DK152653B - Analogy process for preparing (dl)- or (l)-5-(2-furoyl)-, 5-(2-thenoyl)-, 5-(3-furoyl)- or 5-(3-thenoyl)-1,2- dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic esters or salts - Google Patents

Description

DK 152653 BDK 152653 B

2 hvori X betegner oxygen eller svovl, R betegner hydrogen eller en alkylgruppe med 1-4 carbonatomer, betegner hydrogen, methyl, 2 chlor eller brom, og R er en alkylgruppe med 1-12 carbonatomer eller en farmaceutisk acceptabel saltrest, hvilken fremgangsmåde2 wherein X represents oxygen or sulfur, R represents hydrogen or an alkyl group of 1-4 carbon atoms, represents hydrogen, methyl, 2 chloro or bromine, and R is an alkyl group of 1-12 carbon atoms or a pharmaceutically acceptable salt residue, which method

CC

er ejendommelig ved det i kravets kendetegnende del anførte.is peculiar to that specified in the characterizing part of the claim.

De omhandlede forbindelser udøver antiinflammatorisk, analgetisk og antipyretisk virkning og er således nyttige ved behandlingen af inflammation, smerte og/eller pyrexi hos pattedyr som beskrevet ^ nærmere i det følgende. De er også glatmuskelafslappelsesmidler.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.

Typiske alkylestergrupper er methyl-, ethyl-, propyl-, isopropyl-, butyl-, t-butyl-,' isoamyl-, pentyl-, isopentyl-, hexyl-, octyl-, nonyl-, isodecyl-, 6-methyldecyl- og dodecylestere.Typical alkyl ester groups are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl.

1515

Udtrykket "farmaceutisk acceptable, ikke-toksiske salte" anvendes heri til at betegne salte afledt af farmaceutisk acceptable ikke-toksiske uorganiske og organiske baser, idet salte afledt uorganiske baser omfatter· natrium-, kalium-, lithium-, ammonium-, calcium-, 20 magnesium-, ferro-, zink-, kobber-, mangan-, aluminium-, ferri-og mangansalte. Særligt foretrækkes ammonium-, kalium-, natrium-, calcium- og magnesiumsaltene. Saltene afledt af farmaceutisk acceptable organiske ikke-toksiske baser omfatter salte af primære, sekundære og tertiære aminer, substituerede aminer inklusive naturligt 2 5 forekommende substituerede aminer, cykliske aminer og basiske ion-bytterharpikser, såsom isopropylamin, trimethylamin, diethylamin, triethylamin, tripropylamin, ethanolamin, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamin, lysin, arginin, histidin, kaffein, prokain, hydrabamin, cholin, betain, ethylendiamin, glucosamin, J u methylglucamin, theobromin, puriner, piperazin, piperidin, N-ethyl-piperidin eller polyaminharpikser. Særligt foretrukne organiske ikke-toksiske baser er isopropylamin, diethylamin, ethanolamin, piperidin, tromethamin, cholin og kaffein.The term "pharmaceutically acceptable, non-toxic salts" is used herein to mean salts derived from pharmaceutically acceptable non-toxic inorganic and organic bases, salts derived from inorganic, potassium, lithium, ammonium, calcium, 20 magnesium, ferrous, zinc, copper, manganese, aluminum, ferric and manganese salts. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. The salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, triethylamine, , 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidines . Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine.

3535

De omhandlende hidtil ukendte forbindelser eksisterer som par af optiske isomere (eller enantiomorfe), dvs. en (dl)-blanding. Den foreliggende opfindelse omfatter imidlertid fremstillingen af (l)-for-bindelser, såvel som (dl)-blandingerne.The novel compounds exist as pairs of optical isomers (or enantiomorphs), viz. a (dl) mixture. However, the present invention encompasses the preparation of (1) compounds, as well as the (dl) mixtures.

DK 152653BDK 152653B

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-pyrrolo-[1,2-a]pyrrol-l-carboxylsyreestere eller salte af den almene formel R ^ 1 n~~— Ί- R \ ¢7 !L X il ?°or2 li ik [j r , eller li J \ J* Ji COOR2 6 !— b I_i (A') (B')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-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid esters or salts of the general formula R ^1 n ~~ - Ί- R \ ¢ 7! LX il? ° or2 li ik [yr, or li J \ J * Ji COOR2 6! - b I_i (A ') (B')

DK 152653BDK 152653B

3 Når de ifølge opfindelsen fremstillede hidtil ukendte forbindelser skal anvendes til at frembringe en fysiologisk reaktion (f.eks. anti-inflammatorisk, analgetisk eller antipyretisk virkning), dvs. de skal anvendes som medicin, er en foretrukket undergruppe, den gruppe, 5 som består af (dl)- eller (l)-estrene og saltene af formlen (A') eller (B).When the novel compounds of the invention are to be used to produce a physiological reaction (e.g., anti-inflammatory, analgesic or antipyretic), i.e. they are to be used as medicine is a preferred subgroup, the group consisting of (dl) or (l) esters and salts of formula (A ') or (B).

Endnu en undergruppe af forbindelser, der skal anvendes som medicin, er forbindelserne med formlerne (A) og (l)-syreisomeren med formlen 10 (A) og estere og farmaceutisk acceptable salte deraf, og denne under gruppe kan opdeles i to yderligere undergrupper bestående af (a)Yet another subgroup of compounds to be used as medicine are the compounds of formulas (A) and (1) acidomer of formula 10 (A) and esters and pharmaceutically acceptable salts thereof, and this subgroup can be divided into two additional subgroups consisting of by (a)

Nforbindelsen med formlen (A), dvs. (dl)-forbindelsen, hvori R og R1 begge er hydrogen, og X er svovl, og (b) (l)-syreisomeren med formlen (b), hvori R og R"^ begge er hydrogen, og X er svovl, og estrene 15 og de farmaceutisk acceptable salte deraf.The compound of formula (A), i. the (dl) compound wherein R and R 1 are both hydrogen and X is sulfur and the (b) (1) acid isomer of formula (b) wherein R and R 2 are both hydrogen and X is sulfur and the esters 15 and the pharmaceutically acceptable salts thereof.

De hidtil ukendte (dl) forbindelser (A) og (B), der anvendes som udgangsmateriale ved fremgangsmåden ifølge den foreliggende opfindelse, kan fremstilles ved hjælp af en fremgangsmåde, der kan illu-20 streres ved hjælp af følgende reaktionsskema: DK 152653 B- COOCE* COOCH3 I 2 f R = H [Γ CH2 + COOCH, * COOCH3 I HN (III)The novel (dl) compounds (A) and (B) used as starting material in the process of the present invention can be prepared by a process which can be illustrated by the following reaction scheme: COOCE * COOCH3 I 2 f R = H [Γ CH2 + COOCH, * COOCH3 I HN (III)

CH? ICH? IN

I ^ H2C-CH2H₂C-CH₂

OH IOH I

„ 0H Vi (I) COOCH, r COOCH, E"T-if Sn- LJk/C00CH3 ^ 1,nA^/C00CH3"OH We (I) COOCH, R COOCH, E" T-if Sn-LJk / C00CH3 ^ 1, nA ^ / C00CH3

CH2 \ ICH2 \ I

I 2 \ h2c-ch2 ?H2 (V) \ I (IV)I 2 \ h2c-ch2? H2 (V) \ I (IV)

I \ OHI \ OH

ψ 0S02CH3 \ V_^COOCH3 R\_ COOCK3 CJT/ C00CH3 > ii.Nji C00CH3ψ 0S02CH3 \ V_ ^ COOCH3 R \ _ COOCK3 CJT / C00CH3> ii.Nji C00CH3

L i_IL i_I

I (VI) (VII)I (VI) (VII)

IH2CIH2C

VV

rn_/C00H R V._JSX*rn_ / C00H R V._JSX *

Til 2«— ftTo 2 «- ft

’Sn/y™» Vh/S/COOHSn / y ™ Vh / S / COOH

L-J (ιχ) I—JL-J (ιχ) I – J

(IX) (VIII)(IX) (VIII)

"Tl 2 *HtX"Tl 2 * HtX

/ i_r„, 8 lj / (XI) tn (XII) ύ£ »HP 1i/ i_r „, 8 lj / (XI) tn (XII) ύ £» HP 1i

U I IU I I

(x) ' 5 DK 152653B(x) 5 DK 152653B

. 1' '. 1 ''

RR

™ — υΐ^γγ" ' x .(B)™ - υΐ ^ γγ "x" (B)

1 2.' hvori X, R og R har den ovenfor anførte betydning, og R1 2. ' wherein X, R and R are as defined above, and R

er en alkylgruppe med 1-4 carbonatomer, f.eks. methyl, ethyl, isopropyl eller n-butyl.is an alkyl group of 1-4 carbon atoms, e.g. methyl, ethyl, isopropyl or n-butyl.

