-thenoyl) -6-methyl-1,1,2-dihydro-3H-pyrrole [1,2-a] - approx. 20.0 pyrrole-1-carboxylic acid, 5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] - approx. 130 pyrrole-1-carboxylic acid, 5- (3-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylic acid. . 160 B. Test for anti-inflammatory effect using Carrageenin-induced rat protein inflammation in rat. ..

Protokol: Simonsen hunrotter med en vægt på 80-90 g anvendes. Materialerne, der skal afprøves,indgives time 0 oralt ved indgivelse i 1 ml vandig bærer. 1 time senere injiceres 0,05 ml af en 1%'ig opløsning 35 (0,9% NaCl) af carrageenin i højre bagpote. Denne injektion forårsager . en inflammation af poten. Rotterne aflives 4 timer'efter forsøgets start, på hvilket tidsrum begge bagpoter aftages og vejes særskilt.Protocol: Simonsen female rats weighing 80-90 g are used. The materials to be tested are administered hourly orally by administration in 1 ml of aqueous vehicle. One hour later, 0.05 ml of a 1% solution 35 (0.9% NaCl) of carrageenin is injected into the right hind paw. This injection causes. an inflammation of the paw. The rats are sacrificed 4 hours after the start of the experiment, during which time both hind legs are removed and weighed separately.

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1212

Slutpunkt: % forøgelse i potestørrelse beregnet som følger: Vægt af højre pote -vægt af venstre pote χ Vægt af venstre poteEnd point:% increase in paw size calculated as follows: Weight of right leg - weight of left leg χ Weight of left leg

Under anvendelse af den ovennævnte protokol bestemmes det, at 5—{2— 5 thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre har en antiinflammatorisk virkning på 48 (95% konfidensgrænser: 32-72) gange phenylbutazons.Using the above protocol, it is determined that 5- (2- 5 thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an anti-inflammatory effect of 48 (95% confidence limits). : 32-72) times phenylbutazone.

sp

Der blev desuden bestemt følgende virkningsstyrker: i jg 5- (5-methyl-2-thenoyl)-l,2-dihydro-3H-pyrrol[1,2-a]pyrrol- 10 1-carboxylsyre, 5-(3-furoyl)-l,2-dihydro-3H-pyrrol[l,2-a]pyrrol-l-carboxylsyre, 3 5-(2-thenoyl)-6-methyl-l,2-dihydro-3H-pyrrol[1,2-a]pyrrol-1- 27 carboxylsyre, - _ 5- (4-chlor-2-thenoyl)-l,2-dihydro-3H-pyrrol[l,2-a]pyrrol- 19 15 1-carboxylsyre, 5- (3-thenoyl) -1,2-dihydro-3H-pyrrol [ 1,2-a] pyrrol-l-carboxylsyre. CQ. 3θ C. Test for antipyretisk virkning.In addition, the following potencies were determined: in µg 5- (5-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylic acid, 5- (3-furoyl) ) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylic acid, 3- 5- (2-thenoyl) -6-methyl-1,2-dihydro-3H-pyrrole [1,2 -a] pyrrole-1- 27 carboxylic acid, - 5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylic acid, 5- (3-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylic acid. CQ. 3θ C. Test for antipyretic action.

Protokol: Simonsen hunrotter med en vægt på 90-100 g anvendes. "Normal" -2Ό rektaltemperaturen for rotterne bestemmes ved time 0, efterfulgt af en subkutaninjektion af 2 ml af en gærsuspension (1 ml dorsalt, 1 ml ven-tralt). Injektionsstederne masseres for at fordele suspensionen under huden. Gærinjektionen bevirker forhøjet legemstemperatur (pyrese). Ved 25 -time 17 masseres rotterne igen for at stimulere en yderligere forøgelse af legemstemperaturen. Ved - time 18 foretages den anden rektal temperaturmåling, hvorefter materialet, der skal afprøves, administreres oralt ved indgivelse il ml vandig bærer. Den tredje rektal temperaturmåling ( foretages 2 timer efter administrationen af materialet, der skal under-2ø søges.Protocol: Simonsen female rats weighing 90-100 g are used. "Normal" -2Ό rectal temperature of the rats is determined at hour 0, followed by a subcutaneous injection of 2 ml of a yeast suspension (1 ml dorsally, 1 ml venrally). The injection sites are massaged to distribute the suspension under the skin. The yeast injection causes elevated body temperature (pyresis). At 25-hour 17, the rats are massaged again to stimulate a further increase in body temperature. At - hour 18, the second rectal temperature measurement is made, after which the material to be tested is orally administered by administration in 1 ml of aqueous carrier. The third rectal temperature measurement (made 2 hours after the administration of the material to be sub-2u searched.

Slutpunkt: Temperaturfald (°F) fra anden temperaturmåling til tredje > temperaturmåling. * 35 Under anvendelse af den ovennævnte protokol bestemmes det, at 5—(2— thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre har en antipyretisk virkning på 17 gange aspirins.End point: Temperature drop (° F) from second temperature measurement to third> temperature measurement. Using the above protocol, it is determined that 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an antipyretic effect of 17 times aspirin.

1313

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De følgende fremstillingsmetoder og eksempler illustrerer henholdsvis fremstillingen af udgangsmaterialer og fremgangsmåden ifølge opfindelsen. Alle blandingsforhold, der anvendes med hensyn til væsker, refererer til volumenforhold. Hvor det er nødvendigt genta-5 ges fremstillingsmetoder og eksempler for at fremstille yderligere materiale til efterfølgende eksempler, og med mindre andet er anført, gennemføres reaktionerne ved stuetemperatur (20-30°C).The following preparation methods and examples illustrate the preparation of starting materials and the process according to the invention respectively. All mixing ratios used with regard to liquids refer to volume ratios. Where necessary, preparation methods and examples are repeated to prepare additional material for subsequent examples, and unless otherwise stated, the reactions are carried out at room temperature (20-30 ° C).

Fremstillingsmetode 1 10 En blanding af 23. g 4-chlorthiophen-2-ca,rboxylsyre (J, Iriarte et al,, J, Heterocyclic Chem. 13, 3931 og 80 ml thionylchlorid opvarmes til tilbagesvaling under vandfri betingelser i 4 timer, Thionylchlorid-overskudet fjernes, og resten destilleres under reduceret tryk (60°C/2 mm Hg) , hvilket giver 18 g 4-chlorthiophen-'2-carboxylsyrechlorid.Preparation Method 1 A mixture of 23 g of 4-chloro-thiophene-2-carboxylic acid (J, Iriarte et al, J, Heterocyclic Chem. 13, 3931 and 80 ml the excess is removed and the residue is distilled under reduced pressure (60 ° C / 2 mm Hg) to give 18 g of 4-chlorothiophene-2-carboxylic acid chloride.

15 ,15,

En opløsning af 10,5 g 4-chlorthiophen-2-carboxylsyrechlorid i 500 ml vandfri benzen afkøles i et is-vandbad, og dimethylamin bobles langsomt gennem opløsningen i 30 minutter. Is-vandbadet fjernes, idet dimethyl= aminstrømmen opretholdes i yderligere 15 minutter. Reaktionsblandingen 20 fortyndes så med 100 ml 10% natriumchloridopløsning og omrøres i 5 minutter ved stuetemperatur, den organiske fase skilles fra, vaskes med 10% saltsyre, mættet natriumbicarbonatopløsning og mættet natrium= chloridopløsning, tørres over'natriumsulfat og inddampes til tørhed under reduceret tryk. Herved fås N,N-dimethyl-4-chlorthiophen-2-25 carboxamid.A solution of 10.5 g of 4-chlorothiophene-2-carboxylic acid chloride in 500 ml of anhydrous benzene is cooled in an ice-water bath and dimethylamine is slowly bubbled through the solution for 30 minutes. The ice-water bath is removed, maintaining the dimethyl = amine stream for a further 15 minutes. The reaction mixture 20 is then diluted with 100 ml of 10% sodium chloride solution and stirred for 5 minutes at room temperature, the organic phase is separated, washed with 10% hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. There is thus obtained N, N-dimethyl-4-chlorothiophene-2-carboxamide.

På tilsvarende måde omdannes thiophen- og furan-2-carboxylsyrerne, som er anført nedenfor under I til Ν,Ν-dimethylamiderne, som er anført under II: .30Similarly, the thiophene and furan-2-carboxylic acids listed below under I, are converted into the Ν, Ν-dimethylamides listed under II: .30

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1414

^ I II^ I II

Thiophen-2-carboxylsyre N,N-dimethylthiophen-2-carboxamid furan-2-carboxylsyre ‘ N,N-dimethylfuran-2-carboxamid 3- methylthiophen-2-carboxylsyre Ν,Ν-dimethy1-3-methylthiophen-2- carboxamid 4- methylthiophen-2-carboxylsyre N,N-dimethyl-4-methylthiophen-2~ carboxamid g 5-methylthiophen-2-carboxylsyre N,N-dimethyl-5-methylthiophen-2- carboxamid 5- chlorthiophen-2-carboxylsyre N,N-dimethyl-5-chlorthiophen-2- carboxamid 3- bromthiophen-2-carboxylsyre N> N-dimethyl-3-bromthiophen-2- carboxamid 4- bromthiophen-2-carboxylsyre N,N-dimethyl-4-bromthiophen-2- ( carboxamid • v.» % 5- bromthiophen-2-carboxylsyre N,N-dimethyl-5-bromthiophen-2- carboxamid 3-methylfuran-2-carboxylsyre N,N-dimethyl-3-methylfuran-2- carboxamidThiophene-2-carboxylic acid N, N-dimethylthiophene-2-carboxamide furan-2-carboxylic acid N, N-dimethylfuran-2-carboxamide 3- methylthiophene-2-carboxylic acid Ν, Ν-dimethyl-3-methylthiophene-2-carboxamide 4 methylthiophene-2-carboxylic acid N, N-dimethyl-4-methylthiophene-2-carboxamide g 5-methylthiophene-2-carboxylic acid N, N-dimethyl-5-methylthiophene-2-carboxamide 5-chlorothiophene-2-carboxylic acid N, N -dimethyl-5-chlorothiophene-2-carboxamide 3- bromothiophene-2-carboxylic acid N> N-dimethyl-3-bromothiophene-2-carboxamide 4-bromothiophene-2-carboxylic acid N, N-dimethyl-4-bromothiophene-2- ( % 5-bromothiophene-2-carboxylic acid N, N-dimethyl-5-bromothiophene-2-carboxamide 3-methylfuran-2-carboxylic acid N, N-dimethyl-3-methylfuran-2-carboxamide

* . I*. IN

15 4 -methylfuran-2-carboxylsyre N,N-dimethyl-4-methylfuran-2- carboxamid 5-methylfuran-2-carboxylsyre N,N-dimethyl-5-methylfuran-2- carboxamid 3- chlorfuran-2-carboxylsyre N,N-dimethyl-3-chlorfuran-2~ carboxamid 2Q 4-chlorfuran-2-carboxylsyre N,N-dimethyl-4-chlorfuran-2- carboxamid 5-chlorfuran-2-carboxylsyre N,N-dimethyl-5-chlorfuran-2- carboxamid 4- bromfuran-2-carboxylsyre Ν,Ν-dimethyl-4-bromfuran-2- carboxamid 25 5-bromfuran-2-carboxylsyre Ν,Ν-dimethyl-5-bromfuran-2- carboxamid thiophen-3-carboxylsyre N,N-dimethylthiophen-3-carboxamid f uran-3-carboxylsyre N, N-dimetliylf uran-3-carboxamid.4-methylfuran-2-carboxylic acid N, N-dimethyl-4-methylfuran-2-carboxamide 5-methylfuran-2-carboxylic acid N, N-dimethyl-5-methylfuran-2-carboxamide 3-chlorofuran-2-carboxylic acid N, N-dimethyl-3-chlorofuran-2-carboxamide 2Q 4-chlorofuran-2-carboxylic acid N, N-dimethyl-4-chlorofuran-2-carboxamide 5-chlorofuran-2-carboxylic acid N, N-dimethyl-5-chlorofuran-2 - carboxamide 4- bromfuran-2-carboxylic acid Ν, Ν-dimethyl-4-bromfuran-2-carboxamide 5-bromfuran-2-carboxylic acid Ν, Ν-dimethyl-5-bromfuran-2-carboxamide thiophene-3-carboxylic acid N, N-dimethylthiophene-3-carboxamide for uranium-3-carboxylic acid N, N-dimethyl-uranium-3-carboxamide.

