NO132101B - - Google Patents
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- NO132101B NO132101B NO4350/68A NO435068A NO132101B NO 132101 B NO132101 B NO 132101B NO 4350/68 A NO4350/68 A NO 4350/68A NO 435068 A NO435068 A NO 435068A NO 132101 B NO132101 B NO 132101B
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- Prior art keywords
- methyl
- bromo
- hydroxy
- compound
- acid
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000002280 anti-androgenic effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 239000003098 androgen Substances 0.000 description 3
- 239000000051 antiandrogen Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960001712 testosterone propionate Drugs 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- RQETXCPBBLHUIB-UGCZWRCOSA-N benorterone Chemical compound C1C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 RQETXCPBBLHUIB-UGCZWRCOSA-N 0.000 description 1
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
-
- 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
-
- 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
-
- 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
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
-
- G—PHYSICS
- G11—INFORMATION STORAGE
- G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
- G11B33/00—Constructional parts, details or accessories not provided for in the other groups of this subclass
- G11B33/02—Cabinets; Cases; Stands; Disposition of apparatus therein or thereon
- G11B33/04—Cabinets; Cases; Stands; Disposition of apparatus therein or thereon modified to store record carriers
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Oppfinnelsen vedrorer en analogifremgangsmåte for fremstilling av 6oc-brom-17f3-hydroksy-17a-metyl-4-oksa-androstan-3-on med den i kravet angitte formel. Fremgangsmåten ifolge oppfinnelsen erkarakterisert vedat man cykliserer 6oc-brom-5,17(3-dihydroksy-17oc-metyl-3 ,5-seco-A-norandrostan-3-karboksylsyre. The invention relates to an analogous process for the production of 6oc-bromo-17f3-hydroxy-17a-methyl-4-oxa-androstan-3-one with the formula specified in the claim. The method according to the invention is characterized by cyclizing 6oc-bromo-5,17(3-dihydroxy-17oc-methyl-3,5-seco-A-norandrostane-3-carboxylic acid.
Cykliseringen etter oppfinnelsen utfores ved behandling med syre, f.eks. med en organisk syre som eddiksyre eller med en mineralsyre som klorhydrogensyre. Cykliseringen kan foretas ved romtemperatur eller under-romtemperatur, d.v.s. i et temperaturintervall mellom frysepunktet for det anvendte opplos-;ningsmidde1system og romtemperatur. Utgangsmaterialet kan oppnås fra den tilsvarende 5-okso-forbindelse, d.v.s. fra 6a-brom-17(3-hydroksy-17a-metyl-5-okso-3,5-seco-A-norandrostan-3-karboksylsyre ved reduksjon med et alkalimetallborhydrid som natrium-eller litiumborhydrid. Behandlingen med alkalimetall-borhydridet gjennomføres fortrinnsvis i et inert, organisk opplosningsmiddel og kan f.eks. foretas under romtemperatur eller i et temperaturintervall mellom frysepunktet for opplos-ningsmidlet og romtemperatur (hensiktsmessig ved isbadkjoling). Som opplosningsmiddel kommer i betraktning lavere alkanoler som metanol, etanol og isopropanolj tetrahydrofuran, dioksan eller dimetylformamid. Den etter alkalimetallborhydrid-reduk-sjonen erholdte kjolte reaksjonsblanding kan uten isolering av 5-hydroksy-forbindelsen direkte tilsettes syre, hvorved cykliseringen etter oppfinnelsen inntrer. 5-hydroksy-forbindelsen kan imidlertid også isoleres og deretter ansyres for formålet laktonisering (cyklisering). The cyclization according to the invention is carried out by treatment with acid, e.g. with an organic acid such as acetic acid or with a mineral acid such as hydrochloric acid. The cyclization can be carried out at room temperature or below room temperature, i.e. in a temperature interval between the freezing point of the solvent system used and room temperature. The starting material can be obtained from the corresponding 5-oxo compound, i.e. from 6α-bromo-17(3-hydroxy-17α-methyl-5-oxo-3,5-seco-A-norandrostane-3-carboxylic acid by reduction with an alkali metal borohydride such as sodium or lithium borohydride. The treatment with the alkali metal borohydride is preferably carried out in an inert, organic solvent and can, for example, be carried out below room temperature or in a temperature interval between the freezing point of the solvent and room temperature (suitable by cooling in an ice bath). Lower alkanols such as methanol, ethanol and isopropanol, tetrahydrofuran, dioxane or dimethylformamide. The cooled reaction mixture obtained after the alkali metal borohydride reduction can be directly added to acid without isolation of the 5-hydroxy compound, whereby the cyclization according to the invention takes place. However, the 5-hydroxy compound can also be isolated and then acidified for the purpose of lactonization (cyclization).