5 Når den ovennævnte fremgangsmåde gennemføres til fremstilling af forbindelsen med formlen (IV), hvori R er hydrogen, omsættes ækvi-molære mængder af ethanolamin (I) og dimethyl-1,3-acetonedicarboxy= x lat (II) ved en temperatur fra ca. 0°C til omkring stuetemperatur for let at danne en opløsning af vinylaminen med formlen (III), som 10 derpå, fortrinsvis in situ, behandles i et egnet inaktivt organisk 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 15 acetonitril, tetrahydrofuran, dimethoxyethan, chloroform eller dichlormethan. Ved de foretrukne udførelsesformer gennemføres reaktionen i acetonitrilopløsning ved tilbagesvalingstemperatur i ca. 1 time. 2~brom-(chlor)-acetaldehydreagenserne er kendte forbindelser eller kan opnås ved pyrolyse af de tilsvarende diethylacetaler i nær-20 værelse af oxalsyredihydrat.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 = x lat (II) are reacted at a temperature of about . 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 or dichloromethane. In the preferred embodiments, the reaction is carried out in acetonitrile solution at reflux temperature for approx. 1 hour. The 2-bromo (chloro) acetaldehyde reagents are known compounds or can be obtained by pyrolysis of the corresponding diethyl acetals in the vicinity of oxalic acid dihydrate.

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 25 dicarboxylat (II) med en forbindelse med formlen R^-C-CH5X, hvori XTo 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 5 X wherein X

7. c- er brom eller chlor, og R-' er en lavere alkylgruppe, fortrinsvis ligekædet med 1-4 carbonatomer, og især 1-bromacetone, l-brora-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 30 timer. Ved den foretrukne udførelsesform gennemføres reaktionen ved7. c- is bromo or chloro, and R- is a lower alkyl group, preferably straight-chain of 1-4 carbon atoms, and in particular 1-bromoacetone, 1-brora-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 30 hours. In the preferred embodiment, the reaction is carried out at

6 DK 152653 B6 DK 152653 B

en temperatur fra ca0 -10°C til omkring stuetemperatur i fra 1 time til ca. 6 timer. R^-C-CH^X-reagenserne er kendte forbindelser.a temperature from about 0-10 ° C to about room temperature for from 1 hour to approx. 6 hours. The R 1 -C-CH 2 X reagents are known compounds.

Forestring af forbindelse (IV) med methansulfonylchlorid i nærværelse af en tertiær amin, f.eks. triethylamin eller pyridin, eventuelt 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) 0 ved reaktion med natriumiodid i acetonitrilopløsning, ved tilbagesvalingstemperatur i fra ca. 1 til ca. 10 timer.Esterification of compound (IV) with methanesulfonyl chloride in the presence of a tertiary amine, e.g. triethylamine or pyridine, optionally in the presence of a co-solvent, such as dichloromethane, at a temperature of ca. -10 ° C to about room temperature for approx. 10 minutes to approx. 2 hours, the corresponding mesylate of formula (V) which is converted to the corresponding N- (2-iodoethyl) pyrrole of formula (VI) O by reaction with sodium iodide in acetonitrile solution yields at reflux temperature for from ca. 1 to approx. 10 hours.

Efter reaktion af iodethylforbindelser med formlen (VI) med natrium= hydrid i et egnet inaktivt organisk opløsningsmiddel, såsom dimethyl= •5 formamid?fås dimethyl-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-1,7-di= carboxylat og de β-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 -0 ca. 4 timer. De bedste resultater opnås ved at gennemføre reaktionen ved stuetemperatur i ca. 3 minutter, når R er hydrogen.After reaction of iodoethyl compounds of formula (VI) with sodium hydride in a suitable inert organic solvent such as dimethyl = formamide, dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 is obtained. 7-di = carboxylate and the β-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 -0 approx. 4 hours. The best results are obtained by conducting the reaction 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= -5 amidopløsning ved en temperatur fra ca. -10°C til omkring stuetemperatur 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 = -5 amide solution at a temperature of ca. -10 ° C to about room temperature from approx. 30 minutes to approx. 2 hours.

Basisk hydrolyse af en forbindelse med formlen (VII) med et alkali= metalhydroxid eller alkalimetalcarbonat, f.eks. natriumhydroxid, na= 30 triumcarbonat eller kaliumcarbonat i en vandig lavere alifa- 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, Na = 30 triium carbonate or potassium carbonate 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-ålkyl-35 derivaterne deraf. Hydrolysen gennemføres fortrinsvis under anvendelse af vandig methanolisk kaliumhydroxid ved tilbagesvalingstemperaturen i ca. 10 timer.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 using aqueous methanolic potassium hydroxide at the reflux temperature for approx. 10 hours.

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

7 DK 152653 B7 DK 152653 B

methanol, ethanol, isopropanol eller n-butanol, i nærværelse af hydrogenchlorid til fremstilling af den tilsvarende alkyl-1,2-di= hydro-3H-pyrrolo[l,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 or n-butanol, 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 with 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 I5 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 x ved hjælp af kromatografiske metoder. Alternativt og specielt til decarboxyleringen af små portioner af forbindelse (IX) kan reaktions-20 produktet (X) destilleres direkte fra reaktionsbeholderen.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 achieved by heating (IX) at an elevated temperature of the order of ca. 230 ° C to approx. 280 ° C for a time sufficient to cause the reaction to terminate. The course of the reaction can be followed by the extent of carbon dioxide evolution and thin-layer chromatographic analysis, the decarboxylation I5 usually being completed in about 10 minutes. 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 x by chromatographic methods. Alternatively and especially for the decarboxylation of small portions of compound (IX), the reaction product (X) can be distilled directly from the reaction vessel.

Kondensation af en·forbindelse (X) med et amid med formlerne con(ch,)9 25 jjlJT i) n—f R |l eller I | \x^^con(ch3)2 hvori X og R har de ovenfor anførte betydninger, giver de tilsvaren-Condensation of a compound (X) with an amide of the formulas con (ch,) 9 25 jjlJT i) n-f R | 1 or I | x x con (ch 3) 2 wherein X and R have the above meanings give the corresponding

q (Iq (I

de alkyl-5-substitueret-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carb= oxylater med formlerne henholdsvis (XI) eller (XII).the 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 opløsnings middel 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 DK 152653 Be DK 152653 B

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 den 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 it thus obtained reaction mixture for 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 eller carbontetrachlorid, dimethpxyethan og tetrahy.drofuran. Det fore-trukne opløsningsmiddel er 1,2-dichlorethan.Suitable solvents for this reaction are the halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

15 Repræsentative eksempler på N,N-dimethylamiderne, der kan anvendes, er: N, N-dime thyl thi ophen-2-carboxamid, N,N-dimethylfuran-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,· Ν', N-dimethyl-5-chlorthiophen-2-carboxamid, • N,N-dimethyl-3-bromthiophen-2-carboxamid, 25 N,N-dimethyl-5-bromthiophen-2-carboxamid, N,N-dimethyl-3-methylfuran-2-carboxamid, N,N-dimethyl-4-methylfuran-2-carboxamid, N,N-dimethyl-4-chlorfuran-2-carboxarnid, N,N-dimethyl-5-chlorfuran-2-carboxamid, - 30 N,N-dimethyl-4-bromfuran-2-carboxamid, N,N-dimethyl-5-bromfuran-2-carboxamid, N,N-dimethylthiophen-3-carboxamid og _ N,N-dimethylfuran-3-carboxamid.Representative examples of the N, N-dimethylamides that can be used are: N, N-dime thyl thi-ophen-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, · Ν ', N-dimethyl-5-chlorothiophene-2-carboxamide, N, N-dimethyl-3-bromothiophene-2-carboxamide, N, N-dimethyl-5-bromothiophene-2-carboxamide, N, N-dimethyl-3 methyl furan-2-carboxamide, N, N-dimethyl-4-methylfuran-2-carboxamide, N, N-dimethyl-4-chlorofuran-2-carboxamide, N, N-dimethyl-5-chlorofuran-2-carboxamide, N, N-dimethyl-4-bromfuran-2-carboxamide, N, N-dimethyl-5-bromfuran-2-carboxamide, N, N-dimethylthiophene-3-carboxamide, and N, N-dimethylfuran-3-carboxamide.

35 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. by conversion to the acid chlorides followed by treatment with dimethylamine.

Ved alkalisk hydrolyse af alkylestergruppen i en forbindelse med form-^ lerne (XI) eller (XII) fås de tilsvarende fri syrer henholdsvis med formlerne (A) eller (B). Hydrolysen gennemføres på sædvanlig måde madAlkaline hydrolysis of the alkyl ester group in a compound of formulas (XI) or (XII) gives the corresponding free acids of formulas (A) or (B), respectively. The hydrolysis is carried out in the usual way food

9 DK 152653 B9 DK 152653 B

et alkalimetalhydroxid eller alkalimetalcarbonat, f.eks. natrium^ hydroxid, kaliumhydroxid, natriumcarhonat eller kaliumcarbonat i en vandig lavere alifatisk alkohol, f.eks. methanol, eller ethanol 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 or potassium carbonate in an aqueous lower aliphatic alcohol, e.g. methanol, or ethanol at a temperature from about room temperature to the reflux temperature for from about. 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 Ί enkelte isomere deraf. Forbindelsen med formlen (A), hvori R og R begge er hydrogen, og X er svovl kan således f.eks. udsættes for en yderligere behandling i overensstemmelse med følgende diagram: '<' ' ; ^ I . ; . (A^·) . spaJ:t;hin.g_ ^ ' ". · · . · ** e '.1 . ' ‘· ;. , 4 · *** ** ' * . · * • . .The compounds of formulas (A) and (B) can be cleaved according to methods known in the art to obtain the corresponding Ί single isomers thereof. Thus, the compound of formula (A) wherein R and R are both hydrogen and X is sulfur can e.g. is subjected to further treatment according to the following diagram: '<' '; ^ I. ; . (A ^ ·). spaJ: t; hin.g_ ^ "". · ·. · ** e '.1.' '· ·., 4 · *** **' *. · * •.

