NO125050B - - Google Patents
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- NO125050B NO125050B NO15475964A NO15475964A NO125050B NO 125050 B NO125050 B NO 125050B NO 15475964 A NO15475964 A NO 15475964A NO 15475964 A NO15475964 A NO 15475964A NO 125050 B NO125050 B NO 125050B
- Authority
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- Norway
- Prior art keywords
- methyl
- dione
- pregnadiene
- diol
- fluoro
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052736 halogen Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- LLCOIQRNSJBFSN-UHFFFAOYSA-N methane;sulfurochloridic acid Chemical compound C.OS(Cl)(=O)=O LLCOIQRNSJBFSN-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- BUTKIHRNYUEGKB-UHFFFAOYSA-N 3,3-dimethylbutanoyl chloride Chemical compound CC(C)(C)CC(Cl)=O BUTKIHRNYUEGKB-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Fremgangsmåte ved fremstilling av nye Procedure for manufacturing new ones
terapeutisk aktive 16a-methyl-9a-klor-A<1>'<4->pregnadien-llS,21-diol-3,20-dioner eller 21-estere derav. therapeutically active 16α-methyl-9α-chloro-A<1>'<4->pregnadiene-11S,21-diol-3,20-diones or 21-esters thereof.
Norsk patent nr. 122.590 angår en fremgangsmåte ved fremstilling av nye '^-l6a-methylsteroider ved hvilken der blant annet ved å gå ut fra forbindelser med formelen: hvor R1er hydrogen eller en acylgruppe, og R2 er hydrogen eller halogen, ved hydroxylering ved carbonatom 11 ad biokjemisk vei, dehydrering i 1-stilling med dehydrerende virkende mikro-organismer eller ved kjemiske dehydreringsmidler, og eventuelt selektiv acylering av den i 21-stilling stående hydroxylgruppe i hvilken som helst rekkefølge får forbindelser av den generelle formel: Norwegian patent no. 122,590 relates to a method for the production of new '^-16a-methylsteroids in which, among other things, starting from compounds with the formula: where R1 is hydrogen or an acyl group, and R2 is hydrogen or halogen, by hydroxylation at the carbon atom 11 ad biochemical route, dehydration in the 1-position with dehydrating microorganisms or by chemical dehydrating agents, and possibly selective acylation of the hydroxyl group in the 21-position in any order gives compounds of the general formula:
hvor R og R2er som ovenfor angitt. De nevnte fremgangsmåte-produkter har stor terapeutisk betydning for behandling av inflammatoriske sykdommer. where R and R2 are as indicated above. The aforementioned process products have great therapeutic value for the treatment of inflammatory diseases.
Det har nu vist seg at man på fordelaktig vis med vesentlig forbedrede utbytter kan komme til de samme forbindelser II ved at en forbindelse med den generelle formel: It has now been shown that the same compounds II can be obtained advantageously with significantly improved yields by a compound with the general formula:
hvor R^og R2er som ovenfor angitt, behandles med et N-klor-acylamid eller N-kloracylimid i nærvær av en oxygenholdig mineralsyre, hvorved -C10H- adderes ved<11>)-dobbelbindingen. where R1 and R2 are as indicated above, treated with an N-chloroacylamide or N-chloroacylimide in the presence of an oxygen-containing mineral acid, whereby -C10H- is added at the <11>) double bond.
Foreliggende fremgangsmåte belyses ved den efterfølgende formelrekke hvori de ved fremgangsmåten ifølge patent nr. 122.590 utførte fremgangsmåtetrinn fra utgangsforbindelsen III til det hele tiden 11-hydroxylerte mellomprodukt er utelatt for å få en bedre oversikt. The present method is illustrated by the following series of formulas in which the method steps carried out in the method according to patent no. 122,590 from the starting compound III to the always 11-hydroxylated intermediate are omitted to get a better overview.
Den nye fremgangsmåte har også den fordel overfor fremgangsmåten ifølge patent nr. 122.590 at det ikke kommer an på om den primære 11-hydroxylering fører til et lia- eller 11|3-hydroxyler-ingsprodukt. The new method also has the advantage over the method according to patent no. 122,590 that it does not depend on whether the primary 11-hydroxylation leads to a 11- or 11|3-hydroxylation product.
