DE1804796A1 - Process for the preparation of polycyclic compounds - Google Patents
Process for the preparation of polycyclic compoundsInfo
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- DE1804796A1 DE1804796A1 DE19681804796 DE1804796A DE1804796A1 DE 1804796 A1 DE1804796 A1 DE 1804796A1 DE 19681804796 DE19681804796 DE 19681804796 DE 1804796 A DE1804796 A DE 1804796A DE 1804796 A1 DE1804796 A1 DE 1804796A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D315/00—Heterocyclic compounds containing rings having one oxygen atom as the only ring hetero atom according to more than one of groups C07D303/00 - C07D313/00
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- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/04—Saturated ethers
- C07C43/12—Saturated ethers containing halogen
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
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- 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
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
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- 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
- C07D311/94—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 condensed with rings other than six-membered or with ring systems containing such rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/74—Naphthothiophenes
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes
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Description
München, 24.Oktober 1968Munich, October 24, 1968
RAN 4104/55-52 RAN 4104/5 5-52
F. HoflFmann-La Roche & Co. Aktiengesellschaft, Basel/SchweizF. HoflFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland
Die Erfindung betrifft ein Verfahren zur Herstellung polycyclischer Verbindungen der allgemeinen FormelThe invention relates to a process for the preparation of polycyclic compounds of the general formula
Grn/2.10.68Green / 10/2/68
worin R eine primäre Alkylgruppe mit bis zu ;5 C-Atomen, 909826/1348 wherein R is a primary alkyl group with up to; 5 carbon atoms, 909826/1348
BADBATH
•ζ U <γ Q • ζ U <γ Q
R , R , R' und R Wasserstoff oder nieder-Alkyl,R, R, R 'and R are hydrogen or lower-alkyl,
S 2 6S 2 6
R^ nieder-Alkyl, R Wasserstoff, R Hydroxy,R ^ lower-alkyl, R hydrogen, R hydroxy,
o$}ero $} er
undand
R zusammen eine Kohlenstoff-Kohlenstoffbindung, ZR together a carbon-carbon bond, Z
n9n9
Carbonyl oder eine Gruppe der FormelCarbonyl or a group of the formula
1010
,10 ' , 10 '
Wasserstoff oder nieder-Acyl, R Wasserstoff oder einen niederen Kohlenwasserstoffrest und m 1 oderHydrogen or lower acyl, R hydrogen or a lower hydrocarbon radical and m 1 or
2 bedeutet.2 means.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen FormelThe inventive method is characterized in that a compound of the general formula
IIII
worin R nieder-Alkoxy bedeutet,where R is lower alkoxy,
durch Behandlung mit Säure und Wärme zu einer Verbindung der allgemeinen Formelby treatment with acid and heat to a compound of the general formula
909826/1348909826/1348
BAD ORIGINALBATH ORIGINAL
1R 1 row
IaYes
cyclisiert und gewünschtenfalls eine erhaltene Verbindung der allgemeinen Formel Ia durch Behandlung mit Säure zu einer Verbindung der allgemeinen Formelcyclized and, if desired, a compound of the general formula Ia obtained by treatment with acid to give a compound of the general formula
IbIb
hydratisiert.hydrated.
Der hier verwendete Ausdruck "Kohlenwasserstoffrest" bezeichnet einen einwertigen ,nur aus Kohlenstoff und Wasserstoff bestehenden Rest, der Ausdruck "nieder-Alkyl" bezeichnet einen geradkettig oder verzweigten, gesättigten Kohlenwasserstoff rest rr.it bis zu 6 C-Atomen, wie Methyl, Aethyl, Butyl, tert.-Butyl, Hexyl und 2-Aethylhexyl. Der Ausdruck "primäresThe term "hydrocarbon residue" used here denotes a monovalent radical consisting only of carbon and hydrogen, the term "lower-alkyl" denotes a straight-chain or branched, saturated hydrocarbon residue with up to 6 carbon atoms, such as methyl, ethyl, butyl, tert-butyl, hexyl and 2-ethylhexyl. The term "primary
909826/1348909826/1348
Alkyl" bezeichnet eine Alkylgruppe. deren Valenzbindung von einem primären C-Atom ausgeht.Alkyl "denotes an alkyl group whose valence bond of a primary carbon atom.
Die Cyclisation einer Verbindung der Formel II zu einem Enoläther der Formel Ia kann in einem Lösungsmittel wie Benzol oder Toluol durchgeführt werden. Geeignete Säuren für die Cyclisation sind p-Toluolsulfqnsäure, Salzsäure, Phosphorsäure oder Kaliumhydrogensulfat. Die Cyclisation wird vorzugsweise bei Rückflusstemperatur des Reaktionsmediums durchgeführt, es kommen auch Reaktionstemperäturen zwischen 70 und 150° in Betracht.The cyclization of a compound of formula II to an enol ether of formula Ia can in a solvent such as Benzene or toluene can be carried out. Suitable acids for the cyclization are p-toluenesulfuric acid, hydrochloric acid and phosphoric acid or potassium hydrogen sulfate. The cyclization is preferably carried out at the reflux temperature of the reaction medium, reaction temperatures between 70 and 150 ° can also be used.
