DK147390B - METHOD OF ANALOGY FOR THE PREPARATION OF ERGOPEPTIDALCALOID DERIVATIVES - Google Patents
METHOD OF ANALOGY FOR THE PREPARATION OF ERGOPEPTIDALCALOID DERIVATIVES Download PDFInfo
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Description
i 147390in 147390
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af ergopeptidalkaloidderivaterThe present invention relates to an analogous process for the preparation of ergopeptide alkaloid derivatives
Ved analogifremgangsmåden ifølge opfindelsen fremstilles hidtil ukendte forbindelser med den almene formel IBy the analogous process of the invention, novel compounds of general formula I are prepared
O nl OH I—“—O nl OH I - “-
!_H S HfJ! _H S HfJ
CrjCj^ HCrjCj ^ H
5 hvor R1, R2 og R* betegner alkyl med 1-4 carbonatomer, eller syreadditionssalte deraf.5 wherein R 1, R 2 and R * represent alkyl of 1-4 carbon atoms, or acid addition salts thereof.
I den almene formel I betegner R1 fx methyl, ethyl eller isopropyl.In the general formula I, for example, R 1 represents methyl, ethyl or isopropyl.
R2 betegner sædvanligvis n- eller isopropyl, n-, iso- eller sek.butyl.R 2 usually represents n- or isopropyl, n-, iso- or sec-butyl.
R1* betegner sædvanligvis methyl eller isopropyl.R 1 usually represents methyl or isopropyl.
10 De her omhandlede forbindelser afviger strukturelt fra de kendte ergopeptidalkaloidderivater derved, at de har en methylengruppe i stedet for en carbonylgruppe i molekylets 6’-stilIing. Endvidere besidder de her omhandlede forbindelser en uventet nyttig biologisk virkning, der gør dem egnede til behandling af coronarinsufficiens.The compounds of this invention differ structurally from the known ergopeptide alkaloid derivatives in that they have a methylene group instead of a carbonyl group in the 6 'position of the molecule. Furthermore, the compounds of this invention have an unexpectedly useful biological effect which makes them suitable for the treatment of coronary insufficiency.
15 Således er 6'-desoxo-9,10-dihydro-f$-ergocryptin (den i eksempel 1 fremstillede forbindelse) et ergopeptidalkaloidderivat, der reducerer væsentlige determinanter i det myokardiale oxygenforbrug og derved formindsker gennemblødningsbehovet i myokardiet, på lignende måde som en β-blokker. Den nævnte forbindelse udviser endvidere ved iso-20 lerede coronararterier a- og serotoninantagonistisk virkning. På 147390 2 grund af disse egenskaber må det forventes, at de store coronarar-terier beskyttes mod spasmogene påvirkninger, på lignende måde som ved behandling med nitropræpa rater. En o-stimulerende virkning, der er den formodede årsag til ergotamins spasmogene virkninger, er 5 minimal. En serotoninerg egenvirkning blev også påvist på isolerede coronararterier, men den er dog ligeledes ringe.Thus, 6'-desoxo-9,10-dihydro-f $ -ergocryptin (the compound of Example 1) is an ergopeptide alkaloid derivative that reduces essential determinants of myocardial oxygen consumption and thereby reduces the need for blood flow in the myocardium, in a manner similar to a β blocker. Said compound further exhibits α-and serotonin antagonistic activity by isolated coronary arteries. Due to these properties, it is to be expected that the large coronary arteries are protected from spasmogenic influences, in a similar manner to treatment with nitro prep rates. An o-stimulatory effect that is the putative cause of the spasmogenic effects of ergotamine is minimal. A serotonergic intrinsic effect was also detected on isolated coronary arteries, but it is also poor.