. , . * -/ ·· · . * , * t · i. * . . * ' A1- (1) -syreisomer- (d)r^phetaminsalt ·... ,. * - / ·· ·. *, * t · i. *. . * 'A1- (1) -isomeromer- (d) r ^ phetamine salt · ..

>'''.i' -·> '' '. i' - ·

AMD -.•syreisomers! · j IAMD - acid acids! · J I

. · · · ·. · · · ·

- ' 1 . ^ N- '1. ^ N

Blanding ai VA ~ (d) - syreisomexr (d) -araphetaminsal-t. }Mixture a in VA ~ (d) - acid orexr (d) -araphetamine salt. }

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En mere detaljeret beskrivelse af denne fremgangsmåde findes i det efterfølgende eksempel 10 A. ' (l)-syreisomere og (d)-syreisomere af forbindelserne med formlerne 5 (A) og (B) kan alternativt opnås ved at anvende den kendte teknik med højtryksvæskekromatografi (HPLC) på a-phenethyldiastereoisomere estre af forbindelserne med formlerne (A) og (B) efterfulgt af syrespaltning. Forbindelserne med formlen (A), livori R og begge er hydrogen, og X er svovl, kan således f.eks. underkastes en yderligere 10 behandling i overensstemmelse med følgende diagram: V- , - COOH · -:-;-- .A more detailed description of this process can be found in the following Example 10A. (1) Acid isomers and (d) Acid isomers of the compounds of formulas 5 (A) and (B) can alternatively be obtained using the prior art high pressure liquid chromatography. (HPLC) on α-phenethyl diastereoisomeric esters of the compounds of formulas (A) and (B) followed by acid cleavage. Thus, the compounds of formula (A), livory R and both are hydrogen and X is sulfur. is subjected to a further 10 treatment according to the following diagram: V-, - COOH · -: -; -.

- - ^ ^ . -adskilligel, - ' . . . · . -· . · . trin.....’ .. ' ..- - ^^. -different, - '. . . ·. - ·. ·. step ..... '..' ..

' ; C (A^) “ Cl) --syreisomer- (l)va-phénethylest-er-.::^ .'; C (A ^) ClCl) acid isomer- (1) va-phenethyl ester is -:::.

Blanding a-f f i. · CMixture a-f f in. · C

·. ' / (¾1)-(ό)-syreisomer^ 1) -a-phenathylaster- -.S·. Β / (¾1) - (ό) -isomer isomer (1) -α-phenathylaster- -S

separering under * .separation under *.

anvendelse af _ . ·. ' . '' - højtryks væskekromatografi , #'.·*· · .the use of _ . ·. '. '' - high pressure liquid chromatography, # '. · * · ·.

(A^)- (lj-syreisomer- (1) -phenethylester - \ .(A ^) - (lj-acid isomer- (1) -phenethyl ester - \.

(A^j- (d)-syreisomer-(1)-phenethylester - i v . ' ! i (A )** (1) -ayreisomgr^r ' (a} - (d) - syreisomer-_| 11(A ^ j- (d) -isomer isomer (1) -phenethyl ester - in v. '(I) (A) ** (1) -isomer convertor (a} - (d) - acid isomer-_ | 11

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

Ved fremgangsmåden ifølge opfindelsen crrdannes de fri syrer med formlerne (A) og (B) til alkylestere 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.In the process of the invention, the free acids of formulas (A) and (B) are converted to alkyl esters with 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).

1010

Saltderivaterne af forbindelserne med formlerne (A) og (B) og-(1)-isomere deraf fremstilles· ved at behandle disse fri syrer med err^ 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 eller polyaminharpikser.: - 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, 25 fortrinsvis ved stuetemperatur. Typiske inaktive med vand blandbare organiske opløsningsmidler omfatter methanol, ethanol, isopropanol, butanol, acetone, dioxan eller tetrahydrofuran. Det molære forhold af forbindelser med formlerne (A) eller (B) eller (l)-isomere deraf til base, der anvendes, vælges, så der tilvejebringes det til det 30 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 (A) 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) isomers thereof are prepared by treating these free acids with a suitable 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, glucose amine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethyl or polyamine resins .: - The reaction is carried out in water alone or in combination with an inert water-miscible organic solvent at a temperature of about 0 ° C to approx. 100 ° C, preferably at room temperature. Typical inert water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of compounds of formulas (A) or (B) or (1) isomers thereof to base used is selected so as to provide the ratio desired for the particular salt. 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 35 of the compounds of formulas (A) or (B) or (1) acid isomers thereof are prepared, 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 12In the preferred method, the calcium salts and the magnesium salts of 12

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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-5 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 eller aluminiumtripropoxid ^ i et hydrocarbonopløsningsmiddel, såsom benzen, xylen eller cyklo-hexan ved en temperatur fra ca. 20°C til ca. 115oc. Lignende metoder kan anvendes til at fremstille salte af uorganiske basef, 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 5 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 or aluminum tripropoxide in a hydrocarbon solvent such as benzene, xylene or cyclohexane at a temperature of about 20 ° C to approx. 115oc. Similar methods can be used to prepare salts of inorganic basefeds which are not sufficiently soluble to readily react.

1515

Det må forstås, at isolering af de heri beskrevne forbindelser om Ønsket kan gennemføres ved hjælp af enhver egnet separerings- eller rensningsmetode, såsom f.eks. ekstraktion, filtrering, inddampning, ' destillation, krystallisation, tyndtlagskromatografi eller søjlekromatografi, højtryksvæskekromatografi (HPLC) eller en kombination af 20 disse metoder. I eksemplerne belyses egnede separerings- og isoleringsmetoder. Der kan naturligvis også anvendes andre ækvivalente separerings- eller isoleringsmetoder.It is to be understood that isolation of the desirable compounds described herein may be accomplished by any suitable separation or purification method such as e.g. extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or a combination of these methods. Examples illustrate suitable separation and isolation methods. Of course, other equivalent separation or isolation methods can also be used.

De omhandlede forbindelser med formlerne (A1) og (B') og (l)-syre-25 isomere deraf er nyttige som antiinflammatoriske midler, analgetiske midler, blodpladeaggregationsinhibitorer, fibrinolytiske midler, og som glatmuskelafsiappelsesmidler. Disse forbindelser kan anvendes både profylaktisk og terapeutisk. 1 2 3 4 5 6 På basis.af disse forbindelser kan der fremstilles produkter, der 2 således er nyttige ved behandlingen og elimineringen af inflammation, 3 såsom betændelsestilstande i det muskulære skeletsystem, skeletled 4 og andre væv, f.eks. ved behandlingen af betændelsestilstande, såsom 5 rheumatisme, konkussion, laceration, arthritis, benbrud, posttrau- 6 matiske tilstande og 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.The present compounds of formulas (A1) and (B ') and (1) acid isomers thereof are useful as anti-inflammatory agents, analgesics, platelet aggregation inhibitors, fibrinolytic agents, and as smooth muscle relaxants. These compounds can be used both prophylactically and therapeutically. 1 2 3 4 5 6 On the basis of these compounds, products 2 can thus be prepared which are useful in the treatment and elimination of inflammation, 3 such as inflammatory conditions in the muscular skeletal system, skeletal joints 4 and other tissues, e.g. in the treatment of inflammatory conditions such as rheumatism, concussion, laceration, arthritis, fractures, posttraumatic 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.

1313

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Den foretrukne administrationsmåde i forbindelse med de ovenfor beskrevne tilstande er den orale« idet der anvendes en passende daglig dosismængde« der kan justeres i overensstemmelse med lidelsens karakter og omfang. En daglig dosis fra 25 mg til 500 mg af den 5 aktive forbindelse med formlerne (A') eller (B*) eller (l)-syre-isomere deraf anvendes. De fleste lidelser reagerer på behandling« som omfatter en dosismængde af størrelsesordenen 0,5 mg til 6 mg per kg legemsvægt per dag.The preferred mode of administration for the conditions described above is the oral "using an appropriate daily dosage 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 is used. Most disorders respond to treatment, which includes a dose of about 0.5 mg to 6 mg per kg body weight per day.

10 De farmaceutisk acceptable estere og ikke toksiske salte af formlerne (A') og (B') og (L)-isomere deraf som beskrevet ovenfor er også uteringglatmuskelafslappelsesmidler og er således nyttige som midler til at opretholde graviditet hos gravide kvinder og drægtige pattedyr til gavn for moder og/eller foster, indtil afsluttelse af gra-15 viditet fra ét medicinsk synspunkt findes gunstigt eller mere gunstigt for moderen og/eller fosteret.The pharmaceutically acceptable esters and non-toxic salts of formulas (A ') and (B') and (L) isomers thereof as described above are also smooth muscle relaxants and are thus useful as agents for maintaining pregnancy in pregnant women and pregnant mammals. benefit to the mother and / or fetus until completion of pregnancy from one medical point of view is found favorable or more favorable to the mother and / or the fetus.

