DK159389B - CHOLESTAGE STAGE OR TRIEND DERIVATIVES THAT MAY BE USED AS INTERMEDIATES FOR USE IN THE PREPARATION OF 24-HOMOVITAMIN-D3 DERIVATIVES - Google Patents
CHOLESTAGE STAGE OR TRIEND DERIVATIVES THAT MAY BE USED AS INTERMEDIATES FOR USE IN THE PREPARATION OF 24-HOMOVITAMIN-D3 DERIVATIVES Download PDFInfo
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- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- A61P3/02—Nutrients, e.g. vitamins, minerals
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- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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Description
DK 159389BDK 159389B
iin
Den foreliggende opfindelse angår hidtil ukendte chole-stadienr· eller -friender i vater, der kan anvendes som mellemprodukter til brug ved fremstillingen af hydroxylerede 24-homovitamin-D2“derivater. Cholestadien- eller -trien-5 derivaterne ifølge opfindelsen er ejendommelige ved, at de har den i kravets kendetegnende del angivne formel.The present invention relates to novel chole stages or compounds in water which can be used as intermediates for use in the preparation of hydroxylated 24-homovitamin-D 2 derivatives. The cholestatic or tri-derivatives of the invention are peculiar in that they have the formula set forth in the characterizing part of the claim.
Det er velkendt, at vitamin-D regulerer calcium og phos-phormetabolismen hos dyr og mennesker, og det er nu klart 10 fastslået, at den biologiske virkning af vitamin-D afhænger af vitaminets metaboliske omdannelse in vivo til hydroxylerede derivater. Således hydroxyleres vitamin-D^ in vivo til 25-hydroxy vitamin-D^ i leveren, der for sit vedkommende omdannes til la,25-dihydroxyvitamin-D2 i ny-15 rerne. Det er den sidstnævnte forbindelse, der er anerkendt som at være den cirkulerende hormonale form af vitamin-D.It is well known that vitamin-D regulates calcium and phosphorus metabolism in animals and humans, and it is now clearly established that the biological effect of vitamin-D depends on the metabolic conversion of the vitamin in vivo to hydroxylated derivatives. Thus, in vivo, vitamin D 2 is hydroxylated to 25-hydroxy vitamin D 2 in the liver, which in turn is converted to 1α, 25-dihydroxyvitamin-D 2 in the kidneys. It is the latter compound that is recognized as being the circulating hormonal form of vitamin D.
På grund af forbindelsernes biologiske evne til at fremme 20 calcium- og phosphortransporten i tarmen og mobilisere og mineralisere knogler, er disse former af vitamin-D vigtige farmaceutiske forbindelser, der er særdeles velegnede til at anvendes ved behandling af forskellige knoglesygdomme.Due to the biological ability of the compounds to promote calcium and phosphorus transport in the intestine and to mobilize and mineralize bones, these forms of vitamin D are important pharmaceutical compounds which are particularly suitable for use in the treatment of various bone disorders.
2525
Vitamin-derivater og fremstillingen heraf og deres anvendelse er omtalt i en hel række patentskrifter og i anden litteratur. F.eks. omhandler US patentskrift nr.Vitamin derivatives and their preparation and their use are discussed in a variety of patents and other literature. Eg. U.S. Pat.
3 565 924 . 25-rhydroxy cholecalciferol; US patentskrift 30 nr. 3 697 559 omhandler 1,25-dihydroxycholecalciferol; US patentskrift nr. 3 471 996 omhandler la-hydroxychole-calciferol; US patentskrift nr. 3 786 062 omhandler 22-dehydro-25-hydroxycholecalciferol; US patentskrift nr.3 565 924. 25-rhydroxy cholecalciferol; U.S. Patent No. 3,697,559 discloses 1,25-dihydroxycholecalciferol; U.S. Patent No. 3,471,996 discloses 1-hydroxycholecalciferol; U.S. Patent No. 3,786,062 discloses 22-dehydro-25-hydroxycholecalciferol; U.S. Pat.
3 880 894 omhandler 1,25-dihydroxyergocalciferol; US pa-35 tentskrift nr. 4 201 881 omhandler 24,24-difluor-la,25-dihydroxycholecalciferol; US patentskrift nr. 4 196 133 omhandler 24,24-difluor-1a,25-dihydroxycholecalciferol.3,880,894 discloses 1,25-dihydroxyergocalciferol; U.S. Patent No. 4,201,881 discloses 24,24-difluoro-1α, 25-dihydroxycholecalciferol; U.S. Patent No. 4,196,133 discloses 24,24-difluoro-1α, 25-dihydroxycholecalciferol.
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De nævnte derivater af 24-homovitamin-D2 har vist sig at udøve glimrende vitamin-D-lignende virkning, og af den grund kan de let anvendes i stedet for vitamin-Dg eller derivater heraf til kendte formål som f.eks. til behand-5 ling af forskellige sygelige tilstande, der viser sig ved calcium- og phosphorubalance som f.eks. hypoparathy-roidisme, osteodystrofi, osteomalacia og osteoporose.Said derivatives of 24-homovitamin-D2 have been found to exert excellent vitamin-D-like action, and for that reason they can be readily used in place of vitamin-Dg or derivatives thereof for known purposes such as e.g. for the treatment of various morbid conditions which appear in calcium and phosphorous imbalances such as hypoparathyroidism, osteodystrophy, osteomalacia and osteoporosis.
Herudover udviser disse derivater en i forhold til la-10 hydroxyvitamin og la,25-dihydroxyvitamin uventet høj antineoplastisk virkning, og denne virkning udvises uventet og overraskende uden forøget calcæmisk virkning.In addition, these derivatives exhibit an unexpectedly high antineoplastic effect relative to 1α-10 hydroxyvitamin and 1α, 25-dihydroxyvitamin, and this effect is unexpectedly and surprisingly exhibited with no increased calcemic effect.
Disse egenskaber gør homo-forbindelserne særdeles velegnede som erstatninger for Ια-hydroxyvitamin D^ og la,25-15 dihydroxyvitamin D^, de er foreslået til behandling af leukemoide sygdomme.These properties make the homo compounds particularly suitable as substitutes for Ια-hydroxyvitamin D ^ and 1α, 25-15 dihydroxyvitamin D ^, they are proposed for the treatment of leukemoid diseases.
Disse derivater er 24-homovitaminer og specielt la,25-di-hydroxy-22E(eller Z)-dehydro-24-homovitamin-D2 og la,25-20 dihydroxy-24-homovitamin-D2.These derivatives are 24-homovitamins and especially 1α, 25-di-hydroxy-22E (or Z) -dehydro-24-homovitamin-D2 and 1α, 25-20 dihydroxy-24-homovitamin-D2.
Slutprodukterne, de nævnte 24-homoderivater, udviser en uventet høj antineoplastisk virkning uden forøget calcæmisk virkning i modsætning til la-hydroxy-vitamin D^ og 25 la,25-dihydroxyvitamin D^, der i de mængder, der er nød vendige for at opnå antileukæmisk virkning, frembringer et potentielt for højt calciumniveau.The end products, the 24-homo derivatives mentioned, exhibit an unexpectedly high antineoplastic effect without increased calcemic action in contrast to 1α-hydroxy vitamin D 2 and 25 1α, 25-dihydroxyvitamin D 2, which in the amounts necessary to obtain antileukemic effect, produces a potential for high calcium levels.
De nævnte homovitamin-forbindelser kan fremstilles som 30 angivet i følgende reaktionsskema og som beskrevet nedenfor. 1 den skematiske og detaljerede beskrivelse af fremgangsmåden identificerer samme numre samme forbindelser.Said homovitamin compounds can be prepared as indicated in the following reaction scheme and as described below. In the schematic and detailed description of the method, the same numbers identify the same compounds.