Die Enoläther der Formel Ia können durch Behandlung mit Säuren, wie Schwefelsäure , Salzsäure oder p-Toluolsulfonsäure in einem Lösungsmittel bei Raumtemperatur zu Hydroxyäthern der Formel Ib hydratisiert werden. Geeignete Lösungsmittel für diese Umsetzung sind z.B. Aceton, Methanol oder Aethanol.The enol ethers of the formula Ia can be obtained by treatment with acids such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid be hydrated in a solvent at room temperature to form hydroxy ethers of the formula Ib. Suitable solvents for this conversion are e.g. acetone, methanol or ethanol.
Die erfindungsgemäss erhältlicbatneuen polydyclischen Verbindungen können z.B. als Zwischenprodukte in der Totalsynthese von Stercddan Verwendung finden. Die Hydroxyäther der Formel Ib können zu Diketonverbindungen der FormelThe novel polydyclic ones obtainable according to the invention Compounds can be used, for example, as intermediates in the total synthesis of stercddane. The hydroxy ethers of Formula Ib can lead to diketone compounds of the formula
909826/1348909826/1348
SAD ORIQtNALSAD ORIQtNAL
IIIIII
oxydiert werden, beispielsweise mittels Chromsäure, .Kaiiumdichromat oder vorzugsweise mittels Jones 'Reagens (Chromsäure, Schwefeisäure und Aceton). Ausgehend von einer Verbindung der Formel Ib in der R Aethyl, R^ Methyl,Z Cartxr^l, m 1 urxlbe oxidized, for example by means of chromic acid, potassium dichromate or preferably using Jones' reagent (chromic acid, sulfuric acid and acetone). Starting from a connection of the formula Ib in which R Aethyl, R ^ methyl, Z Cartxr ^ l, m 1 urxl
3 4 7 8
R , R , R und R Wasserstoff darstellen, d.h. von 6a,9a-Trans-2-methyl-6aß-&hyl-7-oxo-perhydrocyclopenta[5,6]naphtho[2,ltipyran-lla-ol,
erhält man durch Oxydation 10-(3-0xobutyl)-l8-methyl-19-nor-desA-androstan-5,17-dlon.
Eine Verbindung der Formel III kann dann zu einem 19-Nor-androst-4-en-3-on durch
Behandlung mit einer Säure oder Base cyclisiert werden, z.B. durch Rückflusserhitzen in Gegenwart einer starken und zur Phasentrennung
befähigten Säure, wie p-Toluolsulfonsäure unter Azeotropdestillation
des Reaktionswassers. Beispielsweise liefert 10-(3-0xobutyl)-l8-methyl-19-nor-desA-androstan-5i17-dion
bei der Cyclisation die Verbindung L3ß-Aethyl-gon-4-eri-3,17-dion,
die wiederum selektiv mittels eines geeigneten metallorganischen Acetylids alkinyliert werden kann und Norgestrel
(l3ß-Aethyl-17a-äthinyl-17-hydroxy-gon-4-en-3-on)liefert.Diese3 4 7 8
R, R, R and R represent hydrogen, ie from 6a, 9a-trans-2-methyl-6ass- & hyl-7-oxo-perhydrocyclopenta [5,6] naphtho [2, ltipyran-lla-ol, is obtained by oxidation 10- (3-0xobutyl) -18-methyl-19-nor-desA-androstane-5,17-dlon. A compound of the formula III can then be cyclized to a 19-nor-androst-4-en-3-one by treatment with an acid or base, for example by refluxing in the presence of a strong acid capable of phase separation, such as p-toluenesulfonic acid Azeotropic distillation of the water of reaction. For example, 10- (3-0xobutyl) -18-methyl-19-nor-desA-androstan-5 i 17-dione yields the compound L3ß-ethyl-gon-4-eri-3,17-dione in the cyclization, which in turn can be selectively alkynylated using a suitable organometallic acetylide and norgestrel (13β-ethyl-17a-ethinyl-17-hydroxy-gon-4-en-3-one) supplies
909826/1348909826/1348
BAOBAO
selektive Alkinylierung kann z.B. durch Behandlung mit Kaliumacetylld in Gegenwart von flüssigem Ammoniak in Benzol err folgen. . ,selective alkynylation can be achieved, for example, by treatment with potassium acetylld in the presence of liquid ammonia in benzene err follow. . ,
Die Ausgangsverbindungen der Formel II können in Analogie zu den für bestimmte Verbindungen in den folgenden Beispielen angegebenen Verfahren hergestellt werden.The starting compounds of the formula II can be carried out in analogy to the procedures given for certain compounds in the following examples.