Test for antiinflammatorisk virkning under anvendelse af Carrageenin-induceret poteinflammation i rotte.Test for anti-inflammatory effect using Carrageenin-induced protein inflammation in rat.

2020

Protokol: Simonsen hunrotter med en vægt på 80-90 g anvendes. Forbindelserne (A') eller (B'), 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 (0,9%-NaCl) af carrageenin i højre bagpote.Protocol: Simonsen female rats weighing 80-90 g are used. The compounds (A ') or (B') to be tested are administered hourly orally by administration in 1 ml of aqueous carrier. One hour later, 0.05 ml of a 1% solution (0.9% NaCl) of carrageenin is injected into the right hind paw.

25 Denne injektion forårsager en inflammation af poten. Rotterne aflives 4 timer efter forsøgets start, på hvilket tidsrum begge bagpoter aftages og vejes særskilt.25 This injection causes 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.

Slutpunkt: % forøgelse i potestørrelse beregnet som følger: 30End point:% increase in paw size calculated as follows: 30

Vagt af højre pote - vægt af venstre pote Vægt af venstre poteGuard of right leg - weight of left foot Weight of left foot

De følgende forbindelser blev undersøgt og udviste følgende antiinf lammatoriske virkning versus phenylbutazon:The following compounds were tested and showed the following anti-lammatory activity versus phenylbutazone:

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1414

Forbindelse AktivitetConnection Activity

(dl)-methyl-5-(2-thenoyl)-1,2-dihydro- 6Q(dl) -methyl-5- (2-thenoyl) -1,2-dihydro-6Q

3H-pyrrolo[1,2-a]-pyrrol-l-carboxylat3H-pyrrolo [1,2-a] pyrrole-l-carboxylate

(dl)-octyl-5-(2-thenoyl)-1,2-dihydro- >3Q(dl) -octyl-5- (2-thenoyl) -1,2-dihydro-> 3Q

_ 3H-pyrrolo[1,2-a]-pyrrol-l-carboxylat3H-pyrrolo [1,2-a] pyrrole-1-carboxylate

OISLAND

(dl)-dodecyl-5-(2-thenoyl)-1,2-dihydro- ^2o 3H-pyrrolo[1,2-a]-pyrrol-l-carboxylat (dl)-natrium-5-(5-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat 10 (dl)-natrium-5-(3-furoyl)-1,2-dihydro-3H- _ 3 pyrrolo[1,2-a]pyrrol-l-carboxylat (dl)-natrium-5-(2-thenoyl)-6-methyl-l,2- ^27 dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat(dl) -Dodecyl-5- (2-thenoyl) -1,2-dihydro-2H 3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (dl) sodium 5- (5-methyl) -2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (dl) sodium 5- (3-furoyl) -1,2-dihydro-3H 3 pyrrolo [1,2-a] pyrrole-1-carboxylate (dl) sodium 5- (2-thenoyl) -6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a ] pyrrole-l-carboxylate

De følgende eksempler 1-16 belyser fremstillingen af udgangsmaterialer, 15 og eksempel 17 illustrerer fremgangsmåden ifølge opfindelsen. Alle blandingsforhold, der anvendes med hensyn til væsker, refererer til volumenforhold. Hvor det er nødvendigt, gentages eksempler for at fremstille yderligere materiale til efterfølgende eksempler, og med mindre andet er anført, gennemføres reaktionerne ved stuetemperatur (20-30°C).The following Examples 1-16 illustrate the preparation of starting materials, 15 and Example 17 illustrating the process of the invention. All mixing ratios used with regard to liquids refer to volume ratios. Where necessary, 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).

2020

Fremstilling af thiophen og furancarboxamider til anvendelse ved fremstilling af XI og XII.Preparation of thiophene and furan carboxamides for use in the preparation of XI and XII.

En blanding af 23. g 4^-chlorthiophen-2-carboxylsyre (J, Iriarte et al«, 25 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« 1 2 3 4 5 6A mixture of 23 g of 4β-chlorothiophene-2-carboxylic acid (J, Iriarte et al, 25 J, Heterocyclic Chem. 13, 3931 and 80 ml of thionyl chloride is heated to reflux under anhydrous conditions for 4 hours, the excess thionyl chloride 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 «1 2 3 4 5 6

En opløsning af 10,5 g 4-chlorthiophen-2-carboxylsyrechlorid i 500 ml 2 . vandfri benzen afkøles i et is-vandbad, og dimethylamin bobles langsomt 3 gennem opløsningen i 30 minutter. Is-vandbadet fjernes, idet dimethyl= 4 aminstrømmen opretholdes i yderligere 15 minutter. Reaktionsblandingen 5 .fortyndes så med 100 ml 10% natriumchloridopløsning og omrøres i 5 6 minutter ved stuetemperatur, den organiske fase skilles fra, vaskes med 10% saltsyre, mættet natriumbicarbonatopløsning og mættet natrium= cliloridopløsning, tørres over'natriumsulfat og inddampes til tørhed under reduceret tryk. Herved fås N,N-dimethyl-4~chlorthiophen-2-carboxamid.A solution of 10.5 g of 4-chlorothiophene-2-carboxylic acid chloride in 500 ml of 2. anhydrous benzene is cooled in an ice-water bath and dimethylamine is bubbled slowly 3 through the solution for 30 minutes. The ice-water bath is removed, maintaining the dimethyl = 4 amine stream for a further 15 minutes. The reaction mixture 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. pressure. There is thus obtained N, N-dimethyl-4-chlorothiophene-2-carboxamide.

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

I III II

Thiophen-2-carboxylsyre N,N-dimethylthiophen-2-carboxamid 5 furan-2-carboxylsyre ' N/N-dimethylfuran-2-carboxamid 3- methylthiophen-2—carboxylsyre N/N-dimethyl-3-methylthiophen-2- carboxamid 4- methylthiophen-2—carboxylsyre N,N-dimethyl-4-methylthiophen-2- carboxamid 10 5 -me thy 1 thiophen- 2—carboxy1syre N, N-dime thy 1-5-me thylthiophen-2-' carboxamid 5- chlorthiophen-2-carboxylsyre N/N-dimethyl-5-chlorthiophen-2- carboxamid 3-bromthiophen-2-carboxylsyre N,N-dimethyl~3-bromthiophen-2- carboxamid 15 4-bromthiophen-2-carboxylsyre N/N-dimethyl-4-bromthiophen-2- carboxamid 5-bromthiophen-2-carboxylsyre N,N-dimethyl-5-bromthiophen-2- . carboxamid 3-methylfuran-2~carboxylsyre N,N-dimethyl-3-methylfuran-2- carboxamid • . i 20 4-methylfuran-2-carboxylsyre N/N-diraethyl-i-methylfuran^- carboxamid 5-methylfuran-2-carboxylsyre N,N-dimethyl-5-methylfuran-2- carboxamid 3- chlorfuran-2-carboxylsyre N,N-dimethyl~3-chlorfuran-2~ carboxamid 25 4-chlorfuran-2-carboxylsyre N,N-dimethyl-4-chlorfuran-2- carboxamid 5-chlorfuran-2-carboxylsyre N,N-dimethy1-5-chlorfuran-2- carboxamid 4- bromfuran-2-carboxylsyre NrN-dimethy1-4-bromfuran-2- carboxamid 30 5-bromfuran-2-carboxylsyre N,N-dimethyl-5-bromfuran-2- carboxamid thiophen-3-carboxylsyre ' N,N-dimethylthiophen-3-carboxam.id furan-3-carboxylsyra N,N-diraethylfuran-3-carboxamid* 35 16Thiophene-2-carboxylic acid N, N-dimethylthiophene-2-carboxamide furan-2-carboxylic acid N / N-dimethylfuran-2-carboxamide 3-methylthiophene-2-carboxylic acid N / N-dimethyl-3-methylthiophene-2-carboxamide 4- methylthiophene-2-carboxylic acid N, N-dimethyl-4-methylthiophene-2-carboxamide 5-methyl thiophene-2-carboxylic acid N, N-dime thy 1-5-methylthiophene-2-carboxamide 5- chlorthiophene-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-carboxamide 5-bromothiophene-2-carboxylic acid N, N-dimethyl-5-bromothiophene-2. carboxamide 3-methylfuran-2 ~ carboxylic acid N, N-dimethyl-3-methylfuran-2-carboxamide •. in 4-methylfuran-2-carboxylic acid N / N-diraethyl-1-methylfuran-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 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 No. N-dimethyl-4-bromfuran-2-carboxamide -dimethylthiophene-3-carboxamide furan-3-carboxylic acid N, N-diraethylfuran-3-carboxamide

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Eksempel 1.Example 1.

En 250 ml 3-halset, riindbundet ko3.be 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 5 (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« acetat, som beskrevet af P.Z. Bedoukian, J. Am. Chem. Soc. 66, 651 (1944)), med en 6" Vigreuxkolonne i toppen, med et termometer forbun-l'O det til ovennævnte svaler.A 250 ml 3-neck, ri-bonded co3.be 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 5 (3 ") water purifier to the acetal pyrolysis apparatus. apparatus consists 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" acetate, as described by PZ Bedoukian, J. Am. Chem. Soc. 66, 651 ( 1944)), with a 6 "Vigreux column at the top, with a thermometer forbun-l'O it to the above swallow.