3535
DK 159389 BDK 159389 B
3 5 ^ ά 10 0 * 1 hPfto-^kJ hono-^OO* ~ 2. R=7KP ^ ' . ' JL %- H ^ * oH ' · - * Y^ . Y"^il ν-^-Ά0*3 5 ^ ά 10 0 * 1 hPfto- ^ kJ hono- ^ OO * ~ 2. R = 7KP ^ '. 'JL% - H ^ * oH' · - * Y ^. Y "^ il ν - ^ - Ά0 *
15 **0··; j^yj Møn? f^^fN Ro f T15 ** 0 ··; j ^ yj Mon? f ^^ fN Ro f T
5 Horto-''θό"^ ~ z. V R^MOil5 Horto - '' θό "^ ~ z. V R ^ MOil
S X R~HS X R ~ H
20 .y Λ rmc ii · - ro 35 «o-OCoh «o^OC* J3 * ii20 .y Λ rmc ii · - ro 35 «o-OCoh« o ^ OC * J3 * ii
DK 159389 BDK 159389 B
44
Fremstillingen af homovitamin derivaterne beskrives nærmere nedenfor:The preparation of the homovitamin derivatives is further described below:
Bisnorcholensyreacetat (a) reduceredes med lithiumalumi-5 niumhydrid og oxideredes herefter med dichlordicyanoben-zoquinon til 1,4,6-trien-3-onen (b) i et udbytte på 47%. 22-THP-etheren af (b) behandledes med alkalisk hydrogen-peroxid til opnåelse af Ια,2a-epoxidet (1) i et udbytte på 41%. Reduktion af (1) med lithium og ammoniumchlorid i 10 flydende ammoniak-tetrahydrofuran ved -78 °C og efterfølgende behandling med chlormethylmethylether gav dimetho-xymethyletheren (2) i et udbytte på 38%. Fjernelse af THP-gruppen efterfulgt af Swern-oxidation gav aldehydet (4) i et udbytte på 81%. Dette omsattes med vinylmagnesi-15 umbromid til opnåelse af allylalkoholen (5) i et udbytte på 94%. Alkoholen opvarmedes ved tilbagesvaling i xylen med triethylorthoacetat og en katalytisk mængde propion-syre, hvorved esteren (6) opnåedes i et udbytte på 93%. Herefter omsattes esteren (6) med methylmagnesiumbromid 20 til opnåelse af alkoholen (7) i et udbytte på 93%. Fjernelse af MOM-gruppen efterfulgt af acetylering gav (22E)-la,30-diacetoxy-25-hydroxy-24-homo-cholesta-5,22-dien (9) i et udbytte på 73%.Bisnorcholenoic acid acetate (a) was reduced with lithium aluminum hydride and then oxidized with dichlorodicyanobenzoquinone to 1,4,6-trien-3-one (b) in 47% yield. The 22-THP ether of (b) was treated with alkaline hydrogen peroxide to give the Ια, 2α epoxide (1) in a 41% yield. Reduction of (1) with lithium and ammonium chloride in 10 liquid ammonia tetrahydrofuran at -78 ° C and subsequent treatment with chloromethyl methyl ether gave the dimethoxymethyl ether (2) in a 38% yield. Removal of the THP group followed by Swern oxidation gave the aldehyde (4) in a yield of 81%. This was reacted with vinyl magnesium bromide to give the allyl alcohol (5) in a yield of 94%. The alcohol was heated at reflux in xylene with triethyl orthoacetate and a catalytic amount of propionic acid to give the ester (6) in a 93% yield. Then the ester (6) was reacted with methyl magnesium bromide 20 to give the alcohol (7) in a yield of 93%. Removal of the MOM group followed by acetylation gave (22E) -la, 30-diacetoxy-25-hydroxy-24-homo-cholesta-5,22-diene (9) in 73% yield.
25 Allylbromering åf (9) med N-bromsuccinimid efterfulgt af behandling med tetra-n-butylammoniumbromid og herefter med tetra-n-butylammoniumfluorid gav 5,7,22-trienen (10) som et hovedprodukt i et udbytte på 24%. 5,7,22-trienen (10) bestråledes med en mellemtrykskviksølvlampe i ben-30 zen-ethanol i 5 minutter, opvarmedes herefter 1 time ved tilbagesvaling og hydrolyseredes til opnåelse af (22E)-lcc, 25-dihydroxy-22-dehydro-24-homovitamin-D2 (11) i et udbytte på 22%.Allyl bromination of (9) with N-bromosuccinimide followed by treatment with tetra-n-butylammonium bromide and then with tetra-n-butylammonium fluoride gave 5,7,22-triene (10) as a major product in a 24% yield. The 5,7,22-triene (10) was irradiated with a medium-pressure mercury lamp in benzene-ethanol for 5 minutes, then heated at reflux and hydrolyzed to give (22E) -lcc, 25-dihydroxy-22-dehydro-benzene. 24-homovitamin-D2 (11) in a yield of 22%.
35 5,22-dienen (9) hydrogeneredes selektivt til opnåelse af 5-enen (12) i et udbytte på 92%. Denne forbindelse omdannedes til la,25-dihydroxy-24-homovitamin-Dg (14) via 5,7-The 5,22-diene (9) was selectively hydrogenated to give the 5-ene (12) in a 92% yield. This compound was converted to 1α, 25-dihydroxy-24-homovitamin-Dg (14) via 5.7
DK 159389 BDK 159389 B
5 dienen (13) som beskrevet ovenfor i et totalt udbytte på 12%.5 diene (13) as described above in a total yield of 12%.
I den efterfølgende beskrivelse af fremstillingen af 5 slut-24-homovitamin-D2 forbindelserne bestemtes smeltepunkterne med varmtrinsmikroskop og er angivet ukorrige-1 ret. HNMR-spektrene blev optaget med et Hitachi R-24A (60 MHz) NMR-spektrometer i CDCl^ med Me^Si som indre standard, med mindre andet er angivet. Massespektre blev 10 optaget med et Shimadzu QP-1000 massespektrometer ved 70 eV. UV-spektre blev opnået i ethanolisk opløsning med et Shimadzu UV-200 dobbeltstrålespektrofotometer. Søjlechro-matografi blev udført under anvendelse af silicagel (E.In the following description of the preparation of the 5-end 24-homovitamin-D2 compounds, the melting points were determined by hot-stage microscope and indicated as incorrect. The HNMR spectra were recorded with a Hitachi R-24A (60 MHz) NMR spectrometer in CDCl3 with Me ^ Si as the internal standard, unless otherwise indicated. Mass spectra were recorded with a Shimadzu QP-1000 mass spectrometer at 70 eV. UV spectra were obtained in ethanolic solution with a Shimadzu UV-200 dual-beam spectrophotometer. Column chromatography was performed using silica gel (E.
Merck, kiselgel 60, 70-230 mesh). Præparativ tyndtlags-15 chromatografi blev udført på præcoatede plader af silicagel (E. Merck, kiselgel 60 F254' mm tykkelse).Merck, silica gel 60, 70-230 mesh). Preparative thin-layer chromatography was performed on pre-coated silica gel plates (E. Merck, silica gel 60 F254 mm thick).
Den almindelige oparbejdning sker ved fortynding med vand, ekstraktion med et organisk opløsningsmiddel angivet i parentes, vask af ekstrakten til neutral reaktion, 20 tørring over vandfrit magnesiumsulfat, filtrering og fjernelse af opløsningsmidlet under reduceret tryk. Følgende forkortelser er anvendt: THP - tetrahydropyranyl; THF - tetrahydrofuran; ether - diethylether, MeOH - methanol, MOM - methoxymethyl. Temperaturer er angivet i 25 °C.The ordinary work up is done by dilution with water, extraction with an organic solvent indicated in brackets, washing the extract for neutral reaction, drying over anhydrous magnesium sulfate, filtering and removing the solvent under reduced pressure. The following abbreviations are used: THP - tetrahydropyranyl; THF - tetrahydrofuran; ether - diethyl ether, MeOH - methanol, MOM - methoxymethyl. Temperatures are given in 25 ° C.
