NO131175B - - Google Patents
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- NO131175B NO131175B NO1181/69A NO118169A NO131175B NO 131175 B NO131175 B NO 131175B NO 1181/69 A NO1181/69 A NO 1181/69A NO 118169 A NO118169 A NO 118169A NO 131175 B NO131175 B NO 131175B
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- Prior art keywords
- spirox
- methylene
- compounds
- ether
- approx
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- DKWOHBPRFZIUQL-UHFFFAOYSA-N dimethyl-methylidene-oxo-$l^{6}-sulfane Chemical compound C[S+](C)([CH2-])=O DKWOHBPRFZIUQL-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 9
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 9
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 7
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 7
- 229960002478 aldosterone Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- -1 20-spiroxa-4 Chemical compound 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 2
- 206010019280 Heart failures Diseases 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
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 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
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 208000009928 nephrosis Diseases 0.000 description 1
- 231100001027 nephrosis Toxicity 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K31/58—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
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
-
- E—FIXED CONSTRUCTIONS
- E05—LOCKS; KEYS; WINDOW OR DOOR FITTINGS; SAFES
- E05G—SAFES OR STRONG-ROOMS FOR VALUABLES; BANK PROTECTION DEVICES; SAFETY TRANSACTION PARTITIONS
- E05G1/00—Safes or strong-rooms for valuables
- E05G1/02—Details
- E05G1/024—Wall or panel structure
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Description
Analogifremgangsmåte ved fremstilling av tera- Analogy method in the production of tera-
peutisk aktive 68,7B-methylen-20-spirox-4-en-3-on therapeutically active 68,7B-methylene-20-spirox-4-en-3-one
og -3,21-dion, som er aldosteron-antagonister. and -3,21-dione, which are aldosterone antagonists.
Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av terapeutisk aktive 6|3 , 7P-methylen-20-spirox-4-en-3-on-forbindelser med formelen: The present invention relates to an analogous method for the production of therapeutically active 6|3,7P-methylene-20-spirox-4-en-3-one compounds with the formula:
hvor Z er to hydrogenatomer eller ett oxygenatom. where Z is two hydrogen atoms or one oxygen atom.
Disse nye forbindelser fremstilles ved at en forbindelse med formelen: These new compounds are produced by a compound with the formula:
hvor Z er som ovenfor angitt, omsettes med dimethyl-oxo-sulfonium-methylid under dannelse av en blanding av 6a,7a- og 6(3,7f3-methylen-forbindelser, som skilles. where Z is as stated above, is reacted with dimethyl-oxo-sulfonium-methylide to form a mixture of 6a,7a- and 6(3,7f3-methylene compounds, which are separated.
Disse nye forbindelser, 6|3 , 7|3-methylen-20-spirox-4-en-3-on og 6p , 7(3-methylen-20-spiroxa-1 ,4-dien-3~on er virksomme aldosteron-inhibitorer. De blokkerer de saltgjenholdende virkninger av aldosteron og andre saltgjenholdende steroider og er derfor nyttige for å lindre slike lidelser som hjerteinsuffisiens, nephrosis og nephroci.rrhosis ved hvilke aldosteronsekres jon er øket . These new compounds, 6|3 , 7|3-methylene-20-spirox-4-en-3-one and 6p , 7(3-methylene-20-spiroxa-1 ,4-dien-3~one are active aldosterone -inhibitors They block the salt-retaining effects of aldosterone and other salt-retaining steroids and are therefore useful in alleviating such disorders as heart failure, nephrosis and nephrocirrhosis in which aldosterone secretion is increased.
Fra U.S. patent 3.254-074 er det kjent at beslektede forbindelser hvorav 7-acetylthio-20-spirox-4-en-3-on ansees for å være den mest virksomme. Nedenfor er angitt sammenligningsdata for den nevnte forbindelse (C) og forbindelsen fremstilt i eksempel 1 ifølge foreliggende oppfinnelse, 6j3 ,7(3-methylen-20-spirox-4-en-3~on (A), samt 6(3 , 7P -met hy len -20-spirox-4-en-3 ,21 - dion (B). From the U.S. patent 3,254-074 it is known that related compounds of which 7-acetylthio-20-spirox-4-en-3-one is considered to be the most effective. Below are comparative data for the aforementioned compound (C) and the compound prepared in example 1 according to the present invention, 6j3 ,7(3-methylene-20-spirox-4-en-3~one (A), as well as 6(3 ,7P -meth hylene -20-spirox-4-ene-3,21-dione (B).