Den 3-halsede kolbe forsynes med 3,36 g ethanolamin, afkølet i et isbad til 0-10°C og behandles dråbevis under omrøring med 8,7 g dimethyl-„ 1,3-acetonedicarboxylat. Methyl-3-carbomethoxymethyl-3(21-hydroxyethyl)~ 15 aminoacrylat (III) dannes stråles. Efter endt tilsætning fjernes isbadet, og 100 ml tør acetonitril tilsættes. Apparatets pyro3.ysedel 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 vinylaminen • 20 (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 25 silieagel til resten. Blandingen inddampes til tørhed under vakuum, og anbringes i toppen af en søjle af 200 g silieagel 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-1,3-acetonedicarboxylat, fraktionerne 4-8 giver 30 4,1 g methyl-K-(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-carbomethoxymethyl-3 (21-hydroxyethyl) ~ 15 aminoacrylate (III) is irradiated. After the addition is complete, remove the ice bath and add 100 ml of dry acetonitrile. The pyro3ysh 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 the vinylamine • 20 (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, and then 200 ml of methanol and 20 g of 25 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 K- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H) which, after recrystallization from ether / hexane, has a melting point of 52-54 ° C.

Eksempel 2. ; 35 Til en omrørt opløsning af 4,1 g methyl-N-(2-hydroxyethyl)-3-carbo= 17Example 2.; To a stirred solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carbo = 17

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methoxypyrrol-2-acetat i- 35 ml tør dichlormethan afkølede til -10°C, sættes 2/65 ml trietkylamin og derefter tildryppes 1,46 ml methansulfo= nylchlorid, idet reaktionsblandingens temperatur holdes på -10 - -5°C* Reaktionens forløb følges ved hjælp af tyndtlagskromatografiske ana-5 lyser under anvendelse af chloroform/acetone (90:10)* Når reaktionen viser sig at være forløbet fuldstændig (ca„ 30 minutter efter at methan-sulfonylchloridtilsætningen er ophørt) tilsættes langsomt 10 ml vand«methoxypyrrole-2-acetate in 35 ml of dry dichloromethane cooled to -10 ° C, 2/65 ml of triethylkylamine is added and then 1.46 ml of methanesulfonyl chloride is added dropwise, keeping the reaction mixture at -10 - -5 ° C. followed by thin-layer chromatographic analysis using chloroform / acetone (90:10) * When the reaction turns out to be complete (about "30 minutes after the methanesulfonyl 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 10 af resten fra dichlormethan/hexan giver 4,75 g (77,7%). methyl-N-(2-mesyloxyethyl)-3-carbomethoxypyrrol-2-acetat (V, R = H), smeltepunkt 99-101°C.The organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulfate and evaporated under reduced pressure * Crystallization 10 of the residue from dichloromethane / hexane gives 4.75 g (77.7%). methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), m.p. 99-101 ° C.

Eksempel 3. · ' 15 · .Example 3. · 15.

En opløsning af 785 mg methyl-N-(2-mesyloxyethyl)-3-carbomethoxypyrrol- 2-acetat og 1,83 g natriumiodid i 10 ml acetohitril tilbagesvales i • 1 time. Den afkølede reaktionsblanding inddampes til tørhed under reduceret tryk, og resten sønderdeles med vand. Det uopløselige materiale 20 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 acetohitrile 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 20 is filtered off and air dried. Thus, 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), mp 137-138 ° C is obtained.

Eksempel 4.Example 4

2525

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 minutter ved stuetemperatur og afkøles derpå hurtigt med 100 ml vand. Pro-33 duktet 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-dihydro-3H-pyrrolo[l,2-a]pyrrol-l,7-dicarboxylat (VII, R = H), smelte-35 punkt 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 ml of water. The product-33 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 the eluant gives 500 mg (80%) of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 7-dicarboxylate (VII, R = H), mp 70-71 ° C.

En opløsning af 1,80 g dimethy 1-1,2-dihydro~3II-pyrrolo [1,2-a] pyrrol- 1, 7-dicarboxylat i 20 ml methanol behandles med en opløsning af 4,48 g kaliumhydroxid i 20 ml vand, og reaktionsblandingen tilbagesvales i 6 40 timer. Den afkølede opløsning inddampes til tørhed, og resten behandles 18A solution of 1.80 g of dimethyl 1-1,2-dihydro-3II-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 18

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med 50 ml mættet natriumchloridopløsning. Den resulterende opløsning syrnes med 6N saltsyre og ekstraheres med ethylacetat (3 x 50 ml) . De forenede ekstrakter tørres over magnesiumsulfat og inddampes til tørhed under reduceret tryk. Herved fås 1,51 g (95%) l,2-dihydro-3H-g pyrrolo[l,2-a]pyrrol-l,7-dicarboxylsyre (VIII, R = H), smeltepunkt 220°C under dekomponering.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-g pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H), m.p. 220 ° C during decomposition.

Eksempel 5.Example 5

10 En opløsning af 1,34 g l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l,7-di= carboxylsyre i 50 ml isopropanol, afkøles i et isbad, mættes med hydro= genchloridgas, idet reaktionsblandingens temperatur holdes under 50°C.A solution of 1.34 g, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-di-carboxylic acid in 50 ml of isopropanol is cooled in an ice bath, saturated with hydrogen chloride gas, temperature is kept below 50 ° C.

Isbadet fjernes derpå, og reaktionsblandingen omrøres i 1 1/2 time ved stuetemperatur og inddampes til tørhed under reduceret tryk, 10 ml 15 benzen sættes til resten, og opløsningen inddampes endnu en gang under vakuum, idet denne behandling gentages i alt tre.gange for fuldstændigt at fjerne hydrogenchloridoverskud. Således fås 1,58 g (96%) isopropyl- v 1,2-dihydro--3H-pyrrolo [1,2-a] pyrrol-l-carboxylat-7-carboxylsyre (IX, 2 R = H, R = iso-C^H^), som efter omkrystallisation fra methanol/ethyl= 20 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 a total of three times for completely removing 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 (C ^H H) which, after recrystallization from methanol / ethyl = acetate, has a melting point of 144-145 ° C.

Eksempel 6.Example 6

1,054 g isopropyl-1,2-dihydro-3H-pyrroloII,2-a]pyrrol-l-carboxylat-7-25 carboxylsyre opvarmes til 240-250°C i en tør 10 ml rundbundet kolbe, idet reaktionsproduktet destilleres direkte fra reaktionsbeholderen.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.

På denne måde fås 745 mg (87%) isopropyl-1,2-dihydro-3H-pyrrolo[l,2-a]-pyrrol-1-carboxylat (X, R = H, R = iso-C^II»), en lysegul olie med følgende fysiske konstanter: u*V'v%åks 215 nm (ε 6020), I.R.: 30 1725 cm~^, N.M.R. (kernemagnetisk resonans) : 5^^3 1,22 (d, J = 7 Hz, 611), 2,40-2,90 (m, 2H) , 3,60-4,20 (m, 2il) , 4,65-5,2 (m, IH) , 5,73- 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, R = iso-C , a light yellow oil with the following physical constants: u * V'v% yoke 215 nm (ε 6020), IR: 30 1725 cm ~ ^, NMR (Nuclear Magnetic Resonance): δ 3 3.22 (d, J = 7 Hz, 611), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2il), 4 , 65-5.2 (m, 1H), 5.73- 5.92 (m, 1H), 6.10 (t, J - 3 Hz, 1H), 6.43-6.53 (m, 1H) ).

Eksempel 7.Example 7

35 En 100 ml trehalset rundbundet kolbe forsynet med en svaler, nitrogentilledningsrør og en gasbobler forsynes med 5,0 g isopropyl-l,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-40 19A 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 react-40 19

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tionen følges ved hjælp af carbondioxidudviklingens omfang (gasbobler) og ved hjælp af tynåtlagskromatografi 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-l,2-dihydro-3H-pyrro= 10 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.The reaction is followed by the extent of the 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 almost complete. After 1 hour 5 the container is removed from the oil bath and the contents of the reaction flask are transferred to a round bottom flask with 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography on 100 g of silica gel. The fractions eluted with hexane / benzene (70:30) and hexane / benzene (50:50) give 2.77 g (68%) of isopropyl-1,2-dihydro-3H-pyrro = 10,1 [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.

Eksempel' · 8.Example '8.

15’ 710 mg af en 501'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. Reaktionsblan-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-[1,2-a]pyrrol-l,7-diearboxylat (VII, R = H), der er identisk med det 25 i eksempel 4 opnåede produkt.15 '710 mg of a 501' 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. There is thus obtained dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1,7-diearboxylate (VII, R = H) identical to the product obtained in Example 4.

Eksempel 9Example 9

En opløsning af 300 mg isopropyl-S-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-30 [1,2-aJpyrrol-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 opløsningj der er tilbage, fortyndes med vand og ekstraheres med chloroform til . fjernelse af eventuelt uforsæbeligt produkt. Den vandige alkaliske fase 35 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-(2-thenoyl)-1,2-dihydro” 3H-pyrrolo[l,2-a]pyrrol-l-carboxylsyre, [(A), E og R^ = Η, X = S], med et smeltepunkt på 145-148°C, som efter omkrystallisation fra ethyl= 40 acetat smelter ved 1S2-;1530C under dekomponering.A solution of 300 mg of isopropyl S- (2-thenoyl) -1,2-dihydro-3H-pyrrolo-30 [1,2-a] pyrrole-1-carboxylate in 30 ml of 50% aqueous methanol containing 1% potassium hydroxide is refluxed a nitrogen atmosphere for 2 hours. The methanol is then removed under reduced pressure and the basic solution remaining is diluted with water and extracted with chloroform to. removal of any unsaleable product. The aqueous alkaline phase 35 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- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, [(A), E and R 2 = Η, X = S ], with a melting point of 145-148 ° C which, after recrystallization from ethyl = 40 acetate, melts at 1S2- 1530C during decomposition.