In den Beispielen sind die Temperaturen in Celsiusgraden angegeben.In the examples, the temperatures are given in degrees Celsius.
Eine Lösung von 500 mg 10[3-Tertiärbutoxy-butyl]—18— methyl"-19~nor-desA~and.rostan-5il7-dion in 25 ml Benzol das eine Spur p-Toluolsulfonsäure enthält wird 2 l/2 Stunden zum RUekflussiederi erhitzt. Die organische Phase wird dann mittels wässriger Natriumbicarbonatlösung säurefrei gewaschen und die Lösungsmittel werden unter vermindertem Druck entfernt. Der Rückstand wird in Hexan gelöst und liefert nach Kristallisation reines 6a,'9a"Trans-2-methyl-6aß-äthyl-7-oxo-3f^,5*59-, 6,8,9i10,10a,ll-decahydro-2HJi7H-cyclopenta-[5i63naphtho[2,]^-A solution of 500 mg of 10 [3-tert-butoxy-butyl] -18-methyl "-19-nor-desA-and.rostan-5il7-dione in 25 ml of benzene which contains a trace of p-toluenesulfonic acid is used for 2 1/2 hours The organic phase is then washed free of acid using aqueous sodium bicarbonate solution and the solvents are removed under reduced pressure. The residue is dissolved in hexane and, after crystallization, yields pure 6a, 9a "trans-2-methyl-6ass-ethyl-7- oxo-3f ^, 5 * 59-, 6,8,9 i 10,10a, ll-decahydro-2H Ji 7H-cyclopenta- [5 i 63naphtho [2,] ^ -
°pyran„ vom Schmelzpunkt 111-115°.° pyran "with a melting point of 111-115 °.
^ Beispiel^ Example
co ■}>■ oo Das gemäss Beispiel 1 erhaltene 6a,9a-Trans-2-methyl-6aß- co ■}> ■ oo The 6a, 9a-trans-2-methyl-6ass- obtained according to Example 1
BAD ORIGINALBATH ORIGINAL
äthyl-7-0X0-3,4,5,5a, 6,8,9,10,10a, ll-decahydro-aH^H-cyelopenta15*6}naphtho(2,I^-pyran wird in 75 ml Aceton bei Raumtemperatur gelöst. Die Lösung wird mit 35 ml IN Schwefelsäure versetzt und das Reaktionsgemisch 35 Minuten stehen gelassen. Danach wird mit Kochsalzlösung verdünnt und mit Aether extrahiert. Abdampfen des Lösungsmittel liefert ein Rohprodukt das aus Hexan umkristallisiert das reine Hemiketal nämlich 6a,9a-Trans-2-methyl-6aß-äthyl-7-oxo-perhydrocyclopenta(5*6]naphtho[2,l-b]-pyran-lla-ol vom Schmelzpunkt 114-116° liefert.ethyl-7-0X0-3,4,5,5a, 6,8,9,10,10a, ll-decahydro-aH ^ H-cyelopenta15 * 6} naphtho (2, I ^ -pyran is dissolved in 75 ml of acetone at room temperature. The solution is diluted with 35 ml of IN sulfuric acid added and the reaction mixture left to stand for 35 minutes. Then it is diluted with saline and with Aether extracted. Evaporation of the solvent yields a crude product which recrystallizes the pure hemiketal from hexane namely 6a, 9a-trans-2-methyl-6ass-ethyl-7-oxo-perhydrocyclopenta (5 * 6] naphtho [2, l-b] -pyran-lla-ol with a melting point of 114-116 °.
500 mg 10(3-Tertiärbutoxy-butyl)-l8-methyl-19-nor-desA-androstan-5,17-dion werden in 25 ml Benzol, das 25 mg p-Toluolsulfonsäure enthält, gelöst und 2 l/2 Stunden zum Rückfluss erhitzt. Die organische Phase wird säurefrei gewaschen und das Lösungsmittel im Vakuum entfernt. Der Rückstand wird in 35 ml Aceton gelöst und die Lösung mit 15 ml IN Schwefelsäure versetzt. Man lässt 35 Minuten bei Raumtemperatur stehen, verdünnt mit Kochsalzlösung und extrahiert mit Aether. Nach Abdampfen des Aethers erhält man wachsartiges 6a,9a-Trans-2-methyl-6aß-äthyl-7-oxo-perhydrocyclopenta-[5*6]-naphtho[2,l-b]-pyran-lla-oL , dasjs nach Kristallisation aus Hexan bei 114-116° schmilzt.500 mg of 10 (3-tert-butoxy-butyl) -18-methyl-19-nor-desA-androstane-5,17-dione are in 25 ml of benzene, the 25 mg of p-toluenesulfonic acid contains, dissolved and heated to reflux for 2 l / 2 hours. The organic phase is washed free of acid and the solvent removed in vacuo. The residue is dissolved in 35 ml of acetone and the solution with 15 ml of IN sulfuric acid offset. The mixture is left to stand at room temperature for 35 minutes, diluted with sodium chloride solution and extracted with ether. To Evaporation of the ether gives waxy 6a, 9a-trans-2-methyl-6ass-ethyl-7-oxo-perhydrocyclopenta- [5 * 6] -naphtho [2, l-b] -pyran-IIIa-oL , which melts at 114-116 ° after crystallization from hexane.