6a -brom-17(3 -hydr oksy-17a -metyl- 4-oksa - andro stan- 3-onet som oppnås ifolge oppfinnelsen kan finne anvendelse som anti-androgen. Den anti-androgene virkning ble fastlagt ved dyre.-forsok på den etterpå beskrevne måte: The 6a-bromo-17(3-hydroxy-17a-methyl-4-oxa-androstan-3-one obtained according to the invention can be used as an anti-androgen. The anti-androgenic effect was determined by animal experiments on the subsequently described way:
6a -brom-17(3 -hydroksy-17a -metyl- 4-oksa- andros tan- 3-on admini-streres grupper på hver 5 kastrerte rotter, idet hver rotte veier omtrent 40 - 50 g. Hver rotte mottar den nedenfor angitte dose av eksogen androgen. Kontrollgrupper på 5 rotter mottar utelukkende det angitte androgen (intet eksogen) i den angitte dosering. Etter 7 dagers behandling underkastes alle dyrene autopsi og vekten av sædblæren og prostata bestemmes. Undertrykkelsen av den androgene virkning på disse androgen-omtålelige organer viser den anti-androgene aktivitet. 6a-bromo-17(3-hydroxy-17a-methyl-4-oxa-andros tan-3-one is administered to groups of 5 castrated rats each, each rat weighing approximately 40-50 g. Each rat receives the following dose of exogenous androgen. Control groups of 5 rats receive exclusively the indicated androgen (no exogenous) at the indicated dosage. After 7 days of treatment, all animals are necropsied and the weights of the seminal vesicles and prostate are determined. The suppression of the androgen action on these androgen-tolerant organs shows the anti-androgenic activity.
En kjent anti-androgen virksom forbindelse er 17a-metyl-B-nortestosteron. Om denne forbindelse er det berettet i Steroids 3,687 (1964) og 8,297 (1966); J. Clin. Endbcr. 26 1394 (1966) og J. Invest. Derm..52,95 (1969). Som etterføl-gende forsdksberetning viser er forbindelsen som oppnås ifolge oppfinnelsen denne kjente forbindelse overlegen med hen-syn til virkning: A known anti-androgen active compound is 17α-methyl-B-nortestosterone. This compound is reported in Steroids 3,687 (1964) and 8,297 (1966); J. Clin. Endbcr. 26 1394 (1966) and J. Invest. Derm..52,95 (1969). As the following research report shows, the compound obtained according to the invention is superior to this known compound in terms of effect:
21 dagers gamle rotter ble kastrert 7 dager for bruk. Forbindelser som skal undersokes og testosteron-propionat (T.P.) ble administrert ved separate subkutane injeksjoner til for-skjellige legemsdeler i 7 etterfølgende dager. Testosteron-propionat ble administrert med en daglig dose på 10 /ig i sesamolje. Anti-androgenene (Forbindelse A = 6oc-bromo-17(3-hydroksyl-17a-metyl-4-oksa-androstan-3-on5 Forbindelse B = 17a-metyl-B-nortestosteron ) ble administrert i sesamolje ved molare forhold på 30 til 1 og 100 til 1 mot testosteron. 21-day-old rats were castrated 7 days before use. Test compounds and testosterone propionate (T.P.) were administered by separate subcutaneous injections to different body parts for 7 consecutive days. Testosterone propionate was administered at a daily dose of 10 µg in sesame oil. The anti-androgens (Compound A = 6oc-bromo-17(3-hydroxyl-17a-methyl-4-oxa-androstan-3-one5 Compound B = 17a-methyl-B-nortestosterone ) were administered in sesame oil at molar ratios of 30 to 1 and 100 to 1 against testosterone.
