NO122366B - - Google Patents
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- Publication number
- NO122366B NO122366B NO139888A NO13988861A NO122366B NO 122366 B NO122366 B NO 122366B NO 139888 A NO139888 A NO 139888A NO 13988861 A NO13988861 A NO 13988861A NO 122366 B NO122366 B NO 122366B
- Authority
- NO
- Norway
- Prior art keywords
- hydroxy
- bromine
- compound
- androstadien
- general formula
- Prior art date
Links
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- -1 steroid compounds Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000007269 dehydrobromination reaction Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- UKDOTCFNLHHKOF-FGRDZWBJSA-N (z)-1-chloroprop-1-ene;(z)-1,2-dichloroethene Chemical group C\C=C/Cl.Cl\C=C/Cl UKDOTCFNLHHKOF-FGRDZWBJSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- DIWKDXFZXXCDLF-UHFFFAOYSA-N chloroethyne Chemical compound ClC#C DIWKDXFZXXCDLF-UHFFFAOYSA-N 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- 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)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte til fremstilling av nye, terapeutisk aktive steroidforbindelser.
Foreliggende oppfinnelse angar en fremgangsmåte til fremstilling av nye steroidforbindelser, nemlig A g-analoge av 21-halogen-norethisteroner og deres acylater.
De forbindelser som erholdes ved fremgangsmåten ifdlge oppfinnelsen har fordelaktige oralt og parenteralt progestasjonelle egen-skaper .
Disse forbindelser er 17a-halogenethynyl-17(3-hydroxy-19-nor-4,9(IO)-androstadien-3-oner, samt acylater av disse, som tilsvarer den generelle formel:
i hvilken X betegner klor, brom eller fluor, og R betegner hydrogen eller en acylgruppe.
Ifolge oppfinnelsen fremstilles disse forbindelser ved å dehydrogenere de tilsvarende 17a-halogenethynyl-17p-hydroxy-19-nor-5(10)-androsten-3-oner som tilsvarer den generelle formel:
i hvilken X har den ovenfor angitte betydning.
Denne dehydrogenering utfores ved å behandle 17a-halogen-ethynyl-17(3-hydroxy-19-nor-5(10)-androsten-3-onet med brom i pyridin som opplosningsmiddel, hvorved der dannes den tilsvarende 5,10-di-bromforbindelse, med påfolgende dehydrobromering av denne dibromfor-bindelse. Det er ikke nodvendig å skille dibromitforbindelsen fra opp-losningsmidlet for dehydrobromeringen utfores. Det foretrekkes å an-vende pyridin som dehydrobromeringsmiddel foruten som opplosningsmiddel.
Bromeringen utfores ved en temperatur på ca. 0°C, hvorpå reaksjonsblandingen oppvarmes til ca,. 25°C for å fullstendiggjore dehydrobromeringen, eller bromerings- og dehydrobromeringsreaksjonene kan utfores samtidig ved en temperatur på ca. 25°C.
Produktet gjenvinnes fra reaksjonsblandingen ved å tilsette vann, ekstrahere med et opplosningsmiddel som ether, og fordampe opp-losningsmidlet fra ekstraktet, hvorved man får produktet i krystal-linsk tilstand.
Når det onskes å fremstille et acylat, acyleres produktet ved vanlige fremgangsmåter, som behandling med et syreanhydrid i pyridin •
Utgangsmaterialene for fremgangsmåten ifolge oppfinnelsen, f.eks. 17a-klorethynylforbindelsen, fremstilles på folgende måte: En opplosning av 1,2-diklorethylen (fortrinnsvis cisformen) tilsettes ved ca. 0°C til en opplosning av methyl-lithium, likeledes i ether. Reaksjonsblandingen omrores i nitrogenatmosfære i 1 - 2 timer, hvorved man får en opplosning inneholdende klorethyn. Til denne opplosning tilsettes 3-methoxy-19-nor-2,5(10)-androstadien-17-ol, hvorpå der omrores i flere timer. Den herved erholdte 17a-halogen-ethynyl-3-methoxy-19-nor-2, 5( IO) - andros tadien-17(3-ol omdannes til 17a-klorethynyl-17(3-hydroxy-19-nor-5 (IO) - andros ten-3-on ved omsetning med en svak organisk syre som eddiksyre. Således kan man f.eks. la en blanding av steroidet og iseddik i en vandig opplosning av abso-lutt ethanol og dioxan henstå ved romtemperatur i flere timer.
