SI8910810A

SI8910810A - Process for obtaining esters of 5-chlor-3-chlorsulphonyl-2- thiophenecarboxylic acid

Info

Publication number: SI8910810A
Application number: SI8910810A
Authority: SI
Inventors: Hans Peter Wagner
Original assignee: Hafslund Nycomed Pharma
Priority date: 1988-05-02
Filing date: 1989-04-19
Publication date: 1997-06-30
Also published as: HRP940828A2; HRP940828B1

Abstract

Opisan je postopek za pripravo estrov 5-klor3-klorsulfonil-2-tiofenkarboksilne kisline s formulo so2ci I v kateri R pomeni Ci-C4-alkil, pri katerem aktiviramo kovinsko železo s plinastim klorom in kloriramo spojino s formulo COOR II v kateri ima R gornji pomen, v prisotnosti aktiviranega železa z uvajanjem plinastega klora. Spojine s formulo I so vmesni produkti pri pripravi farmacevtsko učinkovitih snovi.A process for the preparation of 5-chloro 3-chlorosulfonyl-2-thiophenecarboxyl esters is described acids of formula so2ci I in which R is C 1 -C 4 -alkyl at which it is activated metallic iron with chlorine gas and chlorinated a compound of formula COOR II in which R has the above meaning, in the presence of activated of iron by introducing chlorine gas. Compounds with Formula I is an intermediate in the preparation of the pharmaceutical of effective substances.

Description

Postopek za pripravo estrov 5-klor-3-klorsulfonil-2tiofenkarboksilne kislineProcess for the preparation of 5-chloro-3-chlorosulfonyl-2-thiophenecarboxylic acid esters

OpisDescription

Izum se nanaša na postopek za pripravo estrov 5-klor-3klorsulfonil-2-tiofenkarboksilne kisline.The invention relates to a process for the preparation of 5-chloro-3-chlorosulfonyl-2-thiophenecarboxylic acid esters.

Alki lestri 5-klor-3-klorsulfonil-2-tiofenkarboksilne kisline (5-CCT) so vmesni produkti pri pripravi farmacevtsko učinkovitih snovi. Tako so npr. opisane v US-PS 4 801 591 snovi, ki znižujejo maščobe v krvi, pri katerih izhajamo pri pripravi iz 5-CCT. Tudi priprava klortenoksikama (6-klor-4hidroksi-2-metil-3-(2-piridil-karbamoil)-2H-tieno(2,3-e) 1,22 tiazin-1,1-dioksid), antirevmatika, ki je opisan v US-PS 4 180 662, se lahko vrši iz 5-CCT.The 5-chloro-3-chlorosulfonyl-2-thiophenecarboxylic acid (5-CCT) alkyl esters are intermediates in the preparation of pharmaceutically effective substances. Thus, for example, described in U.S. Pat. No. 4,801,591, a blood fat-lowering substance derived from the preparation of 5-CCT. Also the preparation of chlorotenoxycam (6-chloro-4hydroxy-2-methyl-3- (2-pyridyl-carbamoyl) -2H-thieno (2,3-e) 1,22 thiazine-1,1-dioxide), an antirheumatic agent that is described in US-PS 4 180 662, may be made from 5-CCT.

V GB-A 2 159 156 je opisan postopek za pripravo z metilom ali halogenom substituiranih alkilestrov 3-klorsulfonil 2-tiofenkarboksilne kisline, pri katerem diazotirajo alkilestre 5-klor-3-amino-2-tiofenkarboksilne kisline, ki so le težko dostopni, in nastale diazonijeve kloride nato z S0₂presnovijo v sulfokloride. Ta postopek pa je zapleten in daje le nezadostne dobitke.GB-A 2 159 156 describes a process for the preparation of methyl or halogen substituted alkyl esters of 3-chlorosulfonyl 2-thiophenecarboxylic acid, in which diazotizing 5-chloro-3-amino-2-thiophenecarboxylic acid alkyl esters is difficult to access, and the resulting diazonium chlorides are then converted to sulfochlorides with S0 ₂ . This process, however, is complicated and gives only insufficient winnings.

Predmet pričujočega izuma je postopek za pripravo estrov 5-klor-3-klorsulfonil-2-tiofenkarboksilne kisline s formuloIt is an object of the present invention to provide a process for the preparation of 5-chloro-3-chlorosulfonyl-2-thiophenecarboxylic acid esters of the formula

v kateri R pomeni C^-C^-alkil, ki je označen s tem, da spojino s formulowherein R is C 1 -C 4 -alkyl, which is a compound of formula

so₂ciare ₂ ci

COORCOOR

II v kateri ima R gornji pomen, kloriramo v prisotnosti aktiviranega železa z uvajanjem plinastega klora.II in which R has the upper meaning is chlorinated in the presence of activated iron by introducing chlorine gas.