Das 10(3-Tertiärbutoxy-butyl)-l8-methyl-19-nor-desA-909826/1348 The 10 (3-tert-butoxy-butyl) -18-methyl-19-nor-desA-909826/1348
androstan-5il7~dion kann wie folgt hergestellt werden:Androstan-5il7 ~ dione can be made as follows:
71*5 S 5-Chlor-2-pentanon werden in 250 ml Aether gelöst und sodann im Verlauf von 50 Minuten bei -4o° zu einer Aufschlämmung von 12 g Lithiumaluminiumhydrid in Aether ge-71 * 5 S 5-chloro-2-pentanone are dissolved in 250 ml of ether and then over 50 minutes at -4o ° to one Slurry of 12 g lithium aluminum hydride in ether
gegen. Das Reaktionsgomisch wird eine weitere halbe Stunde bei -30° gerührt, und dann mit 115 ml gesättigter, wässriger Natriumsulfatlösung versetzt. Die Feststoffe werden abfiltriert und mit Aether gewaschen. Nach Entfernung des Aethers erhält man 5-Chlor-2-pontanol.against. The reaction mixture is another half an hour stirred at -30 °, and then with 115 ml of saturated, aqueous Sodium sulfate solution added. The solids are filtered off and washed with ether. After removing the ether one obtains 5-chloro-2-pontanol.
g 5~Chlor-2--pentanol werden in 500 ml Methylenchlorid gelöst und darauf zu einer Mischung vo η 24 ml konzentrierter Schwefelsäure in 500 ml Methylenchlorid gegeben. Nach Zusatz von 1 Liter flüssigem Isobutylen wird das Gemisch bei Raumtemperatur 20 Stunden stehen gelassen, die organische Phase wird mit Kochsalzlösung, wässriger Natriumbicarbonatlösung gewaschen und über Magnesiumsulfat getrocknet. Nach Entfernung der Lösungsmittel erhält man 5-Chlor-2-tertiärbutoxy~pentan.g of 5-chloro-2-pentanol are dissolved in 500 ml of methylene chloride dissolved and then concentrated to a mixture of 24 ml Sulfuric acid in 500 ml of methylene chloride. After addition of 1 liter of liquid isobutylene, the mixture is at room temperature Left to stand for 20 hours, the organic phase is washed with brine, aqueous sodium bicarbonate solution washed and dried over magnesium sulfate. After removing the solvent, 5-chloro-2-tert-butoxy-pentane is obtained.
10 g Magnesium werden mit einem Jodkristall aktiviert, und sodann mit 20 ml Tetrahydrofuran Übergossen. Man setzt dann10 g of magnesium are activated with an iodine crystal, and then 20 ml of tetrahydrofuran are poured over them. Then you bet
5 Tropfen Dibromäthan zu und rührt das Gemisch unter Rückfluss-Add 5 drops of dibromoethane and stir the mixture under reflux
r>o sieden während 15 Minuten. Sodann werden von einer Lösung, die σ) boil for 15 minutes. Then from a solution that σ)
^ 6?, 5S 5-Chlor-2-terti:iri-;utox.y-pentan in 250ml Tetrahydrofuran enthält,^ 6 ?, 5S 5-chloro-2-terti: iri-; utox.y-pentane in 250ml tetrahydrofuran contains,
*-. 20 ml dem Reaktionsgemisch zugesetzt. Nachdem die Reaktion in* -. 20 ml were added to the reaction mixture. After the reaction in
Gang gekommen ist (was I5 Minuten bis 24 Stunden dauern kann),Has come into gear (which can take 15 minutes to 24 hours),
BADBATH
werden die restlichen 2^0 ml im Verlauf von 1 Stunde zugesetzt. Das Reaktionsgemisch wird dann noch eine weitere Stunde zum Rückfluss erhitzt, gekühlt und filtriert. Die so erhaltene Grignardlösung wird bei -25° zu einer Lösung von 59 g frischdestilliertem Glutaraldehyd in 400 ml Tetrahydrofuran·gegeben. Man rührt weitere 15 Minuten bei -25° und hält dann dan Reaktionsgemisch 1 Stunde bei 0°. Nach Zusatz von 65O ml 20-iger, wässriger Ammoniumchloridlösung wird das pH der Lösung durch I Zusatz von 100 ml 1 normaler Salzsäure auf 4 eingestellt. Extraktion mit Aether liefert 91 g 6-[4-:Tertiärbutoxy-pentyi] ~ 2-tetrahydropyranol als öliges Rohprodukt. Das Rohprodukt wird zwecks "i&inigung mit 65O ml einer 20^-igea Natriurnsulfitlösung gerührt, wobei das pH der Lösung durch Zusatz von Eisessig auf 6,5 eingestellt wird. Danach wird das pH durch Zusatz von 