30 Fremstillingsmetode 2Preparation Method 2

En 250 ml 3-halset, rundbundet kolbe med magnetisk omrøring og forsynet med et calciumchloridfyldt tørringsrør er forbundet direkte (via en af de udvendige halse) ved hjælp af et tilpasningsstykke og en kort 35 (3") vandsvaler til acetalpyrolyseapparatet. Dette sidstnævnte apparat består af en 100 ml rundbundet kolbe (forud fyldt med 15,6 g oxalsyre= dihydrat og 11,82 g bromacetaldehyddiethylacetal, fremstillet af vinyl= 15A 250 ml 3-neck, round-bottomed flask with magnetic stirring and provided with a calcium chloride-filled drying tube is connected directly (via one of the external necks) by means of an adapter and a short 35 (3 ") water cooler to the acetal pyrolysis apparatus. of a 100 ml round bottom flask (pre-loaded with 15.6 g of oxalic acid = dihydrate and 11.82 g of bromoacetaldehyde diethyl acetal, made of vinyl = 15

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acetat, som beskrevet af P.Z. Bedoukian, J. Am. Chem. Soc. 66, 651 . (1944)), med en 6" Vigreuxkolonne i toppen, med et termometer forbun det til ovennævnte svaler.acetate, as described by P.Z. Bedoukian, J. Am. Chem. Soc. 66, 651. (1944)), with a 6 "Vigreux column at the top, with a thermometer connecting it to the above swallow.

Den 3-halsede kolbe forsynes med 3,36 g ethanolamin, afkølet i et is-5 bad til 0-10°C og behandles dråbevis under omrøring med 8,7 g dimethyl-· 1,3-acetonedicarboxylat. Methyl-3-carbometho:xyinethyl-3 (2 '-hydroxyethyl) -aminoacrylat (III) dannes straks. Efter endt tilsætning fjernes isbadet, og 100 ml tør acetonitril tilsættes. Apparatets pyrolysedel anbringes i et oliebad, og temperaturen heraf hæves til 150 til 160°C. Bromacetaldehydopløsningen, der dannes, destillerer (kogepunkt 80~83°C/ 580 mm Hg) direkte over i den magnetisk omrørte opløsning af vinylaminer (III). Når destillationstemperaturen falder under 80°C, afbrydes forbindelsen til pyrolyseapparatet, og i stedet anbringes en tilbagesvaler forsynet med et tørrerør indeholdende calciumchlorid. Opløsningen opvarmes ved tilbagesvalingstemperaturen i 1 time, opløsningsmidlet fjernes under reduceret tryk, og derpå sættes 200 ml methanol og 20 g silicagel til resten. Blandingen inddampes til tørhed under vakuum, og anbringes i toppen af en søjle af .200 g silicagel pakket i hexan. Søjlen elueres derpå med hexan/ethylacetat (80:20, 500 ml) og hexan/ethyl= ^ acetat (1:1, 9 x 500 ml). Fraktionerne 2 og 3 indeholder mindre polære urenheder, og dimethyl-l,3-acetonedicarboxylat, fraktionerne 4-8 giver 4,1 g methyl-N-(2-hydroxyethyl)~3-carbomethoxypyrrol~2-acetat (IV, R=H), som efter omkrystallisation fra ether/hexan har et smeltepunkt på 52-54°C.The 3-neck flask is charged with 3.36 g of ethanolamine, cooled in an ice-bath to 0-10 ° C and treated dropwise with stirring with 8.7 g of dimethyl-1,3-acetone dicarboxylate. Methyl 3-carbometho: xyinethyl-3 (2'-hydroxyethyl) aminoacrylate (III) is formed immediately. After the addition is complete, remove the ice bath and add 100 ml of dry acetonitrile. The pyrolysis part of the apparatus is placed in an oil bath and its temperature is raised to 150 to 160 ° C. The bromoacetaldehyde solution formed distills (boiling point 80 ~ 83 ° C / 580 mm Hg) directly into the magnetically stirred solution of vinylamines (III). When the distillation temperature drops below 80 ° C, the connection to the pyrolysis apparatus is disconnected and a reflux condenser fitted with a calcium chloride drying tube is instead. The solution is heated at reflux for 1 hour, the solvent is removed under reduced pressure, then 200 ml of methanol and 20 g of silica gel are added to the residue. The mixture is evaporated to dryness under vacuum and placed on top of a column of .200 g of silica gel packed in hexane. The column is then eluted with hexane / ethyl acetate (80:20, 500 mL) and hexane / ethyl = ^ acetate (1: 1, 9 x 500 mL). Fractions 2 and 3 contain minor polar impurities, and dimethyl 1,3-acetone dicarboxylate, fractions 4-8 give 4.1 g of methyl N- (2-hydroxyethyl) ~ 3-carbomethoxypyrrole ~ 2-acetate (IV, R = H ), which after recrystallization from ether / hexane has a melting point of 52-54 ° C.

2525

Fremstillingsmetode 3 s.,Preparation method 3 p.,

Til en omrørt opløsning af 4,1 g methyl-N-(2-hydroxyethyl)-3-carbo= methoxypyrrol-2-acetat i. 35 ml tør dichlormethan afkølede til -10°C, 30 sættes 2,65 ml triethylamin og derefter tildryppes 1,46 ml methansulfo^ nylchlorid, idet reaktionsblandingens temperatur holdes på -10 - -5°C, Reaktionens forløb følges ved hjælp af tyndtlagskromatografiske analyser under anvendelse af chloroform/acetone (90:10), Når reaktionen viser sig at være forløbet fuldstændig (ca., 30 minutter efter at methan=To a stirred solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carboxy methoxypyrrole-2-acetate. 35 ml of dry dichloromethane cooled to -10 ° C, 2.65 ml of triethylamine are added and then 1.46 ml of methanesulfonyl chloride is added dropwise while maintaining the temperature of the reaction mixture at -10 - -5 ° C. The course of the reaction is followed by thin layer chromatographic analysis using chloroform / acetone (90:10). (approx. 30 minutes after methane =

q Cq C

0 sulfonylchloridtilsætningen er ophørt) tilsættes langsomt 10 ml vand,0 the sulfonyl chloride addition has ceased) slowly add 10 ml of water,

Den organiske fase skilles fra, vaskes med vand (3 x 30 ml),tørres over natriumsulfat og inddampes under reduceret tryk. Krystallisation af resten fra dichlormethan/hexan giver 4,75 g (77,7%) methyl-N-(2- mesyloxyethyl)-3-carbomethoxypyrrol-2-acetat (V, R = H), smeltepunkt 40 qq-im0r.The organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from dichloromethane / hexane gives 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), m.p. 40 qq imor.

\ i\ i

Fremstillingsmetode 4 16Method of preparation 4 16

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En opløsning af 785 mg methyl-N-(2-mesyloxyethyl)-3-carbomethoxypyrrol- 2-acetat og 1,83 g natriumiodid i 10 ml acetonitril tilbagesvales i ' 1 time. Den afkølede reaktionsblanding inddampes til tørhed under re-5 ' duceret tryk, og resten sønderdeles med vand. Det uopløselige materiale filtreres fra og lufttørres. Således fås 840 mg (97%) methyl-N-(2-iodethyl)-3-carbomethoxypyrrol-2-acetat (VI, R = H), smeltepunkt 137-138°C.A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is refluxed for 1 hour. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is decomposed with water. The insoluble material is filtered off and air dried. Thus, 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), m.p. 137-138 ° C is obtained.

s 10 Fremstillingsmetode' 5 .· f\ ·s 10 Preparation Method 5.

En opløsning, af 1 g methyl-N-(2-iodethyl)-3-carbomethoxypyrrol-2-acetat i 5 ml tør dimethylformamid omrøres under en argonatmosfære med 137 mg 50% natriumhydrid i mineralolie. Reaktionsblandingen holdes i 30 minut-15 ter ved stuetemperatur og afkøles derpå hurtigt med 100 ral vand. Produktet ekstraheres med ethylacetat (3 x 50 ml), de forenede ekstrakter vaskes med vand, tørres over magnesiumsulfat og inddampes til tørhed. Kromatografi af resten på silicagel (20 g) under anvendelse af hexan/ ethylacetat (4:1) som elueringsmiddel giver 500 mg (80%) dimethyl-1,2-20 dihydro-3H-pyrrolo[l,2-a]pyrrol-l,7-dicarboxylat (VII, R = H), smeltepunkt 70-71°C.A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred under an argon atmosphere with 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is kept at room temperature for 30 minutes and then cooled rapidly with 100 r of water. The product is extracted with ethyl acetate (3 x 50 ml), the combined extracts washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue on silica gel (20 g) using hexane / ethyl acetate (4: 1) as eluent gives 500 mg (80%) of dimethyl-1,2-20 dihydro-3H-pyrrolo [1,2-a] pyrrole 1,7-dicarboxylate (VII, R = H), m.p. 70-71 ° C.

En opløsning af 1,80 g dimethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1, 7-dicarboxylat i 20 ml methanol behandles med en opløsning af 4,48 g 25 kaliumhydroxid i 20 ml vand, og reaktionsblandingen tilbagesvales i 6 timer. Den afkølede opløsning inddampes til tørhed, og resten behandles med 50 ml mættet natriuiuchloridopløsning. Den resulterende opløsning syrnes med 6N saltsyre og ekstraheres med ethylacetat (3 x 50 ml). De forenede ekstrakter tørres over magnesiumsulfat og inddampes til tør-30 hed under reduceret tryk. Herved fås 1,51 g (95%) l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l,7-dicarboxylsyre (VIII, R = H), smeltepunkt 220°C under dekomponering.A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate in 20 ml of methanol is treated with a solution of 4.48 g of potassium hydroxide in 20 ml. water and the reaction mixture is refluxed for 6 hours. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N hydrochloric acid and extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. There is thus obtained 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H), m.p. 220 ° C with decomposition.

Fremstillingsmetode 6 35 En opløsning af 1,34 g 1,2-dihydro-3H-pyrrolo[1,2-aJpyrrol-l,7-di= carboxylsyre i 50 ml isopropanol, afkøles i et isbad, mættes med hydro= genchloridgas, idet reaktionsblandingens temperatur holses under 50°C.Preparation Method 6 A solution of 1.24 g of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1,7-di = carboxylic acid in 50 ml of isopropanol is cooled in an ice bath, saturated with hydrogen chloride gas, the temperature of the reaction mixture is kept below 50 ° C.

1717

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Isbadet fjernes derpå, og reaktfonsblandingen omrøres i 1 1/2 time ved stuetemperatur og inddampes til tørhed under reduceret tryk. 10 ml benzen sættes til resten, og opløsningen inddampes endnu en gang under vakuum, idet denne behandling gentages i alt tre.gange for fuldstændigt 5 at fjerne hydrogenchloridoverskud. Således fås 1,58 g (96%) isopropyl- v 1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat-7-carboxylsyre (IX, 2 R = H, R = iso-C^H^), som efter omkrystallisation fra methanol/ethyl= acetat har et smeltepunkt på 144-145°C.The ice bath is then removed and the reaction mixture is stirred for 1 1/2 hours at room temperature and evaporated to dryness under reduced pressure. 10 ml of benzene is added to the residue and the solution is evaporated again under vacuum, repeating this process for a total of three times to completely remove hydrogen chloride excess. Thus, 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid (IX, 2 R = H, R = iso ), Which after recrystallization from methanol / ethyl = acetate has a melting point of 144-145 ° C.

10 På tilsvarende måde, men ved anvendelse af methanol, ethanol, propanol og n-butanol i stedet' for isopropanol ved den ovennævnte fremgangsmåde opnås henholdsvis: » methyl-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat-7-carboxylsyre, 15 ethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat-7-carboxylsyre, propyl-1,2-dihydro-3H-pyrrolo ti,2-a]pyrrol-l-carboxylat-7-carboxylsyre, butyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-cafboxylat-7-carboxylsyre.Similarly, but using methanol, ethanol, propanol and n-butanol instead of isopropanol by the above process, respectively, is obtained: 'methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole -1-carboxylate-7-carboxylic acid, ethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid, propyl-1,2-dihydro-3H-pyrrolo , 2-a] pyrrole-1-carboxylate-7-carboxylic acid, butyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-cafboxylate-7-carboxylic acid.

20 Fremstillingsmetode 7 1,054 g isopropyl-1,2-dihydro~3H-pyrrolo[1,2-a]pyrrol-l-carboxylat-7- carboxylsyre opvarmes til 240-250°C i en tør 10 ml rundbundet kolbe, idet reaktionsproduktet destilleres direkte fra reaktionsbeholderen.Preparation Method 7 1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid is heated to 240-250 ° C in a dry 10 ml round bottom flask, distilling the reaction product directly from the reaction vessel.