Ved en sammenligning på basilararterien er der fundet følgende procentværdier for den maksimale serotoninvirkning. 7% for 6'-desoxo-9,10-dihydro-0-ergocryptin, 15% for dihydroergotamin og 40% for 10 ergotaminBy a comparison on the basilar artery, the following percentages for the maximum serotonin effect have been found. 7% for 6'-deoxo-9,10-dihydro-O-ergocryptin, 15% for dihydroergotamine and 40% for 10 ergotamine
Fremgangsmåden ifølge den foreliggende opfindelse til fremstilling af en forbindelse med den almene formel I er ejendommelig ved, atThe process of the present invention for the preparation of a compound of general formula I is characterized in that:
a) 6'-carbonylgruppen i en forbindelse med den almene formel IIa) the 6'-carbonyl group in a compound of the general formula II
° „ °H JLah I° ° ° H JLah I
i JL 1_N « i I 4 K< -2 hvor R1, R2 og R* har de ovenfor angivne betydninger, reduceres, 15 eller at 3 U7390in JL 1_N «in I 4 K <-2 where R1, R2 and R * have the above meanings, are reduced, 15 or 3 U7390
b) et syreadditionssalt af en forbindelse med den almene formel IIIb) an acid addition salt of a compound of general formula III
. OH ,-1. OH, -1
R1 ' LaHR1 'LaH
I I N| 111 /—N xCH2I I N | 111 / —N xCH2
~ '' 2 H R~ '' 2 H R
hvor R1 og R2 har den ovenfor angivne betydning, kondenseres med et reaktivt syrederivat af en forbindelse med den almene formel IVwherein R 1 and R 2 are as defined above are condensed with a reactive acid derivative of a compound of general formula IV
COOHCOOH
B,r4j.R4 iv o hvor R* har den ovenfor angivne betydning.B, r4j.R4 iv o where R * has the meaning given above.
5 Fremgangsmådevariant a) kan om ønsket udføres som en éttrinsreak-tion ved anvendelse af reaktivt boran, fx diboran. Fremgangsmåden kan udføres på i og for sig kendt måde til reduktion med diboran under milde betingelser. Pr. mol af forbindelsen med den almene formel II anvendes 5-15 mol reagerende boran. Som opløsningsmiddel 10 kan anvendes tetrahyd rof uran, diethylether eller methylenchlorid. Reduktionen sker fortrinsvis ved temperaturer mellem ca. -20°C og +20°C.Process variant a) may, if desired, be performed as a one-step reaction using reactive borane, e.g. diborane. The process can be carried out in a manner known per se for reduction with diborane under mild conditions. Pr. moles of the compound of the general formula II are used 5-15 moles of reacting borane. As solvent 10 may be used tetrahydro uranium, diethyl ether or methylene chloride. The reduction is preferably effected at temperatures between ca. -20 ° C and + 20 ° C.
147390 4147390 4
Fremgangsmådevariant b) kan udføres analogt til kendte metoder til fremstilling af analoge cycliske peptidergotalkaloider ved kondensation.Process variant b) can be performed analogously to known methods for preparing analogous cyclic peptide gut alkaloids by condensation.
Et egnet syreadditionssalt af en forbindelse med den almene formel III 5 er 2,5-naphthalen-disulfonsyresaftet.A suitable acid addition salt of a compound of general formula III is the 2,5-naphthalene disulfonic acid juice.
Som reaktive funktionelle derivater af en forbindelse med den almene formel IV kan fx anvendes syrechloridet, syreazidet eller det blandede anhydrid med svovlsyre eller trifluoreddikesyre. Fortrinsvis anvendes additionsproduktet af en forbindelse med den almene formel 10 IV med dimethylformamid eller acetamid og thionylchlorid, phosgen eller oxalylchlorid. Fortrinsvis udføres reaktionen i nærværelse af triethylamin eller pyridin. Egnede opløsningsmidler er fx chloroform, methylenchlorid, dimethylformamid eller acetonitril.As reactive functional derivatives of a compound of general formula IV, for example, the acid chloride, acid azide or mixed anhydride may be used with sulfuric acid or trifluoroacetic acid. Preferably, the addition product of a compound of general formula 10 IV is used with dimethylformamide or acetamide and thionyl chloride, phosgene or oxalyl chloride. Preferably, the reaction is carried out in the presence of triethylamine or pyridine. Suitable solvents are, for example, chloroform, methylene chloride, dimethylformamide or acetonitrile.
Omsætningen kan udføres ved temperaturer mellem -30°C og +20°C.The reaction can be carried out at temperatures between -30 ° C and + 20 ° C.