22-hydroxy-23,24-dinorchola-l,4,6-trien-3-on (b)22-Hydroxy-23,24-dinorchola-1,4,6-trien-3-one (b)
Til en opløsning af 30-acetoxydinorcholensyre (a) (7,0 g, 30 18,04 mmol) i THF (20 ml) sattes lithiumaluminiumhydrid (3,0 g, 78,95 mmol). Blandingen omrørtes ved 60 °C i 14 timer. Til reaktionsblandingen sattes forsigtigt vand og ethylacetat. Filtrering og fjernelse af opløsningsmidlet gav en remanens (5,2 g). Denne behandledes i dioxan (140 35 ml) med dichlordicyanobenzoguinon (11,7 g, 51,54 mmol) under tilbagesvaling i 14 timer. Efter afkøling til stuetemperatur filtreredes reaktionsblandingen, og filtratetTo a solution of 30-acetoxydinorcholenic acid (a) (7.0 g, 18.04 mmol) in THF (20 ml) was added lithium aluminum hydride (3.0 g, 78.95 mmol). The mixture was stirred at 60 ° C for 14 hours. To the reaction mixture was gently added water and ethyl acetate. Filtration and removal of the solvent gave a residue (5.2 g). This was treated in dioxane (140 35 ml) with dichlorodicyanobenzoguinone (11.7 g, 51.54 mmol) at reflux for 14 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate
DK 159389BDK 159389B
6 inddampedes til en remanens, der påførtes en søjle af aluminiumoxid (200 g). Eluering med dichlormethan gav trienonen (b) (2,8 g 47%) smp. 156-157 °C (ether) UV\ Et0H/max nm (epsilon): 299 (13000), 252 (9200), 224 5 (12000), 1H-NMR (CDClg) 6: 0,80 (3H, S, 18-Hg), 1,04 (3H, d, J=6 Hz, 21-Hg), 1,21 (3H, s, 19-Hg), 3,10-3,80 (3H, m, 22-H2 og OH), 5,90-6,40 (4H, m, 2-H, 4-H, 6-H og 7-H), 7,05 (IH, d, J=10 Hz, 1-H), MS m/z: 326 (M~), 311, 308, 293, 267, 112.6 was evaporated to a residue applied to a column of alumina (200 g). Elution with dichloromethane gave the trienone (b) (2.8 g 47%) m.p. 156-157 ° C (ether) UV / EtOH / max nm (epsilon): 299 (13000), 252 (9200), 224 (12000), 1 H NMR (CDCl 3) δ: 0.80 (3H, S, 18-Hg), 1.04 (3H, d, J = 6 Hz, 21-Hg), 1.21 (3H, s, 19-Hg), 3.10-3.80 (3H, m, 22- H2 and OH), 5.90-6.40 (4H, m, 2-H, 4-H, 6-H and 7-H), 7.05 (1H, d, J = 10 Hz, 1-H ), MS m / z: 326 (M +), 311, 308, 293, 267, 112.
10 la,2g-epoxy-22-tetrahydropyranyloxy-23,24-dinorchola-4,6-dien-3-on (1)10α, 2β-epoxy-22-tetrahydropyranyloxy-23,24-dinorchola-4,6-dien-3-one (1)
Alkoholen (b) (2,7 g, 8,28 mmol) i dichlormethan (50 ml) 15 behandledes med dihydropyran (1,5 ml, 16,42 mmol) og p-toluensulfonsyre (50 mg) ved stuetemperatur i 1 time. Almindelig oparbejdning (ethylacetat til ekstraktionen) gav en urenset forbindelse. Til en opløsning af denne forbindelse i MeOH (70 ml) sattes 30% H202 (4,8 ml) og 10% 20 NaOH/MeOH (0,74 ml), og blandingen omrørtes 14 timer ved stuetemperatur. Sædvanlig oparbejdning (ethylacetat til ekstraktionen) gav en urenset forbindelse, der påførtes en søjle af silicagel (50 g). Eluering med benzen-ethyl-acetat (100:1) gav epoxidet (1) (1,45 g, 41%): smp. 113-25 115 °C (hexan) UVA E^H/max nm (epsilon): 290 (22000), 1H-NMR (CDC13) 6: 0,80 (3H, s, 18-H3), 1,04 (3H, d, J=6 Hz, 21-H3), 1,21 (3H, s, 19-Hg), 3,38 (IH, dd, J=4 og 1,5 Hz, 1-H), 3,55 (IH, d, J=4 Hz, 2-H), 3,30-4,10 (4H, m, 22-H2 og THP), 4,50 (IH, m, THP), 5,58 (IH, d, J-1,5 Hz, 30 4-H), 6,02 (2H, s, 6-H og 7-H), MS m/z: 342 (M+- DHP), 324 (M+- THPOH), 309, 283, 85.The alcohol (b) (2.7 g, 8.28 mmol) in dichloromethane (50 ml) was treated with dihydropyran (1.5 ml, 16.42 mmol) and p-toluenesulfonic acid (50 mg) at room temperature for 1 hour. Ordinary work-up (ethyl acetate for the extraction) gave a crude compound. To a solution of this compound in MeOH (70 ml) was added 30% H 2 O 2 (4.8 ml) and 10% NaOH / MeOH (0.74 ml) and the mixture was stirred for 14 hours at room temperature. Usual work-up (ethyl acetate for the extraction) gave a crude compound which was applied to a column of silica gel (50 g). Elution with benzene-ethyl acetate (100: 1) gave the epoxide (1) (1.45 g, 41%): m.p. 113-25 115 ° C (hexane) UVA E 1 H / max nm (epsilon): 290 (22000), 1 H NMR (CDCl 3) δ: 0.80 (3H, s, 18-H3), 1.04 ( 3H, d, J = 6 Hz, 21-H3), 1.21 (3H, s, 19-Hg), 3.38 (1H, dd, J = 4 and 1.5 Hz, 1-H), 3 , 55 (1H, d, J = 4 Hz, 2-H), 3.30-4.10 (4H, m, 22-H2 and THP), 4.50 (1H, m, THP), 5.58 (1H, d, J-1.5 Hz, 4-H), 6.02 (2H, s, 6-H and 7-H), MS m / z: 342 (M + - DHP), 324 (M + - THPOH), 309, 283, 85.
la,3fl-dimethoxy-23,24-dinorchol-5-en-22-tetrahydropyra-nylether (2) 351α, 3β-dimethoxy-23,24-dinorchol-5-ene-22-tetrahydropyranyl ether (2)
Lithium (5,00 g ) sattes i små portioner til flydende ammoniak (200 ml) ved -78 "C i en argonatmosfære i løbet afLithium (5.00 g) was added in small portions to liquid ammonia (200 ml) at -78 ° C in an argon atmosphere over time.