25 På denne måde fås 745 mg (87%) isopropyl-1,2-dihydro-3H-pyrrolo[1,2-a]- pyrrol-l-carboxylat (X, R = H, R2 = iso-C3H7), en lysegul olie med følgende fysiske konstanter: U.v,: 215 nm (ε 6020), I.R.: v011.01! · ™aks Pnr1 maks 1725 cm , N.M.R. (kerneraagnetisk resonans) : 5^ 3 1,22 (d, J = 7 IIz, 611), 2,40-2,90 (m, 2H) , 3,60-4,20 (m, 2H) , 4,65-5,2 (m, IH), 5,73-30 5,92 (m, IH), 6,10 (t, J"= 3 Hz, IH), 6,43-6,53 (m, IH).In this way, 745 mg (87%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = H, R2 = iso-C3H7) is obtained. light yellow oil with the following physical constants: Uv,: 215 nm (ε 6020), IR: v011.01! · ™ axis Pnr1 max 1725 cm, N.M.R. (Nuclear Magnetic Resonance): δ 3 1.22 (d, J = 7 IIz, 611), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2H), 4, 65-5.2 (m, 1H), 5.73-30 5.92 (m, 1H), 6.10 (t, J "= 3 Hz, 1H), 6.43-6.53 (m, I H).

Fremstillingsmetode 8Preparation Method 8

En 100 ml trehalset rundbundet kolbe forsynet med en svaler, nitrogen-35 tilledningsrør og en gasbobler forsynes med 5,0 g isopropyl-1,2-di= hydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat-7-carboxylsyre. Apparatet gennemblæses fuldstændig med nitrogen og derpå standses nitrogenstrømmen. Apparatet neddykkes i et oliebad, opvarmet til 270°C., og reak- 18A 100 ml three-necked round bottom flask provided with a cooler, nitrogen supply tube and a gas bubbler is supplied with 5.0 g of isopropyl-1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate. 7-carboxylic acid. The apparatus is completely blown with nitrogen and then the nitrogen flow is stopped. The apparatus is immersed in an oil bath heated to 270 ° C and reacted with 18

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4 i* tionen, følges ved hjælp af carbondioxidudviklingens omfang (gasbobler} og ved hjælp af tyndtlagskromatografi på silicagel under anvendelse af benzen/dioxan/eddikesyre (90:10:1) som fremkaldermiddel. Efter 45 minut-- ' " ters forløb er reaktionen forløbet næsten fuldstændig. Efter 1 times 5 -forløb fjernes beholderen fra oliebadet, og reaktionskolbens indhold overføres til en rundbundet kolbe med 500 ml acetone. Opløsningsmidlet fjernes under reduceret tryk, og resten renses ved søjlekromatografi , på 100 g silicagel. De med hexan/benzen (70:30) og hexan/benzen (50:50) eluerede fraktioner giver 2,77 g (68%) isopropyl-1,2-dihydro-3H-pyrro= lo [l,2-a]pyrrol-l-carboxylat (X, R = H, R2 = iso-C^H^), en olie, hvis fysiske konstanter er identiske med de i eksempel 6 anførte.4 i * is followed by the extent of carbon dioxide evolution (gas bubbles} and by thin layer chromatography on silica gel using benzene / dioxane / acetic acid (90: 10: 1) as the developing agent. After 45 minutes the reaction is After 1 hour 5, the vessel is removed from the oil bath and the contents of the reaction flask are transferred to a 500 ml acetone round bottom flask. The solvent is removed under reduced pressure and the residue is purified by column chromatography on 100 g of silica gel. (70:30) and hexane / benzene (50:50) eluted fractions give 2.77 g (68%) of isopropyl-1,2-dihydro-3H-pyrro = 10 [1,2-a] pyrrole-1-carboxylate (X, R = H, R 2 = iso-C 2 H 2), an oil whose physical constants are identical to those of Example 6.

Fremstillingsmetode 9 15 710 mg af en 50%'ig suspension af natriumhydrid i mineralolie vaskes med vandfri hexan under en nitrogenatmosfære og suspenderes derpå i 50 ml dimethylformamid. Suspensionen afkøles til -5°C, og 4,5 g methyl-N-(2-mesyloxymethyl)-3-carbomethoxypyrrol-2-acetat tilsættes, idet reaktionsblandingen omrøres ved -5°C til 0°C i 1 time. Reaktionsbian- 20 dingen hældes derpå i iskold natriumchloridopløsning og ekstraheres adskillelige gange med benzen. De forenede ekstrakter vaskes med vand, tørres og inddampes til tørhed under reduceret tryk. Den faste rest krystalliseres fra ether. Således fås dimethyl-l,2-dihydro-3H-pyrrolo- [l,2-a]pyrrol-l,7-dicarboxylat (VII, R = H), der er identisk med det 25 i eksempel 4 opnåede produkt.Preparation Method 9 15 710 mg of a 50% suspension of sodium hydride in mineral oil is washed with anhydrous hexane under a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension is cooled to -5 ° C and 4.5 g of methyl N- (2-mesyloxymethyl) -3-carbomethoxypyrrole-2-acetate is added, stirring at 5 ° C to 0 ° C for 1 hour. The reaction mixture is then poured into ice-cold sodium chloride solution and extracted several times with benzene. The combined extracts are washed with water, dried and evaporated to dryness under reduced pressure. The solid residue is crystallized from ether. Thus, dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1,7-dicarboxylate (VII, R = H) identical to the product obtained in Example 4 is obtained.

Fremstillingsmetode 10Preparation Method 10

En opløsning af 232,5 mg N,N-dimethylthiophen-2-carboxamid og 0,15 ml 30 phosphoroxychlorid i 2 ml 1,2-dichlorethan tilbagesvales i 30 minutter. Til denne opløsning sættes en opløsning af 181 mg isopropyl-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat i 2 ml 1,2-dichlorethan. Reaktionsblandingen tilbagesvales under en argonatmosfære i 8 timer, 35 behandles med 450 mg natriumacetat og tilbagesvales i yderligere 5 timer. Den resulterende blanding inddampes .så til tørhed, og resten kromatograferes på 12 g silicagel, idet der elueres med hexan/ethyl= acetat (3:1). Således fås isopropyl-5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat (XI, R og R1 = H, R2 = iso-C^H^, X = 40 S) .A solution of 232.5 mg of N, N-dimethylthiophene-2-carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane was refluxed for 30 minutes. To this solution is added a solution of 181 mg of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and refluxed for an additional 5 hours. The resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel eluting with hexane / ethyl = acetate (3: 1). Thus, isopropyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R and R1 = H, R2 = iso-C , X = 40 S).

1919

Fremstillingsmetode- nThe manufacturing method

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Ved at følge fremgangsmåderne ,fra fraristillingsmetodeqaie 7 eller 8 omdannes d< resterende forbindelser opnået ved fremstillingsmetcde 6 henholdsvis til: ' methyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, -olie, 5 ethyl-l^-dihydro-dH-pyrroin, 2-a] pyrrol-l-carboxylat, propyl~l,2-dihydro-3H~pyrrolo[1,2-a]pyrrol-l-carboxylat, og buty 1-1,2-dihydro-3H-pyrrolo [ 1,2-a] pyrrol-l-carboxylat,Following the procedures, from preparation method 7 or 8, residual compounds obtained by preparation method 6 are converted into: methyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil, respectively. 5-ethyl-1-dihydro-dH-pyrroin, 2-a] pyrrole-1-carboxylate, propyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, and butyl 1- 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate,

Ved kondensation af disse forbindelser med N,N-dimethylthiophen-2-10 carboxamid i overensstemmelse med fremgangsmåden fra eksempel 9 fås henholdsvis: « methyl-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat, ethy1-5-(2-thenoyl]-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, 15 . ^aks 265' 328 nm (ε 7580' 17780)' · .Condensation of these compounds with N, N-dimethylthiophene-2-10 carboxamide according to the procedure of Example 9 gives respectively: «methyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2] -a] pyrrole-1-carboxylate, ethyl 5- (2-thenoyl] -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 15 axis 265 '328 nm ( ε 7580 '17780)' ·.

propyl-5-(2-thenoyl)-1,2-dihydro~3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, og - buty1-5-(2-thenoyl]-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat. Fremstillingsmetode 12 20propyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, and - butyl-5- (2-thenoyl] -1,2-dihydro-1 3H-pyrrolo [1,2-a] pyrrole-1-carboxylate Preparation Method 12 20

En 250 ml 3-halset rundbundet kolbe med magnetisk omrøring og forsynet med et calciumchlorid fyldt tørrerør forsynes med 3,36 g ethanolamin, afkøles på et isbad til 0-10°C og behandles dråbevis under omrøring med 8,7 g dimethyl-l,3-acetonedicarboxylat. Methyl-3-caχ-bomethoxymethy 1 25 3-(2’-hydroxyethyl)-aminoacrylat (III) dannes straks. Efter endt til sætning fjernes isbadet, og 80 ml tør acetonitril tilsættes. Reaktionsblandingen behandles så dråbevis med 6,75 g broraacetaldehyd i 20 ml acetonitril og opvarmes derpå ved tilbagesvalingstemperaturen i 2 timer.A 250 ml 3-necked round-bottomed flask with magnetic stirring and fitted with a calcium chloride-filled drying tube is charged with 3.36 g of ethanolamine, cooled in an ice bath to 0-10 ° C and treated dropwise with stirring with 8.7 g of dimethyl-1. 3-acetonedicarboxylate. Methyl 3-caχ-bomethoxymethyl 1 3- (2'-hydroxyethyl) aminoacrylate (III) is formed immediately. After completion of the addition, the ice bath is removed and 80 ml of dry acetonitrile is added. The reaction mixture is then treated dropwise with 6.75 g of boroacetaldehyde in 20 ml of acetonitrile and then heated at the reflux temperature for 2 hours.

Opløsningsmidlet fjernes derpå under reduceret tryk, og 200 ml methanol 30 og 20 g silicagel sættes til resten. Denne blanding inddampes til tørhed under vakuum og anbringes i toppen af en søjle af 200 g silicagel pakket i hexan, idet søjlen elueres med hexan/ethylacetatblandinger. Fraktioner elueret med hexan/ethylacetat (1:1) giver methyl-N-(2- hydroxyethyl)-3-carbomethoxypyrrol-2-acetat (IV, R = H), der er iden-3 5 tisk med det i .ved fremstillingsmetode 2 opnåede produkt.The solvent is then removed under reduced pressure and 200 ml of methanol 30 and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness under vacuum and placed on top of a column of 200 g of silica gel packed in hexane, eluting with the column with hexane / ethyl acetate mixtures. Fractions eluted with hexane / ethyl acetate (1: 1) give methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H) identical to that used in the preparation method. 2 product obtained.

2020

Fremstillingsmetode 13Preparation Method 13

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Til en opløsning af 6 ml ethanolamin i 5 ml vand sættes 1,74 g d'i= methyl-l,3-acetonedicarboxylat. Den resulterende blanding afkøles hurtigt til -10°C og behandles dråbevis i løbet af en 15 minutters periode under omrøring med 1,67 ml 1“bromacetone, medens reaktions-5 blandingen holdes ved en temperatur på højst 40°C, Efter endt tilsætning omrøres den mørke reaktionsblanding i.yderligere i 1 time. ved stuetemperatur og hældes derpå i en blanding af saltsyre/is mættet x med fast natriumchlorid og ekstraheres med ethylacetat (3 x 100 ml), Den samlede mængde organisk ekstrakt vaskes med koldt vand til neutral reaktion, tørres med vandfri natriumsulfat og inddampes til tørhed under reduceret tryk. Kromatografi af resten på 30 g silicagél under anvendelse af hexan/ethylacetat (70:30) som elueringsmiddel giver 890 mg krystallinsk methyl-N-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrol- 2-acetat, som ved omkrystallisation fra methylenchlorid/hexan smelter ved 78°C og har følgende analyse;To a solution of 6 ml of ethanolamine in 5 ml of water is added 1.74 g of i = methyl 1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and treated dropwise over a 15 minute period with stirring with 1.67 ml of 1 "bromoacetone while maintaining the reaction mixture at a temperature not exceeding 40 ° C. the dark reaction mixture further for 1 hour. at room temperature and then poured into a hydrochloric acid / ice mixture saturated x with solid sodium chloride and extracted with ethyl acetate (3 x 100 ml). The total amount of organic extract is washed with cold water for neutral reaction, dried over anhydrous sodium sulfate and evaporated to dryness. reduced pressure. Chromatography of the residue on 30 g of silica gel using hexane / ethyl acetate (70:30) as the eluent gives 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, which by recrystallization from methylene chloride / hexane melts at 78 ° C and has the following analysis;

Beregnet for ci2H17N05: C, 56,45, H, 6,71 Fundet; C, 56,41, H, 6,73.Calcd for c12 H17 NO5: C, 56.45, H, 6.71 Found; C, 56.41; H, 6.73.

