SE462751B - SET FOR MANUFACTURE OF A BRAND CAPACYL PROLINE - Google Patents
SET FOR MANUFACTURE OF A BRAND CAPACYL PROLINEInfo
- Publication number
- SE462751B SE462751B SE8702654A SE8702654A SE462751B SE 462751 B SE462751 B SE 462751B SE 8702654 A SE8702654 A SE 8702654A SE 8702654 A SE8702654 A SE 8702654A SE 462751 B SE462751 B SE 462751B
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- isotiuronium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
15 20 25 306 I 35 462 75": z Om R betecknar en tertiär-butyl-. bensyl- eller tritylgrupp utgöres den använda reagensen av tertiär-butylmerkaptan. bensylmerkaptan eller tritylmerkaptan, varvid samtliga dessa är farliga, karcinogena och toxiska föreningar. För genom- föring av substitutionen av halogenatomen måste karboxylgrup- pen hos prolin skyddas temporärt. Dessutom är utbytet av en sådan reaktion oacceptabelt lågt. T.ex. K. Hofmann et al. beskriver ett nära analogt fall beträffande bensylmerkaptan [J. Am. Chem. Soc.. ll. 1253 (l949)]: ett 4-klorbutyl-derivat reageras med bensylmerkaptan-natriumsalt för erhållande av S-bensyl-4-merkaptobutyl-derivatet med ett utbyte av 66 %. Den skyddande gruppen avlägsnas medelst nascerande väte, som alstras med natrium i etanol. Således uppgår det totala ut- bytet till 34 2. Annu sämre resultat kan förväntas med ter- tiär-butylmerkaptan och tritylmerkaptan eftersom i de båda fallen det steriska hindrandet är mycket starkare. I allmänhet införes sådana skyddande grupper i molekyler på ett omkastat sätt: de befintliga merkaptoföreningarna reageras med isobuten eller tionylklorid [t.H. Greene. 'Protective Groups in Organic Synthesis'. sid. 193, 1981]. If R represents a tertiary-butyl-, benzyl or trityl group, the reagent used is tertiary-butyl mercaptan, benzyl mercaptan or trityl mercaptan, all of which are dangerous, carcinogenic and toxic compounds. To carry out the substitution of the halogen atom, the carboxyl group of proline must be temporarily protected, and the yield of such a reaction is unacceptably low, for example K. Hofmann et al. describe a near analogous case of benzyl mercaptan [J. Am. Chem. Soc. 111. 1253 (1949)]: a 4-chlorobutyl derivative is reacted with benzyl mercaptan sodium salt to give the S-benzyl-4-mercaptobutyl derivative in a yield of 66% .The protecting group is removed by nascent hydrogen, which is generated with sodium in ethanol, so the total yield is 34 2. Even worse results can be expected with tertiary-butyl mercaptan and trityl mercaptan because in both cases the steric barrier is much stronger. protecting groups in molecules in a reversed manner: the existing mercapto compounds are reacted with isobutylene or thionyl chloride [t.H. Greene. 'Protective Groups in Organic Synthesis'. sid. 193, 1981].