Ena metoda za aktiviranje železa obstoji v tem, da na mol spojine II suspendiramo prednostno 0,2 do 0,4 mola kovinskega železa v obliki prahu ali ostružkov v 0,5 do 5 1, prednostno v 1 do 3 1 organskega topila, ki je pri reakcijskih pogojih inertno, kot npr. metilenklorida, ogljikovega tetraklorida ali v mešanici takih topil, pri čemer je metilenklorid prednosten. Železo aktiviramo z uvajanjem okoli 100 do 500 g, prednostno okoli 200 do 300 g plinastega klora na mol železa. Uvajanje plinastega klora se vrši med močnim mešanjem železove suspenzije v teku 1 do 5, prednostno 2 do 3 ur pri temperaturi od okoli 10 do 50 °C, prednostno 24 do 28 °C.One method for the activation of iron is to suspend, per mole of compound II, 0.2 to 0.4 moles of metallic iron in powder or scrap form, preferably in 0.5 to 5 l, preferably in 1 to 3 l of organic solvent, which is under reaction conditions, inertly, such as e.g. methylene chloride, carbon tetrachloride or in a mixture of such solvents, methylene chloride being preferred. The iron is activated by introducing about 100 to 500 g, preferably about 200 to 300 g of chlorine gas per mole of iron. The introduction of chlorine gas is carried out during vigorous stirring of the iron suspension over a period of 1 to 5, preferably 2 to 3 hours, at a temperature of about 10 to 50 ° C, preferably 24 to 28 ° C.

Nadaljnja metoda aktiviranja obstoji v tem, da predložimo, kot je opisano zgoraj, približno enake količine železa v reakcijsko bučo in jih pustimo stati v atmosferi plinastega klora 12 do 48 ur, prednostno 24 ur. Vendar je prednostno aktiviranje železa v suspenziji v topilu.A further method of activation is to submit, as described above, approximately equal amounts of iron to the reaction flask and allow them to stand in a chlorine gas atmosphere for 12 to 48 hours, preferably 24 hours. However, the activation of the iron in suspension in the solvent is preferred.

Za kloriranje alkilestrov 3-klorsulfonil-2-tiofenkarboksil ne kisline (CT) raztopimo, če se je vršilo aktiviranje železa v suspenziji v topilu, CT v istem topilu ali zmesi topil, v katerem smo suspendirali kovinsko železo, in sicer v okoli 0,3 do 5 1 topila na mol CT, prednostno v 0,5 do 1 1 topila na mol CT, in to raztopino hitro pomešamo s suspenzijo železa. Kloriranje CT se vrši med mešanjem z uvajanjem okoli 5 do 50 g plinastega klora na uro in mol CT, prednostno 15 do 35 g na uro in mol CT, pri temperaturi okoli 20 do 50 °C, prednostno pri temperaturi 30 do 32 °C. Potek reakcije pri tem spremljamo analitsko, prednostno s plinsko kromatografijo. Po nastanku do 70 %, prednostno 62 do 65 % monoklorne spojine zlijemo reakcijsko zmes na ledeno vodo in fazi ločimo. Organsko fazo posušimo in uparimo.For the chlorination of the alkyl esters of 3-chlorosulfonyl-2-thiophenecarboxylic acid (CT), it is dissolved if the activation of the iron is suspended in a solvent, CT in the same solvent or solvent mixture in which the metallic iron is suspended in about 0.3 up to 5 l of solvent per mole of CT, preferably in 0.5 to 1 l of solvent per mole of CT, and this solution is rapidly mixed with the suspension of iron. CT chlorination is carried out during mixing by introducing about 5 to 50 g of chlorine gas per hour and moles of CT, preferably 15 to 35 g per hour and moles of CT, at a temperature of about 20 to 50 ° C, preferably at a temperature of 30 to 32 ° C. The reaction is monitored analytically, preferably by gas chromatography. After formation of up to 70%, preferably 62 to 65% of the monochlorine compound, the reaction mixture is poured onto ice water and the phase is separated. The organic phase is dried and evaporated.

Če se je vršilo aktiviranje železa v atmosferi plinastega klora, raztopimo CT prednostno v 2 do 4 1 enega od zgoraj navedenih topil ali zmesi topil, potek nadaljnjega kloriranja pa je tak, kot je opisano zgoraj. Celotna količina uporabljene ga topila je pri obeh možnostih aktiviranja enaka.If the activation of iron under an atmosphere of gaseous chlorine is carried out, the CT is preferably dissolved in 2 to 4 l of one of the solvents or solvent mixtures mentioned above, and the subsequent chlorination process is as described above. The total amount of solvent used is the same for both activation options.

Čiščenje surovega 5-CCT se lahko vrši po običajnih načinih, kot so prekristalizacija, kolonska ali porazdelitvena kromatografija, ekstrakcija in druge. Prednostno prekristalizi ramo iz diizopropiletra.Purification of crude 5-CCT can be carried out by conventional means such as recrystallization, column or column chromatography, extraction and others. Preferably recrystallizes the diisopropylether shoulder.

Izhodna spojina za kloriranje_f.CT, je znana iz literature. Njena priprava je npr. opisana v US-PS 4 028 373.The starting compound for chlorination of _f .CT is known from the literature. Its preparation is e.g. described in US-PS 4 028 373.