20 På tilsvarende måde, men under anvendelse af en støkiometrisk ækvivalent mængde l-brom-2-butanon, l-brom-2-pentanon og l-brom-2-hexanon i stedet for 1-bromacetone fås henholdsvis: methyl-N-(2-hydroxyethyl)-3-carbomethoxy-4-ethylpyrrol-2-acetat, 25 methyl-N-(2-hydroxyethyl)-3-carbomethoxy-4-propyl-pyrrol-2-acetat, og methyl-N-(2-hydroxyethyl)-3-carbomethoxy~4-butyl-pyrrol-2-acetat%Similarly, but using a stoichiometric equivalent amount of 1-bromo-2-butanone, 1-bromo-2-pentanone and 1-bromo-2-hexanone instead of 1-bromoacetone is obtained respectively: methyl-N- ( 2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-propyl-pyrrole-2-acetate, and methyl-N- (2- hydroxyethyl) -3-carbomethoxy-4-butyl-pyrrole-2-acetate%

Fremstillingsmstode 14 30 ’Preparation Method 14 30 '

Ved at følge fremgangsmåden fra fremstillingsmetode 3 emdannes methyl-N-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrol-"2-acetat (XV, R = CHg) til methyl-N-(2-mesyloxyethyl)-3-carbomethoxy-4-methylpyrrol-2-acetat og derpå omkrystalliseres med natriumhydrid i dimethylformamid i overgå ensstemmelse med fremgangsmåden fra fremstillingsmetode 9 til fremstilling af di= methyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrol-1,7-dicarboxylat, 21Following the method of Preparation Method 3, methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (XV, R = CHg) is converted to methyl N- (2-mesyloxyethyl) -3- carbomethoxy-4-methylpyrrole-2-acetate and then recrystallized from sodium hydride in dimethylformamide in accordance with the method of Preparation Method 9 to prepare di-methyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a ] pyrrole-1,7-dicarboxylate, 21

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Ved hydrolyse af sidstnævnte forbindelse med kaliumhydroxid i. overensstemmelse med fremgangsrråden fra. fremstillingsmetode 5 efterfulgt af selektiv forestring ved C-l og decarboxylering ved C-7 i overensstemmelse med fremgangsmåderne. fra henholdsvis fremstillingsmetoderne 6 og 8, opnås successivt 5 l,2-dihydro-6-methyl-3H-pyrrolo[l,2-a]pyrrol-l,7-dicarboxylsyre,. iso=. propyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]-pyrrol-l-carboxylat-7-carboxylsyre og isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo[l,2-a]pyr= rol-l-carboxylat (Xf R = CH^, = iso-C^Hy], 10 På tilsvarende måde ved anvendelse af methyl-N~(2-hydroxyethyl)-3-carbomethoxy-4-ethylpyrrol-2-acetat, methyl-N- (2-hydroxyethyl 1^-3-' carbomethoxy-4-propylpyrrol-2-acetat og methyl-N-(2-hydroxyethyl)--3- --carbomethoxy-4-butylpyrrol-2-acetat i stedet for methyl-N- (2-hydroxy= ethyl)-3-carbomethoxy-4-methylpyrrol-2-acetat fås som slutprodukter 15 henholdsvis: isopropyl-1,2-dihydro-6-ethyl-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, isopropyl-1,2-dihydro-6-propyl-3H-pyrrolb[1,2-a]pyrrol-l-carboxylat, . % og · · ‘ isopropyl-1,2-dihydro-6-butyl-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat,By hydrolysis of the latter compound with potassium hydroxide in accordance with the procedure of. Preparation method 5 followed by selective esterification at C-1 and decarboxylation at C-7 according to the methods. 5, 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid, respectively, is obtained successively from preparation methods 6 and 8, respectively. = iso. propyl 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid and isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1 , 2-a] pyr = rol-1-carboxylate (Xf R = CH 2, = iso-C 2 Hy], 10 Similarly, using methyl N- (2-hydroxyethyl) -3-carbomethoxy-4 ethylpyrrole-2-acetate, methyl-N- (2-hydroxyethyl 1-3-carbomethoxy-4-propylpyrrole-2-acetate and methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole -2-acetate instead of methyl N- (2-hydroxy = ethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate is obtained as final products, respectively: isopropyl-1,2-dihydro-6-ethyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate,% and isopropyl 1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-l-carboxylate,

Fremstillingsmetode 15 I overensstemmelse med fremgangsmåden fra fremstillingsmetode 10 kondenseres iso= 25 propyl-1,2-dihydro-6-meth.yl-3H-pyrrolo [lf2-a]pyrrol-l-carboxylat med N,N-dim.ethylthiophen-2-carboxamid til fremstilling af isopropyl-5-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1(2-a]pyrrol-l-carboxylat (XI, R = CH^, R"*" - H, R^ = iso-C-jH^, X = S) f med et smeltepunkt på 102,5°C.Preparation Method 15 In accordance with the method of Preparation Method 10, iso = 25 propyl-1,2-dihydro-6-methyl-3H-pyrrolo [l2-a] pyrrole-1-carboxylate is condensed with N, N-dimethylthiophene-2 -carboxamide to prepare isopropyl 5- (2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1 (2-a] pyrrole-1-carboxylate (XI, R = CH = H, R 2 = iso-C-jH 2, X = S) f, with a melting point of 102.5 ° C.

30 På tilsvarende måde·,· men under anvendelse af de ved eksempel 5 anførte . Ν,Ν-dimethylthiophen- eller furan-2-carboxamider i stedet for N,N-dimethylthiophen-2-carboxamid fremstilles henholdsvis; 35 2230 Similarly, but using the ones listed in Example 5. Ν, Ν-dimethylthiophene or furan-2-carboxamides instead of N, N-dimethylthiophene-2-carboxamide are produced, respectively; 35 22

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isopropyl-5- (2-furoyl) -1,2-diliydro-6-methyl-3H-pyrrolo [1,2-¾] pyrrol- l-carboxylat, isopropyl-5-(3-methyl-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo- .isopropyl-5- (2-furoyl) -1,2-diliydro-6-methyl-3H-pyrrolo [1,2-¾] pyrrole-1-carboxylate, isopropyl-5- (3-methyl-2-thenoyl) - 1,2-dihydro-6-methyl-3H-pyrrolo-.

[1,2-a]pyrrol-l-carboxylat, 5 isopropyl-5-(4-methyl-2-thenoyl)-1,2-dihydrp-6-methyl-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat, isopropyl-5- (5-methyl-2-thenoyl} -1,2 - d ihy dr o - 5 -me thy 1-3 Η-py r ro 1 o -[1,2-a]pyrrol-l-carboxylat, isopropyl-5- (4-chlor-2-thenoyl] -1,2-dihydro'-6-methyl-3H-pyrrolo-10 [l,2-a]pyrrol-l-carboxylat, isopropyl-5-(5-chlor-2-thenoyl]-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat, isopropyl-5- (3-brouj-2-thenoyl) -1,2-dihydro-6-metbyl-3H-pyrrolo-' ’ [1,2-a]pyrrol-l-carboxylat, 15 isopropyl-5- (4-brom-2-thenoyl).-l, 2-dihydro-6-meth.yl-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat, isopropyl-5 - (5-brom-2-thenoyl 1 -1 , 2-dihydro-6-iuetbyl~3H-pyrroio-· v [1,2-a]pyrrol-l-carboxylat, isopropyl-5-(3-methyl-2-£nroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-20 [1,2-a]pyrrol-l-carboxylat, isopropyl-5-(4-methyl-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat, isopropyl-5- (5-methyl-2-furoyl). -1,2-dihydro-6-methyl-3H-pyrrolo-. [1,2-a]pyrrol-l-carboxylat, isopropyl-5-(3-chlor-2-furoyll-l,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat, . . .[1,2-a] pyrrole-1-carboxylate, isopropyl-5- (4-methyl-2-thenoyl) -1,2-dihydrp-6-methyl-3H-pyrrolo- [1,2-a] pyrrole -1-carboxylate, isopropyl-5- (5-methyl-2-thenoyl) -1,2-dihydro-5-methyl thy 1-3 Η-py r ro 1 o - [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (4-chloro-2-thenoyl] -1,2-dihydro'-6-methyl-3H-pyrrolo-10 [1,2-a] pyrrole-1-carboxylate, isopropyl -5- (5-chloro-2-thenoyl] -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (3-bromo-2 -thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (4-bromo-2-thenoyl) -1 , 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (5-bromo-2-thenoyl-1,2-dihydro-6- [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (3-methyl-2-phenyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1-carboxylate] [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (4-methyl-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole -1-carboxylate, isopropyl-5- (5-methyl-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carbox ylate, isopropyl-5- (3-chloro-2-furoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate). . .

isopropyl-5-(4-chlor-2-£uroyl}-l,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat, .isopropyl-5- (4-chloro-2-uroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate ,.

isopropyl-5-(5-chlor~2-furoyl]-1,2-dihydro-6-methyl-3H-pyrrolo- qn ° [1,2-a]pyrrol-l-carboxylat, isopropyl-5-(4-brom-2-£uroyl]-1,2-dihydro-6-methyl-3H-pyrrolo-Γ1,2-a]pyrrol-l-carboxylat, og isopropyl-5-(5-brom-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrrolo- . [1,2-a]pyrrol-l-carboxylat, 35 *isopropyl-5- (5-chloro-2-furoyl] -1,2-dihydro-6-methyl-3H-pyrrolo [N] [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (4- bromo-2-uroyl] -1,2-dihydro-6-methyl-3H-pyrrolo-1,1,2-a] pyrrole-1-carboxylate, and isopropyl-5- (5-bromo-2-furoyl) -1 , 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, 35 *

De resterende ved fremstillingsnetqde 14 opnåede slutforbindelser omdannes ligeledes -til de tilsvarende 5-furoyl eller thenoylsubstituerede derivater, Eksempler på således opnåede forbindelser ers isopropyl-5-(2-thenoyl)-1,2-dihydro-6-ethyl-3H-pyrrolo[1,2-a]pyrrol-^ 1-carboxylat, 23The remaining compounds obtained by preparation network 14 are also converted to the corresponding 5-furoyl or thenoyl substituted derivatives. Examples of isopropyl-5- (2-thenoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [ 1,2-a] pyrrole-1-carboxylate, 23

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isopropyl-5-(2-furoyl)-1,2-dihydro~6-propyl-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, isopropyl-5-(3-methyl-2-thenoyl)-1,2-dihydro-6-butyl-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat, 5 isopropyl-5- (4-chlor-2-thenoyl) -Γ, 2-di'hydro-6-ethyl~3H-pyrrolo [1,2-a] - pyrrol-l-carboxylat, isopropyl-5-(5-methyl-2-furoyl)-l,2-dihydro~6~propyl-3H-pyrrolo[1,2-a]-pyrrol-l-carboxylat, og . isopropyl-5-(3-chlor-2-furoyl)-1,2-dihydro-6-butyl-3H-pyrrolofl,2-a]-10 pyrrol-l-carboxylat.isopropyl-5- (2-furoyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (3-methyl-2-thenoyl) - 1,2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (4-chloro-2-thenoyl) -2,2-dihydro- 6-ethyl ~ 3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (5-methyl-2-furoyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1 , 2-α] pyrrole-1-carboxylate, and. isopropyl 5- (3-chloro-2-furoyl) -1,2-dihydro-6-butyl-3H-pyrrolophyl-2-a] pyrrole-1-carboxylate.

Fremstillingsmetode .16Manufacturing method .16

En opløsning af 232,5 mg N,N-dimethylthiophen-3-carboxamid og 0,15 ml 15 phosphoroxychlorid i 2 ml 1,2-dichlorethan tilbagesvales i 30 minutter. Til denne opløsning sættes en opløsning af 181 mg isopropyl-1,2-di= hydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat i 2 ml 1,2-dichlorethan.A solution of 232.5 mg of N, N-dimethylthiophene-3-carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane was refluxed for 30 minutes. To this solution is added a solution of 181 mg of isopropyl-1,2-di-hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane.

Reaktionsblandingen tilbagesvales under en argonatmosfære i 8 timer, behandles med 450 mg natriumacetat og tilbagesvales i yderligere 5 20 timer. Den resulterende blanding inddampes så til tørhed, og resten kromatograferes på 12 g silicagel, idet der elueres med hexan/ethyl= acetat (3:1). Således fås isopropyl-5-(3-thenoyl)-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat (XII, R = H, R^ = iso-C^H^, X = S).The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and refluxed for a further 5 20 hours. The resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel eluting with hexane / ethyl = acetate (3: 1). Thus isopropyl-5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XII, R = H, R X = S).