15 Udgangsprodukterne er kendte eller kan på kendt måde fremstilles ud fra kendte forbindelser. Således kan en forbindelse med den almene formel III fremstilles ved de til fremstilling af en aminocyclol ud fra en forbindelse med den almene formel VThe starting products are known or can be prepared in known manner from known compounds. Thus, a compound of general formula III can be prepared by those for the preparation of an aminocyclol from a compound of general formula V
• r1 ?h ci c2h5ooc J-• r1? H ci c2h5ooc J-
o To T
* R2 hvor R1 og R2 har de ovenfor angivne betydning, i og for sig kendte 20 metoder.* R2 wherein R1 and R2 have the above meanings, known per se, 20 per se.
147390 5147390 5
Fx kan først den tilsvarende syre fremstilles, hvorpå den via syre-chloridet omdannes til det tilsvarende syreamid, som derefter omdannes til aminen.For example, the corresponding acid may first be prepared and then converted via the acid chloride to the corresponding acid amide which is then converted to the amine.
En forbindelse med den almene formel V kan fremstilles ved at lade en 5 forbindelse med den almene formel VIA compound of general formula V can be prepared by leaving a compound of general formula VI
R1 POCH2-C6H5R1 POCH2-C6H5
VIWE
COC11 COCl
hvor R1 har den ovenfor angivne betydning, reagere med en forbindelse med den almene formel VIIwherein R1 is as defined above, react with a compound of general formula VII
"Y® VH2 s 2 H * tf hvor R2 har den ovenfor angivne betydning, hvorefter det fremkomne produkt hydrogeneres."Y® VH2 s 2 H * tf where R2 has the meaning given above and then the resulting product is hydrogenated.
10 En forbindelse med den almene formel VII kan fremstilles ved, at en forbindelse med den almene formel VIIIA compound of general formula VII may be prepared by a compound of general formula VIII
HN IHN I
H k2 147390 6 hvor R2 har den ovenfor angivne betydning, reduceres med lithium-aluminiumhydrid.H k2 147390 6 where R 2 has the meaning given above is reduced with lithium aluminum hydride.
Ud fra de frie baser af forbindelserne med den almene formel I kan på kendt måde fremstilles syreadditionssalte og omvendt. Egnede salte 5 omfatter hydrochloridet og methansulfonatet.From the free bases of the compounds of the general formula I, acid addition salts can be prepared in known manner and vice versa. Suitable salts include the hydrochloride and methanesulfonate.
Forbindelserne med den almene formel I i fri form eller i form af fysiologisk tolerable syreadditionssalte med syrer udmærker sig ved interessante farmakologiske egenskaber; de kan anvendes som lægemidler.The compounds of general formula I in free form or in the form of physiologically tolerable acid addition salts with acids are characterized by interesting pharmacological properties; they can be used as medicines.
10 Således kan de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser anvendes til behandling af hjertesygdomme og som anti-hypertensiva. De ved fremgangsmåden ifølge opfindelsen tilvejebragte forbindelser med den almene formel I kan i fri form eller i form af deres fysiologisk tolerable syreadditionssalte anvendes i lægemidler.Thus, the compounds prepared by the process of the invention can be used to treat heart disease and as anti-hypertensives. The compounds of the general formula I provided by the process of the invention can be used in pharmaceutical form in free form or in the form of their physiologically tolerable acid addition salts.
15 Disse lægemidler kan fx være udformet som en opløsning eller tablet og kan på i og for sig kendt måde fremstilles under anvendelse af de sædvanlige hjælpe- og bærestoffer.For example, these drugs may be designed as a solution or tablet and may be prepared in a manner known per se using the usual adjuvants and carriers.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved de følgende eksempler. Temperaturerne er ikke korrigerede.The process according to the invention is illustrated in more detail by the following examples. Temperatures are not corrected.
20 EKSEMPEL 1 6'-Desoxo-9,10-dihydro-p-ergocryptin (fremgangsmådevariant a).EXAMPLE 1 6'-Desoxo-9,10-dihydro-β-ergocryptin (process variant a).