Om R betecknar en grupp med formeln Rl-g-. kan captopril framställas med mycket lågt utbyte. 0 Enligt detta exempel i UK-patentet l 576 161 framställes den analoga l-(2-merkaptoacetyl)-prolinen med användning av tio- bensoesyra med ett utbyte så lågt som 15 2, räknat på prolin.» I UK-patentet 2 065 643 beskrives det fall. då R betecknar väteš en N-[3-halo(2S)-metylpropionyl]-(S)-prolin reageras med en vattenlösning av natriumvätesulfid. Reaktionsprodukten bildas vid en lång tids värmning. Aven motsvarande disulfid alstras emellertid i en mängd av 5 molprocent. Denna biprodukt måste reduceras med zink i ett separat steg i närvaro av en syra. Utbytet uppgår till 71 %. Om natriumvätesulfiden löses i 1,1-dimetylformamid minskas det ovan angivna utbytet till 65 t. Det bästa resultatet erhålles uppenbarligen med en vatten- lösning av ammoniumvätesulfid men reaktionsprodukten och när- 10 15 20 so. 35 ÅÄÖ 7É1 “TuJL :vi varande biprodukter kan emellertid separeras endast medelst kolonnkromatografi. Aven på detta sätt erhålles en blandning av 92 % captopril, 6 2 disulfid och 0,5 2 av den symmetriska sulfiden. Sistnämnda förorenande biprodukt bildas irreversi- belt. dvs. den kan inte omvandlas till captopril. Dessutom är lösligheten för denna sulfid mycket nära densamma för capto- pril. Således kan de inte separeras på ett enkelt preparativt sätt. Ovanstående fakta bekräftas i en artikel av H. Shimazaki et al. [Chem. Pharm. Bull.. §Q. 3129 (l982)]. Således lämpar sig sistnämnda förfarande inte för framställning i industriell skala.If R represents a group of the formula R1-g-. captopril can be prepared in very low yields. According to this example in UK patent 1,576,161, the analogous 1- (2-mercaptoacetyl) -proline is prepared using thiobenzoic acid in a yield as low as 2, based on proline. The UK patent 2,065,643 describes that case. when R represents hydrogen an N- [3-halo (2S) -methylpropionyl] - (S) -proline is reacted with an aqueous solution of sodium hydrogen sulfide. The reaction product is formed during a long period of heating. However, the corresponding disulfide is also produced in an amount of 5 mol%. This by-product must be reduced with zinc in a separate step in the presence of an acid. The yield amounts to 71%. If the sodium hydrogen sulphide is dissolved in 1,1-dimethylformamide, the above yield is reduced to 65 h. The best result is obviously obtained with an aqueous solution of ammonium hydrogen sulphide but the reaction product and proximity. 35 ÅÄÖ 7É1 “TuJL: the by-products present can, however, be separated only by column chromatography. Also in this way a mixture of 92% captopril, 6 2 disulfide and 0.5 2 of the symmetrical sulfide is obtained. The latter polluting by-product is formed irreversibly. i.e. it cannot be converted to captopril. In addition, the solubility of this sulfide is very close to that of captopril. Thus, they cannot be separated in a simple preparative manner. The above facts are confirmed in an article by H. Shimazaki et al. [Chem. Pharm. Bull .. §Q. 3129 (l982)]. Thus, the latter process is not suitable for production on an industrial scale.
Enligt US-patentet 4 332 725 omvandlas halogenatomen till merkaptogrupp medelst natriumtiosulfat. I detta fall bildas först ett s.k. Bunte's salt. som värmes med koncentrerad klor- vätesyra för att ge captopril med ett utbyte av 70 %.According to U.S. Patent 4,332,725, the halogen atom is converted to the mercapto group by sodium thiosulfate. In this case, a so-called Bunte's salt. which is heated with concentrated hydrochloric acid to give captopril in a yield of 70%.
Enligt den publicerade tyska patentansökningen 3 526 023 reageras en N-[3-halo-(28)-metylpropionyl]-(S)-prolin med tiokarbamid i vatten, en alkanol eller en vattenhaltig alkanol vidl 60-l00°C för att ge en förening med formeln - CH H2IKC _ | 3 (mcooH _? -ß-0H2-cH-co-1J n, Hqh c. + - (S) X' där X betecknar en halogenatom. Denna förening hydrolyseras i I reaktionsblandningen. utan isolering; med en alkalimetall- hydroxid eller ett -karbonat.According to published German patent application 3,526,023, an N- [3-halo- (28) -methylpropionyl] - (S) -proline is reacted with thiourea in water, an alkanol or an aqueous alkanol at 60-100 ° C to give a compound of the formula - CH H2IKC _ | 3 (mcooH -? -Ss-OHH-cH-co-1J n, Hqh c. + - (S) X 'where X represents a halogen atom. This compound is hydrolysed in the reaction mixture, without isolation; with an alkali metal hydroxide or a -carbonate.
Det var emellertid praktiskt omöjligt att reproducera sist- nämnda kända process.However, it was practically impossible to reproduce the latter known process.