Hanrotter som veiet ca. 150 g, og som var bilateralt adren-alectomisert, ble anvendt som forsøksdyr. En kontrollgruppe ble gitt 12 ug deoxycorticosteron-acetat (DOCA) subcutant pr. dyr, og forsøksgruppene ble gitt forsøksforbindelsene oralt i forskjellige dosemengder i tillegg til 12 |j,g DOCA. Natrium- og kalium innholdet av urin oppsamlet i løpet av en 7-timers periode ble bestemt, og fra disse data ble graden hvori forsøksforbindelsene inhiberte virkningen av DOCA, beregnet. Male rats that weighed approx. 150 g, and which was bilaterally adrenalectomized, was used as an experimental animal. A control group was given 12 ug of deoxycorticosterone acetate (DOCA) subcutaneously per animals, and the experimental groups were given the test compounds orally in different dosage amounts in addition to 12 µg DOCA. The sodium and potassium content of urine collected over a 7-hour period was determined, and from these data the degree to which the test compounds inhibited the action of DOCA was calculated.
Disse data viser at 6|3, 73-methylenf orbindelsene fremstilt ifølge foreliggende fremgangsmåte er mere virksomme enn 7-acetyl-thioforbindelsen til å inhibere virkningen av deoxycorticosteron-acetat (DOCA). Det kan i denne forbindelse pekes på at den fysio-logiske virkning av DOCA ligner den av aldosteron, og at da DOCA er lettere tilgjengelig, anvendes det ofte istedenfor aldosteron i dyreforsøk på aldosteron-inhibitorer. These data show that the 6|3,73-methylene compounds produced according to the present method are more effective than the 7-acetyl-thio compound in inhibiting the action of deoxycorticosterone acetate (DOCA). In this connection, it can be pointed out that the physiological effect of DOCA is similar to that of aldosterone, and that as DOCA is more readily available, it is often used instead of aldosterone in animal experiments on aldosterone inhibitors.
Den forbausende egenskap ved foreliggende fremgangsmåtefor-bindelser er økningen i inhiberLng av DOCA, og således aldosteron, når 7-acetylthiogruppen i spiroxenonene i US patent 3.254.074 er-stattes med 60 , 7(3-methylengruppen . The surprising property of the present process compounds is the increase in inhibition of DOCA, and thus aldosterone, when the 7-acetylthio group in the spiroxenones in US patent 3,254,074 is replaced by the 60 , 7(3-methylene group).
Forbindelsene fremstilles bekvemt ifølge oppfinnelsen ved å omsette dimethyl-oxo-sulfonium-methylid med en forbindelse med formel II, dvs. 20-spiroxa-4,6-dien-3-on eller 20-spiroxa-4,6-dLen - 3,21-dion, hvorved det tilsvarende 6,7-methylenderivat dannes. Reaksjonen utføres bekvemt ved å bringe sammen under nitrogen, en minera loijedispersjon av nat riumhydrid og trimethylsulfoxoniumjodid og langsomt tilsete tørt dimethylsulfoxyd, hvorpå reaksjon inntrer med dannelse av dimethyl-oxo-sulfonium-methylid. Til den dannede blanding tilsettes så en slik mengde av forbindelsen med formel II at mola rforholdet av dimethyl-oxo-sulfonium-methylid til steroid er innen området av ca. 1:1 til 5:1, idet der vanligvis foretrekkes å anvende et molforhold på ca. 1:1. Reaksjonen får lov til å foregå i ca. 15 timer ved ca. værelsetemperatur , og steroidproduktet utvinnes bekvemt fra reaksjonsblandingen ved å tilsette reaksjonsblandingen til isvann, ekstrahere steroidproduktet med • et med vann ublandbart organisk oppløsningsmiddel, som ether, for-dampe det