1,15 g 9,10-dihydro-(5-ergocryptin (2 millimol) suspenderes i 25 ml absolut tetrahydrofuran (THF) og tilsættes under omrøring ved 0°C dråbevis en frisklavet opløsning af 20 millimol BHg i 35 ml absolut 25 THF (fx fremstillet af natriumborhydrid og bortrifluoretherat). Efter omrøring i 4 timer ved 0°C afkøles der kraftigt, og reaktionsblandingen sønderdeles forsigtigt i 9 ml 6N saltsyre. Derefter omrøres i endnu 30 minutter ved +60°C, reaktionsblandingen gøres efter afkøling alkalisk med 30%'s natriumhydroxidopløsning og ekstraheres grun- 147390 7 digt med methylenchlorid. Efter chromatografi af methylenchloridek-strakterne på 100 g Alox ved aktivitetstrin 2-3 krystalliseres titelforbindelsen af metylenchlorid/ether i den fri basiske form. Smeltepunkt 159-160°C; [a]^ = -4° (c = 0,5 i dimethylformamid).1.15 g of 9,10-dihydro- (5-ergocryptin (2 millimoles)) is suspended in 25 ml of absolute tetrahydrofuran (THF) and, while stirring at 0 ° C, a freshly prepared solution of 20 millimoles of BHg in 35 ml of absolute 25 THF ( for example, prepared from sodium borohydride and boron trifluoro etherate) After stirring for 4 hours at 0 ° C, vigorously cool and the reaction mixture is gently decomposed into 9 ml of 6N hydrochloric acid, then stirred for another 30 minutes at + 60 ° C, the reaction mixture is cooled to 30 ° C with cooling. % sodium hydroxide solution and extracted thoroughly with methylene chloride After chromatography of the methylene chloride extracts of 100 g of Alox at activity steps 2-3, the title compound of methylene chloride / ether is crystallized in the free basic form, m.p. 159-160 ° C; = -4 ° (c = 0.5 in dimethylformamide).
5 Titelforbindelsen kan også fremstilles ifølge fremgangsmåden i det nedenstående eksempel 5.The title compound can also be prepared according to the procedure of Example 5 below.
De nedenstående forbindelser med den almene formel I kan fremstilles analogt til den i eksempel 1 beskrevne fremgangsmåde: EKSEMPEL 2 10 6'-Desoxo-9,10-dihydro-a-ergocryptin.The following compounds of general formula I may be prepared by analogy to the procedure described in Example 1: EXAMPLE 2 6'-Desoxo-9,10-dihydro-α-ergocryptin.
Smeltepunkt 182-185°C; Hq0 = +14° (c = 0,3 i dimethylformamid).Melting point 182-185 ° C; Hq O = + 14 ° (c = 0.3 in dimethylformamide).
EKSEMPEL 3 6'-Desoxo-9,10-dihydroergocornin.EXAMPLE 3 6'-Desoxo-9,10-dihydroergocornin.
Smeltepunkt 166-167°C (sønderdeling); [o]q^ = -18,5° (c = 0,66 i di-15 methylformamid).Melting point 166-167 ° C (dec.); = -18.5 ° (c = 0.66 in dimethylformamide).
EKSEMPEL 4 6'-Desoxo-9,10-dihydro-p-ergosin.Example 4 6'-Desoxo-9,10-dihydro-p-ergosine.
Smeltepunkt 194-196°C (sintring fra 185°C); [o]^ = -18° (c = 0,3 i dimethylformamid).Melting point 194-196 ° C (sintering from 185 ° C); [α] D = -18 ° (c = 0.3 in dimethylformamide).
147390 8 EKSEMPEL 5 6’ - Desoxo-9,10-dihyd ro- β-ergocry pti n 10,8 g (40 miliimol) 9,10-dihydrolysergsyre suspenderes i 100 ml absolut dimethylformamid og afkøles til -10°C. Derefter dryppes i 5 løbet af 5 minutter 4,72 g (40 miliimol) thionylchlorid til, og reaktionsblandingen omrøres i endnu 30 minutter ved mellem -5 og 0°C.EXAMPLE 5 6 '- Desoxo-9,10-dihydro-β-ergocrylate 10.8 g (40 mil) mole of 9,10-dihydrolyseric acid is suspended in 100 ml of absolute dimethylformamide and cooled to -10 ° C. Then, for the course of 5 minutes, 4.72 g (40 milimoles) of thionyl chloride is added dropwise and the reaction mixture is stirred for another 30 minutes at between -5 and 0 ° C.