20 På tilsvarende måde omdannes isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat og isopropyl-1,2-dihydro-6-propyl~3H-pyr= rolo [1,2-a]pyrrol-l-carboxylat henholdsvis til isopropyl-5-(3-thenoyl)-1,2-dihydro-6-methyl-3H~pyrrolo(1,2-a]pyrrol-l-carboxylat og isopropyl- 5- (3-thenoyl) -l,2-dihydro-6-propyl-3H-pyrrol'o [l,2-a]pyrrol~l-carboxy= j?° lat. ‘ ‘i På samme måde anvendes N,N-dimethylfuran-3-carboxamid i stedet for N,N-dimethylt'hiophen-3-carboxamid fås på samme måde de tilsvarende 5- (3-furoyl)-derivater, nemlig; \ isopropyl-5-(3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxy= lat, en olie med følgende fysiske konstanter; 35Similarly, isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate and isopropyl-1,2-dihydro-6-propyl ~ 3H-pyr = rolo [1,2-a] pyrrole-1-carboxylate to isopropyl-5- (3-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo (1,2-a] pyrrole-1-carboxylate, respectively and isopropyl-5- (3-thenoyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = l-lat. N, N-dimethylfuran-3-carboxamide is used in place of N, N-dimethylthiophene-3-carboxamide similarly to the corresponding 5- (3-furoyl) derivatives, namely, isopropyl-5- (3- furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, an oil having the following physical constants;

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24 U*V* · Amaks 222' 244"277 (skulder), 314 nm (ε 6750, 4250, 14800); I.R. vmaks3 1730· 1610' 1560 cnf1; '5 N.M.R. .. 1,23 [d, 6H, J = 6 Hz; (CH^CH], - 2,50-3,00 (m, 2H) , 3,92 (dd, 2H, JRX = 6 Hz, JBX = 7 Hz; H-l), 4,10-4,60 (m, 2H), 4,95 [sept,, 1H, J = 6 Hz; (CH3)2CH], 5,95 (d, 1H, J = 4 Hz; H-7), 6,78 (m, 1H), 6,83 (d, 1H, 10 J = 4 Hz; H-6), 7,30 (m, 1H), 7,83 ppm (m, 1H); M.S. m/e 270. (M+) , isopropyl-5-(3-furoyl)-l,2-dihydro-6-methyl-3H-pyrrolo Γ1,2-a]pyrrol-1-carboxylat, og isopropyl-5-(3-furoyl)-l,2-dihydro-6-propyl-3H-pyrrolo[1,2-a]pyrrol-15 1-carboxylat.24 U * V * Amax 222 '244 "277 (shoulder), 314 nm (ε 6750, 4250, 14800); IR vmax3 1730 · 1610' 1560 cnf1; 5 NMR .. 1.23 [d, 6H, J = 6 Hz; (CH 2 CH], 2.50-3.00 (m, 2H), 3.92 (dd, 2H, JRX = 6 Hz, JBX = 7 Hz; H1), 4.10-4 , 60 (m, 2H), 4.95 [sept, 1H, J = 6 Hz; (CH 3) 2CH], 5.95 (d, 1H, J = 4 Hz; H-7), 6.78 ( m, 1H), 6.83 (d, 1H, 10 J = 4 Hz; H-6), 7.30 (m, 1H), 7.83 ppm (m, 1H); MS m / e 270. ( M +), isopropyl-5- (3-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, and isopropyl-5- (3-furoyl) -1 , 2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Fremstillingsmetode 17Method of preparation 17

Til en opløsning af 300 mg 5-(2-thenoyl)-l,2-dihydro-3H~pyrrolo[l,2-a]- 20 pyrrol-l-carboxylsyre i 5 ml methanol sættes 1 molærækvivalent natrium= hydroxid i form af 0,1N opløsning. Opløsningsmidlet afdampes under reduceret tryk, og resten optages i 2 ml methanol efterfulgt af udfældning med ether til fremstilling af rå natrium-5-(2-thenoyl)-l,2-di= hydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat, der kan omkrystalliseres fra isopropanol.To a solution of 300 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] -20 pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of sodium = hydroxide in the form of 0.1N solution. The solvent is evaporated under reduced pressure and the residue is taken up in 2 ml of methanol followed by precipitation with ether to give crude sodium 5- (2-thenoyl) -1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate which can be recrystallized from isopropanol.

Andre salte, f.eks. ammonium- og kaliumsalte af 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylsyre fremstilles ved at anvende ammoniumhydroxid og kaliumhydroxid i stedet for natriumhydroxid.Other salts, e.g. ammonium and potassium salts of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are prepared using ammonium hydroxide and potassium hydroxide in place of sodium hydroxide.

30 De 5-substituerede l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylsyre= forbindelser, der blev opnået ved fremstillingsmetoderne 12, 13,. 14, ' 21 og 23,irkan på tilsvarende måde omdannes til de tilsvarende natrium-, kalium- og ammoniumsalte.The 5-substituted 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid = compounds obtained by the preparation methods 12, 13,. 14, 21 and 23, ircan is similarly converted to the corresponding sodium, potassium and ammonium salts.

35 Eksempler på således opnåede forbindelser er: . ; f >Examples of compounds thus obtained are:. ; f>

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25 natrium- (1) -5- (2~thenoyl) -1 ,2-dihydro-3H-pyrrolo [1,2-a]pyrrol-1-carboxylat, natrium-5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, med en 670 gange så kraftig analgetisk virkning som aspirin, 5 natrium-5-(4-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol- l-carboxylat, kalium-5-(4-chlor-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, kalium-5- (5-brom-2-thenoyl). -1,2-dihydro-3H-pyrrolo 11,2-a] pyrrol-1-10 carboxylat, ' · .Sodium (1) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5- (2-furoyl) -1,2 -dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, with a 670 times as strong analgesic effect as aspirin, 5 Sodium 5- (4-methyl-2-thenoyl) -1,2-dihydro -3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, potassium 5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 -carboxylate, potassium 5- (5-bromo-2-thenoyl). -1,2-dihydro-3H-pyrrolo 11,2-a] pyrrole-1-10 carboxylate,

natrium-5-(3-methyl-2-furoyl)-1(2-dihydro-3H-pyrro3o[1,2-a]pyrrol-l-carboxylat, ammonium-5-(2-furoyl)-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, ammonium-5-(3-chlor-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l~ 15 carboxylat, natrium-5-(4-methyl-2-thenoyl)-l,2-dihydro-6-ethyl-3H-pyrrolo[1,2-a]-pyrrol-l-carboxylat, kalium-5-(5-chlor-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]-pyrrol-l-carboxylat, 20 ammonium-5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxy= lat, og natrium-5-(3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat.sodium 5- (3-methyl-2-furoyl) -1 (2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, ammonium-5- (2-furoyl) -1,2-dioxide dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, ammonium 5- (3-chloro-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1 ~ 15 carboxylate, sodium 5- (4-methyl-2-thenoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, potassium-5 (5-chloro-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, ammonium 5- (3-thenoyl) -1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, and sodium 5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole -L-carboxylate.

Natrium-5-(5-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-25 1-carboxylat med en ~1Q gange så kraftig antiinflammatorisk virk som phenylbutazon, natrium-5-(3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxy= lat, der har en -¾ gange så kraftig antiinflammatorisk virksom som phenylbutazon, og 30 natrium-5-(2-thenoyl)-6-methyol-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1-carboxylat, der har en ~;27 g^ge så kraftig antiinflammatorisk virkning som phenylbutazon.Sodium 5- (5-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate with a ~ 1x times as potent anti-inflammatory activity as phenylbutazone, sodium 5- (3-Furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, which has an anti-inflammatory effect twice as strong as phenylbutazone, and sodium 5 - (2-thenoyl) -6-methyol-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate having a ~; 27 g ^ as strong anti-inflammatory effect as phenylbutazone.

35 2635 26

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Fremstillingsmetode 18Preparation Method 18

Til en opløsning af 237 mg 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]-pyrrol-l-carboxylsyre i 8 ml methanol sættes 1 molærækvivalent kalium= hydroxid i form af 0,1N opløsning til fremstilling af en opløsning 5 indeholdende kalium-5-(2-thenoyl)-1,2-ditiydro-3H-pyrrolo[1,2-a]pyrrol-' 1-carboxylat. En opløsning af 50 mg calciumcarbonat opløst i den mindst mulige mængde IN saltsyre, som er nødvendig til at bevirke opløsning af calciumcarbonat, pufres med 10:0 mg fast ammoniumchlorid efterfulgt af yderligere tilsætning af 5 ml vand. Den Således opnåede pufrede calciumopløsning sættes derpå til opløsning af kalium-5-(2-thenoyl)- l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat, og det dannede bundfald filtreres fra, vaskes med vand og lufttørres. Herved fås calcium-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat.To a solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 8 ml of methanol is added 1 molar equivalent of potassium = hydroxide in the form of 0 1N solution to prepare a solution 5 containing potassium 5- (2-thenoyl) -1,2-dithydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate. A solution of 50 mg of calcium carbonate dissolved in the least amount of 1N hydrochloric acid necessary to effect dissolution of calcium carbonate is buffered with 10: 0 mg of solid ammonium chloride followed by further addition of 5 ml of water. The buffered calcium solution thus obtained is then added to the solution of potassium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and the precipitate formed is filtered off, washed with water and air-dried. There is thus obtained calcium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

1® Magnesium-5-(2-thenoyl)-Ϊ,2-dihydro-3H-pyrrolo[1,2-a)pyrrol-l-carboxy= lat fremstilles ligeledes ved at anvende magnesiumcarbonat i stedet for calciumcarbonat^1® Magnesium 5- (2-thenoyl) -2,2-dihydro-3H-pyrrolo [1,2-a) pyrrole-1-carboxylic acid is also prepared by using magnesium carbonate instead of calcium carbonate ^

Ved i stedet for 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-20 l-carboxylat at anvende ·,.By using 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-20-1-carboxylate.

(1)-5- (2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre, 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre, 5-(4-chlor-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= 25 syre, , 5- (3-methyl-2-thenoyl) -l,.2-dihydro-3H-pyrrolo [1,2-a] pyrrol-l-carboxyl= syre, 5-(5-brom-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrol-l- carboxylsyre , og 20 5-(3-chlor-2-furoyl)-1,2-dihydro-6-ethyl-3H-pyrrolo[1,2-a]pyrrol- l-carboxylsyre fås de tilsvarende calcium- og magnesiumsalte.(1) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (2-furoyl) -1,2-dihydro-3H pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid , 5- (3-Methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (5-bromo-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, and 5- (3-chloro-2-furoyl) -1,2-dihydro-6-ethyl -3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid gives the corresponding calcium and magnesium salts.

Fremstillingsmetode 19 . Til en opløsning af 237 mg 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]- qc pyrrol-l-carboxylsyre i 8 ml methanol sættes 1 molærækvivalent kalium^Preparation Method 19. To a solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] - qc pyrrole-1-carboxylic acid in 8 ml of methanol is added 1 molar equivalent of potassium ^

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27 hydroxid i form af 0,1N opløsning. Opløsningsmidlet afstrippes, og resten opløses i 5 ml vand. Den således opnåede vandige opløsning af kalium-5- (2-thenoyl) -1,2-dihydro-3H-pyr'rolo [1,2-a] pyrrol-l-carboxylat sættes til en opløsning af 110 mg cuprinitrattrihydrat i 5 ml vand.27 hydroxide in the form of 0.1N solution. The solvent is stripped and the residue dissolved in 5 ml of water. The aqueous solution of potassium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate thus obtained is added to a solution of 110 mg of cuprinitrate trihydrate in 5 ml. water.

Det dannede bundfald opsamles, vaskes med vand og lufttørres. Således fås kobber-5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[1,2-aJpyrrol-l-carboxy= lat.The formed precipitate is collected, washed with water and air dried. There is thus obtained copper-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = lat.

x På tilsvarende måde kan de ved. eksempel 2, 3,:-4, 6 og 7 opnåede fri syreforbindelser omdannes til de tilsvarende kobbersalte.x Similarly, they can know. Examples 2, 3: - 4, 6 and 7 obtained free acid compounds are converted to the corresponding copper salts.

Fremstillingsmetode 20 15Preparation Method 20 15

En opløsning af 237 mg 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrol-l-carboxylsyre i 15 ml varm benzen behandles med 59 mg isopro= pylamin. Opløsningen får lov til at afkøle til stuetemperatur, og produktet affiltreres, vaskes med vand og tørres. Herved fås isopropyl= aminsaltet af 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-1-20 carboxylsyre.A solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 15 ml of hot benzene is treated with 59 mg of isopropyl-pylamine. The solution is allowed to cool to room temperature and the product is filtered off, washed with water and dried. Thereby the isopropyl = amine salt of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-20 carboxylic acid is obtained.