Eksempel
lOO mg 17a-klorethynyl-17p-hydroxy-19-nor-5(10)-androsten-3-on i 5 ml pyridin blev tilsatt en ekvivalent brom. Den erholdte reaksjonsblanding blev omrort i to timer ved romtemperatur, hvorpå den blev heldt i isvann, og blandingen ekstrahert med ether. Ether-ekstraktet blev vasket med vann, befridd for vann over natriumsulfat og inndampet i vakuum, hvorved man fikk 17a-klo.rethynyl-17p-hydroxy-19-nor-4,9(10)-androstadien-3-on. Smp. 151 - 152°C, a 24D -276 (kloroform), U.V. Å<Me>?<H>303 m|x, 8 19,500, infl. 235 mp., £ 5,600.
Funnet ved analyse: C 72,57 %, H 7,10 %.
Ved acyleringen av denne 17p-hydroxyforbindelse ved behandling med eddiksyre i pyridin fikk man 17a-klorethynyl-17p-hydroxy-19-nor-4,9(IO)-androstadien-3-on-acetat. Forbindelsens smeltepunkt var 144 - 145°C.
a<25>D -282 (kloroform), U.V. Å<Me>°<H>304 m\ i, £ 20,200, infl. 237 mu-,
l 5,600.
Funnet ved analyse: C 71,35 %, H 6,77 %.
Claims (1)
- Fremgangsmåte til fremstilling av terapeutisk aktive, nye s teroidf orbindelser, nemlig 17a-halogenethynyl-17(3-hydroxy-19-nor-4, 9-androstadien-3-oner og acylater av disse, tilsvarende den generelle formel:i hvilken X betegner klor, brom eller fluor, og R betegner hydrogen eller en acylgruppe, karakterisert ved at man dehyd-rogenerer en forbindelse med den generelle formel:i hvilken X har den ovenfor angitte betydning, ved behandling med bron i pyridinopplosning, hvorpå man eventuelt acylerer den derved erholdte forbindelse.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88575A US3072646A (en) | 1961-03-02 | 1961-03-02 | Novel 6-chloro-17alpha-haloethynyl-19-norandrostadienes and processes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO122366B true NO122366B (no) | 1971-06-21 |
Family
ID=22212174
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO139888A NO122366B (no) | 1961-03-02 | 1961-04-19 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US3072646A (no) |
| DE (2) | DE1593072C3 (no) |
| DK (1) | DK108227C (no) |
| NO (1) | NO122366B (no) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3248405A (en) * | 1962-02-09 | 1966-04-26 | Merck & Co Inc | Process for the preparation of 21-halo-19-nor-ethisterones and the 3-enol ethers thereof |
| DE1249264B (de) * | 1962-08-24 | 1967-09-07 | The British Drug Houses Limited London | Verfahren zur Her Stellung von neuen YIi Chlorathmyl 17ß alkoxysteroiden |
| US3409643A (en) * | 1966-03-11 | 1968-11-05 | Schering Corp | Process for the preparation of 17alpha-alkynl-17beta-alkanoyloxy steroids of the androstane and estrane series |
| GB1108276A (en) * | 1966-03-14 | 1968-04-03 | British Drug Houses Ltd | 17ª‡-alka-1',3'-diynyl-oestra-4,9(10)-dien-3-ones |
| US3471531A (en) * | 1966-04-07 | 1969-10-07 | Herchel Smith | Synthesis of gona-3,5-dienes |
-
1961
- 1961-03-02 US US88575A patent/US3072646A/en not_active Expired - Lifetime
- 1961-04-17 DE DE1593072A patent/DE1593072C3/de not_active Expired
- 1961-04-17 DE DE19611468333 patent/DE1468333A1/de active Pending
- 1961-04-19 DK DK267663AA patent/DK108227C/da active
- 1961-04-19 NO NO139888A patent/NO122366B/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK108227C (da) | 1967-10-23 |
| DE1593072B2 (de) | 1973-08-23 |
| DE1593072C3 (de) | 1974-04-18 |
| US3072646A (en) | 1963-01-08 |
| DE1468333A1 (de) | 1968-12-19 |
| DE1593072A1 (de) | 1970-07-30 |
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