Efter tilsætning af 40 ml absolut pyridin ved -15°C under kraftig omrøring sættes 12,68 g (20 miliimol) 2-amino-2-isopropyl-3-oxo-5-sec.butyl-l0b-hydroxy-perhydroxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-10 2,5-naphthalendisulfonsyre til, der omrøres kraftigt i 2 timer, og temperaturen tillades at stige langsomt fra -10 til 0°C. Til oparbejdning gøres blandingen under afkølingen basisk med 2N sodaopløsning, og reaktionsblandingen ekstraheres grundigt med methylenchlorid.After the addition of 40 ml of absolute pyridine at -15 ° C with vigorous stirring, 12.68 g (20 millimoles) of 2-amino-2-isopropyl-3-oxo-5-sec.butyl-10b-hydroxy-perhydroxazolo [3, 2-a] pyrrolo [2,1-c] pyrazine-10 2,5-naphthalene disulphonic acid is stirred vigorously for 2 hours and the temperature is allowed to rise slowly from -10 to 0 ° C. For working up, the mixture is basified with 2N soda solution under cooling and the reaction mixture is extracted thoroughly with methylene chloride.
Efter chromatografi af methylenchloridekstrakterne på 100 g alox ved 15 aktivitetstrin 2-3 krystalliseres titelforbindelsen af methylenchlorid/- 9 Π ether i form af den frie base. Smeltepunkt 159-160°C; [«]q = -4° (c = 0,5 i dimethylformamid).After chromatography of the methylene chloride extracts of 100 g of alox at activity steps 2-3, the title compound of methylene chloride / - 9 Π ether is crystallized as the free base. Mp 159-160 ° C; [Α] q = -4 ° (c = 0.5 in dimethylformamide).
Den som udgangsmateriale nødvendige 2-amino-2-isopropyl-3-oxo-5-sec.butyl-10b-hydroxy-perhydroxazolo[3,2-a]pyrrolo[3,1-c]pyrazin.-20 2,5-naphthalendisulfonsyre fås på følgende måde: a) (2S,7aS)-2-sec.butyl-perhydro-8-oxo-pyrrolo[2,1-c]pyrazinThe 2-amino-2-isopropyl-3-oxo-5-sec-butyl-10b-hydroxy-perhydroxazolo [3,2-a] pyrrolo [3,1-c] pyrazine as starting material required naphthalene disulphonic acid is obtained as follows: a) (2S, 7aS) -2-sec.butyl-perhydro-8-oxo-pyrrolo [2,1-c] pyrazine
Under nitrogen suspenderes 36,4 g lithiumaluminiumhydrid i 1,3 I absolut tetrahyd rof uran, og i løbet af 45 minutter dryppes en opløsning af 115,5 g L-lle-L-Pro-Iactam i 1,4 I absolut tetrahyd rof uran til.Under nitrogen, 36.4 g of lithium aluminum hydride is suspended in 1.3 liters of absolute tetrahydric uranium, and within 45 minutes a solution of 115.5 g of L-lle-L-Pro-Iactam in 1.4 liters of absolute tetrahydric uranium is dropped. to.
25 Efter omrøring i 18 timer ved -10°C fortyndes der ved denne temperatur forsigtigt og i den nævnte rækkefølge med 350 ml ethylacetat og 350 ml vand. Reaktionsblandingen filtreres, hvorefter det af reaktionsproduktet, der endnu hænger fast, ekstraheres ved gentagen ekstraktion af filterkagen med kogende methylenchlorid. De forenede 30 organiske faser tørres over natriumsulfat og inddampes, hvilket giver titelforbindelsen.After stirring for 18 hours at -10 ° C, this temperature is gently diluted with 350 ml of ethyl acetate and 350 ml of water at this temperature. The reaction mixture is filtered, and that of the reaction product still stuck is extracted by repeated extraction of the filter cake with boiling methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to give the title compound.