Andre aminsalte, f.eks. diethylamin-, ethanolamin-, piperidin—, tro= .methamin-, cholin-og kaffeinsaltene af 5-(2-thenoyi)-1,2-dihydro-3H-pyrrol0[l,2-a]pyrrol-l-carboxylsyre fremstilles ligeledes ved i 25 stedet for isopropylamin at anvende hvert af de respektive aminer.Other amine salts, e.g. diethylamine, ethanolamine, piperidine, tro = methamine, choline and caffeine salts of 5- (2-thenoyi) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are prepared also by using each of the respective amines instead of isopropylamine.

På tilsvarende måde Eån de ved fremstillingsmetode ‘3,. 4, 6 og 7 opnåede fri syreforbindelser omdannes til de tilsvarende iso= propylamin-, diethy larnin-, ethanolamin-, piperidin-, tromethamin-, 30 cholin- og kaffeinsalte.Similarly, one of the manufacturing methods' 3,. 4, 6 and 7 obtained free acid compounds are converted to the corresponding iso = propylamine, diethylarnine, ethanolamine, piperidine, tromethamine, choline and coffee salts.

Eksempel- 1 o-g.. En opløsning af 300 mg isopropyl-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrol-l-carboxylat i 30 ml 50% vandig methanol indeholdende 1% kaliumhydroxid, tilbagesvales under en nitrogenatmosfære i 2 timer. Methanolen fjernes derpå under reduceret tryk, og den basiske opløsning, der er tilbage, fortyndes med vand og ekstraheres med chloroform til „ fjernelse af eventuelt uforsæbeligt produkt. Den vandige alkaliske fase syrnes med 20% saltsyre og ekstraheres tre gange med ethylacetat. De 28Example 1 and .. A solution of 300 mg of isopropyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 30 ml of 50% aqueous methanol containing 1% potassium hydroxide is refluxed under a nitrogen atmosphere for 2 hours. The methanol is then removed under reduced pressure and the residual basic solution is diluted with water and extracted with chloroform to remove any unsaponifiable product. The aqueous alkaline phase is acidified with 20% hydrochloric acid and extracted three times with ethyl acetate. The 28th

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forenede ekstrakter tørres over natriumsulfat og inddampes til tørhed linder reduceret tryk. Således fås 250 mg rå 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylsyre, [ (2¾ , R og R1 = Η, X = S], med et smeltepunkt på 145-148°C, som efter omkrystallisation fra ethyl= 5 acetat smelter ved 152-153°C under dekomponering.The combined extracts are dried over sodium sulfate and evaporated to dryness to relieve reduced pressure. Thus, 250 mg of crude 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, [(2¾, R and R = = Η, X = S], with a melting point of 145-148 ° C which after recrystallization from ethyl = 5 acetate melts at 152-153 ° C during decomposition.

^ ·, · Eksempel 2 '410 mg 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylsyre og 212,3 mg (d)-amphetamin opløses i 15 ml absolut methanol og opvarmes under tilbagesvaling i 15 minutter, efterfulgt af fjernelse af methano= let under vakuum. Den resulterende diastereoisomere (d)-amphetaminsalt-blanding (612,3 mg) opløses i det mindst mulige volumen varm (55°C) acetone, afkøles til stuetemperatur og filtreres, og vaskes med 2 ml 15 kold (-10°C) acetone. Denne omkrystallisationsmetode gentages yderligere tre gange. Herved fås 247 mg (1)-5-('2-thenoyl)-l,2~dihydro-3H-pyrrolo-[l,'2-a]pyrrol-l-carboxylsyre-(d)-amphetaminsalt med et ct° 3 = -181,3° og et smeltepunkt på 168-170°C, 20 Det umiddelbart ovenfor opnåede (1)-syreisomer-(d)-amphetaminsalt sættes til 30 ml methylenchlorid og omrystes tre gange med 10 ml 0,1N vandig saltsyre. JMethylenchloridopløsningen vaskes tre gange med 15 ml mættet natriumchlorid/vand (2:l/volumen:volumen) og tørres over vandfri natriumsulfat. Filtrering og fjernelse af det organ-iske opløsnings- 25 middel under vakuum giver 90 mg (1)-5-(2-thenoyl)-l,2-dihydro-3H- * CHC1 o pyrrolo[l,2-a]pyrrol-l-car.boxylsyre, der har et 3 = -177 og et smeltepunkt på 134-135,5°C.Example 2 '410 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and 212.3 mg (d) -amphetamine are dissolved in 15 ml of absolute methanol and reflux for 15 minutes, followed by removal of methanol under vacuum. The resulting diastereoisomeric (d) -amphetamine salt mixture (612.3 mg) is dissolved in the smallest volume of hot (55 ° C) acetone, cooled to room temperature and filtered, and washed with 2 ml of cold (-10 ° C) acetone. . This recrystallization method is repeated three more times. There is thus obtained 247 mg of (1) -5 - ('2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2'-a] pyrrole-1-carboxylic acid (d) -amphetamine salt with a ct. 3 = -181.3 ° and a melting point of 168-170 ° C. The immediately obtained (1) -isomer isomer (d) -amphetamine salt is added to 30 ml of methylene chloride and shaken three times with 10 ml of 0.1N aqueous hydrochloric acid. . The methylene chloride solution is washed three times with 15 ml of saturated sodium chloride / water (2: 1 / v / v) and dried over anhydrous sodium sulfate. Filtration and removal of the organic solvent in vacuo gives 90 mg of (1) -5- (2-thenoyl) -1,2-dihydro-3H- * CHCl1 pyrrolo [1,2-a] pyrrole 1-carboxylic acid having a 3 = -177 and a melting point of 134-135.5 ° C.

Acetonemoderluden, som fås fra spaltningen (dvs. de gentagne krystal-30 lisationef) af den diastereoisomere-(d)-amphetaminsaltblanding, der er beskrevet ovenfor, forenes og omdannes under anvendelse af saltsyrespaltningsmetoden som beskrevet ovenfor. Herved fås 245 mg af en blan-35 ding beriget på (d)-5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[l,2-a3pyrrol-^ 1-carboxylsyre og indeholdende (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyr= rolo[l,2-a]pyrrol-l-carboxylsyre. Denne blanding racemiseres (recirkuleres) tilbage til en 1;1 blanding af de (d)— og.(1)-isomere af 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1-carboxylsyre som følger: De 245 mg af blandingen, der er beriget på den (d)-isomere og 40 . indeholdende den (1)-isomere, der er beskrevet ovenfor, opløses i 15 ml 29The acetone mother liquor obtained from the cleavage (i.e., the repeated crystallization) of the diastereoisomeric (d) -amphetamine salt mixture described above is combined and converted using the hydrochloric acid cleavage method as described above. There is thus obtained 245 mg of a mixture enriched in (d) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a3pyrrole-1-carboxylic acid and containing (1) - 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. This mixture is racemized (recycled) back to a 1; 1 mixture of the (d) and. (1) isomers of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a ] pyrrole-1-carboxylic acid as follows: The 245 mg of the mixture enriched on the (d) isomer and 40. containing the (1) isomer described above is dissolved in 15 ml of 29

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methanol. 1,5 ml methanol og 350 mg natriumhydroxid tilsættes, og opløsningen opvarmes under tilbagesvaling under nitrogen i 1 time. Metha= nolet ijernes under vakuum, 2,5 ml vand tilsættes, og opløsningen syr-5 nes til' pH-yærdi 2 med 10% yandig saltsyre. Blandingen ekstraheres med * . tre 10 ml portioner methylenchlorid, og methylenchloridekstrakterne forenes og vaskes neutrale igen (pH-værdi 7), tørres over vandfri natriumsulfat og koncentreret i vakuum. Herved fås 230. mg rå krystal-: j linsk produkt, som efter omkrystallisation fra ethylacetat/hexan giver 180 mg 5- (2-thenoyl)—1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= syre med et a^e<^H = 0,0° og et smeltepunkt på 152-154°C, På tilsvarende måde kan andre (d)-optisk aktive baser anvendes i stedet for (d)-amphetamin i den oyennævnte proces. Særligt egnede er: 15 (d)-p-brom-a-phenethylamin, (d)-a-phenethylamin, (d)-α-1-naphthethylamin, og (d)-α-2-naphthethylamin, 20 idet (d)-p-brom-a-phenethylamin er den foretrukne efter (d)-amphetamin.methanol. 1.5 ml of methanol and 350 mg of sodium hydroxide are added and the solution is refluxed under nitrogen for 1 hour. The methanol is ironed under vacuum, 2.5 ml of water is added and the solution is acidified to pH 2 with 10% aqueous hydrochloric acid. The mixture is extracted with *. Three 10 ml portions of methylene chloride and the methylene chloride extracts are combined and washed neutral again (pH 7), dried over anhydrous sodium sulfate and concentrated in vacuo. There is thus obtained 230 mg of crude crystalline product, which after recrystallization from ethyl acetate / hexane gives 180 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 -carboxylic acid with an a ^ e <^ H = 0.0 ° and a melting point of 152-154 ° C. Similarly, other (d) -optically active bases can be used instead of (d) -amphetamine in the the aforementioned process. Particularly suitable are: (d) -β-bromo-α-phenethylamine, (d) -α-phenethylamine, (d) -α-1-naphthethylamine, and (d) -α-2-naphthethylamine, ) -p-bromo-α-phenethylamine is the preferred one for (d) -amphetamine.

På tilsvarende måde fås de (d)-syreisomere, f.eks, (d)-5-(2-thenoyl)- 1,2-dihydro-3H-pyrrolo.[l, 2-a] pyrrol-l-carboxylsyre, ved at anvende de (1)-optisk aktive baser i stedet for de (dj-optisk aktive baser, 25 f.eks. erstatning af (d)-amphetamin med (1)-amphetamin.Similarly, the (d) acid isomers, for example, (d) -5- (2-thenoyl) - 1,2-dihydro-3H-pyrrolo are obtained. [1,2-a] pyrrole-1-carboxylic acid, by using the (1) -optically active bases instead of the (dj-optically active bases, for example, replacing (d) -amphetamine with (1) -amphetamine.

Eksempel 2Example 2

Til en opløsning af 118 mg 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]” 30 pyrrol-l-carboxylsyre i 8 ml tør benzen sættes 0,234 g trifluoreddike= syreanhydrid. Blandingen omrøres ved stuetemperatur i 10 minutter, og den resulterende opløsning afkøles til 0-5°C, og 0,55 g tør triethyl= amin tilsættes umiddelbart fulgt af tilsætningen af 0,2 g (l)-a-phenyl= ethylalkohol. Den således opnåede reaktionsopløsning omrøres ved stue-""‘535 temperatur i 15 minutter og hældes i 20 ml vand indeholdende 1 ml tri= ethylamin, efterfulgt af ekstraktion med éthylacetat, Ethylacetatekstrakten tørres over natriumsulfat, efterfulgt af fjernelse af opløsningsmidlet og overskud af (1)-α-phenylethylalkohol under vakuum. Herved fås 0,166 g af en blanding af (i).-5-(2-thenoyl]-l,2-dihydro-3H- 30To a solution of 118 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1-carboxylic acid in 8 ml of dry benzene is added 0.234 g of trifluoroacetic acid anhydride. The mixture is stirred at room temperature for 10 minutes and the resulting solution is cooled to 0-5 ° C and 0.55 g of dry triethyl = amine is added immediately followed by the addition of 0.2 g of (1) -α-phenyl = ethyl alcohol. The reaction solution thus obtained is stirred at room temperature 535 for 15 minutes and poured into 20 ml of water containing 1 ml of tri = ethylamine, followed by extraction with ethyl acetate, the ethyl acetate extract is dried over sodium sulfate, followed by removal of the solvent and excess (1). ) -α-phenylethyl alcohol under vacuum. There is thus obtained 0.166 g of a mixture of (i) - 5- (2-thenoyl] -1,2-dihydro-3H-30