Vei 1:Way 1:
Vei 2 : Way 2 :
De nye forbindelser har stor terapeutisk betydning ved behandling av inflammatoriske sykdommer. De i den efterfølgende tabell eksempelvis oppførte fremgangsmåteforbindelser II - V har således i Granuloma pouch-Test efter oral tilførsel av det som standardsubstans kjente hydrocortisonacetat (I) vist seg mange ganger overlegent: The new compounds have great therapeutic value in the treatment of inflammatory diseases. The method compounds II - V listed as examples in the following table have thus proven many times superior in the Granuloma pouch test after oral administration of the standard substance known as hydrocortisone acetate (I):
Eksempel 1 Example 1
a) Fremstilling av l6a-methyl-6a-fluor-9a-klor-A^ '^-pregnadien-llg, 21- diol- 3, 20- dion- 21- acetat a) Preparation of 16a-methyl-6a-fluoro-9a-chloro-A^'^-pregnadiene-llg,21-diol-3,20-dione-21-acetate
1 g l6a-methyl-6a-f luor-A1 ,/+'9^ 11) -pregnatrien-21-ol-3 ,20-dion-21-acetat (fremstilt ifølge tysk patent nr. 1.211.194) ble oppløst i 52,4 ml dioxan, tilsatt 3,53 g N-klorsuccinimid og 26,3 ml ln perklorsyre og omrørt i 6 timer ved 25°C under argon. Oppløsningen ble helt i natriumthiosulfatholdig isvann, omrørt i 1 time, og det utfelte stoff ble avsuget, vasket nøytralt, tørret og omkrystallisert fra methanol/methylenklorid. Smeltepunkt 252°C under spaltning. Utbytte 0,79 g. ^237= l6lo°-b) Fremstilling av l6a-methyl-6a-fluor-9a-klor-A1 '^-pregnadien-110, 21- diol- 3, 2Q- dion 1 g of 16a-methyl-6a-fluoro-Al,/+'9^ 11)-pregnatrien-21-ol-3,20-dione-21-acetate (produced according to German patent no. 1,211,194) was dissolved in 52.4 ml dioxane, added 3.53 g N-chlorosuccinimide and 26.3 ml ln perchloric acid and stirred for 6 hours at 25°C under argon. The solution was poured into ice water containing sodium thiosulfate, stirred for 1 hour, and the precipitated substance was filtered off with suction, washed neutral, dried and recrystallized from methanol/methylene chloride. Melting point 252°C during decomposition. Yield 0.79 g. ^237= 16lo°-b) Preparation of 16a-methyl-6a-fluoro-9a-chloro-A1 '^-pregnadiene-110, 21-diol-3, 2Q-dione
400 mg l6a-methyl-6a-fluor-ga-klor-A<1>'^-pregnadien-lip,21-diol-3,20-dion-21-acetat ble suspendert i 1,6 ml methylenklorid og 1,6 ml methanol og ved 0 - 5°C under argon tilsatt en oppløsning av 24 mg kaliumhydroxyd i 0,8 ml methanol. Det ble omrørt ved O - 5°C i 80 minutter, nøytralisert med noen dråper iseddik, fortynnet med methylenklorid, vasket nøytralt med vann og inndampet. Residuet ble omkrystallisert fra methanol/methylenklorid. Smeltepunkt 254°C under spaltning. Utbytte 265 mg, £ = 16200. 400 mg of 16α-methyl-6α-fluoro-ga-chloro-α<1>'^-pregnadiene-lip,21-diol-3,20-dione-21-acetate was suspended in 1.6 ml of methylene chloride and 1.6 ml of methanol and at 0 - 5°C under argon added a solution of 24 mg of potassium hydroxide in 0.8 ml of methanol. It was stirred at 0 - 5°C for 80 minutes, neutralized with a few drops of glacial acetic acid, diluted with methylene chloride, washed neutral with water and evaporated. The residue was recrystallized from methanol/methylene chloride. Melting point 254°C during decomposition. Yield 265 mg, £ = 16200.