Det fblgende eksempel forklarer oppfinnelsen og fremstillingen av det hittil ikke kjente utgangsmateriale. The following example explains the invention and the production of the previously unknown starting material.
EKSEMPEL EXAMPLE
Til en opplosning av 12,88 g 17(3-hydroksy-17a-metyl-5-okso-3,5-seco-A-norandrostan-3-karboksylsyre i 150 ml iseddik og 1500 ml vannfri eter tilsettes under roring og isbadkjoling 2 ml iseddik, som er mettet med hydrogenbromid. Etter 5 minutter tilsettes dråpevis 2 ml av en opplosning av 33 % brom i iseddik, som er fortynnet med 200 ml eter- Den sistnevnte tilsetning av bromoppldsningen trenger ca. 1 time, og dråpe-hastigheten tilpasses avfargningshastigheten for bromopplos-ningen i reaksjonsblåndingen. Til den således erholdte reaksjonsblanding tilsettes under fortsettelse av roringen og av-kjølingen porsjonsvis 2-n vandig natriumkarbonatopplosning (1700 ml). Blandingen bringes så i en skilletrakt, rystes og det karbonholdige skikt skilles fra. Det eteriske skikt vaskes tre ganger hver gang med 100 ml vandig 2-n natriumkarbonatopplosning. De karbonatholdige oppløsninger forenes og ansyres etter tilføring av is med konsentrert saltsyre inntil pH 1. Man lar stå i 1 time, filtrerer den utfelte syre fra, utvasker godt med vann og tørker i torkeskap ved 45°. Man oppnår rå 6p-brom-17p-hydroksy-17oc-metyl-5-okso-3,5-seco-A-norandrostån-3-karboksylsyre, som smelter ved 192-194°. Add 2 ml of glacial acetic acid, which is saturated with hydrogen bromide. After 5 minutes, 2 ml of a solution of 33% bromine in glacial acetic acid, which has been diluted with 200 ml of ether, is added dropwise. The latter addition of the bromine solution needs about 1 hour, and the drop rate is adjusted the decolorization rate for the bromine solution in the reaction mixture. To the reaction mixture thus obtained, while continuing to stir and cool, 2-n aqueous sodium carbonate solution (1700 ml) is added in portions. The mixture is then placed in a separatory funnel, shaken and the carbonaceous layer is separated. The ethereal layer is washed three times each time with 100 ml of aqueous 2-n sodium carbonate solution. The carbonate-containing solutions are combined and acidified after the addition of ice with concentrated hydrochloric acid until pH 1. It is allowed to stand for 1 hour, filtered tfelte acid from, wash out well with water and dry in a drying oven at 45°. Crude 6p-bromo-17p-hydroxy-17oc-methyl-5-oxo-3,5-seco-A-norandrostane-3-carboxylic acid is obtained, which melts at 192-194°.
Til en opplosning av 17 g rå 6p-brom-17(3-hydroksy-17a-metyl-5-okso-3,5-seco-A-norandrostan-3-karboksylsyre i 540 ml metanol tilfores 51 ml l-n natriumhydroksydopplosning, og reak-sjonsblandingen står til henstand natten over ved 0°. Man nøy-traliserer så med 51 ml l-n saltsyre og fortynner med 3 liter vann. Den utfelte syre filtreres fra, vaskes med vann og torkes i torkeskap ved 45°. Man oppnår rå 6a-brom-17p-hydroksy-17a-metyl-5-okso-3,5-seco-A-norandrostan-3-karboksylsyre, som etter gjentatt omkrystallisasjon fra metanol smelter ved 201 - 202,5°; [ct]^<4>-13,7 (c =0,59 i tetrahydrofuran) bestemmes i et automatisk polarimeter og [oc]D 25 -18,2 o (c = 1 i tetrahydrofuran) bestemmes i et klassisk polarimeter. To a solution of 17 g of crude 6p-bromo-17(3-hydroxy-17a-methyl-5-oxo-3,5-seco-A-norandrostane-3-carboxylic acid in 540 ml of methanol is added 51 ml of 1-n sodium hydroxide solution, and -tion mixture is allowed to stand overnight at 0°. It is then neutralized with 51 ml 1-n hydrochloric acid and diluted with 3 liters of water. The precipitated acid is filtered off, washed with water and dried in a drying oven at 45°. Crude 6a- bromo-17p-hydroxy-17a-methyl-5-oxo-3,5-seco-A-norandrostane-3-carboxylic acid, which after repeated recrystallization from methanol melts at 201 - 202.5°; [ct]^<4> -13.7 (c = 0.59 in tetrahydrofuran) is determined in an automatic polarimeter and [oc]D 25 -18.2 o (c = 1 in tetrahydrofuran) is determined in a classical polarimeter.