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7 30 minutter. Efter omrøring i 1 time ved -78 °C til-dryppedes lo,2a-epoxy-22-tetrahydropyranyloxy-23,24- dinorchola-4,6-dien-3-on (1) (2,00 g, 4,69 mmol) i tør THF (50 ml) ved -78 °C i løbet af 30 minutter, og blan-5 dingen omrørtes 1 time ved -78 °C. Til reaktionsblandingen sattes vandfrit NH^Cl (60 g) i små portioner i løbet af 1 time ved -78 °C. Efter 1,5 timers forløb fjernedes afkølingsbadet, og det meste af ammoniakken fjernedes ved gennembobling med argon. Sædvanlig opar-10 bejdning (ether anvendtes som opløsningsmiddel) gav en urenset forbindelse. Denne behandledes med chlor-methyl-methylether (2,0 ml, 26,34 mmol) og N,N-diethylcyclohe-xylamin (4,6 ml, 24,93 mmol) i dioxan (20 ml) ved 45 °C i 24 timer. Sædvanlig oparbejdning (ethylacetat) gav en 15 urenset forbindelse, der påførtes en søjle af silicagel (40 g). Eluering med hexan-ethylacetat (5:1) gav dime-thoxymethyletheren (2) (922 mg, 38%) som en olie. ^H-NMR δ: 0,70 (3H, s, 18-H3), 1,02 (3H, s, 19-H3), 1,04 (3H, d, J=6 Hz, 21-H3), 3,34 (3H, s, -0-CH3), 3,37 (3H, s, -0-20 CH3), 4,63 (2H, ABq, J=7 Hz, δ AB=11 Hz, la-0-CH2-0-), 4,64 (2H, s, 30-0-CH2-0-) og 5,50 (IH, m, 6-H).7 30 minutes. After stirring for 1 hour at -78 ° C, 2,2-epoxy-22-tetrahydropyranyloxy-23,24-dinorchola-4,6-dien-3-one (1) (2.00 g, 4.69) was added dropwise. mmol) in dry THF (50 ml) at -78 ° C over 30 minutes and the mixture was stirred for 1 hour at -78 ° C. To the reaction mixture was added anhydrous NH 2 Cl (60 g) in small portions over 1 hour at -78 ° C. After 1.5 hours, the cooling bath was removed and most of the ammonia was removed by bubbling with argon. Conventional processing (ether was used as the solvent) gave an impure compound. This was treated with chloromethyl methyl ether (2.0 ml, 26.34 mmol) and N, N-diethylcyclohexylamine (4.6 ml, 24.93 mmol) in dioxane (20 ml) at 45 ° C for 24 hours. hours. Usual work-up (ethyl acetate) gave a crude compound which was applied to a column of silica gel (40 g). Elution with hexane-ethyl acetate (5: 1) gave the dimethoxymethyl ether (2) (922 mg, 38%) as an oil. 1 H NMR δ: 0.70 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 1.04 (3H, d, J = 6 Hz, 21-H3), 3.34 (3H, s, -0-CH3), 3.37 (3H, s, -0-20 CH3), 4.63 (2H, ABq, J = 7 Hz, δ AB = 11 Hz, 0-CH 2 -O-), 4.64 (2H, s, 30-O-CH 2 -O-) and 5.50 (1H, m, 6-H).
lg,3fl-dimethoxy-23,24-dinorchol-5-en-22-ol (3)Ig, 3fl-dimethoxy-23,24-dinorchol-5-en-22-ol (3)
25 THP-etheren (2) (922 mg, 177 mmol) i THF (8 ml) og MeOHThe THP ether (2) (922 mg, 177 mmol) in THF (8 ml) and MeOH
(8 ml) behandledes med 2 M HC1 (1 ml) i 2 timer ved stuetemperatur. Sædvanlig oparbejdning (ethylacetat) gav en urenset forbindelse, der påførtes en søjle af silicagel (40 g). Eluering med hexan-ethylacetat (2:1) gav alkohol-30 en (3) (678 mg, 88%) som et amorpht fast stof. ^H-NMR δ: 0,70 (3H, s, 18-H3), 1,02 (3H, s, 19-H3), 1,04 (3H, d, J=6 Hz, 21-H3), 3,34 (3H, s, -O-CHg), 3,38 (3H, s, -0-CHg), 4,65 (2H, ABq, J=7 Hz, δ AB<= 11 Hz, l«-0-CH2-0-), 4,66 (2H, s, 30-0-CH2-0-), 5,53 (IH, m, 6-H).(8 ml) was treated with 2 M HCl (1 ml) for 2 hours at room temperature. Usual work-up (ethyl acetate) gave an impure compound which was applied to a column of silica gel (40 g). Elution with hexane-ethyl acetate (2: 1) gave the alcohol (3) (678 mg, 88%) as an amorphous solid. 1 H NMR δ: 0.70 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 1.04 (3H, d, J = 6 Hz, 21-H3), 3.34 (3H, s, -O-CHg), 3.38 (3H, s, -0-CHg), 4.65 (2H, ABq, J = 7 Hz, δ AB <= 11 Hz, l -0-CH 2 -O-), 4.66 (2H, s, 30-O-CH 2 -O-), 5.53 (1H, m, 6-H).
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8 lg,3g-dimethoxy-23,24-dinorchol-5-en-22-al (4)8 lg, 3g-dimethoxy-23,24-dinorchol-5-en-22-al (4)
Til en opløsning af oxalylchlorid (0,27 ml, 3,09 mmol) i dichlormethan (8 ml) sattes ved -78 °C under argon dime-5 thylsulfoxid (0,44 ml, 6,21 mmol). Blandingen omrørtes 10 minutter ved -78 °C. Til opløsningen sattes alkoholen (3) (660 mg, 1,51 mmol) i dichlormethan (5 ml) ved -78 °C.To a solution of oxalyl chloride (0.27 mL, 3.09 mmol) in dichloromethane (8 mL) was added at -78 ° C under argon dimethyl sulfoxide (0.44 mL, 6.21 mmol). The mixture was stirred for 10 minutes at -78 ° C. To the solution was added the alcohol (3) (660 mg, 1.51 mmol) in dichloromethane (5 ml) at -78 ° C.
Efter omrøring i 15 minutter tilsattes triethylamin (1,89 ml, 13,6 mmol). Blandingen omrørtes ved -78 °C under 10 argon i 5 minutter og opvarmedes til stuetemperatur. Sædvanlig oparbejdning (ether) gav en urenset forbindelse, der påførtes en søjle af silicagel (30 g). Eluering med hexan-ethylacetat (4:1) gav aldehydet (4) (607 mg, 92%) som en krystallinsk masse med smeltepunkt 71-72 °C (hex-15 an), 1H-NMR δ: 0,74 (3H, s, 18-Hg), 1,04 (3H, s, 19-Hg), 1,12 (3H, d, J=6 Hz, 21-Hg),3,35 (3H, s, -O-CHg), 3,39 (3H, S, -O-CHg), 3,7 (IH, m, 10-H), 4,65 (2H, ABq, J=7 Hz, δ AB=11 Hz, l«-0-CH2-0-), 4,66 (2H, s, 30-0-CH-0-), 5,52 (IH, m, 6-H) og 9,61 (IH, d, J=3 Hz, -CH0), analyse 20 beregnet for C26H42°5: C/ 71,85; H 9/74. Fundet: C, 71,71; H, 9,68.After stirring for 15 minutes, triethylamine (1.89 mL, 13.6 mmol) was added. The mixture was stirred at -78 ° C under 10 argon for 5 minutes and warmed to room temperature. Usual work-up (ether) yielded an impure compound applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (4: 1) gave the aldehyde (4) (607 mg, 92%) as a crystalline mass, m.p. 71-72 ° C (hex-15 an), 1 H-NMR δ: 0.74 (3H , s, 18-Hg), 1.04 (3H, s, 19-Hg), 1.12 (3H, d, J = 6 Hz, 21-Hg), 3.35 (3H, s, -O- CHg), 3.39 (3H, S, -O-CHg), 3.7 (1H, m, 10-H), 4.65 (2H, ABq, J = 7 Hz, δ AB = 11 Hz, l -O-CH 2 -O-), 4.66 (2H, s, 30-O-CH-O-), 5.52 (1H, m, 6-H) and 9.61 (1H, d, J = 3 Hz, -CHO), analysis calculated for C 26 H 42 ° 5: C / 71.85; H 9/74. Found: C, 71.71; H, 9.68.