c) Fremstilling av l6a-methyl-6a-fluor-Qa-klor-A<1>'^-pregnadien-110, 21- diol- 3, 2Q- dion- 21- capronat c) Preparation of 16a-methyl-6a-fluoro-Qa-chloro-A<1>'^-pregnadiene-110,21-diol-3,2Q-dione-21-capronate
200 mg l6a-methyl-6a-fluor-9a-klor-A1 '^-pregnadien-llg,21 - diol-3,20-dion i 5 ml pyridin ble tilsatt 3 ml capronsyreanhydrid. Efter ca. 20 - 24 timers henstand ved værelsetemperatur ble reak-sjonsblandingen helt i isvann og efter spaltning av overskuddet av capronsyreanhydrid med ether, ekstrahert. Den fraskilte etherfase ble vasket med fortynnet saltsyre og med vann, tørret over natrium-sulfat, filtrert og inndampet i vakuum til tørrhet. Residuet ble 200 mg of 16a-methyl-6a-fluoro-9a-chloro-Al'^-pregnadiene-11,21-diol-3,20-dione in 5 ml of pyridine was added to 3 ml of caproic anhydride. After approx. After standing for 20 - 24 hours at room temperature, the reaction mixture was poured into ice water and, after cleavage of the excess caproic anhydride with ether, extracted. The separated ether phase was washed with dilute hydrochloric acid and with water, dried over sodium sulfate, filtered and evaporated in vacuo to dryness. The residue was
omkrystallisert fra eddikester-hexan.recrystallized from ethyl acetate-hexane.
Utbytte 178 mg, ^37= 1d00°-Yield 178 mg, ^37= 1d00°-
Eksempel 2Example 2
Fremstilling av utgangsmaterialeProduction of starting material
a) Fremstilling av léa-methyl-Qa-klor-A1 '^-pregnadien-11(3 ,21 -diol-3, 2Q- dion- 21- acetat a) Preparation of lea-methyl-Qa-chloro-A1'^-pregnadiene-11(3,21-diol-3,2Q-dione-21-acetate
11,6 g l6a-methyl-A<1>'^-pregnadien-110,21-diol-3,20-dion-21-acetat ble oppløst i 58 ml dimethylformamid og 11 ml pyridin, tilsatt 5,1 ml methansulfoklorid og omrørt i 1 time ved 8o°C. Efter avkjøling til 20 oC ble oppløsningen innrørt i isvann, bunnfallet frasuget, tørret og omkrystallisert fra aceton/hexan. Det erholdte l6a-methyl-A1 '^11)-pregnatrien-21-ol-3,20-dion-21-acetat smeltet ved 157 - 158°C. Utbyttet var 80% av det teoretiske. 11.6 g of 16α-methyl-α<1>'^-pregnadiene-110,21-diol-3,20-dione-21-acetate was dissolved in 58 ml of dimethylformamide and 11 ml of pyridine, added 5.1 ml of methanesulfochloride and stirred for 1 hour at 8o°C. After cooling to 20 oC, the solution was stirred in ice water, the precipitate was sucked off, dried and recrystallized from acetone/hexane. The obtained 16α-methyl-α1 (α11)-pregnatrien-21-ol-3,20-dione-21-acetate melted at 157-158°C. The yield was 80% of the theoretical.
Fremstilling av sluttproduktProduction of final product
b) 3 g l6a-methyl-A<1>'<Zf>'<9>(<11>)-pregnatrien-21-ol-3,20-dion-acetat ble oppløst i 157 ml dioxan, tilsatt IO,6 g N-klorsuccinimid og 79 ml ln perklorsyre og omrørt i 6 timer under argon ved 30°C. Oppløsningen ble rørt i natriumsulfatholdig isvann, bunnfallet frasuget, tørret og omkrystallisert fra iso-propylether/methylenklorid. l6a-methyl-9a-klor-A1 '^-pregnadien-lip , 21-diol-3 ,20-dion-21-acetat et smeltet ved 215°C under spaltning. Utbyttet var 65% av det teoretiske, UVf^g =15500.c) Fremstilling av l6a-methyl-90,-klor-A1 '^-pregnadien-HB .21-diol- 3. 20- dion 80 mg l6a-methyl-9a-klor-A1 '^-pregnadien-110,21-diol-3,20-dion-21-acetat ble forsåpet som beskrevet i eksempel 1 b), og opparbeidet. Residuet ble omkrystallisert fra methanol/methylenklorid. Smeltepunktet var 234°c under spaltning, b) 3 g of 16a-methyl-A<1>'<Zf>'<9>(<11>)-pregnatrien-21-ol-3,20-dione-acetate were dissolved in 157 ml of dioxane, added 10.6 g of N-chlorosuccinimide and 79 ml of ln perchloric acid and stirred for 6 hours under argon at 30°C. The solution was stirred in sodium sulfate-containing ice water, the precipitate was filtered off with suction, dried and recrystallized from iso-propyl ether/methylene chloride. 16α-methyl-9α-chloro-α1′-pregnadiene-lip , 21-diol-3,20-dione-21-acetate a melted at 215°C with cleavage. The yield was 65% of the theoretical, UVf^g =15500.c) Preparation of l6a-methyl-90,-chloro-A1 '^-pregnadiene-HB .21-diol- 3.20-dione 80 mg l6a-methyl- 9α-Chloro-α1′-pregnadiene-110,21-diol-3,20-dione-21-acetate was saponified as described in example 1 b), and worked up. The residue was recrystallized from methanol/methylene chloride. The melting point was 234°c during cleavage,
UV<£>238=i^OO. Utbyttet var 60% av det teoretiske.UV<£>238=i^OO. The yield was 60% of the theoretical.