Han har funnit att föreningen med formeln I kan framställas på ett ekonomiskt sätt från en omega-halo-acylprolin med formeln 10 15 20 30 35 462 751 4 01-1 (S) 1 3 coon x-cnz-cii-co-N (S) III där X betecknar halogen, om omega-halo-acylprolinen ned formel III eller ett salt därav reageras ned tiokarbamid i ett or- ganiskt, dipolärt, aprot lösningsmedel för att ge en isotiuro- niumförening med formeln cH (S) Hzlkc s en ÅHB COOH H _ _ 2 "' _ " N mi” (S) eller en vätehalogenid därav. vilken, eventuellt efter isole- ring, hydrolyseras och on så önskas produkten ned formeln I omvandlas till ett salt eller frigöres från ett salt.He has found that the compound of formula I can be prepared in an economical manner from an omega-haloacylproline of the formula co-x-cnz-cii-co-N ( S) III where X represents halogen, if the omega-halo-acylproline down of formula III or a salt thereof is reacted down thiourea in an organic, dipolar, aprotic solvent to give an isotiuronium compound of the formula cH (S) Hzlkc s a ÅHB COOH H _ _ 2 "'_" N mi "(S) or a hydrogen halide thereof. which, optionally after isolation, is hydrolyzed and the product of formula I is desired to be converted into a salt or liberated from a salt.
Den fria karboxylgruppen hos föreningen med formeln I kan om- vandlas till ett salt med en oorganisk eller organisk bas. Om i förfarandet enligt uppfinningen ett salt av föreningen med formeln I erhålles kan den fria karboxylsyran frigöras på i och för sig känt sätt.The free carboxyl group of the compound of formula I can be converted into a salt having an inorganic or organic base. If in the process according to the invention a salt of the compound of formula I is obtained, the free carboxylic acid can be liberated in a manner known per se.
I formeln III betecknar X en halogenatom. företrädesvis en bronaton.In formula III, X represents a halogen atom. preferably a bronaton.
Reaktionen av föreningen med formeln III eller ett salt därav “ned tiokarbamid fortgår endast i ett organiskt. dipolärt.I I aprot lösningsmedel såsom N,N-dimetylformamid, N.N-dimetyl- acetanid eller dinetylsulfoxid. I allmänhet genomföres reak- tionen vid 20-80°C, företrädesvis vid 50-70°C. under atmosfär- tryck. Vanligen uppgår reaktionstiden till 15-25 timmar. Om man använder ett syrabindemedel sâson en organisk bas erhålles föreningen med formel II som en fast substans. I frånvaro av ett syrabindenedel bildas motsvarande vätehalogenid-additions- salt. Om så önskas isoleras föreningen med formeln II före 0'- 10 15 20 30 35 s 462 751 nästa reaktionssteg. dvs. hydrolysen. Som regel kvarstannar vätehalogenid-additionssaltet av föreningen med formeln II i lösningen och det hydrolyseras därför vanligen utan isolering.The reaction of the compound of formula III or a salt thereof thiourea proceeds only in an organic. dipolar.I In aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetanide or dinethylsulfoxide. In general, the reaction is carried out at 20-80 ° C, preferably at 50-70 ° C. under atmospheric pressure. Usually the reaction time is 15-25 hours. If an acid binder is used as an organic base, the compound of formula II is obtained as a solid. In the absence of an acid linker, the corresponding hydrogen halide addition salt is formed. If desired, the compound of formula II is isolated before the next reaction step. i.e. the hydrolysis. As a rule, the hydrogen halide addition salt of the compound of formula II remains in the solution and is therefore usually hydrolyzed without isolation.
Isotiuronium-föreningen med formeln II eller vätehalogenid- -additionssaltet därav hydrolyseras företrädesvis i närvaro av en bas såsom hydrazin, vid 0-30°C, lämpligen vid 10-l5°C, under atmosfärtryck. Produkten med formeln I isoleras från reaktionsblandningen på och för sig känt sätt, t.ex. genom extrahering och indunstning.The isotiuronium compound of formula II or the hydrogen halide addition salt thereof is preferably hydrolyzed in the presence of a base such as hydrazine, at 0-30 ° C, suitably at 10-15 ° C, under atmospheric pressure. The product of formula I is isolated from the reaction mixture in a manner known per se, e.g. by extraction and evaporation.
Isotiuronium-föreningen med formeln Il både erhålles och hydrolyseras till captopril med ett nästan kvantitativt ut- byte. Aven om sistnämnda produkt omkristalliseras kvarstannar det totala utbytet över 80 2. Den erhållna captoprilen är inte förorenad av varken motsvarande disulfid eller av den sym- metriska sulfiden och således har den en renhet (bestämd medelst jodometri) av minst 99,5 %.The isotiuronium compound of formula II is both obtained and hydrolyzed to captopril in an almost quantitative yield. Even if the latter product is recrystallized, the total yield remains above 80 2. The captopril obtained is not contaminated by either the corresponding disulfide or by the symmetrical sulphide and thus has a purity (determined by iodometry) of at least 99.5%.