20^-igej« Natriumhydroxidlösung auf 7*5 gebracht. Man rührt eine weitere Stunde bei 40° und extrahiert das Reaktionsgernisch mit Aether. Die wässrige Schicht wird auf pH 12,5 durch Zusatz von 20^-iger Natronlauge gestellt und erneut mit Aether extrahiert. Abdampfen des Aethers liefert das reine Hemiacetal, 6-[4-Tertiärbutoxy-penty13-2-tetrahydropyranol, in flüssiger Form.the remaining 2 ^ 0 ml are added over the course of 1 hour. The reaction mixture is then refluxed for a further hour, cooled and filtered. The thus obtained Grignard solution becomes a solution of 59 g freshly distilled at -25 ° Glutaraldehyde was added to 400 ml of tetrahydrofuran. The mixture is stirred for a further 15 minutes at -25 ° and then holds Reaction mixture for 1 hour at 0 °. After the addition of 650 ml of 20% aqueous ammonium chloride solution, the pH of the solution is increased by I. Addition of 100 ml of 1 normal hydrochloric acid adjusted to 4. Extraction with ether yields 91 g of 6- [4-: tertiary butoxy-pentyi] ~ 2-tetrahydropyranol as an oily crude product. The crude product is cleaned with 65O ml of a 20% sodium sulfite solution stirred, the pH of the solution being adjusted to 6.5 by adding glacial acetic acid. Then the pH is adjusted by adding 20% sodium hydroxide solution brought to 7 * 5. One stirs one another hour at 40 ° and extracted the reaction mixture with Ether. The aqueous layer is adjusted to pH 12.5 by adding 20% sodium hydroxide solution and extracted again with ether. Evaporation of the ether gives the pure hemiacetal, 6- [4-tert-butoxy-penty13-2-tetrahydropyranol, in liquid form.
4,6 g 6-[4-Tertiärbutoxy-pentyl]-2-tetrahydropyranol4.6 g of 6- [4-tert-butoxy-pentyl] -2-tetrahydropyranol
co werden in 200 ml Tetrahydrofuran gelöst und sodann langsam οco are dissolved in 200 ml of tetrahydrofuran and then slowly ο
^ im Verlauf von 20 Minuten zu einer Lösung von J> ml Vinyl- <x magnesiumchlorid in Tetrahydrofuran bei 0° gegeben. Man rührt^ added in the course of 20 minutes to a solution of J> ml vinyl <x magnesium chloride in tetrahydrofuran at 0 °. One stirs
^t eine weitere Stunde bei Zimmertemperatur, setzt 200 ml Aether und anschliessend 100 ml einer 20%-igen wässrigen Ammoniurnchlorid-^ t another hour at room temperature, add 200 ml of ether and then 100 ml of a 20% aqueous ammonium chloride
lösung zu. Extraktion mit Aether liefert eine» wachs ar ti gen Peststoff, JjT-Dihydroxy-ll-tertiärbutoxy-dodec-l-en,solution to. Extraction with ether provides a »waxy pesticide, JjT-Dihydroxy-ll-tertiary-butoxy-dodec-l-en,
41,3 g JjT-Dihydroxy-ll-tertiärbutoxy-dodec-l-en werden in Benzol gelöst und zu einer Aufschlämmung von 320 g aktiviertem Mangandioxid in l6ÖO ml Benzol, das 120 ml Diäthylamin enthält, gegeben. Das Reaktionsgemisch wird 20 Stunden bei Raumtemperatur gerührt und dann filtriert, Entfernung der Lösungsmittel im Vakuum liefert ein hellbraunes OeI. Das OeI wird in Aether gelöst, und die ätherische Lösung mit wässriger IN Salzsäure extrahiert. Der saure Extrakt wird mit Natriumhydroxid versetzt. Danach mit Aether extrahiert. Abdampfen der Lösungsmittel liefert 2-(21-Diäthylaminoäthyl)~6-(4-tert.butoxy-pentyl)-2~tetrahydropyranol. 41.3 g of JjT-dihydroxy-II-tertiary-butoxy-dodec-l-ene are dissolved in benzene and added to a slurry of 320 g of activated manganese dioxide in 160 ml of benzene containing 120 ml of diethylamine. The reaction mixture is stirred for 20 hours at room temperature and then filtered, removal of the solvents in vacuo yields a light brown oil. The oil is dissolved in ether and the ethereal solution extracted with aqueous IN hydrochloric acid. Sodium hydroxide is added to the acidic extract. Then extracted with ether. Evaporation of the solvent gives 2- (2 1 -diethylaminoethyl) ~ 6- (4-tert-butoxypentyl) -2 ~ tetrahydropyranol.