PRIMEREXAMPLE

Metilester 5-klor-3-klorsulfoniltiofen-2-karboksilne kisline5-Chloro-3-chlorosulfonylthiophene-2-carboxylic acid methyl ester

V 20 1 buči s štirimi vratovi smo suspendirali 96 g železovega prahu (1,71 mola) (Baker, reducirano s H₂, najmanj 96 %-no) v 12 1 absolutnega metilenklorida. Med močnim mešanjem smo v teku 2 do 3 ur uvedli 440 g plinastega klora, pri čemer je znašala temperatura med 24 in 28 °C. Nato smo raztopili 1,44 kg (5,98 mola) metilestra 3-klorsulfoniltiofenkarboksilne kisline v 5 1 absolutnega metilenklorida in ga hitro dodali. Med mešanjem smo pri temperaturi 30 do 32 °C uvajali 100 do 200 g plinastega klora na uro in potek reakcije spremljali s plinsko kromatografijo. Po nastanku 62 do 65 % monoklorne spojine smo zlili reakcijsko zmes na 24 1 ledene vode in močno mešali 15 min. Po ločen ju faz smo organsko fazo posušili in ostanek uparili pri temperaturi kopeli 40 °C v vakuumu.96 g of ferrous powder (1.71 mol) (Copper reduced by H ₂ at least 96%) in 12 l of absolute methylene chloride were suspended in 20 l four-necked flasks. During vigorous stirring, 440 g of chlorine gas were introduced over a period of 2 to 3 hours, with a temperature between 24 and 28 ° C. Subsequently, 1.44 kg (5.98 mol) of 3-chlorosulfonylthiophenecarboxylic acid methyl ester was dissolved in 5 l of absolute methylene chloride and quickly added. During stirring, 100 to 200 g of chlorine gas per hour were introduced at 30 to 32 ° C and the reaction was monitored by gas chromatography. After formation of 62 to 65% of the monochlorine compound, the reaction mixture was poured onto 24 l of ice water and stirred vigorously for 15 min. After separation of the phases, the organic phase was dried and the residue was evaporated at a bath temperature of 40 ° C in vacuo.

Ostanek smo prevzeli v 1,5 1 diizopropiletra, filtrirali in filtrat ohladili na -30 do -35 °C. Po cepljenju z monoklorno spojino smo pustili kristalizirati okoli 15 do 30 min. Kristalizat smo odsesali, sprali z 0,5 1 diizopropiletra z -30 °C in v vakuumskem sušilniku sušili pri 25 °C.The residue was taken up in 1.5 l of diisopropylether, filtered and the filtrate cooled to -30 to -35 ° C. After vaccination with the monochlorine compound, it was allowed to crystallize for about 15 to 30 min. The crystalline was suction filtered, washed with 0.5 l diisopropylether at -30 ° C and dried in a vacuum oven at 25 ° C.

Dobitek: 800 g monoklorne spojine (48,7 %)Yield: 800 g of a monochlorine compound (48.7%)

GC: 95 % monoklorne spojine, ostanek nekloriran in dikloriran produkt.GC: 95% monochlorine compound, residue chlorinated and dichlorinated product.

Tal.: 50 do 52 °C.M.p .: 50 to 52 ° C.

Claims

1. A process for the preparation of 5-chloro-3-chlorosulfonyl-2-thiophenecarboxylic acid esters of the formula ₂ ci

I

COOR in which R is C 1 -C 1 -C 6 alkyl, characterized in that the activated iron is chlorine gas and the chlorinated compound of the formula is ₂ ci

COOR

II in which R has the upper meaning, in the presence of activated iron by introducing chlorine gas.

Process according to claim 1, characterized in that the metallic iron is activated in a chlorine gas atmosphere with chlorine gas.

Method according to one of Claims 1 or 2, characterized in that the metallic iron is activated in an atmosphere of chlorine gas for about 12 to 48 hours, preferably about 24 hours.

Method according to claim 1, marked ^! by activating the ferrous metal with chlorine gas in suspension in a solvent, suspending per mol of compound II 0.1 to 1.0 mol, preferably 0.2 to 0.4 mol of metallic iron in 0.5 to 5 1, preferably 1 to 3 l of a solvent which is inert under reaction conditions, such as methylene chloride or carbon tetrachloride, or in mixtures of such solvents, and the iron is activated by introducing 100 to 500 g of chlorine gas per mole of iron, preferably 200 to 300 g, during 1 up to 5 hours, preferably within 2 to 3 hours.

Process according to one of Claims 1 to 4, characterized in that the course of the chlorination reaction of compound II is monitored analytically, preferably by gas chromatography.

Process according to one of Claims 1, 4 or 5, characterized in that the activation of iron and the chlorination of the compound of formula II are carried out in the same solvent or solvent mixture.

Process according to one of Claims 1 to 6, characterized in that the chlorination of the compound of formula II is carried out by introducing 5 to 50 g of chlorine gas per hour and mol of compound II, preferably

15 to 35 g per hour and mol of compound II, at 20 to 50 ° C, preferably at 30 to 32 ° C, until 50 to 70%, preferably 62 to 65% of the monochlorine compound is formed, and then the reaction mixture is poured on ice water.