Förfarandet enligt uppfinningen belyses ytterligare medelst följande icke begränsande utföringsexempel.The process according to the invention is further illustrated by the following non-limiting examples.
Framställning av atgångsföreningen: l-[3-bron-(25)-mety1-pro- pionyl]-pyrrolidin-(28)-karboxylsyra-monohydrat. 3,34 g (0.02 mol) 3-brom-2-metylpriopionsyra och 4,60 g (0,02 mol) bensyl-pyrrolidin-(28)-karboxylat-hydroklorid löses i 50 ml vattenfri metylenklorid. Till den erhållna omrörda bland- ningen sättes vid 0°C under kylning 1,9 g trietylamin i 5 ml I vattenfri metylenklorid och därefter tillsättes vid samma' temperatur 3,92 g (0,0l9 mol) N.N'-dicyklohexyl-karbodiimid i 20 ml metylenklorid. Reaktionsblandningen omröres 2 timmar vid 0°C och därefter vid rumstemperatur under ytterligare 12 tim- mar. Den filtrerade blandningen extraheras med 20 ml 9-procen- tig klorvätesyra. 20 ml vatten, 20 ml 5-procentig vattenhaltig natriumvätekarbonatlösning och sedan med 20 nl vatten. Den organiska lösningen torkas över glödgat magnesiumsulfat och indunstas. Han erhåller 6.40 g (95 2) bensyl-1-(3-brom-2-ne- 10 15 20 35 462 751 s tylpropionyl)-pyrro1idin-(28)-karboxylat i forn av en ljusgul olja.Preparation of the starting compound: 1- [3-Bron- (25) -methyl-propionyl] -pyrrolidine- (28) -carboxylic acid monohydrate. 3.34 g (0.02 mol) of 3-bromo-2-methylpriopionic acid and 4.60 g (0.02 mol) of benzyl-pyrrolidine (28) -carboxylate hydrochloride are dissolved in 50 ml of anhydrous methylene chloride. To the resulting stirred mixture is added at 0 ° C while cooling 1.9 g of triethylamine in 5 ml of anhydrous methylene chloride and then 3.92 g (0.019 mol) of N, N'-dicyclohexylcarbodiimide are added at the same temperature. in 20 ml of methylene chloride. The reaction mixture is stirred for 2 hours at 0 ° C and then at room temperature for a further 12 hours. The filtered mixture is extracted with 20 ml of 9% hydrochloric acid. 20 ml of water, 20 ml of 5% aqueous sodium bicarbonate solution and then with 20 ml of water. The organic solution is dried over annealed magnesium sulphate and evaporated. He obtains 6.40 g (95%) of benzyl 1- (3-bromo-2-phenylpropionyl) -pyrrolidine (28) -carboxylate in the form of a light yellow oil.
Tlc. (kiselgel, bensen/isättika i ett förhållande av 3:l): två fläckar, Rf = 0.44 och 0.48. notsvarande 1:1-förhållande för diastereomererna.Tlc. (silica gel, benzene / glacial acetic acid in a ratio of 3: 1): two spots, Rf = 0.44 and 0.48. corresponding 1: 1 ratio for the diastereomers.
Oljan löses i 60 nl etylacetat och till den erhållna lösningen sättes 0,6 g l0 procentig palladiun/kol-katalysator. Reak- tionsblandningen hydreras under atnosfärtryck tills ingen ester föreligger, vilket indikeras nedelst tlc. Katalysatorn avlägsnas genom avfiltrering. tvättas ned etylacetat. det organiska lösningsnedlet avdestilleras och återstoden kristalliseras ur vatten. På detta sätt erhålles 2.00 g (42.5 2) av titelföreningen med snältpunkt 69,72°C. [a]å5 = -88,l° (c = l; etanol).The oil is dissolved in 60 nl of ethyl acetate and to the resulting solution is added 0.6 g of 10% palladium / carbon catalyst. The reaction mixture is hydrogenated under atmospheric pressure until no ester is present, which is indicated below tlc. The catalyst is removed by filtration. washed down with ethyl acetate. the organic solvent is distilled off and the residue is crystallized from water. In this way, 2.00 g (42.5 2) of the title compound with a melting point of 69.72 ° C are obtained. [α] D 25 = -88.1 ° (c = 1; ethanol).