147390 9 b) (2R,5S,10aS,10bS)-2-carbethoxy-2-isopropyl-3-oxo-5-sec.butyl-10b-hydroxy-perhydro-oxazolo[3,2-a]pyrrolo[2/1-c]pyrazin 40,55 g (2S,7aS)-2-sec.butyl-perhydro-8-oxo-pyrrolo[2,1-c]pyrazin i 160 ml absolut dioxan blandes med 74,4 g S(+)-isopropylbenzyloxy-5 malonsyreethylesterchlorid og 34,9 g N-ethyldiisopropylamin og omrøres i 1 time ved 70°C. Efter fortynding med 1 I ether rystes blandingen to gange med mættet natriumhydrogencarbonatopløsning og tørres over natriumsulfat. Efter afdampning af opløsningsmidlet fås rå (2S,-7aS)-(2'-S-2'-benzyloxy-2,-isopropyl-0-ethylmalononyl)-2-sec.butyl-10 perhydro-8-oxo-pyrrolo[2,1-c]pyrazin, der opløses i 1,5 I ethanol og efter tilsætning af 60 g palladium-aktivkul (10% Pd) hydrogeneres ved 60°C, hvorved der efter 14 timer er absorberet ca. 6,5 I hydrogen.B) (2R, 5S, 10aS, 10bS) -2-carbethoxy-2-isopropyl-3-oxo-5-sec.butyl-10b-hydroxy-perhydro-oxazolo [3,2-a] pyrrolo [2 1-c] pyrazine 40.55 g (2S, 7aS) -2-sec.butyl-perhydro-8-oxo-pyrrolo [2,1-c] pyrazine in 160 ml of absolute dioxane are mixed with 74.4 g of S (+ ) -isopropylbenzyloxy-malonic acid ethyl ester chloride and 34.9 g of N-ethyl diisopropylamine and stirred for 1 hour at 70 ° C. After dilution with 1 L of ether, the mixture is shaken twice with saturated sodium hydrogen carbonate solution and dried over sodium sulfate. After evaporation of the solvent, crude (2S, -7aS) - (2'-S-2'-benzyloxy-2, -isopropyl-O-ethylmalononyl) -2-sec.butyl-10-perhydro-8-oxo-pyrrolo [2 , 1-c] pyrazine, which is dissolved in 1.5 L of ethanol and, after the addition of 60 g of palladium activated carbon (10% Pd), is hydrogenated at 60 ° C, whereupon about 14 hours are absorbed. 6.5 in hydrogen.
Efter filtrering og inddampn i ng af filtratet fås titelforbindelsen.After filtration and evaporation of the filtrate, the title compound is obtained.
c) (2R,5S,10aS,10bS)-2-carboxy-2-isopropyl-3-oxo-5-sec.butyl-10b-15 hydroxy-perhydro-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin 35,9 g (2R,5S,10aS,10bS)-2-carbethoxy-2-isopropyl-3-oxo-5-sec.but-yl-10b-hydroxy-perhydro-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin opløses i 245 ml methanol og 245 ml 2N natriumhydroxyd og omrøres i 3 timer ved stuetemperatur. Til oparbejdning justeres ved 0°C til en pH-vær-20 dl på 4,5 ved hjælp af 2N saltsyre, og der ekstraheres flere gange med ethylacetat. Efter tørring af det organiske ekstrakt og inddamp-ning af opløsningsmidlet under 30°C fås titelforbindelsen.c) (2R, 5S, 10aS, 10bS) -2-carboxy-2-isopropyl-3-oxo-5-sec.butyl-10b-hydroxy-perhydro-oxazolo [3,2-a] pyrrolo [2,1 -c] pyrazine 35.9 g (2R, 5S, 10aS, 10bS) -2-carbethoxy-2-isopropyl-3-oxo-5-sec.butyl-10b-hydroxy-perhydro-oxazolo [3.2- a] pyrrolo [2,1-c] pyrazine is dissolved in 245 ml of methanol and 245 ml of 2N sodium hydroxide and stirred for 3 hours at room temperature. For work up, adjust at 0 ° C to a pH value of 4.5 d by 4.5N with 2N hydrochloric acid and extract several times with ethyl acetate. After drying the organic extract and evaporation of the solvent below 30 ° C, the title compound is obtained.