Eksempel 3Example 3
Fremstilling av utqanqsmaterialeProduction of output material
a) 10 g l6a-methyl-6a-fluor-^1 '^-pregnadien-113,21-diol-3,20-dion-21-capronat (størknepunkt 242 - 245°C, fremstilt av 21-OH-forbindelsen ved hjelp av capronsyreanhydrid/pyridin ved værelsetemperatur, utbytte 90%) ble oppløst i 50 ml dimethylformamid og 8,8 ml pyridin og omsatt med 4,4 ml methansulfoklorid som beskrevet i eksempel 2a. a) 10 g of 16a-methyl-6a-fluoro-^1'^-pregnadiene-113,21-diol-3,20-dione-21-capronate (solidification point 242 - 245°C, prepared from the 21-OH compound by using caproic anhydride/pyridine at room temperature, yield 90%) was dissolved in 50 ml of dimethylformamide and 8.8 ml of pyridine and reacted with 4.4 ml of methanesulfochloride as described in example 2a.
Det erholdte l6a-methyl-6a-fluor-A1'^'^11^-pregnatrien-21-ol-3,20-dion-capronat ble omkrystallisert fra isopropylether/methylenklorid og smeltet ved 120 - 122°C. Utbytte: 85% av det teoretiske, UV €23^= 16900.The 16a-methyl-6a-fluoro-Al'^'^11^-pregnatrien-21-ol-3,20-dione capronate obtained was recrystallized from isopropyl ether/methylene chloride and melted at 120-122°C. Yield: 85% of the theoretical, UV €23^= 16900.
Fremstilling av sluttproduktProduction of final product
b) 7,8 g l6a-methyl-6a-fluor-A<1>'<Zf>'<9>^<11>^-prégnatrien-21-O1-3.20-dion-capronat ble oppløst i 4lO ml dioxan, omsatt med 27,5 g N-klorsuccinimid og 205 ml ln perklorsyre som beskrevet i eksempel lb. l6a-methyl-6a-fluor-9a-klor-A1 '^-pregnadien-llp,21-diol-3,20-dion-21-capronatet ble omkrystallisert fra isopropylether/methylenklorid og smeltet ved 154,5 - 155,5°C. b) 7.8 g of 16a-methyl-6a-fluoro-A<1>'<Zf>'<9>^<11>^-prégnatriene-21-O1-3.20-dione-capronate were dissolved in 410 ml of dioxane, reacted with 27.5 g of N-chlorosuccinimide and 205 ml of perchloric acid as described in example 1b. The 16a-methyl-6a-fluoro-9a-chloro-A1'^-pregnadiene-11p,21-diol-3,20-dione-21-capronate was recrystallized from isopropyl ether/methylene chloride and melted at 154.5-155.5° C.
Utbytte: 60% av det teoretiske, UV ^42= lDOO°-Yield: 60% of the theoretical, UV ^42= lDOO°-
Eksempel 4Example 4
2 g l6a-methyl-6a-fluor-ga-klor-A1'^-pregnadien-llp,21-diol-3,20-dion fikk stå i 10 ml pyridin med 4 ml capronsyreanhydrid i 16 timer ved værelsetemperatur. Det utkrystalliserte capronat ble avsuget og omkrystallisert flere ganger fra methylenklorid/iso-propylether. 2 g of 16a-methyl-6a-fluoro-ga-chloro-A1'^-pregnadiene-11p,21-diol-3,20-dione was allowed to stand in 10 ml of pyridine with 4 ml of caproic anhydride for 16 hours at room temperature. The crystallized capronate was filtered off with suction and recrystallized several times from methylene chloride/isopropyl ether.