organiske oppløsningsmiddel og rense det gjenværende materiale ved kromatografi over aluminiumoxyd. The compounds are conveniently prepared according to the invention by reacting dimethyl-oxo-sulfonium methylide with a compound of formula II, i.e. 20-spiroxa-4,6-dien-3-one or 20-spiroxa-4,6-dLen-3, 21-dione, whereby the corresponding 6,7-methylene derivative is formed. The reaction is conveniently carried out by bringing together under nitrogen, a mineral liquid dispersion of sodium hydride and trimethylsulfoxonium iodide and slowly adding dry dimethylsulfoxide, after which reaction occurs with the formation of dimethyl-oxo-sulfonium methylide. An amount of the compound of formula II is then added to the resulting mixture such that the molar ratio of dimethyl-oxo-sulfonium methylide to steroid is within the range of approx. 1:1 to 5:1, it being usually preferred to use a molar ratio of approx. 1:1. The reaction is allowed to take place for approx. 15 hours at approx. room temperature, and the steroid product is conveniently recovered from the reaction mixture by adding the reaction mixture to ice water, extracting the steroid product with • a water-immiscible organic solvent, such as ether, evaporating the organic solvent and purifying the remaining material by chromatography over aluminum oxide.
Det følgende eksempel illustrerer foreliggende fremgangsmåte. The following example illustrates the present method.
Eks empel Example
Til en helt tørr blanding av 1,8 9 av en 56,37%-ig dispersjon av natriumhydrid i mineralolje (0,04246 mol) og 9,81 9 (0,o4246 mol + 5% overskudd) trimethylsulfoxoniurajodid, holdt under en nitrogenatmosfære og avkjølt til en temperatur på ca. 10°C, ble langsomt tilsatt 50 ml tørr dimethylsulfoxyd med en slik hastighet at skumningen ikke var for sterk. Den dannede blanding ble omrørt ved en temperatur på ca. 20°C i ca. 2,5 timer, eller inntil alt natriumhydrid hadde reagert. Til den således dannede dimethyl-oxo-sulfonium-methylid-reaksjonsblanding, som ble holdt praktisk talt vannfri og under en nitrogenatmosfære, ble hurtig tilsatt under omrøring ved værelseteinperatur en oppløsning av 3,0 g (0,00947 mol) 20-spiroxa-4,6-dien-3-on i 5 ml dimethylsulfoxyd. Reaksjonen tillates å forløpe over natten ved værelseteinperatur, og r e.« ks jonsblandingen tilsettes så til ca. lOO ml av en is-vannblanding. Den dannede vandige blanding ble ekstrahert med 2 x 100 ml ether, og de' forenede ekstrakter ble vasket med 3 x 25 ml vann. De vaskede ether-ekstrakter ble tørret over vannfritt natriumsulfat og inndampet til tørr-het i vakuum. Det dannede gule skum, ca. 3,9 g, ble suspendert i petrolether og brakt i oppløsning ved tilsetning av benzen. Den dannede oppløsning ble kromatografert på en aluminiumoxydkolonne (forhold 30 vektdeler aluminiumoxyd til 1 vektdel urent reaksjonsprodukt) våtpakket med petrolether. Kolonnen ble eluert-med 10:90 blanding av ether:petrolether inntil mineralolje ble eluert. Forholdet av ether i eluerings-oppløsningsmidlet ble så hevet i 10% trinn inntil en 60:40 blanding av ether:petrolether ble nådd. inndampning av 6o:40-eluatet ga 6a,7a-meth-ylen-20-spirox-4-en-3-on, smp. 101-103°C Økende konsentrasjoner av ether opptil 100% ether ble så anvendt for å eluere kolonnen. Inndampning av 100% av ethereluatet ga praktisk talt rent 63,7S-mechylen-20-spirox-4-en-3-on som krystallinsk materiale. Hver fraksjon fra