d) (2R,5S,10aS,10bS)-2-amino-2-isopropyl-3-oxo-5-sec.butyl-10b-hy-droxy-perhydro-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin.2,5-naphthalen- 25 disulfonsyred) (2R, 5S, 10aS, 10bS) -2-amino-2-isopropyl-3-oxo-5-sec.butyl-10b-hydroxy-perhydro-oxazolo [3,2-a] pyrrolo [2, 1-c] pyrazine, 2,5-naphthalene disulfonic acid
Til en til -15°C afkølet og omrørt blanding af 4,33 ml absolut dimeth-ylformamid og 30 ml absolut acetonitril dryppes i løbet af 10 minutter en opløsning af 3,84 ml oxalylchlorid i 15 ml absolut acetonitril, og der omrøres i endnu 10 minutter. Efter fortynding med 45 ml absolut 30 ether sættes 10,87 g (2R,5S,10aS,10bS)-2-carboxy-2-isopropyl-3-oxo-5-sec. butyl-10b-hydroxy-perhydro-oxazolo[3,2-b] pyrrolo[2,1 -c] -pyrazin,1/2 HjO hurtigt til, hvorved der opstår en klar opløsning 147390 10 indeholdende syrechloridet, og som omrøres i endnu 10 minutter ved -10°C. Der tilsættes en fase af en opløsning af 20 g natriumacid i 100 ml vand og fortyndes med 300 ml methylenchlorid, hvorefter 2-fase-blandingen rystes kraftigt i 4 minutter. Derefter føjes 150 ml iskold 5 mættet natriumhydrogenopløsning til, og den organiske fase skilles fra og tørres grundigt over natriumsulfat. Efter koncentration af opløsningsmidlet ved under 30°C tilsættes en opløsning af 7,78 g 2,5-naphthalendisulfonsyre i 200 ml dimethoxyethan og 20 ml acetonitril, og der inddampes langsomt i vakuum. Efter fortynding med absolut 10 ether isoleres syreacidet som salt i form af et beigefarvet pulver.To a -15 ° C cooled and stirred mixture of 4.33 ml of absolute dimethylformamide and 30 ml of absolute acetonitrile, drop over 10 minutes a solution of 3.84 ml of oxalyl chloride in 15 ml of absolute acetonitrile and stir 10 minutes. After dilution with 45 ml of absolute ether, 10.87 g (2R, 5S, 10aS, 10bS) of 2-carboxy-2-isopropyl-3-oxo-5-sec are added. butyl 10b-hydroxy-perhydro-oxazolo [3,2-b] pyrrolo [2,1-c] -pyrazine, 1/2 H₂O rapidly to give a clear solution containing the acid chloride and stirring for a further period of time. 10 minutes at -10 ° C. A phase of a solution of 20 g of sodium acid in 100 ml of water is added and diluted with 300 ml of methylene chloride, after which the 2-phase mixture is shaken vigorously for 4 minutes. Then 150 ml of ice-cold 5 saturated sodium hydrogen solution is added and the organic phase is separated and dried thoroughly over sodium sulfate. After concentration of the solvent at below 30 ° C, a solution of 7.78 g of 2,5-naphthalenedisulfonic acid in 200 ml of dimethoxyethane and 20 ml of acetonitrile is added and evaporated slowly in vacuo. After dilution with absolute 10 ether, the acidic acid is isolated as salt in the form of a beige powder.
6,35 g af det tørrede pulver opvarmes sammen med 120 ml dimethoxyethan, der indeholder 0,166 ml vand, til 80°C i 1 time, hvorved der under stadig kradsning udfældes et brunligt halvkrystallinsk pulver, der efter afkøling, filtrering og tørring ved stuetemperatur i højva-15 kuum kan anvendes direkte til kondensationen.6.35 g of the dried powder is heated together with 120 ml of dimethoxyethane, containing 0.166 ml of water, to 80 ° C for 1 hour, whereby a still brownish semi-crystalline powder is precipitated which, after cooling, filtration and drying at room temperature. high vacuum can be used directly for the condensation.