Til en opplosning av 21 g rå 6a-brom-17p-hydroksy-17a-metyl-5-okso-3,5-seco-A-norandrostan-3-karboksylsyre i 700 ml meta- noi tilsettes under roring og isbadavkjoling 21 g natriumbor-hydrid over et tidsrom på 30 minutter. Etter tilsetningen ro-res reaksjonsblåndingen ytterligere i 1 time under kjoling og ansyres så med konsentrert saltsyre på pH 1. Man oppnår en suspensjon, som konsentreres i vakuum til et volum på 200ml, fortynnes med 600 ml vann og ekstraheres deretter tre ganger hver gang med 500 ml eter. Eteruttrekket vaskes to ganger med 50 ml 2-n vandig natriumkarbonatopplosning og så to ganger med 100 ml vann, torkes over vannfritt magnesiumsulfat og inn-dampes til torrhet. Resten krystalliserer ved anrivning med eter. Som tynnskiktskromatogrammet viser, inneholder dette produkt som hovedbeslanddel 6a-brom-17(3-h<y>droks<y>l-17a-metyl-4-ok-sa-5a-androstan-3-on og 6a-brom-17p-hydroksy-17a-metyl-4-oksa-5(3-androstan-3-on. Disse forbindelser skilles fra råproduktet ved fraksjonert krystallisasjon under anvendelse av aceton som opplosningsmiddel. To a solution of 21 g of crude 6a-bromo-17p-hydroxy-17a-methyl-5-oxo-3,5-seco-A-norandrostane-3-carboxylic acid in 700 ml of methanol, add 21 g of sodium boron while stirring and cooling in an ice bath -hydride over a period of 30 minutes. After the addition, the reaction mixture is stirred for a further 1 hour under cooling and then acidified with concentrated hydrochloric acid to pH 1. A suspension is obtained, which is concentrated in vacuo to a volume of 200 ml, diluted with 600 ml of water and then extracted three times each time with 500 ml of ether. The ether extract is washed twice with 50 ml of 2-n aqueous sodium carbonate solution and then twice with 100 ml of water, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue crystallizes by trituration with ether. As the thin layer chromatogram shows, this product contains as the main component 6a-bromo-17(3-hydroxyl-17a-methyl-4-ox-sa-5a-androstan-3-one and 6a-bromo-17p -hydroxy-17a-methyl-4-oxa-5(3-androstan-3-one. These compounds are separated from the crude product by fractional crystallization using acetone as solvent.