Utbytte: 85% av det teoretiske. Smeltepunkt 154,5 - 155,5°C. Yield: 85% of the theoretical. Melting point 154.5 - 155.5°C.
Eksempel 5Example 5
Fremstilling av utganqsmaterialeProduction of starting material
a) lg l6a-methyl-6a-f luor-A.1'^-pregnadien-lip ,21-diol-3,20-dion ble oppløst i 25 ml absolutt pyridin, tilsatt 2 ml t-butyl-acetylklorid (inneholdende ca. 5% thionylklorid) under isavkjøling og fikk stå i 16 timer ved 20°C. Derpå ble der fortynnet med methylenklorid og vasket i rekkefølge med fortynnet svovelsyre, vann, 1%-ig natriumhydrogencarbonatoppløsning og vann. Methylen-kloridoppløsningen ble inndampet i vakuum, og det erholdte l6a-methyl-6a-fluor-A1'^ >9(11)-pregnat rien-21-ol-3,20-dion-t-buty1-acetat ble omkrystallisert fra methylenklorid/isopropylether og smeltet ved 167 - l68°C. a) lg 16a-methyl-6a-fluoro-A,1'^-pregnadiene-lip,21-diol-3,20-dione was dissolved in 25 ml of absolute pyridine, to which 2 ml of t-butyl-acetyl chloride (containing approx. .5% thionyl chloride) under ice-cooling and allowed to stand for 16 hours at 20°C. It was then diluted with methylene chloride and washed in sequence with dilute sulfuric acid, water, 1% sodium bicarbonate solution and water. The methylene chloride solution was evaporated in vacuo, and the obtained 16a-methyl-6a-fluoro-Al'^>9(11)-pregnatrien-21-ol-3,20-dione-t-butyl1-acetate was recrystallized from methylene chloride /isopropyl ether and melted at 167 - 168°C.
Utbytte: 65% av det teoretiske, UV f2371^ >7°°-Yield: 65% of the theoretical, UV f2371^ >7°°-
Fremstilling av sluttproduktProduction of final product
b) 800 mg l6a-methyl-6a-f luor-A1 '^'^ -pregnatrien-21-ol-3,20-dion-5-butylacetat ble oppløst i 42 ml dioxan, omrørt med b) 800 mg of 16a-methyl-6a-fluoro-A1 '^'^ -pregnatrien-21-ol-3,20-dione-5-butyl acetate was dissolved in 42 ml of dioxane, stirred with
2,8 g N-klorsuccinimid og 21 ml ln perklorsyre i 3,5 timer ved 30°C og opparbeidet som beskrevet i eksempel la. Det således erholdte l6a-methyl-6a-f luor-Qa-klor-A^" '^-pregnadien-llp ,21-diol-3,20-dion-21-butylacetat ble omkrystallisert fra isopropyl-ether/methylenklorid og smeltet ved 231,5 - 232°C. 2.8 g of N-chlorosuccinimide and 21 ml of ln perchloric acid for 3.5 hours at 30°C and worked up as described in example la. The thus obtained 16a-methyl-6a-fluoro-Qa-chloro-A^"'^-pregnadiene-11p,21-diol-3,20-dione-21-butyl acetate was recrystallized from isopropyl ether/methylene chloride and melted at 231.5 - 232°C.
Utbytte: 50% av det teoretiske, UV £238= l6^°°-Yield: 50% of the theoretical, UV £238= l6^°°-
Eksempel 6Example 6
Fremstilling av utgangsmaterialeProduction of starting material
a) 3 g 16a-methyl-6a-fluor-A<1>'^-pregnadien-lip,21-diol-3,20-dion ble oppløst i 75 ml tørr pyridin, tilsatt 6 ml trimethyl-acetylklorid og 0,06 ml thionylklorid under isavkjøling og fikk stå i l6 timer ved værelsetemperatur. a) 3 g of 16a-methyl-6a-fluoro-A<1>'^-pregnadiene-lip,21-diol-3,20-dione were dissolved in 75 ml of dry pyridine, added with 6 ml of trimethyl-acetyl chloride and 0.06 ml of thionyl chloride under ice-cooling and allowed to stand for 16 hours at room temperature.