la,3g-dimethoxychola-5,23 dien-22-ol (5) 25 Til magnesium (70 mg, 2,92 mmol) i THF (3 ml) sattes en 50% opløsning af vinylbromid i THF (0,42 ml, 2,98 mmol). Blandingen omrørtes under argon ved stuetemperatur i 30 minutter. Til det fremstillede Grignard-reagens sattes aldehydet (4) (5,95 mg, 1,37 mmol) i THF (6 ml) ved stue-30 temperatur. Blandingen omrørtes 1 time ved stuetemperatur. Sædvanlig oparbejdning (ether) gav en urenset forbindelse, der påf ørtes en søjle af silicagel (30 g). Eluering med hexan-ethylacetat (3:1) gav allylalkoholen (5) (595 mg, 94%) som et amorpht fast stof. ^H-NMR 6: 35 0,70 (3H, s, 18-H3), 1,02 (3H, s,m 19-H3), 3,35 (3H, s, - 0-CH3), 3,38 (3H, s, -0-CH3), 3,69 (IH, m, 10-H), 4,20 (IH, m, 22-H), 4,64 (2H, ABq, J=7 Hz, δ AB= 11 Hz, la-0-1a, 3g-dimethoxychola-5.23 dien-22-ol (5) To magnesium (70 mg, 2.92 mmol) in THF (3 ml) was added a 50% solution of vinyl bromide in THF (0.42 ml, 2.98 mmol). The mixture was stirred under argon at room temperature for 30 minutes. To the prepared Grignard reagent, the aldehyde (4) (5.95 mg, 1.37 mmol) in THF (6 ml) was added at room temperature. The mixture was stirred for 1 hour at room temperature. Usual work-up (ether) gave an impure compound which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (3: 1) gave the allyl alcohol (5) (595 mg, 94%) as an amorphous solid. 1 H-NMR 6: 0.70 (3H, s, 18-H3), 1.02 (3H, s, m 19-H3), 3.35 (3H, s, -O-CH 3), 38 (3H, s, -0-CH 3), 3.69 (1H, m, 10-H), 4.20 (1H, m, 22-H), 4.64 (2H, ABq, J = 7 Hz , δ AB = 11 Hz, 1a-0-
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9 CH2-0-), 4,65 (2H, s, 30-0-0^-0-), 5,52 (IH, m, 6-H), 4,90-6,0 (3H, m, 23-H og 24-H2).9 CH2-0-), 4.65 (2H, s, 30-0-0 ^ -0-), 5.52 (1H, m, 6-H), 4.90-6.0 (3H, m , 23-H and 24-H2).
(22E)-lg,30-dimethoxymethoxy-27-norcholesta-5,22-dien-26-5 onsyreethylester (6)(22E) -lg, 30-dimethoxymethoxy-27-norcholesta-5,22-diene-26-5-acid ethyl ester (6)
En opløsning af allylalkoholen (5) (590 mg, 1,28 mmol), triethylorthoacetat (1,0 ml, 5,64 mmol), propionsyre (4 dråber) og xylen (8 ml) opvarmedes under argon i 2 timer 10 ved tilbagesvaling. Fjernelse af opløsningsmidlet under reduceret tryk gav en remanens, der påførtes en søjle af silicagel (30 g). Eluering med hexan/ethylacetat (4:1) gav esteren (6) (630 mg, 93%) som en olie. H-NMR 6: 0,68 (3H, s, 18-H3), 0,97 (3H, d, J=6 Hz, 21-H3), 1,03 (3H, s, 15 19-Hg), 1,24 (3H, t, J=7 Hz, -CC>2CH2CH3), 3,35 (3H, s, - 0-CH3), 3,39 (3H, s, -0-CH3), 3,70 (IH, m, 10-H), 4,11 (2H, q, J=7 Hz, -C02CH2CH3)., 4,64 (2H, ABq, J=7 Hz, Delta AB= 11 Hz, la-0-CH2-0-), 4,65 (2H, s, 30-0-0^-0-), 5,29 (2H, m, 22-H og 23-H), 5,52 (IH, m, 6-H).A solution of the allyl alcohol (5) (590 mg, 1.28 mmol), triethyl orthoacetate (1.0 ml, 5.64 mmol), propionic acid (4 drops) and xylene (8 ml) was heated under argon for 2 hours at reflux . Removal of the solvent under reduced pressure gave a residue applied to a column of silica gel (30 g). Elution with hexane / ethyl acetate (4: 1) afforded the ester (6) (630 mg, 93%) as an oil. H-NMR δ: 0.68 (3H, s, 18-H3), 0.97 (3H, d, J = 6 Hz, 21-H3), 1.03 (3H, s, 19-Hg), 1.24 (3H, t, J = 7 Hz, -CC> 2CH 2 CH 3), 3.35 (3H, s, - O-CH 3), 3.39 (3H, s, -0-CH 3), 3.70 (1H, m, 10-H), 4.11 (2H, q, J = 7 Hz, -CO 2 CH 2 CH 3)., 4.64 (2H, ABq, J = 7 Hz, Delta AB = 11 Hz, Ia-0 -CH2-0-), 4.65 (2H, s, 30-0-0 ^ -0-), 5.29 (2H, m, 22-H and 23-H), 5.52 (1H, m , 6-H).
2020
Eventuelt kan den 22E stereoisomere forbindelse (6) let omdannes til 22Z stereoisomeren ved behandling med iod. Behandling af forbindelsen (6) i ethex' med en katalytisk mængde iod (2%) i forhold til forbindelsen (6) bevirker 25 således under diffust dagslys i 1 time en trans til cis isomerisering, der efter HPLC-rensning (Zorbax-Sil søjle, 4,6 x 25 cm, 6% 2-propanol/hexan) giver 22Z-stereoiso-meren.Optionally, the 22E stereoisomeric compound (6) can be readily converted to the 22Z stereoisomer by iodine treatment. Thus, treatment of the compound (6) in ethex with a catalytic amount of iodine (2%) relative to the compound (6) causes a trans to cis isomerization under HPLC purification (Zorbax-Sil column) under diffuse daylight for 1 hour. , 4.6 x 25 cm, 6% 2-propanol / hexane) gives the 22Z stereoisomer.
30 ( 22E)-1α,3 0-dimethoxymethoxy-24-homo-cholesta-5,22-dien- 25-pl (7)30 (22E) -1α, 30-dimethoxymethoxy-24-homo-cholesta-5,22-diene-25-pl (7)
Til en opløsning af esteren (6) (605 mg, 1,14 mmol) i THF (6 ml) sattes en 1 M opløsning af methylmagnesiumbromid i 35 THF (4,5 ml, 4,5 mmol) ved stuetemperatur. Blandingen om-rørtes 1 time ved stuetemperatur. Sædvanlig oparbejdning (ether) gav en urenset forbindelse, der påførtes en søjleTo a solution of the ester (6) (605 mg, 1.14 mmol) in THF (6 ml) was added a 1 M solution of methyl magnesium bromide in THF (4.5 ml, 4.5 mmol) at room temperature. The mixture was stirred for 1 hour at room temperature. Usual work-up (ether) gave an unclean compound applied to a column
10 DK 159389 BDK 159389 B
af silicagel (30 g). Eluering med hexan/ethylacetat (3:1) gav alkoholen (7) (548 mg, 93%) som en olie. "^H-NMR δ: 0,68 (3H, s, 18-H3), 0,97 (3H, d, J=6 Hz, 21-H3), 1,01 (3H, s, 19-H3), 1,21 (6H, s, 26-H3 og 27-H3), 3,33 (3H, 5 s, -0-CH3), 3,38 (3H, s, -0-CHg), 3,70 (IH, m, 10-H), 4,64 (2H, ABq, J=7 Hz, δ AB= 11 Hz, la-O-CHg-O-), 4,65 (2H, s, 35-0-CH2-0-), 5,29 (2H, m, 22-H og 23-H) og 5,50 (IH, m, 6-H).of silica gel (30 g). Elution with hexane / ethyl acetate (3: 1) gave the alcohol (7) (548 mg, 93%) as an oil. 1 H-NMR δ: 0.68 (3H, s, 18-H3), 0.97 (3H, d, J = 6 Hz, 21-H3), 1.01 (3H, s, 19-H3) , 1.21 (6H, s, 26-H3 and 27-H3), 3.33 (3H, 5 s, -0-CH 3), 3.38 (3H, s, -0-CH 3), 3.70 (1H, m, 10-H), 4.64 (2H, ABq, J = 7 Hz, δ AB = 11 Hz, Ia-O-CHg-O-), 4.65 (2H, s, 35-0 -CH 2 -O-), 5.29 (2H, m, 22-H and 23-H) and 5.50 (1H, m, 6-H).