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Eksempel 10 AExample 10A

410 mg 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylsyre og 212,3 mg (d)-amphetarain opløses i 15 ml absolut methanol og opvarmes under tilbagesyaling i 15 minutter, efterfulgt af fjernelse af methano= 5 let under vakuum. Den resulterende diastereoisomere (d) -amphetaminsa.lt- blanding (612,3 mg) opløses i det mindst mulige volumen varm (55°C) acetone, afkøles til stuetemperatur og filtreres, og vaskes med 2 ml kold (-10°C) acetone. Denne omkrystallisationsraetode gentages yderligere tre gange. Herved fås 247 mg (1)-5-(-2-thenoyl)-l,2-dihydro-3H-pyrrolo-10 [l,'2-a]pyrrol-l-carboxylsyre- (d) -amphetaminsalt med et 3 = -181,3 og et smeltepunkt på 168-170°C,410 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and 212.3 mg (d) -amphetaraine are dissolved in 15 ml of absolute methanol and heated under reflux for 15 minutes, followed by removal of methano = 5 slightly under vacuum. The resulting diastereoisomeric (d) -amphetaminesa.lt 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-10,2,2-a] pyrrole-1-carboxylic acid (d) -amphetamine salt with a 3 = -181.3 and a melting point of 168-170 ° C,

Det umiddelbart ovenfor opnåede (1) -syreisomer- (d) -amphetaminsalt sættes til 30 ml methylenchlorid og omrystes tre gange med 10 ml 0,1N 15 vandig saltsyre. Methylenchloridopløsningen vaskes tre gange med 15 ml mættet natriumchlorid/vand (2:l/volumen:volumen) og tørres over vandfri natriumsulfat. Filtrering og fjernelse af det organiske opløsningsmiddel under vakuum giver 90 mg (1)-5-(2-thenoyl)-l,2-dihydro-3H- CHC1 o pyrrolo[l,2-a]pyrrol-l-carboxylsyre, der har et aD 3 = -177 og et 20 smeltepunkt på 134-135,5°C.The (1) -isomeromer (d) -amphetamine salt obtained immediately above 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-CHClC pyrrolo [1,2-a] pyrrole-1-carboxylic acid having an aD 3 = -177 and a melting point of 134-135.5 ° C.

Acetonemoderluden, som fås fra spaltningen (dvs. de gentagne krystallisationer) af den diastereoisomere-(d)-amphetaminsaltblanding, der er beskrevet ovenfor, forenes og omdannes under anvendelse af saltsyre-25 spaltningsmetoden som beskrevet ovenfor. Herved fås 245 mg af en blanding beriget på (d)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol~ 1-carboxylsyre og indeholdende (1)-5-(2-thenoyl)~l,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 5-3 0 (2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-aJpyrrol-l-carboxylsyre som følger: De 245 mg af blandingen, der er beriget på den (d)-isomere og . indeholdende den (1)-isomere, der er beskrevet ovenfor, opløses i 15 ml methanol. 1,5 ml methanol og 350 mg natriumhydroxid tilsættes, og opløsningen opvarmes under tilbagesvaling under nitrogen i 1 time. Metha= 35 nolet fjernes under vakuum, 2,5 ml vand tilsættes, og opløsningen syr-nes til pH-yærdi 2 med 10S vandig saltsyre. Blandingen ekstraheres med . tre 10 ml portioner methylenchlorid, og methylenchloridekstrakterne forenes og vaskes neutrale igen (pH-værdi 7), tørres over vandfriThe acetone mother liquor obtained from the cleavage (i.e., the repeated crystallizations) 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-a] pyrrole-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 5-3 O (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2- α-Pyrrole-1-carboxylic acid as follows: The 245 mg of the mixture enriched on the (d) isomeric and. containing the (1) isomer described above is dissolved in 15 ml of 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 metha = 35 is removed under vacuum, 2.5 ml of water is added and the solution is acidified to pH 2 with 10S 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

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natriumsulfat og koncentreret i vakuum. Herved fås 230. mg rå krystallinsk produkt, som efter omkrystallisation fra ethylacetat/hexan giver 180 mg 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l~carboxyl= syre med et = ©,,0° og et smeltepunkt på 152-154°C,sodium sulfate and concentrated in vacuo. This gives 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 having a = 0, 0 ° and a melting point of 152-154 ° C,

' Eksempel' TO' B'Example' TO 'B

5 _5 _

Til en opløsning af 118 mg 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[1,2-a)-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= 10 amin tilsættes umiddelbart fulgt af tilsætningen af 0,2 g (l)-a-phenyl= ethylalkohol. Den således opnåede reaktionsopløsning omrøres ved stuetemperatur i 15 minutter og hældes i 20 ml vand indeholdende 1 ml tri= ethylamin, efterfulgt af ekstraktion med éthylacetat, Ethylacetateks-trakten tørres over natriumsulfat, efterfulgt af fjernelse af opløs-15 ningsmidlet og overskud af (11-α-phenylethylalkohol under vakuum. Herved fås 0,166 g af en blanding ar (l).-5-(2-thenoyl)-l,2-dih.ydro-3H-' pyrrolo[l,2-a]pyrrol-l-carboxylsyre-(U-a-phenethylester og (d)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-1-carboxylsyre-(1) -α-phenethylester, som separeres ved højtryksvæskekromatografi (under 20 anvendelse af 4% EtOAc/hexan på en 11 mm. x 50 cm lQjun "Lichrosorb'^1-60-søjlel. Herved fås 68 mg af en mere polær ester (αϊ?θ0Η =.149,1°) og 73To a solution of 118 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a) -pyrrole-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 = 10 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 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 ( α-phenylethyl alcohol in vacuo to give 0.166 g of a mixture of ar (1) - 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 carboxylic acid (Ua-phenethyl ester and (d) -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 20% EtOAc / hexane on an 11 mm x 50 cm lQjun "Lichrosorb" 1-60 column) to give 68 mg of a more polar ester (αϊ? θ0Η = .149.1 °) and 73

MpOR n ^ mg af en mindre polær ester (a“ = +105,2), 62,1 mg af den mere polære ester opløses i. 3 ml tør benzen, Opløsningen 25 afkøles til 15-20°C, og 2,5 ml trifluoreddikesyre tilsættes, pg opløsningen omrøres ved stuetemperatur i 1 time og 40 minutter. Reaktionsopløsningen 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)- 5-(2-thenoyl)-1,2-ditoydro-3H-pyrrolo[1,2-a)pyrrol-l-carboxylsyre med aMeOH _ 0g et smeltepunkt på 130-132°C, 35 Spaltning af den mindre polære ester i overensstemmelse med den ovenfor beskrevne metode for spaltning af den mere polære ester giver på lignenMpOR n + mg of a less polar ester (a + = +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. The 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). There is thus obtained 41 mg (1) - 5- (2-thenoyl) -1,2-ditoydro-3H-pyrrolo [1,2-a) pyrrole-1-carboxylic acid with aMeOH and a melting point of 130-132 ° C. Cleavage of the less polar ester according to the method described above for cleavage of the more polar ester gives the resin

DK 152653BDK 152653B

22 de måde (d)-5-(2-thenoyl)-l,2-dihydro-3H-pyrroloU,2-a]pyrrol-l-carb= oxylsyre med a^e0H = +142,4°C og et smeltepunkt på 127-129°C. Den således opnåede (d)-syreisomer kan om ønsket racemiseres (og recirkuleres i overensstemmelse med.i teknikken kendte metoder.22 the ways (d) -5- (2-thenoyl) -1,2-dihydro-3H-pyrroloyl, 2-a] pyrrole-1-carb = oxylic acid with a 2 eOH = + 142.4 ° C and a melting point at 127-129 ° C. The (d) acidomer thus obtained can, if desired, be racemized (and recycled according to methods known in the art).

Andre (dl)-forbindelser kan ligeledes omdannes til deres respektive 5 (1)-isomere og (d)-isomere.Other (dl) compounds can also be converted to their respective 5 (1) isomers and (d) isomers.

Eksempel· 11.Example · 11.

En opløsning af 336 mg isopropyl-5-(2-thenoyl)-l,2-dihydro~3H-pyrrolo-10 . (1,2-a]pyrrol-l-carboxylat i 10 ml methanol behandles med en opløsning af 690 mg kaliumcarbonat i 5 ral vand. Reaktionsblandingen tilbagesva-, les under en nitrogenatmosfære i 2 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 (2 x 50 ml). De 15 forenede ekstrakter tørres over magnesiumsulfat og inddampes til tørhed under reduceret tryk. Krystallisation af resten fra ethylacetat giver 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a)pyrrol-l-carboxylsyre, uer er identisk med det i eksempel 9 opnåede produkt.A solution of 336 mg of isopropyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo-10. (1,2-a] pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution of 690 mg of potassium carbonate in 5 rals of water. The reaction mixture is refluxed under a nitrogen atmosphere for 2 hours, cooled and evaporated to dryness. 10 ml of 10% aqueous hydrochloric acid and 50 ml of water, and the resulting mixture is extracted with ethyl acetate (2 x 50 ml) The 15 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 is identical to the product obtained in Example 9.