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' pyrrolo[1,2-a]pyrrol-l-carboxylsyre-(IJ-a-phenethylester og (5)-5-(2-thenoyl) -1,2-dihydro-3H-pyrrolo[1,2-a] pyrrol-l-carboxylsyre- (1)-α-phenethylester, som separeres ved højtryksvæskekromatografi (under anvendelse af 4% EtOAc/hexan på en 11 .mm x 50 cm lOjJim Lichrosorb Sl-60-søjlé), Herved fås 68 mg af en mere polær ester (ape0H =.149,1°) og 73 * 5 mg af en mindre polær ester (α^β0Η = +105,2°), 62,1 mg af den mere polære ester opløses i. 3 ml tør benzen. Opløsningen afkøles til 15-20°C, og 2,5 ml trifluoreddikesyre tilsættes, og opløsningen omrøres ved stuetemperatur i 1 time og 40 minutter. Reaktions-10 opløsningen hældes i 60 ml tør benzen, og opløsningsmidlerne fjernes under vakuum og ved omgivelsernes temperatur. Rensningen gennemføres ved hjælp af højtryksvæskekromatografi (under anvendelse af en søjle, som den ovenfor beskrevne, bortset fra at 35% EtOAc/hexan i 1/2% eddikesyre anvendes i stedet for 4% EtOAc/hexan), Herved fås 41 mg (1)-15 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre med QMeOH _ _144oc og efc sjnelteplln]ct på 130-132°C,pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1J-α-phenethyl ester and (5) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1) -α-phenethyl ester, which is separated by high-pressure liquid chromatography (using 4% EtOAc / hexane on an 11 mm x 50 cm 100 µM Lichrosorb S1-60 column), thereby giving 68 mg of a more polar ester (ape0H = .149.1 °) and 73 * 5 mg of a less polar ester (α ^ β0Η = + 105.2 °), 62.1 mg of the more polar ester is dissolved in. 3 ml of dry benzene The solution is cooled to 15-20 ° C and 2.5 ml of trifluoroacetic acid is added and the solution is stirred at room temperature for 1 hour and 40 minutes. The reaction solution is poured into 60 ml of dry benzene and the solvents are removed under vacuum and at ambient temperature. Purification is carried out by high-pressure liquid chromatography (using a column such as the one described above, except that 35% EtOAc / hexane in 1/2% acetic acid is used instead of 4% EtOAc / hexane), thus obtaining 41 mg (1 ) -15 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid with QMeOH -144oC and ephemeral platelets] at 130-132 ° C,

Spaltning af den mindre polære ester i overensstemmelse med den ovenfor 1 * beskrevne metode for spaltning af den mere polære ester giver på lignen- i 20 de måde (d)-5-(2-thenoyl) j-l,2-dihydro-3H-pyrrolo [1,2-a]pyrrol-l-carb= oxylsyre med a^e0H = +142,4°C og et smeltepunkt på 127-129°C. Den så- i ledes opnåede (d)-syreisomer kan om ønsket racemiseres (og recirkuleres) i overensstemmelse med.i teknikken kendte metoder, Ϊ » . iCleavage of the less polar ester according to the method of cleavage of the more polar ester described above gives in the similar manner (d) -5- (2-thenoyl) jl, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid with a ^ eOH = + 142.4 ° C and a melting point of 127-129 ° C. The (d) acidomer thus obtained can be racemized (and recycled) in accordance with methods known in the art, if desired. in

25 Andre (dl)-forbindelser kan ligeledes omdannes til deres respektive ' IOther (dl) compounds can also be converted to their respective 'I'

i (1)-isomere og (d)-isomere. \in (1) -isomers and (d) -isomers. \

Ekjgémpel 4Equator 4

En opløsning af 336 mg isopropyl-5-(2-thenoyl)-l,2-dihydro-3lI-pyrrolo- q η ϊ . [l,2-a]pyrrol-l-carboxylat i 10 ml methanol behandles med en opløsning ! af 690 mg kaliumcarbonat i 5 ml vand. Reaktionsblandingen tilbagesva-, ! les under en nitrogenatmosfære i 2 timer, afkøles og inddampes til . 1 tørhed. Resten optages i 10 ml 10% vandig saltsyre og 50 ml vand, og ^ den resulterende blanding ekstraheres med ethylacetat (2x50 ml). De j forenede ekstråkter tørres over magnesiumsulfat og inddampes til tørhed under reduceret tryk. Krystallisation af resten fra ethylacetat i giver 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre, •der er identisk med .det ved eksempel 1 opnåede produkt.A solution of 336 mg of isopropyl-5- (2-thenoyl) -1,2-dihydro-3L-pyrrolo-q η ϊ. [1,2-a] pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution! of 690 mg of potassium carbonate in 5 ml of water. The reaction mixture was refluxed. is read under a nitrogen atmosphere for 2 hours, cooled and evaporated. 1 dryness. The residue is taken up in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water, and the resulting mixture is extracted with ethyl acetate (2x50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate gives 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid identical to the product obtained in Example 1.

3131

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Eksempel 5Example 5

Ved at følge fremgangsmåden fra fremstillingsmetode 10 og anvende 1,1-2 molærækvivalenter N,N-dimethylfuran-2-carboxamid, o N,N-dimethyl-3-methylthiophen-2-carboxamid, N,N-dimethyl~4~methylthiophen-2-carboxamid,' H,N-dimethyl-5~methylthiophen-2-carboxamid, N,N-dimethyl~4-chlorthiophen-2-carboxamid, N,N-dimethyl-5-chlorthiophen-2-carboxamid, 10 N, N-dime thyl-3-bromthiophen-2-carboxam.id, N ,N-dimethyl-4-bromthiophen~2-carboxamid, N,N-dimethy1-5-bromthiophen-2-carboxamid, N,N-dimethyl-3-methylfuran-2-carboxamid, N,N-dimethy1-4-methylfuran-2-carboxamid, 15 N,N-dimethyl-5-methylfuran-2-carboxamid, N,N-dimethyl-3-chlorfuran~2-carboxamid, N,N-dimethyl-4-chlorfuran-2-carboxamid, s N,N-dimethyl-5-chlorfuran-2-carboxamid, N,N-dimethyl-4-bromfuran~2-carboxamid, og 20 N,N-dimethyl-5-bromfuran-2-carboxamid, i stedet for N,N-dimethylthiophen-2-carboxamid og følge reaktionens forløb ved hjælp åf tyndtlagskromatografi/ fås henholdsvis: 25 isopropyl-5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, en olie med følgende fysiske konstanter:Following the method of Preparation Method 10 and using 1.1-2 molar equivalents N, N-dimethylfuran-2-carboxamide, N, N-dimethyl-3-methylthiophene-2-carboxamide, N, N-dimethyl ~ 4 ~ methylthiophene 2-carboxamide, 1H, N-dimethyl-5-methylthiophene-2-carboxamide, N, N-dimethyl-4-chlorothiophene-2-carboxamide, N, N-dimethyl-5-chlorothiophene-2-carboxamide, 10 N, N-dimethyl-3-bromothiophene-2-carboxamide, N, N-dimethyl-4-bromothiophene ~ 2-carboxamide, N, N-dimethyl-5-bromothiophene-2-carboxamide, N, N-dimethyl-3 -methylfuran-2-carboxamide, N, N-dimethyl-4-methylfuran-2-carboxamide, N, N-dimethyl-5-methylfuran-2-carboxamide, N, N-dimethyl-3-chlorofuran ~ 2-carboxamide, N, N-dimethyl-4-chlorofuran-2-carboxamide, s N, N-dimethyl-5-chlorofuran-2-carboxamide, N, N-dimethyl-4-bromfuran-2-carboxamide, and 20 N, N-dimethyl -5-bromfuran-2-carboxamide, instead of N, N-dimethylthiophene-2-carboxamide and follow the course of the reaction by thin layer chromatography / obtain respectively: 25 isopropyl-5- (2-furoyl) -1,2-dihydro-1 3H-pyrrolo [1,2-a] pyrrole-L- carboxylate, an oil with the following physical constants:

UV Me0HUV MeOH

Xmaks 275, 332,5 nm (ε 8900, 17800); CHC1 30 ImRm vmaks3 1735, 1685, 1605 cm'1; N M R CDC1, * * * 6TMS 1,23 [d, 6H, J = 6 Hz; (CH^CH], 2,60-3,00 (m, 2H), 3,90 (dd, IH, J&x= 6 Hz; JBX = 7 Hz; H-l), 4,10-4,67 (m, 2H), 4,95 [sept., IH, J = 6 Hz; (CHo)~CH], 35 ' J z — 6,00 (d, IH, J = 4 Hz; H-7), 6,40 (m, IH) , 7,10 (m, IH), 7,23 (d, IH, J = 4 Hz; H-6), 7,43 ppm im, IH); M.S. m/e 287 (M+),Λ max 275, 332.5 nm (ε 8900, 17800); CHCl3 ImRm vmax3 1735, 1685, 1605 cm -1; N M R CDCl 1, * * * 6TMS 1.23 [d, 6H, J = 6 Hz; (CH 2 CH], 2.60-3.00 (m, 2H), 3.90 (dd, 1H, J & x = 6 Hz; JBX = 7 Hz; H1), 4.10-4.67 (m, 2H), 4.95 [Sept., 1H, J = 6 Hz; (CH 2) ~ CH], 35 'J z - 6.00 (d, 1H, J = 4 Hz; H-7), 6.40 (m, 1H), 7.10 (m, 1H), 7.23 (d, 1H, J = 4 Hz; H-6), 7.43 ppm im, 1H); M.S. m / e 287 (M +),

32 DK 152654 B32 DK 152654 B

isopropyl-5- (3-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyr= rol-l-carboxylat, ‘ ' isopropyl-5-(4-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyr= rol-l-carboxylat, 5 isopropyl-5-(5-methyl-2-thenoyl)-1,2-dihydrp-3Ii-pyrrolo ti,2-a]pyr= rol-l-carboxylat, med smeltepunkt 82°-82,5°C, isopropyl-5-(4-chlor-2-thenoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1-carboxylat, olie, isopropyl-5-(5-chlor-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-10 1-carboxylat, isopropyl-5-(3-brom-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-.1-carboxylat, . · ^. isopropyl-5-(4-brom-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol- 1-carboxylat, 15 isopropyl-5-(5-brom-2-thenoyl)-1,2-dihydro-3H-pyrrol6T172-a]pyrrdl- 1-carboxylat, isopropvl-5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrol-1-carboxylat, sitro. 67-68°C, isopropyl-5-(3-methyl-2-furoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-' 1-carboxylat, isopropyl-5-(4-methyl-2-£uroyl)-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-20 1-carboxylat, isopropyl-5- (5-methyl-2-£uroyl) -1,2-dihydro-3l-I-pyrrolo ti, 2-a] pyrrol-1-carboxylat, • isopropyl-5-(3-chlor-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1-carboxylat, 25 isopropyl-5-(4-chlor-2-£uroyl)-1,2-dihydro-3H-pyrrolo[1,2-a3pyrrol-J 1-carboxylat·, isopropyl-5-(5-chlor-2-£uroyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1-carboxylat, isopropyl-5-(4-brom-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1-3° carboxylat, isopropyl-5-(5-brom-2-furoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l- carboxylat og iscpropyl-5- (3-furoyl)-l,2-dihydro-3H-pyrrolo-[l,2-a]-pyrrol-l-carboxylat, olie.isopropyl-5- (3-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylate, isopropyl-5- (4-methyl-2 -thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylate, isopropyl-5- (5-methyl-2-thenoyl) -1,2-dihydrp-3Ii -pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 82 ° -82.5 ° C, isopropyl-5- (4-chloro-2-thenoyl-1,2-dihydro-3H-pyrrolo [ 1,2-a] pyrrole-1-carboxylate, oil, isopropyl-5- (5-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate isopropyl-5- (3-bromo-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate. Isopropyl-5- (4-bromo 2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (5-bromo-2-thenoyl) -1,2-dihydro-3H -pyrrole6T172-a] pyridyl-1-carboxylate, isopropyl-5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, citr. 67-68 ° C, isopropyl-5- (3-methyl-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (4-methyl-2- (Uroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (5-methyl-2-uroyl) -1,2-dihydro-3- [1-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (3-chloro-2-furoyl) -1 , 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5- (4-chloro-2-uroyl) -1,2-dihydro-3H-pyrrolo [1,2 -a-pyrrol-1H-carboxylate ·, isopropyl-5- (5-chloro-2-uroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5 (4-bromo-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-3 ° carboxylate, isopropyl-5- (5-bromo-2-furoyl) -1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and iscropyl-5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole l-carboxylate, oil.