10 (22E)-24-homocholesta-5,22-dien-lg,3fl,25-trlol (8)(22E) -24-homocholesta-5,22-diene-lg, 3fl, 25-trol (8)
En opløsning af dimethoxymethyletheren (7) (540 mg, 1,04 mmol) i THF (15 ml) behandledes med 6 M HC1 (3 ml) ved 50 °C i 2,5 timer. Sædvanlig oparbejdning (ethylacetat) gav 15 en urenset forbindelse, der påførtes en søjle af silicagel (20 g). Eluering med hexan/ethylacetat (1:1) gav triolen (8) (428 mg, 95%) som et krystallinsk produkt.A solution of the dimethoxymethyl ether (7) (540 mg, 1.04 mmol) in THF (15 ml) was treated with 6 M HCl (3 ml) at 50 ° C for 2.5 hours. Usual work-up (ethyl acetate) gave an impure compound which was applied to a column of silica gel (20 g). Elution with hexane / ethyl acetate (1: 1) gave the triol (8) (428 mg, 95%) as a crystalline product.
Smp. 164-166 °C (hexan/ethylacetat) ^H-NMR δ: 0,68 (3H, s, 18-Hg), 0,95 (3H, S, J=6 Hz, 21-Hg), 1,00 (3H, s, 19-20 Hg), 1,20 (6H, s, 26-Hg og 27-H3), 3,80 (IH, m, 10-H), 3,92 (IH, m, 3a-H), 5,30 (2H, 22-H og 23-H) og 5,53 (IH, m, 6-H).Mp. 164-166 ° C (hexane / ethyl acetate) 1 H-NMR δ: 0.68 (3H, s, 18-Hg), 0.95 (3H, S, J = 6 Hz, 21-Hg), 1.00 (3H, s, 19-20 Hg), 1.20 (6H, s, 26-Hg and 27-H3), 3.80 (1H, m, 10-H), 3.92 (1H, m, 3a) -H), 5.30 (2H, 22-H and 23-H) and 5.53 (1H, m, 6-H).
(22E)-la,3fl-diacetoxy-25-hydroxy-24-homocholesta-5,22-25 dien (9)(22E) -1α, 3β-diacetoxy-25-hydroxy-24-homocholesta-5,22-25 diene (9)
En opløsning af triolen (8)· (395 mg, 0,919 mmol) i pyri-din (2 ml) behandledes med eddikesyreanhydrid (1 ml) ved stuetemperatur i 16 timer. Sædvanlig oparbejdning (ethyl-30 acetat) gav en urenset forbindelse, der påførtes en søjle af silicagel (20 g). Eluering med hexan/ethylacetat (2:1) i gav diacetatet (9) (361 mg, 77%) som en olie. H-NMR 6: 0,67 (3H, s, 18-H3), 0,97 (3H, d, J=6 Hz, 21-Hg), 1,07 (3H, s, 19-H3), 1,21 (6H, s, 26-Hg og 27-H3), 2,01 (3H, 35 s, acetyl), 2,04 (3H, s, acetyl), 4 98 (IH, m, 3a-H), 5,05 (IH, m, lfi-H), 5,31 (2H m 22-H og 23-H) og 5,52 (IH, m, 6-H).A solution of the triol (8) · (395 mg, 0.919 mmol) in pyridine (2 ml) was treated with acetic anhydride (1 ml) at room temperature for 16 hours. Usual work-up (ethyl acetate) gave an impure compound applied to a column of silica gel (20 g). Elution with hexane / ethyl acetate (2: 1) gave the diacetate (9) (361 mg, 77%) as an oil. H-NMR δ: 0.67 (3H, s, 18-H3), 0.97 (3H, d, J = 6 Hz, 21-Hg), 1.07 (3H, s, 19-H3), 1 , 21 (6H, s, 26-Hg and 27-H3), 2.01 (3H, 35 s, acetyl), 2.04 (3H, s, acetyl), 4 98 (1H, m, 3a-H) , 5.05 (1H, m, lfi-H), 5.31 (2H m 22-H and 23-H) and 5.52 (1H, m, 6-H).
1111
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(22E)-Ια,30-diacetoxy-25-hydroxy-24-homocholesta-5,7 , 22-trien (10)(22E) -Ια, 30-diacetoxy-25-hydroxy-24-homocholesta-5,7, 22-triene (10)
En opløsning af 5-enen (9) (51 mg, 0,0992 mmol) og N-5 bromsuccinimid (21 mg, 0,118 mmol) opvarmedes med tilbagesvaling under argon i 20 minutter i carbontetrachlorid (3 ml). Efter at blandingen var afkølet til 0 °C frafil-treredes det udfældede bundfald. Filtratet koncentreredes under 40 °C til opnåelse af en remanens. Denne behandle-10 des i THF (5 ml) med en katalytisk mængde tetra-n-bu-tylammoniumbromid i 50 minutter ved stuetemperatur. Herefter behandledes blandingen med en opløsning af tetra-n-butylammoniumfluorid i THF (3,5 ml, 3,5 mmol) i 30 minutter ved stuetemperatur. Sædvanlig oparbejdning (ethyl-15 acetat) gav en urenset forbindelse, der underkastedes præparativ tyndtlagschromatografi (hexan/ethylacetat, 4:1, fremkaldt 5 gange). Båndet med Rf-værdien 0,48 fjernedes og elueredes med ethylacetat. Fjernelse af opløsningsmidlet gav 5,7,22-trienen (10) (12,5 mg, 24%), UVA 20 Et0H/max nm: 293, 282 og 271.A solution of 5-ene (9) (51 mg, 0.0992 mmol) and N-5 bromosuccinimide (21 mg, 0.118 mmol) was heated under reflux under argon for 20 minutes in carbon tetrachloride (3 ml). After the mixture was cooled to 0 ° C, the precipitated precipitate was filtered off. The filtrate was concentrated below 40 ° C to give a residue. This was treated in THF (5 ml) with a catalytic amount of tetra-n-butylammonium bromide for 50 minutes at room temperature. Then the mixture was treated with a solution of tetra-n-butylammonium fluoride in THF (3.5 ml, 3.5 mmol) for 30 minutes at room temperature. Usual work-up (ethyl acetate) gave an crude compound which was subjected to thin-layer preparative chromatography (hexane / ethyl acetate, 4: 1, developed 5 times). The band with Rf value 0.48 was removed and eluted with ethyl acetate. Removal of the solvent gave the 5,7,22 triene (10) (12.5 mg, 24%), UVA 20 EtOH / max nm: 293, 282 and 271.
la,25-dihydroxy-22E-dehydro-24-homovitamin-Dg (11)1α, 25-dihydroxy-22E-dehydro-24-homovitamin-Dg (11)
En opløsning af 5,7,22-trienen (10) (7,3 mg, 0,0143 mmol) 25 i benzen (90 ml) og ethanol (40 ml) bestråledes med en mellemtrykskviksølvlampe gennem et Vycor-filter ved 0 °C i 5 minutter under argon. Reaktionsblandingen opvarmedes under argon i 1 time med tilbagesvaling. Fjernelse af opløsningsmidlet under reduceret tryk gav en urenset for-30 bindelse, der underkastedes præparativ tyndtlagschromatografi (hexan/ethylacetat, 4:1, der blev fremkaldt 5 gange). Båndet med Rf-værdien 0,38 fjernedes og elueredes med ethylacetat. Fjernelse af opløsningsmidlet gav vita-min-Dg-diacetatet (1,8 mg, 25%). Båndet med Rf-værdien 35 0,43 fjernedes, og der elueredes med ethylacetat. Fjer nelse af opløsningsmidlet genudvandt 5,7,22-trienen (10) (2,1 mg, 29%).A solution of 5,7,22-triene (10) (7.3 mg, 0.0143 mmol) in benzene (90 ml) and ethanol (40 ml) was irradiated with a medium-pressure mercury lamp through a Vycor filter at 0 ° C. for 5 minutes under argon. The reaction mixture was heated under argon for 1 hour at reflux. Removal of the solvent under reduced pressure gave an crude compound which was subjected to preparative thin layer chromatography (hexane / ethyl acetate, 4: 1, which was developed 5 times). The band with Rf value 0.38 was removed and eluted with ethyl acetate. Removal of the solvent gave the vitamin Dg diacetate (1.8 mg, 25%). The band with Rf value of 0.43 was removed and eluted with ethyl acetate. Removal of the solvent recovered the 5,7,22-triene (10) (2.1 mg, 29%).