Zu einer Lösung von 22 g 2-Aethyi-cyclQpentan-lJj5-(äiori in einer Lösung von 440 ml Xylol, das# 220 ml Essigsäure enthält, werden unter RUckflussieden 42,2 g 2-(2'-Diäthylaniinoäthyl)-6-(4·-tertiärbufcoxy-pentyl)-2-tetrahydropyranol gegeben, Das Gemisch wird 1 Stunde zum Rückfluss erhitzt, ciarauf auf Zimmertemperatur abgekühlt und mit Wasser säurefrei gewaschen. Die Lösungsmittel werden unter vermindertem Druck entfernt, wobei rohes 3~(4-Tertiärbutoxy~pentyl)-6aa-äthyl-2,3>5>6,6a,8-hexahydrocyclopenta[f][l]benzopyran-7(lH)-on als hellrotes OeI zurückbleibt. Durch Chromatographie an 1,2 kg Aluminiumoxid (Aktivität III, neutral) werden 3>8,8 g reines Material er-42.2 g of 2- (2'-diethylaniinoethyl) -6 are added under reflux to a solution of 22 g of 2-ethyl-cyclic pentane-1 J j5- ( aiori in a solution of 440 ml of xylene containing 220 ml of acetic acid The mixture is refluxed for 1 hour, cooled to room temperature and washed free of acid with water. The solvents are removed under reduced pressure, whereby crude 3 ~ (4-tert-butoxy ~ pentyl) -6aa-ethyl-2,3>5> 6,6a, 8-hexahydrocyclopenta [f] [l] benzopyran-7 (lH) -one remains as a light red oil. Chromatography on 1.2 kg of aluminum oxide (activity III, neutral) 3> 8.8 g of pure material are
halten* 909826/1348 hold * 909826/1348
BAD ORIGINALBATH ORIGINAL
Eine Lösung von 8,6 g 3-(4-Tertlärbutoxy-pentyl) -6actäthyl-2,3,5,6,6a,8-hexahydrocyclopenta[f] [l]benzopyran-7(lH)~ on in 80 ml Aether wird bei -10° zu einer Aufschlämmung von 4 g Lithiumaluminiumhydrid in 200 ml Aether gegeben. Man rührt 1 Stunde bei Zimmertemperatur und setzt dann 20 ml gesättigte Natriumsulfatlösung zu. Die Peststoffe werden abfiltriert und »it 150 ml Aether gewaschen. Nach Abdampfen der Lösungsmittel erhält man 3-(4-Tertiärbutoxy-pentyl)-6aß-äthyl-2,3,5>6,6a,8-hexahydrocyclopenta[f ] (l"3benzopyran-7(lH)-ol, dasaf nach Kri~ stallisation aus Hexan bei 71-74° schmilzt.A solution of 8.6 g of 3- (4-tert-butoxy-pentyl) -6actethyl-2,3,5,6,6a, 8-hexahydrocyclopenta [f] [l] benzopyran-7 (lH) ~ one in 80 ml of ether is added at -10 ° to a suspension of 4 g of lithium aluminum hydride in 200 ml of ether. The mixture is stirred for 1 hour at room temperature and then 20 ml of saturated sodium sulfate solution are added. The pests are filtered off and washed with 150 ml of ether. After evaporation of the solvent, 3- (4-tert-butoxy-pentyl) -6ass-ethyl-2,3,5> 6,6a, 8-hexahydrocyclopenta [f] (l "3benzopyran-7 (1H) -ol, dasaf after Crystallization from hexane melts at 71-74 °.
Eine Lösung von 5,3 g 3-(4~Tertiärbutoxy-pentyl)-6aßäthyl-2,3,5,6,6a,8-hexahydrocyclopenta[f ] [] ]benzopyran-7(IH)-öl in 100 ml Toluol wird in Gegenwart von 1,5 g Pallacliuw-Kohleflkatalysator bei Raumteinperatur und Atmosphärendruuk hydriert bis kein Wasserstoff mehr aufgenommen wird. Dies ist nach der Aufnahme von 1,05 Mol Wasserstoff der Fall. Die Feststoffe werden abfiltriert und Lösungsmittel im Vakuum entfernt, wobei öliges 6a,9a-Trans-3-(4-tertiärbutoxy-pentyl)--6aß-äthyl 2,3,5,6,6a,8,9j9a-ootahydroeyclopenta[f ] (l]benzopyran-7(lll)-ol erhalten wird. Das Produkt ist dünnschichtchromatographisch rein.A solution of 5.3 g of 3- (4-tert-butoxy-pentyl) -6assethyl-2,3,5,6,6a, 8-hexahydrocyclopenta [f ] []] Benzopyran-7 (IH) oil in 100 ml of toluene is added in the presence of 1.5 g of Pallacliuw carbon catalyst at room temperature and atmospheric pressure hydrogenated until no more hydrogen is absorbed. This is the case after the absorption of 1.05 mol of hydrogen. The solids are filtered off and the solvent is removed in vacuo, whereby oily 6a, 9a-trans-3- (4-tert-butoxy-pentyl) -6ass-ethyl 2,3,5,6,6a, 8,9j9a-ootahydroeyclopenta [f ] (l] benzopyran-7 (III) -ol is obtained. The product is thin-layer chromatography pure.