Derpå ble reaksjonsoppløsningen utrørt i 1,5 1 isvann, ekstrahert med methylenklorid og methylenkloridfasen i rekkefølge vasket med fortynnet svovelsyre (1 + 9), n/10 natronlut og vann, tørret og inndampet. Det erholdte rå l6a-methyl-6a-fluor-A<1>'<9>(<11>)-pregnatrien-21-ol-3,20-dion-trimethylacetat ble kromatografert på silicagel og omkrystallisert fra methylen-1 klorid/isopropylether. Smeltepunkt: 209 - 210°C. UV £338= 1^300 Utbytte: 90 - 95% av det teoretiske. The reaction solution was then stirred in 1.5 1 of ice water, extracted with methylene chloride and the methylene chloride phase successively washed with dilute sulfuric acid (1 + 9), n/10 caustic soda and water, dried and evaporated. The crude 16a-methyl-6a-fluoro-A<1>'<9>(<11>)-pregnatrien-21-ol-3,20-dione-trimethylacetate obtained was chromatographed on silica gel and recrystallized from methylene-1 chloride/ isopropyl ether. Melting point: 209 - 210°C. UV £338= 1^300 Yield: 90 - 95% of the theoretical.
Fremstilling av sluttproduktProduction of final product
b) 4 g l6a-methyl-6a-fluor-A<1>'<Zf>'<9>^<11>^-pregnatrien-21-ol-3,20-dion-trimethylacetat ble oppløst i 250 ml dioxan, omrørt med 14 g b) 4 g of 16a-methyl-6a-fluoro-A<1>'<Zf>'<9>^<11>^-pregnatrien-21-ol-3,20-dione-trimethylacetate were dissolved in 250 ml of dioxane, stirred with 14 g
N-klorsuccinimid og 105 ml ln perklorsyre i 4 timer ved 30°C under argon og opparbeidet, som beskrevet i eksempel la. Det således erholdte l6g-methyl-6g-fluor-9a-klor-/^ '^-pregnadien-lip ,21-diol-3 ,20-dion-21-trimethylacetat ble omkrystallisert fra N-chlorosuccinimide and 105 ml of perchloric acid for 4 hours at 30°C under argon and worked up, as described in example la. The thus obtained 16g-methyl-6g-fluoro-9a-chloro-/^'^-pregnadiene-lip,21-diol-3,20-dione-21-trimethylacetate was recrystallized from
aceton/hexan og smeltet ved 230,5 - 232°C.acetone/hexane and melted at 230.5 - 232°C.
UV ^ 238 = 1^ lo°- Utbytte: 60% av det teoretiske. UV ^ 238 = 1^ lo°- Yield: 60% of the theoretical.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DESC034140 | 1963-11-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO125050B true NO125050B (en) | 1972-07-10 |
Family
ID=7433039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO15475964A NO125050B (en) | 1963-11-09 | 1964-09-15 |
Country Status (9)
| Country | Link |
|---|---|
| BE (1) | BE655494A (en) |
| BR (1) | BR6464017D0 (en) |
| DE (1) | DE1249270B (en) |
| DK (1) | DK118556B (en) |
| FR (1) | FR4556M (en) |
| GB (1) | GB1068058A (en) |
| NL (1) | NL155266B (en) |
| NO (1) | NO125050B (en) |
| SE (1) | SE324765B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2596007B1 (en) * | 2010-07-20 | 2016-01-06 | Taro Pharmaceutical Industries Ltd | Process for the preparation of 17-desoxy-corticosteroids |
-
0
- BE BE655494D patent/BE655494A/xx unknown
- DE DENDAT1249270D patent/DE1249270B/en active Pending
-
1964
- 1964-09-15 NO NO15475964A patent/NO125050B/no unknown
- 1964-10-13 GB GB41756/64A patent/GB1068058A/en not_active Expired
- 1964-10-27 DK DK529264A patent/DK118556B/en unknown
- 1964-11-02 NL NL646412708A patent/NL155266B/en not_active IP Right Cessation
- 1964-11-06 BR BR16401764A patent/BR6464017D0/en unknown
- 1964-11-09 SE SE1348664A patent/SE324765B/xx unknown
-
1965
- 1965-02-05 FR FR4502A patent/FR4556M/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NL155266B (en) | 1977-12-15 |
| DE1249270B (en) | 1967-09-07 |
| BE655494A (en) | |
| DK118556B (en) | 1970-09-07 |
| GB1068058A (en) | 1967-05-10 |
| SE324765B (en) | 1970-06-15 |
| BR6464017D0 (en) | 1973-07-26 |
| NL6412708A (en) | 1965-05-10 |
| FR4556M (en) | 1966-11-02 |
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