kromato-grammet ble podet med dette materiale, og fraksjonene som krystalliserte delvis eller helt, ble forenet, hvorved man fikk ca. 900 mg 6(3,7(3-methylen-20-spirox-4-en-3-on. Ved omkrystallisasjon en gang fra ether, to ganger fra hexan og derpå fra methanol, fikk man analytisk rent 6(3,7(3-methylen-20-spirox-4-en-3-on med smp. 153-155°C To a completely dry mixture of 1.8 9 of a 56.37% dispersion of sodium hydride in mineral oil (0.04246 mol) and 9.81 9 (0.04246 mol + 5% excess) of trimethylsulfoxonium iodide, kept under a nitrogen atmosphere and cooled to a temperature of approx. 10°C, 50 ml of dry dimethylsulfoxide was slowly added at such a rate that the foaming was not too strong. The resulting mixture was stirred at a temperature of approx. 20°C for approx. 2.5 hours, or until all the sodium hydride had reacted. To the dimethyl-oxo-sulfonium-methylide reaction mixture thus formed, which was kept practically water-free and under a nitrogen atmosphere, was quickly added with stirring at room temperature a solution of 3.0 g (0.00947 mol) of 20-spiroxa-4 ,6-dien-3-one in 5 ml of dimethyl sulfoxyd. The reaction is allowed to proceed overnight at room temperature, and the r e.«ks ion mixture is then added to approx. lOO ml of an ice-water mixture. The resulting aqueous mixture was extracted with 2 x 100 ml of ether, and the combined extracts were washed with 3 x 25 ml of water. The washed ether extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. It formed yellow foam, approx. 3.9 g, was suspended in petroleum ether and dissolved by the addition of benzene. The resulting solution was chromatographed on an aluminum oxide column (ratio 30 parts by weight of aluminum oxide to 1 part by weight of impure reaction product) wet-packed with petroleum ether. The column was eluted with a 10:90 mixture of ether:petroleum ether until mineral oil was eluted. The ratio of ether in the elution solvent was then increased in 10% increments until a 60:40 mixture of ether:petroleum ether was reached. evaporation of the 6o:40 eluate gave 6a,7a-meth-ylene-20-spirox-4-en-3-one, m.p. 101-103°C Increasing concentrations of ether up to 100% ether were then used to elute the column. Evaporation of 100% of the ether eluate gave practically pure 63,7S-mechylen-20-spirox-4-en-3-one as crystalline material. Each fraction from the chromatogram was seeded with this material, and the fractions that crystallized partially or completely were combined, whereby approx. 900 mg 6(3,7(3-methylene-20-spirox-4-en-3-one). By recrystallization once from ether, twice from hexane and then from methanol, analytically pure 6(3,7( 3-methylene-20-spirox-4-en-3-one with mp 153-155°C
Ved foregående metode, men ved å anvende 20-spiroxa-4,6-dien-3,21-dion som steroid-utgangsmateriale (istedenfor 20-spiroxa-4,6-dien-3-on) sammen med en omtrent ekvimolekylær mengde av dimethyl-oxo-sulf onium-methylid , fikk man 6(3 , 7p-met hylen-20-spirox-4-en-3 ,21-dion i 30% utbytte og 6a,7a-methylen-20-spirox-4-en-3,21-dion i 10% utbytte. Smeltepunktet for 6(3,7(3 -forbindelsen er 170-171°C, og den optiske dreining er aD -186,2 (c = 1, CHCl^)• By the preceding method, but using 20-spiroxa-4,6-dien-3,21-dione as steroid starting material (instead of 20-spiroxa-4,6-dien-3-one) together with an approximately equimolecular amount of dimethyl-oxo-sulfonium-methylide, 6(3,7p-meth hylene-20-spirox-4-ene-3,21-dione was obtained in 30% yield and 6a,7a-methylene-20-spirox-4- en-3,21-dione in 10% yield. The melting point of the 6(3,7(3) compound is 170-171°C, and the optical rotation is aD -186.2 (c = 1, CHCl^)•