NJ 35*9 g 6a,9a-Trans-3-(^-tertiärbutoxy-pentyl)-6aß-äthyl-NJ 35 * 9 g 6a, 9a-Trans-3 - (^ - tertiary-butoxy-pentyl) -6ass-ethyl-
2^ 2,3»5j6,6a,8,9,9a-octaliydrocyclopenta[f ] [l]benzopyran-7 (IH)-ol2 ^ 2,3 »5j6,6a, 8,9,9a-octaliydrocyclopenta [f] [l] benzopyran-7 (IH) -ol
co werden are co
*- in 700 ml Aceton 4 mit 200 ml 3 normaler Schwefelsäure ver-* - in 700 ml acetone 4 mixed with 200 ml 3 normal sulfuric acid
setzt und 2 Tage bei Raumtemperatur stehen gelassen. Die Lösungsets and left to stand for 2 days at room temperature. The solution
wird dann mit Kochsalzlösung verdünnt und mit Aether extrahiert. Verdampfung des Lösungsmittels liefert ein Gemisch von 6a,.9a-Trans-5-(4-tertiärbutoxy-pentyl)-6aß-äthyl-perhydrocyclopenta [f][l]benzopyran-4a,7-diol und 3a,7a~Trans-4-(7!-tertiärbutoxy-3'-hydroxy-octyl)-7aoc-äthyl-perhydroindan-l,5-dion. 4,65 gis then diluted with saline and extracted with ether. Evaporation of the solvent yields a mixture of 6a, .9a-Trans-5- (4-tert-butoxy-pentyl) -6ass-ethyl-perhydrocyclopenta [f] [l] benzopyran-4a, 7-diol and 3a, 7a-Trans-4 - (7 ! -Tertiary-butoxy-3'-hydroxy-octyl) -7aoc-ethyl-perhydroindane-1,5-dione. 4.65 g
inin
dieses Gemisches werden/200 ml Aceton gelöst und mit 10 ml Chromsäurelösung (Jones 'Reagenz) JO Minuten bei Raumtemperaturthis mixture are / 200 ml of acetone and dissolved with 10 ml Chromic acid solution (Jones' reagent) JO minutes at room temperature
wirdwill
gerührt. Das Reaktionsgemisch/dann mit Kochsalzlösung verdünnt und in Aether aufgenommen. Entfernung des Lösungsmittels im Vakuum liefert ;5a,7a-Trans-4-(7'-tertiärbutoxy-^'-oxo-octyl)-7aa-äthyl-perhydroindan-l,5-dion als OeI, das/ dünnschichtchromatographisch einheitlich ist.touched. The reaction mixture / then diluted with saline and taken up in ether. Removal of the solvent in vacuo gives; 5a, 7a-Trans-4- (7'-tertiary-butoxy - ^ '- oxo-octyl) -7aa-ethyl-perhydroindane-1,5-dione as OeI, das / by thin layer chromatography is uniform.
Eine Lösung von 25,4 g j5a,7a-Trans-4-(7'-rtertiärbutoxy-3'-oxo-octyl)-7aa-äthyl-perhydroindan-l,5-dion in 70 ml Tertiärbutanol wird zu 250 ml Tertiärbutanol gegeben, das 1 g Natriumhydroxid enthält. Das Reaktionsgemisch wird 1 Stunde unter Stickstoff bei 55° gehalten, danach gekühlt, mit Kochsalzlösung behandelt und in Aether aufgenommen. Nach Entfernung des Lösungsmittels und Chromatographie an neutralem Aluminiumbxid (Aktivität III) erhält man reines 10(j5-Tertiärbutoxy-butyl)-l#- methyl-19-nor-desA-androst-9-en-5il7-dion.A solution of 25.4 g of j5a, 7a-trans-4- (7'-tert-butoxy-3'-oxo-octyl) -7aa-ethyl-perhydroindane-1,5-dione in 70 ml of tertiary butanol is added to 250 ml of tertiary butanol, the 1 g of sodium hydroxide contains. The reaction mixture is kept at 55 ° under nitrogen for 1 hour, then cooled with brine treated and taken up in ether. After removing the solvent and chromatography on neutral aluminum oxide (activity III) pure 10 (j5-tert-butoxy-butyl) -l # - is obtained methyl-19-nor-desA-androst-9-en-5il7-dione.
^° Dieses Produkt wird in 50 ml Aethanol gelöst. Die Lösung er.^ ° This product is dissolved in 50 ml of ethanol. The solution he.