20 Eksempel 12Example 12

Ved at følge fremgangsmåden:By following the procedure:

En opløsning af 232,5 mg N,N-dimethylthiophen~2-carboxamid og 0,15 ml phospboroxychlorid i 2 ml 1,2-dichlorethan tilbagesvales i 30 minutter.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.

25 Til denne opløsning sættes en opløsning af 181 mg isopropyl-1,2- dihydro-3lI“pyrrolo[1,2-a]pyrrol-l-carboxylat i 2 ml 1,2-dichlorethan.To this solution is added a solution of 181 mg of isopropyl-1,2-dihydro-3LI 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 timer. Den resulterende blanding inddampes .så til tørhed, og resten 30 kromatograferes på 12 g silieagel, idet der' elueres med hexan/ethyl= acetat (3:1). Således fås isopropyl-5-(2-thenoyl)-l,2-dihydro-3H- 1 2· pyrrolo[1,2-a]pyrrol-l-carboxylat (XI, R og R = H, R = iso-C^H^, X - S); og anvende 1,1-2 molærækvivalenter N, N-dimethylf uran-r-2-carboxamid, N, N-dimethyl^5-inethylthiophen-2^carboxamid, N,N-dimethy1-5-thiophen-2-carboxamid 23The 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-1,2-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R and R = H, R = iso-C H, X - S); and using 1.1-2 molar equivalents N, N-dimethylfuran-r-2-carboxamide, N, N-dimethyl-5-methyl-thiophene-2-carboxamide, N, N-dimethyl-5-thiophene-2-carboxamide 23

: DK 152653 B: DK 152653 B

V«·*.V '· *.

i stedet for N,N-dimethylthiophen-2-carboxamid og følge reaktionens • forløb ved hjælp af tyndtlagskroniatografi, fås henholdsvis: isopropyl-5-(2-furoyi)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, en olie med følgende fysiske konstanter:instead of N, N-dimethylthiophene-2-carboxamide and follow the course of the reaction by thin layer chromatography, respectively: isopropyl-5- (2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a ] pyrrole-1-carboxylate, an oil having the following physical constants:

• MeOH• MeOH

5 u,v* Xmaks 275, 332,5 nm (ε 8900, 17800);5 µm, λ max 275, 332.5 nm (ε 8900, 17800);

Cjjci I,R* vmaks3 1735, 1685, 1605 cm"1; Μ' μ n CDC1, * 6TMS 1,23 Id, 6H, J = 6 Hz; (CH^CH], 2,60-3,00 (ra, 2H), 3,90 (dd, IH, JÅX= 6 Hz; 10 JBX = 7 Hz; H-l), 4,10-4,67 (m, 2H), 4,95 [sept., IH, J = 6 Hz; (CK3)2CH], 6,00 (d, IH, J = 4 Hz; H-7), 6,40 (m, IH), 7,10 (m, IH) , 7,23 (d, III, J = 4 Hz; H-6) , 7,43 ppm (m, IH); 15 M.S. m/e 287 (M+) , isopropyl-5-(5-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat , med smp. 82-8?,5°C, isopropyl-5-(4-chlor-2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol- 2^ 1-carboxylat, olie, U.V. 212, 261, 333 nm (ε 7100, 6600, 14800); rnrl ·? max -1 + 1735, 1605 cm ; M.S. 337 (M ).Cjjci I, R * vmax3 1735, 1685, 1605 cm "1; Μ 'µ n CDCl1, * 6TMS 1.23 Id, 6H, J = 6 Hz; (CH ^CH], 2.60-3.00 (ra , 2H), 3.90 (dd, 1H, YES = 6 Hz; 10 JBX = 7 Hz; H1), 4.10-4.67 (m, 2H), 4.95 [Sept., 1H, J = 6 Hz; (CK 3) 2CH], 6.00 (d, 1H, J = 4 Hz; H-7), 6.40 (m, 1H), 7.10 (m, 1H), 7.23 (d , III, J = 4 Hz; H-6), 7.43 ppm (m, 1H); MS MS / e 287 (M +), isopropyl-5- (5-methyl-2-thenoyl) -1,2 -dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 82-8 °, 5 ° C, isopropyl-5- (4-chloro-2-thenoyl) -1,2-dihydro -3H-pyrrolo [1,2-a] pyrrole-2β-carboxylate, oil, UV 212, 261, 333 nm (ε 7100, 6600, 14800); rnrl · max -1 + 1735, 1605 cm; MS 337 (M).

ΙΠΗΧ isopropyl-5-(3-thenoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-car-boxylat, smp. 67-68°C og isopropyl-5-(3-furoyl)—1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-1-carboxy- 25 lat, olie, U.V. \Me0H 222, 260 (skulder), 314 nm (ε 6750, 4250, 17800); mn max , I.R. 1730, 1610 cm ; M.S. 287 (M ).ΙΠΗΧ isopropyl 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 67-68 ° C and isopropyl-5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil, U.V. \ MeOH 222, 260 (shoulder), 314 nm (ε 6750, 4250, 17800); mn max, I.R. 1730, 1610 cm; M.S. 287 (M).

maxmax

Ved hydrolyse af isopropylestergruppen i overensstemmelse med fremgangsmåderne fra eksemplerne 9 eller 11 fås de tilsvarende fri syrer, nemlig: 30 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre, smp. 184-184,5°C, 5-(5-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo [ 1,2-a]pyrrol-l-carb= oxylsyre, smp. 169-170°C, 5- (4-chlor-2-thenoyl) -1,2-dihydro-3H^-pyrrolo [ 1,2-a] pyrrol-l-carb= oxylsyre, smp. 169-169,5°C, 35By hydrolysis of the isopropyl ester group according to the procedures of Examples 9 or 11, the corresponding free acids are obtained, namely: 5- (2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1- carboxylic acid, m.p. 184-184.5 ° C, 5- (5-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, m.p. 169-170 ° C, 5- (4-Chloro-2-thenoyl) -1,2-dihydro-3H ^-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, m.p. 169-169.5 ° C, 35

DK 152653 BDK 152653 B

24 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol->-l-carboxylsyre, smp. 166-167,5°C, og 5-(3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylsyre, smp. 156°C.5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 166-167.5 ° C and 5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 156 ° C.

5 Eksempel 13Example 13

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 10 med 8,7 g dimethyl-l,,3-acetonedicarboxylat. Methyl-3-carbomethoxymethyl- 3-(2’-hydroxyethyl)-aminoaerylat (III) dannes straks. Efter endt tilsætning fjernes isbadet, og 80 ml tør acetonitril tilsættes. Reaktions-blandingen behandles så dråbevis med 6,75 g bromacetaldehyd i 20 ml acetonitril og opvarmes derpå ved tilbagesvalingstemperaturen i 2 timer. 15 Opløsningsmidlet fjernes derpå under reduceret tryk, og 200 ml methanol og 20 g silieagel sættes til resten. Denne blanding inddampes til tørhed under vakuum og anbringes i toppen af en søjle af 200 g silieagel pakket i hexan, idet søjlen elueres med hexan/ethylacetatblandinger. Fraktioner elueret med hexan/ethylacetat (1:1) giver methyl-N-(2-20 hydroxyethyl)-3-carbomethoxypyrrol~2-acetat (IV, R = H), der er identisk med det i eksempel 1 opnåede produkt.A 250 ml 3-neck 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 10 with 8.7 g of dimethyl-1 ,, 3-acetonedicarboxylate. Methyl 3-carbomethoxymethyl-3- (2'-hydroxyethyl) amino aerylate (III) is formed immediately. After the addition is complete, remove the ice bath and add 80 ml of dry acetonitrile. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated at the reflux temperature for 2 hours. The solvent is then removed under reduced pressure and 200 ml of methanol 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- (2-20 hydroxyethyl) -3-carbomethoxypyrrole ~ 2-acetate (IV, R = H) identical to the product obtained in Example 1.

Eksempel 14 25 Til en opløsning af 6 ml ethanolamin i 5 ml vand sættes 1,74 g di= 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 reaktionsblandingen holdes ved en temperatur på højst 40°C. Efter endt tilsæt-30 ning omrøres den mørke reaktionsblanding i yderligere i 1 time ved stuetemperatur og hældes derpå i en blanding af saltsyre/is mættet „ med fast natriumchlorid og ekstraheres med ethylacetat (3 x 100 ml).Example 14 To a solution of 6 ml of ethanolamine in 5 ml of water is added 1.74 g of di-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. After completion of the addition, the dark reaction mixture is stirred for a further 1 hour at room temperature and then poured into a hydrochloric acid / ice saturated mixture with solid sodium chloride and extracted with ethyl acetate (3 x 100 ml).