Exemgel 1 l-[3-nerkapto-(25)-netylpropionyl]-pyrrolidin-(28)-karboxylsyra. 10.56 g (0.0374 nol) l-[3-bron-(28)-netylpropionyl]-pyrroli- din-(ZS)-karboxylsyra och 3.04 g (0.040 nol) tiokarbanid löses i 30 ml N,N-dinetylacetanid och reaktionsblandningen onröres vid 60°C under kväve under 15 till 20 tinnar. Det organiska lösningsmedlet avlägsnas vid ninskat tryck och återstoden löses i 50 nl destillerat vatten. Till den erhållna lösningen sättes 6,00 g (0.l2 nol) hydrazinhydrat under kväve under det att flaskan kyles ned isvatten. Reaktionsblandningen onröres W 30 ninuter under kylning och därefter ytterligare 30 ninuter vid runstenperatur. Han tillsätter 100 nl 5-procentig svavel- syra och den vita fällningen filtreras, tvättas ned vatten och därefter ned netylenklorid. Piltratet extraheras ned 4 x 30 ml netylenklorid. de organiska lösningarna sannanföres. tvättas ned 2 x 20 nl vatten och vattenfasen extraheras ned 2 x 15 nl netylenklorid. De organiska faserna sannanföres, torkas över glödgat nagnesiunsulfat. filtreras och indunstas under ninskat 10 15 20 30 35 n flgjn L l-Jl GN A 7 ~ ~ w tryck. Restoljan. 7,54 g (99 2), kristalliseras från 25 ml trikloretylen. På detta sätt erhåller man 6.10 g (80 2) av titelföreningen med smältpunkt 104-l06°C. [a1š5= -129.5° (c = 2; etanol).Example 11 1- [3-Nerkapto- (25) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid. 10.56 g (0.0374 nol) of 1- [3-bron- (28) -nethylpropionyl] -pyrrolidine- (ZS) -carboxylic acid and 3.04 g (0.040 nol) of thiocarbanide are dissolved in 30 ml of N, N-dinethylacetanide and the reaction mixture is stirred at 60 ° C under nitrogen for 15 to 20 tins. The organic solvent is removed under reduced pressure and the residue is dissolved in 50 nl of distilled water. To the resulting solution is added 6.00 g (0.12 nol) of hydrazine hydrate under nitrogen while the bottle is cooled in ice water. The reaction mixture is stirred for 30 minutes while cooling and then for a further 30 minutes at rune temperature. He adds 100 nl of 5% sulfuric acid and the white precipitate is filtered, washed down with water and then down with ethylene chloride. The filtrate is extracted into 4 x 30 ml of ethylene chloride. the organic solutions are verified. washed down 2 x 20 nl water and the aqueous phase is extracted down 2 x 15 nl methylene chloride. The organic phases are evaporated, dried over annealed nitrogen sulphate. filtered and evaporated under reduced pressure 10 l 20-Jl GN A 7 ~ ~ w pressure. Restoljan. 7.54 g (99 2), are crystallized from 25 ml of trichlorethylene. In this way, 6.10 g (80 2) of the title compound, m.p. 104 DEG-106 DEG C., are obtained. [α] 25 D = -129.5 ° (c = 2; ethanol).
Exemgel 2 l-[3-merkapto-(25)-metylpropionyl]-pyrrolidin-(28)-karboxylsyra. 2,64 g (0,0l0 mol) l-[3-brom-(ZS)-metylpropionyl]-pyrrolidin- -(28)-karboxylsyra och 0,76 g (0,0l0 mol) tiokarbamid löses i 10 ml dimetylsulfoxid. Lösningen omröres 24 timmar vid 60-70°C och därefter tillsättes 30 ml 10 procentig vattenhaltig natriumhydroxid, varefter blandningen omröres under ytter- ligare l timme. Blandningen surgöres med 20 % klorvätesyra under kylning tills man uppnår ett pH-värde av 1, varefter extraheras med 4 x 20 ml metylenklorid. De organiska lösnin- garna sammanföres, torkas över glödgat magnesiunsulfat och indunstas vid minskat tryck. Den resterande oljan kristallise- ras från trikloretylen. Man erhåller 1.64 g (81 %) av titel- föreningen med smältpunkt 104-l06°C. [alâs = -129,5” (c = 2; etanol).Example 2 2- [3-mercapto- (25) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid. 2.64 g (0.010 mol) of 1- [3-bromo- (ZS) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid and 0.76 g (0.010 mol) of thiourea are dissolved in 10 ml of dimethyl sulfoxide. The solution is stirred for 24 hours at 60-70 ° C and then 30 ml of 10% aqueous sodium hydroxide are added, after which the mixture is stirred for a further 1 hour. The mixture is acidified with 20% hydrochloric acid under cooling until a pH of 1 is reached, after which it is extracted with 4 x 20 ml of methylene chloride. The organic solutions are combined, dried over annealed magnesium sulphate and evaporated under reduced pressure. The remaining oil is crystallized from trichlorethylene. 1.64 g (81%) of the title compound are obtained, m.p. 104 DEG-106 DEG. [α] D = -129.5 ”(c = 2; ethanol).