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71516068A | 1968-03-22 | 1968-03-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO131175B true NO131175B (en) | 1975-01-06 |
| NO131175C NO131175C (en) | 1975-04-16 |
Family
ID=24872890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1181/69A NO131175C (en) | 1968-03-22 | 1969-03-21 |
Country Status (14)
| Country | Link |
|---|---|
| AT (1) | AT297948B (en) |
| BE (1) | BE730163A (en) |
| BR (1) | BR6907426D0 (en) |
| CH (1) | CH525876A (en) |
| DK (1) | DK123353B (en) |
| FI (1) | FI47354C (en) |
| FR (1) | FR2004562A1 (en) |
| GB (1) | GB1235768A (en) |
| IE (1) | IE33205B1 (en) |
| IL (1) | IL31769A (en) |
| NL (1) | NL166267C (en) |
| NO (1) | NO131175C (en) |
| SE (1) | SE351636B (en) |
| YU (1) | YU34303B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE792624A (en) * | 1972-05-22 | 1973-06-12 | Merck & Co Inc | ALDOSTERONE INHIBITORS AND THEIR OBTAINING |
| DE2652761C2 (en) * | 1976-11-16 | 1985-11-21 | Schering AG, 1000 Berlin und 4709 Bergkamen | 15,16-methylene-spirolactones, processes for their preparation and pharmaceuticals containing them |
| AT351191B (en) * | 1976-12-20 | 1979-07-10 | Hoffmann La Roche | METHOD FOR PRODUCING NEW D-HOMOSTEROIDS |
| DE3222265A1 (en) * | 1982-06-09 | 1983-12-15 | Schering AG, 1000 Berlin und 4709 Bergkamen | 6SS.7SS-METHYLENE-17 (ALPHA) -PREGN-4-EN-21.17-CARBOLACTONE, METHOD FOR THE PRODUCTION AND USE THEREOF AS A MEDICINAL PRODUCT |
| JPS59139400A (en) * | 1983-01-31 | 1984-08-10 | Shionogi & Co Ltd | Steroid derivative with antialdosteronic activity |
-
1969
- 1969-03-04 NL NL6903322.A patent/NL166267C/en not_active IP Right Cessation
- 1969-03-10 YU YU581/69A patent/YU34303B/en unknown
- 1969-03-10 IL IL31769A patent/IL31769A/en unknown
- 1969-03-11 FI FI690718A patent/FI47354C/en active
- 1969-03-11 IE IE317/69A patent/IE33205B1/en unknown
- 1969-03-13 SE SE03497/69A patent/SE351636B/xx unknown
- 1969-03-17 GB GB03874/69A patent/GB1235768A/en not_active Expired
- 1969-03-20 CH CH421969A patent/CH525876A/en not_active IP Right Cessation
- 1969-03-20 BE BE730163D patent/BE730163A/xx unknown
- 1969-03-20 AT AT277969A patent/AT297948B/en not_active IP Right Cessation
- 1969-03-21 NO NO1181/69A patent/NO131175C/no unknown
- 1969-03-21 FR FR6908468A patent/FR2004562A1/fr not_active Withdrawn
- 1969-03-21 DK DK157269AA patent/DK123353B/en unknown
- 1969-03-21 BR BR207426/69A patent/BR6907426D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK123353B (en) | 1972-06-12 |
| FI47354B (en) | 1973-07-31 |
| YU58169A (en) | 1978-10-31 |
| BR6907426D0 (en) | 1973-05-31 |
| CH525876A (en) | 1972-07-31 |
| IL31769A0 (en) | 1969-05-28 |
| BE730163A (en) | 1969-09-22 |
| GB1235768A (en) | 1971-06-16 |
| YU34303B (en) | 1979-04-30 |
| DE1914507A1 (en) | 1969-10-09 |
| FI47354C (en) | 1973-11-12 |
| FR2004562A1 (en) | 1969-11-28 |
| IE33205L (en) | 1969-09-22 |
| AT297948B (en) | 1972-04-10 |
| SE351636B (en) | 1972-12-04 |
| IE33205B1 (en) | 1974-04-17 |
| NL6903322A (en) | 1969-09-24 |
| NL166267C (en) | 1981-07-15 |
| IL31769A (en) | 1973-08-29 |
| NO131175C (en) | 1975-04-16 |
| NL166267B (en) | 1981-02-16 |
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