DK 159389 BDK 159389 B
1212
Vitamin-Dg-diacetat (1,8 mg, 2,15 mmol) i THF (4 ml) behandledes med 5% KOH/MeOH (1 ml) ved stuetemperatur i 20 minutter. Sædvanlig oparbejdning (ethylacetat) gav en urenset forbindelse, der underkastedes præparativ tyndt-5 lagschromatografi (hexan/ethylacetat, 1:2, fremkaldt 3 gange). Båndet med Rf-værdien 0,43 fjernedes og elueredes med ethylacetat. Fjernelse af opløsningsmidlet gav vita-min-Dg analogen (11) (1,4 mg, 90%). Renheden af forbindelsen (11) bestemtes til 100% ved højtryksvæskechro-10 matografi (Shimadzu LC-3A; søjle Zorbax ZIL normalfase, 4,6 mm indre diameter x 15 cm; opløsningsmiddel MeOH-CHgClg, 1:49, strømningshastighed 3 ml/minut; tilbageholdelsestid 11,5 minutter). Den vitamin-D« analoge (11)Vitamin Dg diacetate (1.8 mg, 2.15 mmol) in THF (4 mL) was treated with 5% KOH / MeOH (1 mL) at room temperature for 20 minutes. Usual work-up (ethyl acetate) gave an crude compound which was subjected to thin-layer preparative chromatography (hexane / ethyl acetate, 1: 2, induced 3 times). The band with the Rf value 0.43 was removed and eluted with ethyl acetate. Removal of the solvent gave the vitamin-Dg analogue (11) (1.4 mg, 90%). The purity of the compound (11) was determined to 100% by high-pressure liquid chromatography (Shimadzu LC-3A; column Zorbax ZIL normal phase, 4.6 mm internal diameter x 15 cm; solvent MeOH-CHgClg, 1:49, flow rate 3 ml / minute ; retention time 11.5 minutes). The Vitamin D «Analog (11)
EtrOH ^ havde følgende spektraldata: UV λ /max: 265 nm, UV λ 15 Et0H/min: 228 nm, MS m/z: 428 (M+), 410, 392 (basetop), 374, 287, 269, 251, 152, 134, 123, 59 1H-NMR (360 MHz) 6: 0,55 (3H, s, 18-Hg), 1,02 (3H, d, J=6,6 Hz, 21-Hg), 1,22 (6H, s, 26-Hg og 27-Hg), 2,32 (IH, dd, J=13,2 og 6,7 Hz), 2,60 (IH, dd, J=13,0 og 3,0 Hz), 2,83 (IH, dd, J=12,0 og 20 3,0 Hz), 4,23 (IH, m, W1/2 = 18,4 Hz, 3a-H), 4,43 (IH, m, W!/2 = 16,9 Hz, 10-H), 5,00 (IH, bs, W1/2 = 3,2 Hz, 19-H), 5,30 (IH, dd, J=15,0 og 7,1 Hz, 22-H eller 23-H), 5,33 (IH, bs, W1/2 = 3,2 Hz, 19-H), 5,37 (IH, dd, J=15,0 og 5,8 Hz, 22-H eller 23-H), 6,01 (IH, d, J=11,0 Hz, 7-25 H), 6,32 (IH, d, J=11,0 Hz, 6-H).EtrOH had the following spectral data: UV λ / max: 265 nm, UV λ EtOH / min: 228 nm, MS m / z: 428 (M +), 410, 392 (base peak), 374, 287, 269, 251, 152 1 H-NMR (360 MHz) δ: 0.55 (3H, s, 18-Hg), 1.02 (3H, d, J = 6.6 Hz, 21-Hg), 1, 22 (6H, s, 26-Hg and 27-Hg), 2.32 (1H, dd, J = 13.2 and 6.7 Hz), 2.60 (1H, dd, J = 13.0 and 3 , 0 Hz), 2.83 (1H, dd, J = 12.0 and 3.0 Hz), 4.23 (1H, m, W1 / 2 = 18.4 Hz, 3a-H), 4, 43 (1H, m, W / 2 = 16.9 Hz, 10-H), 5.00 (1H, bs, W1 / 2 = 3.2 Hz, 19-H), 5.30 (1H, dd , J = 15.0 and 7.1 Hz, 22-H or 23-H), 5.33 (1H, bs, W1 / 2 = 3.2 Hz, 19-H), 5.37 (1H, dd , J = 15.0 and 5.8 Hz, 22-H or 23-H), 6.01 (1H, d, J = 11.0 Hz, 7-25 H), 6.32 (1H, d, J = 11.0 Hz, 6-H).
lg,3g-diacetoxy-24-homocholesta-5-en-25-ol (12)Ig, 3g-diacetoxy-24-homocholesta-5-en-25-ol (12)
En blanding af 5,22-dienen (9) (40 mg, 0,0778 mmol) og 30 10% Pd-C (4 mg) i ethylacetat (2 ml) omrørtes under hy drogen i 3 timer ved stuetemperatur. Pd-katalysatoren frafiltreredes, og filtratet koncentreredes til opnåelse af en remanens, der påførtes en søjle af silicagel (5 g). Eluering med hexan/ethylacetat (4:1) gav 5-enen (12) (37 35 mg, 92%) som en olie. ^H-NMR δ: 0,66 (3H, s, 18-Hg), 1,08 (3H, s, 19-Hg), 1,20 (6H, s, 26-Hg og 27-Hg), 2,02 (3H, s, acetyl), 2,05 (3H, s, acetyl), 4,97 (IH, m, 3a-H),A mixture of 5,22-diene (9) (40 mg, 0.0778 mmol) and 10% Pd-C (4 mg) in ethyl acetate (2 ml) was stirred under the hydrogen for 3 hours at room temperature. The Pd catalyst was filtered off and the filtrate was concentrated to give a residue applied to a column of silica gel (5 g). Elution with hexane / ethyl acetate (4: 1) gave 5-ene (12) (37 35 mg, 92%) as an oil. 1 H NMR δ: 0.66 (3H, s, 18-Hg), 1.08 (3H, s, 19-Hg), 1.20 (6H, s, 26-Hg and 27-Hg), 2 , 02 (3H, s, acetyl), 2.05 (3H, s, acetyl), 4.97 (1H, m, 3a-H),
DK 159389 BDK 159389 B
13 5,07 (IH, m, lfl-H), 5,53 (IH, m, 6-H).13, 5.07 (1H, m, 1f-H), 5.53 (1H, m, 6-H).
1«,3fl-diacetoxy-24-homocholesta-5,7-dien-25-ol (13) 5 5-enen (12) (19 mg, 0,037 mmol) omdannedes som beskrevet for forbindelsen (9) til 5,7-dienen (13) (5,8 mg, 31%).1β, 3β-diacetoxy-24-homocholesta-5,7-dien-25-ol (13) The 5-ene (12) (19 mg, 0.037 mmol) was converted as described for the compound (9) to 5.7 dienes (13) (5.8 mg, 31%).
UVX Et0H/max: 293, 282, 271 nm.UVX EtOH / max: 293, 282, 271 nm.
1α,25-dihydroxy-24-homovitamin-Dg (14) 10 5,7-dienen (13) (5,8 mg, 0,0113 mmol) omdannedes som beskrevet for forbindelsen (10) til den vitamin-Dg analoge (14) (890 ^ug, 19%). Tilbageholdelsestiden for (14) under de ovenfor beskrevne HPLC-betingelser var 11,0 minutter 15 UV\ Et0Hmax: 265 nm, UVX Et0H/min: 228 nm. MS m/z: 430 (M+), 412, 394 (basetop), 376, 287, 269, 251, 152, 134, 59.1α, 25-dihydroxy-24-homovitamin-Dg (14) 10,7,7-diene (13) (5.8 mg, 0.0113 mmol) was converted as described for compound (10) to the vitamin Dg analogue (14). (890 µg, 19%). The retention time of (14) under the HPLC conditions described above was 11.0 minutes UV / EtOHmax: 265 nm, UVX EtOH / min: 228 nm. MS m / z: 430 (M +), 412, 394 (base top), 376, 287, 269, 251, 152, 134, 59.