Exemgel 3 1-[3-merkapto-(28)-metylpropionyl]-pyrrolidin-(28)-karboxylsyra. 5,28 g (0,02 mol) l-[3-brom-(28)-metylpropionyl]-pyrrolidin- -(28)-karboxylsyra och 1,67 g (0.022 mol) tiokarbanid löses i '15 ml N,N-dimetylformamid och blandningen onröres 24 timmar' vid 60°C. Lösningsmedlet avdestilleras vid minskat tryck och återstoden löses i 30 ml destillerat vatten. Till den med isvatten kylda lösningen sättes 6.0 g 50 procentig hydrazin och reaktionsblandningen omröres sedan l timme under kylning med isvatten. Därefter tillsättes 50 ml 5 procentig svavel- syra, fällningen filtreras, tvättas med vatten och netylen- klorid. Man sätter sedan 10 g natriumklorid till vattenfasen och sistnämnda extraheras därefter med 4 x 30 ml netylen- 10 15 20 25 30' 35 462 751 a klorid. De organiska lösningarna kombineras. torkas över vattenfritt magnesiumsulfat, filtreras och lösningsnedlet avlägsnas vid minskat tryck. Den resterande oljan kristallise- ras från 20 ml trikloretylen. Han erhåller 3.33 g (82 2) av titelföreningen med smältpunkt 104-l06°C. [«]š5= -1z9.s° (C = 2; etanol).Example Gel 3 1- [3-mercapto- (28) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid. 5.28 g (0.02 mol) of 1- [3-bromo- (28) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid and 1.67 g (0.022 mol) of thiocarbanide are dissolved in 15 ml of N, N -dimethylformamide and the mixture is stirred for 24 hours at 60 ° C. The solvent is distilled off under reduced pressure and the residue is dissolved in 30 ml of distilled water. To the ice-cooled solution is added 6.0 g of 50% hydrazine, and the reaction mixture is stirred for 1 hour while cooling with ice-water. Then 50 ml of 5% sulfuric acid are added, the precipitate is filtered, washed with water and methylene chloride. 10 g of sodium chloride are then added to the aqueous phase and the latter is then extracted with 4 x 30 ml of methylene chloride. The organic solutions are combined. dried over anhydrous magnesium sulfate, filtered and the solvent is removed under reduced pressure. The residual oil is crystallized from 20 ml of trichlorethylene. He obtains 3.33 g (82 2) of the title compound, m.p. 104-106 ° C. [Α] D 5 = -1z9.s ° (C = 2; ethanol).