Claims (2)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1128676A CH623591A5 (en) | 1976-09-06 | 1976-09-06 | Process for the preparation of ergopeptide alkaloid derivatives |
| CH1128776 | 1976-09-06 | ||
| CH1128676 | 1976-09-06 | ||
| CH1128776A CH623592A5 (en) | 1976-09-06 | 1976-09-06 | Process for the preparation of ergopeptide alkaloid derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK382777A DK382777A (en) | 1978-03-07 |
| DK147390B true DK147390B (en) | 1984-07-16 |
| DK147390C DK147390C (en) | 1985-02-04 |
Family
ID=25708069
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK382777A DK147390C (en) | 1976-09-06 | 1977-08-29 | METHOD OF ANALOGY FOR THE PREPARATION OF ERGOPEPTIDALCALOID DERIVATIVES |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5331698A (en) |
| AU (1) | AU512027B2 (en) |
| CA (1) | CA1105007A (en) |
| DE (1) | DE2738730A1 (en) |
| DK (1) | DK147390C (en) |
| ES (1) | ES462080A1 (en) |
| FI (1) | FI64942C (en) |
| FR (1) | FR2363571A1 (en) |
| GB (2) | GB1590150A (en) |
| IE (1) | IE46152B1 (en) |
| IL (1) | IL52896A (en) |
| NL (1) | NL7709683A (en) |
| NZ (1) | NZ185098A (en) |
| PT (1) | PT67003B (en) |
| SE (1) | SE435839B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8604035B2 (en) * | 2011-06-23 | 2013-12-10 | Map Pharmaceuticals, Inc. | Fluoroergoline analogs |
-
1977
- 1977-06-02 ES ES462080A patent/ES462080A1/en not_active Expired
- 1977-08-27 DE DE19772738730 patent/DE2738730A1/en not_active Withdrawn
- 1977-08-29 SE SE7709645A patent/SE435839B/en unknown
- 1977-08-29 DK DK382777A patent/DK147390C/en active
- 1977-08-29 FI FI772557A patent/FI64942C/en not_active IP Right Cessation
- 1977-08-31 GB GB9862/80A patent/GB1590150A/en not_active Expired
- 1977-08-31 GB GB36338/77A patent/GB1590149A/en not_active Expired
- 1977-09-02 NL NL7709683A patent/NL7709683A/en not_active Application Discontinuation
- 1977-09-02 CA CA286,056A patent/CA1105007A/en not_active Expired
- 1977-09-05 NZ NZ185098A patent/NZ185098A/en unknown
- 1977-09-05 IL IL52896A patent/IL52896A/en unknown
- 1977-09-05 PT PT67003A patent/PT67003B/en unknown
- 1977-09-05 FR FR7726893A patent/FR2363571A1/en active Granted
- 1977-09-05 IE IE1838/77A patent/IE46152B1/en unknown
- 1977-09-05 JP JP10596277A patent/JPS5331698A/en active Pending
- 1977-09-06 AU AU28572/77A patent/AU512027B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IL52896A0 (en) | 1977-11-30 |
| DK147390C (en) | 1985-02-04 |
| FR2363571A1 (en) | 1978-03-31 |
| JPS5331698A (en) | 1978-03-25 |
| GB1590149A (en) | 1981-05-28 |
| GB1590150A (en) | 1981-05-28 |
| NL7709683A (en) | 1978-03-08 |
| CA1105007A (en) | 1981-07-14 |
| PT67003B (en) | 1979-05-14 |
| AU2857277A (en) | 1979-03-15 |
| IE46152L (en) | 1978-03-06 |
| FI772557A (en) | 1978-03-07 |
| SE7709645L (en) | 1978-03-07 |
| AU512027B2 (en) | 1980-09-18 |
| ES462080A1 (en) | 1978-12-01 |
| DK382777A (en) | 1978-03-07 |
| IL52896A (en) | 1980-07-31 |
| IE46152B1 (en) | 1983-03-09 |
| FI64942C (en) | 1984-02-10 |
| FI64942B (en) | 1983-10-31 |
| DE2738730A1 (en) | 1978-03-16 |
| PT67003A (en) | 1977-10-01 |
| NZ185098A (en) | 1980-04-28 |
| FR2363571B1 (en) | 1980-04-18 |
| SE435839B (en) | 1984-10-22 |
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