Den samlede mængde organisk ekstrakt vaskes med koldt vand til neutral reaktion, tørres med vandfri natriumsulfat og inddampes til tørhed un-35 der reduceret tryk. Kromatografi af resten på 30 g silieagel 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 ___3 -7θΟ^__,______. ______The total organic extract is washed with cold water for neutral reaction, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue on 30 g of silica gel using hexane / ethyl acetate (70:30) as the eluent gives 890 mg. crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, which upon recrystallization from methylene chloride / hexane melts ___3-7θΟ ^ __, ______. ______

DK 152653 BDK 152653 B

2525

Beregnet for c^2H17i;r05: C' ^6,45, h, 6f7iCalcd for c2H17i; r05: C12.45, h, 6f7i

Fundet; C, 56,41, H, 6,73. . ·found; C, 56.41; H, 6.73. . ·

Eksempel 15Example 15

En opløsning af 500 mg isopropyl-5-(2-thenoyl)-1,2-dihydro-6-methyl-5 3H-pyrrolo[1,2-a]pyrrol-l-carboxylat, smp. 102,5°C i 15 ml methanol behandles ned en opløsning af 1,05 g kaliumcarbonat i 8 ml vand, Reaktionsblandingen tilbagesvales under en nitrogenatmosfære i tre timer, afkøles og ind-, dampes til tørhed. Resten optages·i 10 ml 10% vandig saltsyre og 50 ml vand, og den resulterende blanding ekstraileres med ethylacetat (3 x 10 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[1,2-a]pyrrol-l-carboxylsyre [(A), R = CH3, R^ = . Η, X = S] med et smeltepunkt på 166°C.A solution of 500 mg of isopropyl-5- (2-thenoyl) -1,2-dihydro-6-methyl-5H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 102.5 ° C 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 10 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 [(A), R = CH 3, R 2 =. Η, X = S] with a melting point of 166 ° C.

15 · Eksempel' 16Example 15

En opløsning af 232,5 mg N,N-dimethylthiophen-3-carboxamid og 0,15 ml phosphoroxychlorid i 2 ml 1,2-dichlorethan tilbagesvales i 30 minutter. Til denne opløsning sættes en opløsning af 181 mg isopropyl-1,2-di= 20 hydro-3H-pyrrolo[1,2-a]pyrrol-l-carboxylat i 2 ml 1,2-dichlorethan. Reaktionsblandingen tilbagesvales under en argonatmosfære i 8 timer, 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= 25 acetat (3:1). Således fås isopropyl-5-(3-thenoyl)~l,2-dihydro-3lI~ pyjrrolo [1,2-a] pyrrol-1—carboxylat (XII, R - H, R^ = iso-C^II^, X = S) f smp. 67-68°C.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 = 20 hydro-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 = 25 acetate (3: 1). Thus, isopropyl-5- (3-thenoyl) -1,2-dihydro-3,1-pyrrolo [1,2-a] pyrrole-1-carboxylate (XII, R - H, R 2 = iso-C X = S) m.p. 67-68 ° C.

Når på same måde anvendes N,N-dimethylfuran-3-carboxamid i stedet for N,N-dimethylthiophen-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; 35 U.V. . Amaks 222' 244-277 (skulder), 314 nm (ε 6750, 4250, 14800);Similarly, when N, N-dimethylfuran-3-carboxamide is used instead of N, N-dimethylthiophene-3-carboxamide, the corresponding 5- (3-furoyl) derivatives are similarly obtained, namely; isopropyl-5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = lat, an oil having the following physical constants; 35 U.V. . Amax 222 '244-277 (shoulder), 314 nm (ε 6750, 4250, 14800);

Claims (4)

26 DK 152653 B I.R. Vmaks3 1730' 1610' 1560 Cm"1? N.M.R. .- 1,23 [d, 6H, J = 6 Hz; (CH^CH], : 2,50-3,00 (m, 2H) , 3,92 (dd, 2H, JAX = 6 Hz, g JBx = 7 Hz; H-l), 4,10-4,60 (m, 2H), 4,95 [sept., 1H, J = 6 Hz; (CHj^CH], 5,95 (d, 1H, * J = 4 Hz; H-7), 6,78 (m, 1H), 6,83 (d, 1H, J = 4 Hz; H-6), 7,30 (m, 1H), 7,83 ppm (m, 1H); M.s. m/e 270. (M+) ,26 DK 152653 B I.R. Ν max 3 1730 "1610" 1560 Cm -1 NMR. 1.23 [d, 6H, J = 6 Hz; (CH 2 CH],: 2.50-3.00 (m, 2H), 3.92 ( dd, 2H, JAX = 6 Hz, g JBx = 7 Hz; H1), 4.10-4.60 (m, 2H), 4.95 [sept., 1H, J = 6 Hz; (CH 2 , 5.95 (d, 1H, * J = 4 Hz; H-7), 6.78 (m, 1H), 6.83 (d, 1H, J = 4 Hz; H-6), 7.30 (m, 1H), 7.83 ppm (m, 1H); Ms m / e 270. (M +), 10 Eksempel 17 Analogt med følgende fremgangsmåde: En opløsning af 300 mg 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[l,2-a]-pyrrol-l-carboxylsyre i 5 ml isoamylalkohol mættes med hydrogen-15 chlorid. Efter 24 timers forløb afdestilleres alkoholoverskuddet i vakuum, og resten renses ved kromatografi på aluminiumoxid til opnåelse af iso-amyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [ 1,2-a[pyrrol-l-carboxylat: fås andre estere, f. eks. dodecylesteren, af 5-(2-thenoyl)-2Q l,2-dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylsyre ved at anvende andre alkoholer, f.eks. dodecylalkohol i stedet for isoamylalkohol, f.eks. dodecyl-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrol- 1-carboxylat, smp. 48-50°C. Ved anvendelse af fremgangsmåden ifølge opfindelsen kan ligeledes 2 5 fremstilles octyl-5-{2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol- 1-carboxylat, olie, U.V. 214, 233, 266,5, 332,5 nm (ε 4270, lUciX 3160, 6025, 13500); I.R. i)CHC13 1735, 1599 cm"1; M.S. (M+), og ethyl-5-(2-thenoyl)-1,2- MeOH dihydro-3H-pyrrolo[l,2-a]pyrrol-l-carboxylat, ^max 265, 328 nm 30 (ε 7580, 17880). Patentkrav .Example 17 Analogous to the following procedure: A solution of 300 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen. -15 chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue is purified by chromatography on alumina to give isoamyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a [pyrrole-1 -carboxylate: other esters, such as the dodecyl ester, are obtained from 5- (2-thenoyl) -2Q 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid using other alcohols, eg. dodecyl alcohol instead of isoamyl alcohol, e.g. dodecyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 48-50 ° C. Using the process of the invention, octyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil, U.V. can also be prepared. 214, 233, 266.5, 332.5 nm (ε 4270, lUciX 3160, 6025, 13500); I.R. i) CHCl 3 1735, 1599 cm -1; MS (M +), and ethyl 5- (2-thenoyl) -1,2-MeOH dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, max 265, 328 nm 30 (ε 7580, 17880). 1. Analogifremgangsmåde til fremstilling af (dl)- eller (1)-5-(2- furoyl)-, 5-(2-thenoyl)-, 5-(3-furoyl)- eller 5-(3-thenoyl)-l,2-di-hydro-3H-pyrrolo[1,2-a3pyrrol-1-carboxylsyreestere eller salte af den almene formel DK 152653B R\_ r1—I 1 i 1 r-oOR2 R N_ i—i!\ . i 0. eller k v y \ Λ, /k/ COOR2 i- x S 51 T 0 (Åf) (B !) hvori X betegner oxygen eller svovl, R betegner hydrogen eller en alkylgruppe med 1-4 carbonatomer, R^ betegner hydrogen, methyl, 2 chlor eller brom, og R er en alkylgruppe med 1-12 carbonatomer eller en farmaceutisk acceptabel saltrest, kendetegnet 5 ved, at en fri syre af (l)-form eller som (d,l)-blanding, og med den almane formel -_1 x-- - R x R ^ i Ji COOH [j j \ Il I ^ ^V"’ eller k^ y) \ COOH ίί I ir1. Analogous Process for Preparing (dl) - or (1) -5- (2-Furoyl) -, 5- (2-thenoyl) -, 5- (3-furoyl) - or 5- (3-thenoyl) - 1,2-di-hydro-3H-pyrrolo [1,2-a3pyrrole-1-carboxylic acid esters or salts of the general formula DKR265B in 0. or kvy \ Λ, / k / COOR2 i- x S 51 T 0 (Åf) (B!) wherein X represents oxygen or sulfur, R represents hydrogen or an alkyl group of 1-4 carbon atoms, R methyl, 2 chloro or bromine, and R is an alkyl group having 1-12 carbon atoms or a pharmaceutically acceptable salt residue, characterized in that a free acid of (1) form or as (d, 1) mixture, and with the general formula -_1 x-- - R x R ^ i Ji COOH [jj \ Il I ^^ V "'or k ^ y) \ COOH ίί I ir 0 I- & I__ (A) (B) hvori X, R og R^ har ovennævnte betydning forestres til dannelse af nævnte alkylestre eller omsættes med en base til dannelse af nævnte salte af formlen (A') eller (B1). 10(I) (A) (B) wherein X, R and R 2 have the above meaning esterified to form said alkyl esters or reacted with a base to form said salts of formula (A ') or (B1). 10