_> wird mit 0,3 ml Triäthylamin und 100 mg eines 5$-xgen Palladiumco _> Is with 0.3 ml of triethylamine and 100 mg of a 5 $ -xgen Palladium Co
*"*· Kohle|ikatalysators versetzt und bgjs Raumtemperatur und Atmosoc * "* · Coal | ikatalysators added and bgjs room temperature and Atmosoc
phärendruck hydriert, bei kein Wasserstoff mehr aufgenommenhydrogenated spherical pressure, absorbed no more hydrogen
BAD ORIGINALBATH ORIGINAL
wird. Die Peststoffe werden dann abfiltriert und Lösungsmittel im Vakuum entfernt, wobei man 10-(3-Tertiärbutoxybutyl)-l8-methyl-19-nor-desA-androstan-5il7-dion als dünnschichtchromatographisch einheitliches Produkt erhält.will. The pests are then filtered off and solvents removed in vacuo, 10- (3-tert-butoxybutyl) -18-methyl-19-nor-desA-androstane-5il7-dione obtained as a product which is uniform by thin layer chromatography.
909826/1348909826/1348
tete
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67998967A | 1967-11-02 | 1967-11-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1804796A1 true DE1804796A1 (en) | 1969-06-26 |
Family
ID=24729197
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19681804796 Pending DE1804796A1 (en) | 1967-11-02 | 1968-10-24 | Process for the preparation of polycyclic compounds |
| DE19681806410 Pending DE1806410A1 (en) | 1967-11-02 | 1968-10-31 | Method of making steroids |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19681806410 Pending DE1806410A1 (en) | 1967-11-02 | 1968-10-31 | Method of making steroids |
Country Status (11)
| Country | Link |
|---|---|
| BE (2) | BE723188A (en) |
| BR (1) | BR6803655D0 (en) |
| CH (2) | CH503050A (en) |
| DE (2) | DE1804796A1 (en) |
| DK (1) | DK126041B (en) |
| ES (1) | ES359765A1 (en) |
| FR (2) | FR1590470A (en) |
| GB (2) | GB1207048A (en) |
| IL (1) | IL30982A0 (en) |
| NL (3) | NL6815381A (en) |
| SE (2) | SE356297B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH568336A5 (en) * | 1969-04-04 | 1975-10-31 | Hoffmann La Roche |
-
1968
- 1968-10-07 CH CH1492568A patent/CH503050A/en not_active IP Right Cessation
- 1968-10-18 CH CH1560468A patent/CH503713A/en not_active IP Right Cessation
- 1968-10-24 DE DE19681804796 patent/DE1804796A1/en active Pending
- 1968-10-28 NL NL6815381A patent/NL6815381A/xx unknown
- 1968-10-30 DK DK527568AA patent/DK126041B/en unknown
- 1968-10-31 BE BE723188D patent/BE723188A/xx unknown
- 1968-10-31 NL NL6815555A patent/NL6815555A/xx unknown
- 1968-10-31 ES ES359765A patent/ES359765A1/en not_active Expired
- 1968-10-31 SE SE14757/68A patent/SE356297B/xx unknown
- 1968-10-31 SE SE14756/68A patent/SE355804B/xx unknown
- 1968-10-31 FR FR1590470D patent/FR1590470A/fr not_active Expired
- 1968-10-31 DE DE19681806410 patent/DE1806410A1/en active Pending
- 1968-10-31 IL IL30982A patent/IL30982A0/en unknown
- 1968-10-31 FR FR1586571D patent/FR1586571A/fr not_active Expired
- 1968-10-31 BE BE723187D patent/BE723187A/xx unknown
- 1968-11-01 GB GB51935/68A patent/GB1207048A/en not_active Expired
- 1968-11-01 NL NL6815622A patent/NL6815622A/xx unknown
- 1968-11-01 GB GB51934/68A patent/GB1207047A/en not_active Expired
- 1968-11-01 BR BR203655/68A patent/BR6803655D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB1207048A (en) | 1970-09-30 |
| DE1806410A1 (en) | 1969-06-19 |
| CH503713A (en) | 1971-02-28 |
| IL30982A0 (en) | 1969-01-29 |
| NL6815555A (en) | 1969-05-06 |
| BE723187A (en) | 1969-04-30 |
| CH503050A (en) | 1971-02-15 |
| BE723188A (en) | 1969-04-30 |
| DK126041B (en) | 1973-06-04 |
| FR1590470A (en) | 1970-04-13 |
| ES359765A1 (en) | 1970-06-16 |
| SE356297B (en) | 1973-05-21 |
| FR1586571A (en) | 1970-02-20 |
| BR6803655D0 (en) | 1973-03-15 |
| NL6815381A (en) | 1969-05-06 |
| GB1207047A (en) | 1970-09-30 |
| SE355804B (en) | 1973-05-07 |
| NL6815622A (en) | 1969-05-06 |
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