Exempel 4 A. 1-[(28)-metyl-3-isotiuroniunpropionyl]-pyrrolidin-(2S)-kar- boxylat. 5,64 g (0,02 mol) l-[3-bron-(25)-netylpropionyl]-pyrrolidin- -(28)-karboxylsyra-monohydrat löses i 50 ll netylenklorid och den erhållna lösningen omröres med 5 g glödgat nagnesiumsulfat under en timme. Torknedlet avfiltreras, tvättas ned 10 nl netylenklorid och de organiska lösningarna kombineras och indunstas vid minskat tryck. återstoden löses i 15 nl vatten- fri N,N-dimetylacetamid, behandlas ned 1,52 g (0,02 nol) tio- karbamid och onröres sedan 24 tinnar under kväve nedan flaskan, son innehåller reaktionsblandningen. hålles i ett oljebad med en temperatur av 70°. Blandningen kyles sedan med isvatten och utspädes ned 150 nl acetonitril. Till den erhåll- na blandningen sättes droppvis 2.8 nl (0,02 nol) trietylanin i 20 nl acetonitril under loppet av 30-40 ninuter och under kraftig omrörning. Reaktionsblandningen onröres under ytter- ligare 2 tinnar, den bildade fällningen filtreras, suspenderas i 20 nl acetonitril, filtreras, suspenderas på nytt i 20 nl acetonitril, filtreras och torkas. Han erhåller 4.2 g (81 2) av titelföreningen. Snältpunkt: 187-l89°C. [a1š5=H-io? :111 -111° (c = 1; äuuixsyra).Example 4 A. 1 - [(28) -Methyl-3-isoturonium propionyl] -pyrrolidine- (2S) -carboxylate. 5.64 g (0.02 mol) of 1- [3-bron- (25) -methylpropionyl] -pyrrolidine- - (28) -carboxylic acid monohydrate are dissolved in 50 l of ethylene chloride and the resulting solution is stirred with 5 g of annealed magnesium sulfate under one hour. The desiccant is filtered off, washed with 10 nl of ethylene chloride and the organic solutions are combined and evaporated under reduced pressure. the residue is dissolved in 15 nl of anhydrous N, N-dimethylacetamide, treated with 1.52 g (0.02 nol) of thiourea and then stirred for 24 hours under nitrogen below the flask containing the reaction mixture. kept in an oil bath with a temperature of 70 °. The mixture is then cooled with ice water and diluted with 150 nl of acetonitrile. To the resulting mixture is added dropwise 2.8 nl (0.02 nol) of triethylanine in 20 nl of acetonitrile over the course of 30-40 minutes and with vigorous stirring. The reaction mixture is stirred under an additional 2 tins, the precipitate formed is filtered, suspended in 20 nl of acetonitrile, filtered, resuspended in 20 nl of acetonitrile, filtered and dried. He receives 4.2 g (81 2) of the title compound. Melting point: 187-189 ° C. [a1š5 = H-io? : 111 -111 ° (c = 1; acetic acid).
Tlc (6 delar av en 20:ll:6-blandning av pyridin. vatten och isättika. 4 delar etylacetat): Rf = 0.41: (en blandning av butanol, isåttika och vatten i ett förhållan- de av 7:l:3). Rf = 0.2.Tlc (6 parts of a 20: 11: 6 mixture of pyridine. Water and glacial acetic acid. 4 parts of ethyl acetate): Rf = 0.41: (a mixture of butanol, glacial acetic acid and water in a ratio of 7: 1: 3) . Rf = 0.2.
B. l-[3-nerkapto-(28)-netylpropionyl]-pyrrolidin-(2S)-kar- boxylsyra. (5- 10 15 *'75 9 462 2 ml (0.02 mol) 50 procentig hydrazin sättes droppvis till en omrörd lösning av 2,59 g (0.0l mol) 1-[(2S)-metyl-3-isotiuro- nium-propionyl]-pyrrolidin-(25)-karboxylat i 25 ml vatten under kväve och med kylning med isvatten.B. 1- [3-Nerkapto- (28) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid. 2 ml (0.02 mol) of 50% hydrazine are added dropwise to a stirred solution of 2.59 g (0.01 mol) of 1 - [(2S) -methyl-3-isotiuronium- propionyl] -pyrrolidine- (25) -carboxylate in 25 ml of water under nitrogen and with cooling with ice water.