Homovitamin-forbindelserne kan eventuelt let fås i kry-20 stallinsk form ved omkrystallisation med passende opløsningsmidler som hexan, ether, alkohol, eller blandinger heraf, hvilket vil være klart for fagmanden.Optionally, the homovitamin compounds can be readily obtained in crystalline form by recrystallization with appropriate solvents such as hexane, ether, alcohol, or mixtures thereof, as will be apparent to those skilled in the art.
25 30 3525 30 35
Claims (1)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65754984A | 1984-10-04 | 1984-10-04 | |
| US65754984 | 1984-10-04 | ||
| PCT/US1985/001571 WO1986002078A1 (en) | 1984-10-04 | 1985-08-19 | Vitamin d derivatives and methods for preparing same |
| US8501571 | 1985-08-19 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK111188A DK111188A (en) | 1988-03-02 |
| DK111188D0 DK111188D0 (en) | 1988-03-02 |
| DK159389B true DK159389B (en) | 1990-10-08 |
| DK159389C DK159389C (en) | 1991-03-11 |
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Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK260086A DK154290C (en) | 1984-10-04 | 1986-06-03 | VITAMIN-D DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE |
| DK111188A DK159389C (en) | 1984-10-04 | 1988-03-02 | CHOLESTAGE STAGE OR TRIEND DERIVATIVES THAT MAY BE USED AS INTERMEDIATES FOR USE IN THE PREPARATION OF 24-HOMOVITAMIN-D3 DERIVATIVES |
| DK177489A DK158989C (en) | 1984-10-04 | 1989-04-13 | CHOLESTA STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATE FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES |
| DK015290A DK158990C (en) | 1984-10-04 | 1990-01-19 | CHOLESTA STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATE FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES |
| DK015390A DK158991C (en) | 1984-10-04 | 1990-01-19 | CHOLE STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATES FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
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| DK260086A DK154290C (en) | 1984-10-04 | 1986-06-03 | VITAMIN-D DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
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| DK177489A DK158989C (en) | 1984-10-04 | 1989-04-13 | CHOLESTA STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATE FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES |
| DK015290A DK158990C (en) | 1984-10-04 | 1990-01-19 | CHOLESTA STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATE FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES |
| DK015390A DK158991C (en) | 1984-10-04 | 1990-01-19 | CHOLE STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATES FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0197949A1 (en) |
| JP (3) | JPS62500301A (en) |
| AU (2) | AU582789B2 (en) |
| BE (1) | BE903376A (en) |
| CH (1) | CH672920A5 (en) |
| DE (2) | DE3590488T (en) |
| DK (5) | DK154290C (en) |
| FR (1) | FR2571369B1 (en) |
| GB (2) | GB2167070B (en) |
| IE (1) | IE58104B1 (en) |
| IT (1) | IT1190401B (en) |
| NL (1) | NL8520265A (en) |
| WO (1) | WO1986002078A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1989010351A1 (en) * | 1988-04-21 | 1989-11-02 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis | Novel vitamin d analogues |
| US4927815A (en) * | 1988-04-29 | 1990-05-22 | Wisconsin Alumni Research Foundation | Compounds effective in inducing cell differentiation and process for preparing same |
| HU206316B (en) * | 1988-04-29 | 1992-10-28 | Wisconsin Alumni Res Found | Process for producing 1-alpha-hydroxy-d-vitamine homologues with unsaturated side-chain and pharmaceutical compositions containing them |
| US5063221A (en) * | 1989-04-05 | 1991-11-05 | Chugai Seiyaku Kabushiki Kaisha | Treatment for hyperparathyroidism with use of vitamin d derivatives |
| DE3933034A1 (en) * | 1989-10-02 | 1991-04-11 | Schering Ag | 24-HOMO-VITAMIN-D DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF |
| US5260290A (en) * | 1990-02-14 | 1993-11-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
| US5030772A (en) * | 1990-02-14 | 1991-07-09 | Deluca Hector F | Process for preparing vitamin D2 compounds and the corresponding 1 α-hydroxylated derivatives |
| US5891865A (en) * | 1996-10-04 | 1999-04-06 | Wisconsin Alumni Research Foundation | Treatment of arthritic disease induced by infectious agents |
| US20080293647A1 (en) | 2004-11-12 | 2008-11-27 | Luciano Adorini | Combined Use Of Vitamin D Derivatives And Anti-Proliferative Agents For Treating Bladder Cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3833622A (en) * | 1969-03-17 | 1974-09-03 | Upjohn Co | Crystalline 25-hydroxycholecalciferol hydrate and structurally related compounds |
| US3880894A (en) * | 1974-05-24 | 1975-04-29 | Wisconsin Alumni Res Found | 1,25-Dihydroxyergocalciferol |
| AU527805B2 (en) * | 1978-07-27 | 1983-03-24 | Research Institute For Medicine And Chemistry Inc. | 1alpha, 1beta dihydroxy steroid-5-enes |
| US4225596A (en) * | 1978-10-13 | 1980-09-30 | Wisconsin Alumni Research Foundation | Method for treating calcium imbalance and improving calcium absorption in mammals |
| US4448721A (en) * | 1982-09-20 | 1984-05-15 | Wisconsin Alumni Research Foundation | Hydroxyvitamin D2 compounds and process for preparing same |
| US4508651A (en) * | 1983-03-21 | 1985-04-02 | Hoffmann-La Roche Inc. | Synthesis of 1α,25-dihydroxyergocalciferol |
| DE3490215T (en) * | 1983-05-09 | 1985-05-15 | Wisconsin Alumni Research Foundation, Madison, Wis. | Process for the preparation of 1α, 25-dihydroxylated vitamin D? 2? and related compounds |
-
1985
- 1985-08-19 DE DE19853590488 patent/DE3590488T/en active Pending
- 1985-08-19 JP JP60503924A patent/JPS62500301A/en active Granted
- 1985-08-19 EP EP85904336A patent/EP0197949A1/en not_active Withdrawn
- 1985-08-19 WO PCT/US1985/001571 patent/WO1986002078A1/en active Application Filing
- 1985-08-19 CH CH2351/86A patent/CH672920A5/de not_active IP Right Cessation
- 1985-08-19 AU AU47761/85A patent/AU582789B2/en not_active Ceased
- 1985-08-19 NL NL8520265A patent/NL8520265A/en unknown
- 1985-08-19 DE DE3590488A patent/DE3590488C2/de not_active Expired - Lifetime
- 1985-10-04 FR FR8514758A patent/FR2571369B1/en not_active Expired
- 1985-10-04 IE IE244385A patent/IE58104B1/en not_active IP Right Cessation
- 1985-10-04 GB GB08524479A patent/GB2167070B/en not_active Expired
- 1985-10-04 IT IT22359/85A patent/IT1190401B/en active
- 1985-10-04 BE BE0/215682A patent/BE903376A/en not_active IP Right Cessation
-
1986
- 1986-06-03 DK DK260086A patent/DK154290C/en active
-
1987
- 1987-04-23 GB GB08709579A patent/GB2188932B/en not_active Expired
-
1988
- 1988-03-02 DK DK111188A patent/DK159389C/en active
- 1988-12-29 AU AU27614/88A patent/AU605007B2/en not_active Ceased
-
1989
- 1989-04-13 DK DK177489A patent/DK158989C/en active
-
1990
- 1990-01-19 DK DK015290A patent/DK158990C/en active
- 1990-01-19 DK DK015390A patent/DK158991C/en active
-
1992
- 1992-05-19 JP JP4150044A patent/JPH0635475B2/en not_active Expired - Lifetime
- 1992-05-19 JP JP4150045A patent/JPH0689022B2/en not_active Expired - Lifetime
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