Ved hydrolyse af isopropylestergruppen i overensstemmelse med frem-35 gangsmåderne fra eksempélll eller 4 fas de fcilsvar^ftde ..... .By hydrolysis of the isopropyl ester group in accordance with the procedures of Example 4 or 4, they are followed by the same.

fri syrer, nemlig: 5- (2-furoyl) -1,2-dihydro-:3H-pyrrolo [ 1,2-a] pyrrol-l-carboxylsyre, smeltepunkt 184-184,5°C, 5-(3-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= syre, 33free acids, namely: 5- (2-furoyl) -1,2-dihydro-: 3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 184-184.5 ° C, 5- (3- methyl 2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 33

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5- (4-inethyl-2~thenoyl) -1,2-dihydro-3II-pyrrolo [1,2-a] pyrrol-l-carboxyl= syre, 5-(5-methyl-2-thenoy1)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= syre, smeltepunkt 169-170°C, 5 5- (4-chlor-2-thenoyl) -1,2-dihydro~3H-pyrro.lo [1,2-a] pyrrol-l~carboxyl= syre, snip. 169-169,5 C, 5-(5-chlor-2-thenoyl)-1,2-dihydro-3H-pyrrolb[1,2-a]pyrrol-l-carboxyl= syre, 5-(3-brom-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l~carboxyl= 10 syre, 5-(4-brom-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= syre, 5- (5-bronv-2-thenoyl) ~1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= ( 3-thenoyil -1,2-dihydro-3H-pyrrolo [i)2-a] pyrrol-l-carboxylsyre, smp. 16 6-). 7 10 5- (/3-methyl-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-l-carboxyl= syre, . · 5-(4-methyl-2-furoyi)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= v syre, 5-(5-methyl-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= 20 1 syre, · 5- (3-chlor-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= syre, - • 5-(4-chlor-2-furoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxyl= syre, . · ^ 5- (5-chlor-2—furoyl) -1,2-dihydro-3H-pyrro3.o [1,2-a] pyrrol-l-carboxyl= % syre, 5-.(4-brQm-2-furoyl) -1,2-dihydro-3H~pyrrolo [1,2-a] pyrrol-l-carboxyl= syre,.5- (4-methyl-2-thenoyl) -1,2-dihydro-3II-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (5-methyl-2-thenoyl) -1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 169-170 ° C, 5- (4-chloro-2-thenoyl) -1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1 ~ carboxyl = acid, snip. 169-169.5 C, 5- (5-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (3-bromo 2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-bromo-2-thenoyl) -1,2-dihydro-3H-carboxylic acid pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (5-bronyl-2-thenoyl) ~ 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxyl = (3-thenoyil-1,2-dihydro-3H-pyrrolo [i) 2-a] pyrrole-1-carboxylic acid, m.p. 16 6-). 5- (/ 3-methyl-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-methyl-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (5-methyl-2-furoyl) - 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (3-chloro-2-furoyl) -1,2-dihydro-3H-pyrrolo [1 , 2-a] pyrrole-1-carboxylic acid - 5- (4-chloro-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid ,. 5- [5-Chloro-2-furoyl) -1,2-dihydro-3H-pyrro [3- [1,2-a] pyrrole-1-carboxyl =% acid, 5- (4-bromo-2) -furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

5-(5-brom-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxvlsvre 30 og 5-(3-furoyl).-1,2-dihydro-3H-pyrrolo[ 1,2-a]pyrrol-l-carbaxylsyre,sitip. 156¾.-1 y5- (5-bromo-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and 5- (3-furoyl) -1,2-dihydro-1-carboxylic acid 3H-pyrrolo [1,2-a] pyrrole-1-carbaxyl acid, sitip. 156¾.-1 y

Eksempel 6 J En opløsning af 500 mg isopropyl-5-(2-thenoyl)-1,2-dihydro-6-methyl-35 3H-pyrrolo[1,2-a]pyrrol-l-carboxylat i 15 ml methanol behandles med en opløsning af 1,05 g kaliumcarbonat i 8 ml vand. Reaktionsblandingen tilbagesvales under en nitrogenatmosfære i tre timer, afkøles og inddampes til tørhed. Resten optages i 10 ml 10% vandig saltsyre og 50 ml vand, og den resulterende blanding ekstraheres med ethylacetat (3 x 34Example 6 J A solution of 500 mg of isopropyl-5- (2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 15 ml of methanol is treated with a solution of 1.05 g of potassium carbonate in 8 ml of water. The reaction mixture is refluxed under a nitrogen atmosphere for three hours, cooled and evaporated to dryness. The residue is taken up in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water and the resulting mixture is extracted with ethyl acetate (3 x 34).

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50 ml). De forenede ekstrakter tørres over magnesiumsulfat og inddampes til tørhed under reduceret tryk. Herved fås 5-(2-thenoyl)-l,2-dihydro- 6-methyl-3H-pyrrolo[i,2-a]pyrrol-l-carboxylsyre [ (k), R = CH^, = . Η, X = S] med et smeltepunkt på 166°C.50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. There is thus obtained 5- (2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid [(k), R = CH 2, =. Η, X = S] with a melting point of 166 ° C.

5 På tilsvarende måde eller alternativt ved hjælp af hydrolysemetoden ϊ fra .eksempel 1 omdannes de resterende ved fremstillingsmetode 15 opnåede isopropylesterførbiisfelser til de tilsvarende fri syrer, nemlig: 5- (2-furoyl) -1,2-dihydro-6-inethyl-3H-pyrrolo [1,2-a] -pyrrol-l-carboxyl= 10 syre, 5-(3-methyl-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrol-1-carboxylsyre, 5-(4-methyl-2-thenoyl)-1,2-dihydro~6-methyl-3H-pyrrolo[1,2-a]pyrrol-1-carboxylsyre, 15 5-(5-methyl-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre, 5-(4-chlor-2-thenoyi)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre, 5-(5-chlor-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrol- i 20 1-carboxylsyre, 5-(3-brom-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrol-1-carboxylsyre, 5-(4-brom-2-thenoy1)-1,2-dihydro-6-methyl-3H-pyrrolo[1(2-a]pyrrole 1-carboxylsyre, 25 5-(5-brom-2-thenoyl)-l,2-dihydro-<5-.meth.yl-3H-pyrrolo[l,2-a]pyrrol- 1-carboxy lsyre, -- ' 5-(3-methyl-2-furoyl)-1,2-dihydro-6-methy1-3H-pyrrolo[1,2-aJpyrrol- i 1-carboxylsyre, 5-(4-methyl-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-aJ pyrrol- 30 1-carboxylsyre, ‘ ' 5- (5-methyl-2-furoyl) -1,2-dihydro-6-raethyl-3H-pyrrolo [ 1,2-a] pyrrol-1-carboxylsyre, 5- (3-chlor-2-f uroyl) -1,2-dihydro-6-ji}ethyl-3H-pyrrolo [1,2’-aJpyrrol-l- .Similarly or alternatively, by the hydrolysis method ϊ of Example 1, the residual isopropyl ester feed obtained by Preparation Method 15 is converted to the corresponding free acids, namely: 5- (2-furoyl) -1,2-dihydro-6-ethyl-3H -pyrrolo [1,2-a] pyrrole-1-carboxyl = acid, 5- (3-methyl-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a ] pyrrole-1-carboxylic acid, 5- (4-methyl-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (5) -methyl-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-chloro-2-thenoyo) -1,2 dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (5-chloro-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid, 5- (3-bromo-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-bromo-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1 (2-a] pyrrole 1-carboxylic acid, 5- (5-bromo-2-thenoyl) - 1,2-Dihydro-5-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (3-methyl-2-fu - (1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylic acid, 5- (4-methyl-2-furoyl) -1,2-dihydro-6-methyl 3H-pyrrolo [1,2-aJ pyrrole-1-carboxylic acid, 5- (5-methyl-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (3-chloro-2-furoyl) -1,2-dihydro-6-yl} ethyl-3H-pyrrolo [1,2'-a] pyrrole-1-.

3, carboxylsyre, i; 35 5-(4-chlor-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrrolb[1,2-a]pyrrol-1- j ! carboxylsyre, 5- (5-chlor-2-furoyl) -1,2-dihydro-6-meth.yl-3H-pyrrolo [1,2-a] pyrrol-1-carboxylsyre, 353, carboxylic acid, i; 5- (4-Chloro-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-yl carboxylic acid, 5- (5-chloro-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 35

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• 5- (4-brom-2-furoyl3>-l,2-dihydro-6-methyl-3H-pyrrolo [l,2-a]pyrrol-l-carboxylsyre, 5- (5-brom-2-furoyl3>~l , 2-dihydro--6-methyl-3H-pyrrolo [1,2-a] pyrrol-1-carboxylsyre, 5 5- (2-thenoyl) -l,2-dihydro-6-ethyl--3H-pyfrolb [1,2-a]pyrrol-l-carboxyl= syre/ · · ' 5-(2-furoyl) -1,2-dihydro-6-propyl-3H-pyrrolo[1,2-a] pyrrol-l-carboxyl= syre, 5™ (3-methyl-2-thenoyl) -1,2-dihydro-6-butyl-3H-pyrrolo [l,2-a]pyrrol-l-10 carboxylsyre, 5-(4-chlor-2~thenoyl} -l,2-dihydro-6-ethyl-3H-pyrrolo [l,2-a]pyrrol-l-carboxylsyre, 5-.(5-methyl-2-furoyl) -1,2-dihydro-6~propyl-3H-pyrrolo [1,2-a] pyrrol-1-carboxylsyre, og · 15 5-(3-chlor-2-furoyl)-1,2-dihydro-6-butyl~3H-pyrrolo [l,2-a]pyrrol-l- carboxylsyre.5- (4-bromo-2-furoyl3> -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (5-bromo-2-furoyl3> -1,2-Dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (2-thenoyl) -1,2-dihydro-6-ethyl-3H - pyrrolb [1,2-a] pyrrole-1-carboxyl = acid / 5- (2-furoyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1 -carboxylic acid, 5 ™ (3-methyl-2-thenoyl) -1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-chloro) 2-Thenoyl} -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (5-methyl-2-furoyl) -1,2-dihydro -6 ~ propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, and 5- (3-chloro-2-furoyl) -1,2-dihydro-6-butyl ~ 3H-pyrrolo [ 1,2-a] pyrrole-1-carboxylic acid.

Eksempel 7 2q En opløsning af 300 mg isopropyl-5-(3-thenoyl)-l,2-dihydro-3H~pyrrolo~ [1,2-a]pyrrol-l-carboxylat i. 30 ml 50% vandig methanol indeholdende 1% kaliumhydroxid tilbagesvales under en nitrogenatmosfære i 2 timer« Methanolet fjernes derpå under reduceret tryk, og den basiske opløsning, der er tilbage, fortyndes med vand, og ekstraheres med chloro= . 25 form til fjernelse af eventuelt uforsæbeligt produkt« Den vandige alkaliske· fase syrnes med 20% saltsyre og ekstraheres tre gange med ethylacetat. De forenede ekstrakter tørres over natriumsulfat og inddampes til tørhed under reduceret tryk. Således fås 250 mg rå 5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre, [(B), 30 R = Η, X - S]*Example 7 2q A solution of 300 mg of isopropyl-5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 30 ml of 50% aqueous methanol containing 1 The% potassium hydroxide is refluxed under a nitrogen atmosphere for 2 hours. The methanol is then removed under reduced pressure and the residual basic solution is diluted with water and extracted with chloro =. 25 form to remove any unsaponifiable product. The aqueous alkaline phase is acidified with 20% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. Thus, 250 mg of crude 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, [(B), R = Η, X - S]

De resterende ved fremstillingsmetode 1€ opnåede forbindelser om-- ·,„ dannes ved hjælp af samme metode til de fri syrer, nemlig: tf 35 5- (3-thenoyi) -1,2-dihydro-6-methy'l-3H-pyrrolo [1,2-a] pyrrol-l-carboxyl= syre, 5- (3-thenoyl)-1,2~dihydro-6-propyl-3H-pyrrolo[1,2-a]pyrrol-l-carboxyl= - syre,The residues obtained by Preparation Method 1 € are obtained by the same method for the free acids, namely: tf 5- (3-thenoyi) -1,2-dihydro-6-methyl-3H -pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (3-thenoyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxyl = - acid,

Claims (1)

0. I X 20 (A*) (B') hvori X er oxygen eller svovl, R er hydrogen eller en alkylgruppe med 1-4 carbonatomer, og R1 er hydrogen, methyl, chlor eller brom, 25 kendetegnet ved, at et tilsvarende salt omdannes til den frie syre med formlen (A') eller (B')* eventuelt efterfulgt af spaltning af den frie syre med formlen (A') eller (B') i de optiske isomerer og isolering af (1)-syreisomeren.0. IX 20 (A *) (B ') wherein X is oxygen or sulfur, R is hydrogen or an alkyl group of 1-4 carbon atoms and R 1 is hydrogen, methyl, chlorine or bromine, characterized in that a corresponding salt is converted to the free acid of formula (A ') or (B') * optionally followed by cleavage of the free acid of formula (A ') or (B') in the optical isomers and isolation of the (1) acid isomer.