Blandningen omröres under ytterligare 30 minuter med kylning och därefter avlägsnas kylbadet och omrörningen fortsättes under ytterligare 30 minuter. Reaktionsblandningen kyles på nytt till en temperatur av under l0°C och behandlas med en blandning av 10 ml koncentrerad klorvätesyra och 2 ml vatten. blandningen omröres under 30 minuter och därefter tillsättes 6-10 g natriumklorid och produkten extraheras därefter med 3 x 20 ml metylenklorid. De organiska lösningarna kombineras, tvättas med 15 ml vatten och vattenfasen extraheras med 5 ml metylenklorid. De organiska faserna kombineras. torkas över vattenfritt magnesiumsulfat. filtreras och indunstas vid minskat tryck. Den resterande oljan (2,03 g) kristalliseras från 10 ml trikloretylen. Produkten tvättas med n-hexan och torkas. Man erhåller 1,62 g (80 %) av titelföreningen med smältpunkt l03-l04°C. [a]š5 = -129 till -l30° (c = 2; etanol).The mixture is stirred for a further 30 minutes with cooling and then the cooling bath is removed and stirring is continued for another 30 minutes. The reaction mixture is recooled to a temperature of below 10 ° C and treated with a mixture of 10 ml of concentrated hydrochloric acid and 2 ml of water. the mixture is stirred for 30 minutes and then 6-10 g of sodium chloride are added and the product is then extracted with 3 x 20 ml of methylene chloride. The organic solutions are combined, washed with 15 ml of water and the aqueous phase is extracted with 5 ml of methylene chloride. The organic phases are combined. dried over anhydrous magnesium sulfate. filtered and evaporated under reduced pressure. The residual oil (2.03 g) is crystallized from 10 ml of trichlorethylene. The product is washed with n-hexane and dried. 1.62 g (80%) of the title compound with a melting point of 103-104 ° C are obtained. [α] D 25 = -129 to -13 ° (c = 2; ethanol).
I iI i
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU862689A HU196959B (en) | 1986-06-27 | 1986-06-27 | Process for producing merkapto-acyl-proline derivatives |
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| SE8702654D0 SE8702654D0 (en) | 1987-06-26 |
| SE8702654L SE8702654L (en) | 1987-12-28 |
| SE462751B true SE462751B (en) | 1990-08-27 |
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| JP (1) | JPS6327475A (en) |
| KR (1) | KR900007217B1 (en) |
| CN (1) | CN87104388A (en) |
| AR (1) | AR243159A1 (en) |
| AT (2) | AT395012B (en) |
| CH (1) | CH673279A5 (en) |
| CS (1) | CS276394B6 (en) |
| DD (1) | DD263757A5 (en) |
| DE (1) | DE3721430A1 (en) |
| DK (1) | DK329787A (en) |
| ES (1) | ES2004451A6 (en) |
| FI (1) | FI87770C (en) |
| GR (1) | GR871012B (en) |
| HU (1) | HU196959B (en) |
| IT (1) | IT1206792B (en) |
| NO (1) | NO168941C (en) |
| PL (1) | PL153449B1 (en) |
| PT (1) | PT85190B (en) |
| SE (1) | SE462751B (en) |
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| US4440244A (en) * | 1980-03-26 | 1984-04-03 | Santrade Ltd. | Drill tool |
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| HU208954B (en) * | 1990-09-21 | 1994-02-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing 1-(3-mercapto-(2s)-methyl-1-oxo-propyl)-l-prolyn |
| JPS62125081A (en) * | 1985-11-21 | 1987-06-06 | キングプリンテイング株式会社 | Printing method |
| ATE222758T1 (en) * | 1996-09-26 | 2002-09-15 | Meditor Pharmaceuticals Ltd | PHARMACEUTICAL COMPOSITIONS CONTAINING S-ALKYLISOTHIOURONIUM DERIVATIVES |
| CN103086939A (en) * | 2011-10-28 | 2013-05-08 | 华中药业股份有限公司 | Recrystallization method of 1-(3-bromo-2-D-methyl propionyl)pyrrolidine-2-carboxylic acid |
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| AU509899B2 (en) * | 1976-02-13 | 1980-05-29 | E.R. Squibb & Sons, Inc. | Proline derivatives and related compounds |
| IL58849A (en) * | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
| GB2065643B (en) * | 1979-12-13 | 1983-08-24 | Kanegafuchi Chemical Ind | Optically active n-mercaptoalkanoylamino acids |
| IE54551B1 (en) * | 1982-01-22 | 1989-11-22 | Ici Plc | Amide derivatives |
| KR860001391B1 (en) * | 1984-07-23 | 1986-09-22 | 보령제약 주식회사 | Method for preparing pyrrolidine derivative |
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1986
- 1986-04-07 AT AT0091186A patent/AT395012B/en not_active IP Right Cessation
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- 1987-06-26 KR KR1019870006546A patent/KR900007217B1/en active Pre-grant Review Request
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- 1987-06-26 IT IT8721085A patent/IT1206792B/en active
- 1987-06-26 SU SU874202836A patent/SU1650007A3/en active
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- 1987-06-26 JP JP62159491A patent/JPS6327475A/en active Pending
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| US4440244A (en) * | 1980-03-26 | 1984-04-03 | Santrade Ltd. | Drill tool |
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