6a -brom-17(3-hy droksy-17a -metyl- 4-oksa-andro stan- 3-on vi ser seg ved lengre oppvarmning som ustabil forbindelse. Dette fak-tum påvirker smeltepunktet, som bestemmes på en "Kofler-plate". Legges forbindelsen ved romtemperatur på platen og oppvarmes langsomt, så smelter den under spaltning ved 202 - 204°. Legges den på den allerede til 170° forvarmede plate, så smelter den ved 213 - 213,5° og etter en omdannelse ved 207°. Bringes forbindelsen på den til 210° forvarmede pifete, så smelter den under spaltning ved 223 - 223,5° og ved anbringelse av forbindelsen på en til 220° forvarmet plate smelter den under spaltning ved 226 - 226,5° [ct]^<5>'<8>+ 93,2° (c = 0,68 i tetrahydrofuran). •a.. L . ■ 6a-bromo-17(3-hydroxy-17a-methyl-4-oxa-androstan-3-one we see on prolonged heating as an unstable compound. This fact affects the melting point, which is determined on a "Kofler plate ". If the compound is placed on the plate at room temperature and heated slowly, it melts during decomposition at 202 - 204°. If it is placed on the plate already preheated to 170°, it melts at 213 - 213.5° and after a conversion at 207 °. If the compound is placed on the pipe preheated to 210°, it melts during cleavage at 223 - 223.5° and when the compound is placed on a plate preheated to 220°, it melts during cleavage at 226 - 226.5° [ct] ^<5>'<8>+ 93.2° (c = 0.68 in tetrahydrofuran). •a.. L . ■
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68030867A | 1967-11-03 | 1967-11-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO132101B true NO132101B (en) | 1975-06-09 |
| NO132101C NO132101C (en) | 1975-09-17 |
Family
ID=24730576
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO4350/68A NO132101C (en) | 1967-11-03 | 1968-11-01 |
Country Status (14)
| Country | Link |
|---|---|
| AT (2) | AT297236B (en) |
| BE (1) | BE723189A (en) |
| BR (1) | BR6803654D0 (en) |
| CH (1) | CH505855A (en) |
| DK (1) | DK131576C (en) |
| ES (1) | ES359842A1 (en) |
| FI (1) | FI48098C (en) |
| FR (2) | FR1605466A (en) |
| GB (1) | GB1247022A (en) |
| IE (1) | IE33567B1 (en) |
| IL (1) | IL30879A (en) |
| NL (1) | NL6815623A (en) |
| NO (1) | NO132101C (en) |
| SE (1) | SE352360B (en) |
-
1968
- 1968-10-16 IL IL30879A patent/IL30879A/en unknown
- 1968-10-21 CH CH1567068A patent/CH505855A/en not_active IP Right Cessation
- 1968-10-29 IE IE1298/68A patent/IE33567B1/en unknown
- 1968-10-30 DK DK527668A patent/DK131576C/en active
- 1968-10-31 FR FR172162A patent/FR1605466A/fr not_active Expired
- 1968-10-31 SE SE14758/68A patent/SE352360B/xx unknown
- 1968-10-31 AT AT416970A patent/AT297236B/en not_active IP Right Cessation
- 1968-10-31 AT AT1062768A patent/AT287932B/en not_active IP Right Cessation
- 1968-10-31 FR FR172161A patent/FR8435M/fr not_active Expired
- 1968-10-31 BE BE723189D patent/BE723189A/xx unknown
- 1968-11-01 NO NO4350/68A patent/NO132101C/no unknown
- 1968-11-01 NL NL6815623A patent/NL6815623A/xx unknown
- 1968-11-01 GB GB29584/70A patent/GB1247022A/en not_active Expired
- 1968-11-01 BR BR203654/68A patent/BR6803654D0/en unknown
- 1968-11-02 ES ES359842A patent/ES359842A1/en not_active Expired
- 1968-11-04 FI FI683140A patent/FI48098C/en active
Also Published As
| Publication number | Publication date |
|---|---|
| ES359842A1 (en) | 1970-06-16 |
| BR6803654D0 (en) | 1973-01-16 |
| DE1805857A1 (en) | 1969-06-26 |
| FI48098B (en) | 1974-02-28 |
| SE352360B (en) | 1972-12-27 |
| IE33567B1 (en) | 1974-08-21 |
| FR8435M (en) | 1971-07-15 |
| BE723189A (en) | 1969-04-30 |
| FR1605466A (en) | 1976-05-14 |
| GB1247022A (en) | 1971-09-22 |
| NO132101C (en) | 1975-09-17 |
| IE33567L (en) | 1969-05-03 |
| DK131576B (en) | 1975-08-04 |
| AT297236B (en) | 1972-03-10 |
| NL6815623A (en) | 1969-05-06 |
| DE1805857B2 (en) | 1977-06-23 |
| DK131576C (en) | 1976-01-05 |
| FI48098C (en) | 1974-06-10 |
| AT287932B (en) | 1971-02-10 |
| IL30879A (en) | 1972-11-28 |
| IL30879A0 (en) | 1968-12-26 |
| CH505855A (en) | 1971-04-15 |
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