DE1568052C3 - 3beta-acetoxy-5alpha-hydroxy-17 alpha-bromopregnan-6, 20-dione and process for the preparation of 3beta, 5alpha-dihydroxy-17alpha-methyl-17 beta-carbo-methoxyandrostan-6-one - Google Patents
3beta-acetoxy-5alpha-hydroxy-17 alpha-bromopregnan-6, 20-dione and process for the preparation of 3beta, 5alpha-dihydroxy-17alpha-methyl-17 beta-carbo-methoxyandrostan-6-oneInfo
- Publication number
- DE1568052C3 DE1568052C3 DE19661568052 DE1568052A DE1568052C3 DE 1568052 C3 DE1568052 C3 DE 1568052C3 DE 19661568052 DE19661568052 DE 19661568052 DE 1568052 A DE1568052 A DE 1568052A DE 1568052 C3 DE1568052 C3 DE 1568052C3
- Authority
- DE
- Germany
- Prior art keywords
- dione
- acetoxy
- 5alpha
- 3beta
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 6
- 150000002978 peroxides Chemical class 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 5
- OMPJBNCRMGITSC-UHFFFAOYSA-N Incidol Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 5
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 3
- VBTQNRFWXBXZQR-UHFFFAOYSA-N N-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 230000002194 synthesizing Effects 0.000 description 10
- 238000005893 bromination reaction Methods 0.000 description 7
- KRVSOGSZCMJSLX-UHFFFAOYSA-L Chromic acid Chemical compound O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 6
- CRRKVZVYZQXICQ-RJJCNJEVSA-N Pregnenolone acetate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](C(C)=O)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 CRRKVZVYZQXICQ-RJJCNJEVSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000004432 carbon atoms Chemical group C* 0.000 description 5
- 239000000583 progesterone congener Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N 5-(7-(4-(4,5-DIHYDRO-2-OXAZOLYL)PHENOXY)HEPTYL)-3-METHYL ISOXAZOLE Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- -1 methylmagnesium halide Chemical class 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940040526 Anhydrous Sodium Acetate Drugs 0.000 description 1
- WHQLSTXAMVLDOE-ROFYHFRESA-N Br[C@H]1[C@H]2[C@@H]3CC[C@H](C(C)=O)[C@]3(CC[C@@H]2[C@]2(CCCCC2C1=O)C)C Chemical compound Br[C@H]1[C@H]2[C@@H]3CC[C@H](C(C)=O)[C@]3(CC[C@@H]2[C@]2(CCCCC2C1=O)C)C WHQLSTXAMVLDOE-ROFYHFRESA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Description
Die Erfindung bezieht sich auf ein Verfahren zur Herstellung von 3ß,5a - Dihydroxy - 17« - methyl-17/i-carbomethoxyandrostan-6-on der FormelThe invention relates to a process for the preparation of 3ß, 5a- dihydroxy-17 "- methyl-17 / i-carbomethoxyandrostan-6-one of the formula
COOCH3 COOCH 3
HOHO
3°3 °
3535
sowie auf Sß-Acetoxy-Sa-hydroxy-na-brompregnan-6,20-dion. as well as on Sß-acetoxy-Sa-hydroxy-na-bromopregnane-6,20-dione.
Die Verbindung der obigen Formel ist verwendbar bei der Synthese des hochwirksamen, oral verabreichbaren progestationalen Mittels 6,17a-Dimethyl-4,6-pregnadien-3,20-dion. Dieses orale progestationale Mittel ist beschrieben in der USA.-Patentschrift 3133 913 von Deghenghi, ein Verfahren'45 zu seiner Herstellung in · der USA.-Patentschrift 31 70 936 von M ο r a η d und Deghenghi. Die Verbindung der obigen Formel ist beschrieben in der letzterwähnten Patentschrift (als III a); sie läßt sich gemäß dieser Vorveröffentlichung zur Synthese von Progestin 6,17« - Dimethyl - 4,6 - pregnadien-3,20-dion benutzen.The compound of the above formula is useful in the synthesis of the potent, orally administrable one progestational agent 6,17a-dimethyl-4,6-pregnadiene-3,20-dione. This oral progestational Agent is described in U.S. Patent 3,133,913 to Deghenghi, a method'45 for its manufacture in the USA patent specification 31 70 936 by M ο r a η d and Deghenghi. the Compound of the above formula is described in the last-mentioned patent specification (as III a); she lets according to this prior publication for the synthesis of progestin 6,17 «- dimethyl - 4,6 - pregnadiene-3,20-dione use.
Bei dem gemäß dieser Patentschrift anzuwendenden Verfahren wird das 3ß,5a-Dihydroxy-17«-methyl-17ß-carbomethoxyandrostan-6-on mit einem Methylmagnesiumhalogenid zu 3ß,5a,6ß - Trihydroxy - 6«, 17ra-dimethylpregnan-20-on umgesetzt, das dann mit Chromsäure zu 5a,6/i-Dihydroxy-6a,17a-dimethylpregnan-3,20-dion oxydiert wird. Das so erhaltene Dion wird schließlich mit einer Mineralsäure, z. B. mit konzentrierter Chlorwasserstoffsäure, gelöst in einem niedrigeren Alkanol, zu 6,17a-Dimethyl-4,6-pregnadien-3,20-dion dehydratisiert.In the process to be used according to this patent specification, the 3ß, 5a- dihydroxy-17 «-methyl-17ß-carbomethoxyandrostan-6-one is reacted with a methylmagnesium halide to give 3ß, 5a, 6ß -trihydroxy-6«, 17ra-dimethylpregnan-20-one , which is then oxidized with chromic acid to 5a, 6 / i-dihydroxy-6a, 17a-dimethylpregnan-3,20-dione. The dione thus obtained is finally treated with a mineral acid, e.g. B. with concentrated hydrochloric acid dissolved in a lower alkanol, dehydrated to 6,17a-dimethyl-4,6-pregnadiene-3,20-dione.
Das erfindungsgemäße Verfahren ermöglicht die Herstellung der Verbindung der obigen Formel durch eine vereinfachte Arbeitsweise und in hoher Ausbeute. Die Synthese des oral aktiven Progestin 6,1 Ta - Dimethyl - 4,6 - pregnadien - 3,20 - dions durch ein Verfahren, worin die obenerwähnten Verbindungen als Zwischenprodukte fungieren, wurde damit wesentlich vereinfacht und verbilligt.The process of the invention enables the compound of the above formula to be prepared by a simplified procedure and in high yield. The synthesis of the orally active progestin 6.1 Ta- dimethyl-4,6-pregnadiene-3,20-dione by a process in which the above-mentioned compounds function as intermediates has thus been considerably simplified and made cheaper.
Bei der Herstellung von 3/S,5a-Dihydroxy-Πα-methyl -17/? - carbomethoxyandrostan - 6 - on mit Pregnenolonacetat (Verbindung I) als Ausgangsprodukt war es bisher notwendig, eine reichlich umständliche sechsstufige Arbeitsweise anzuwenden. Diese sechsstufige Synthese kann durch das folgende Formelbild dargestellt werden:In the production of 3 / S, 5a-dihydroxy-Πα-methyl -17 /? - carbomethoxyandrostan - 6 - one with pregnenolone acetate (Compound I) as a starting product, it was previously necessary to use a rather cumbersome to apply six-step working method. This six-step synthesis can be represented by the following formula being represented:
CH3
Pregnenolonacetat C =CH 3
Pregnenolone acetate C =
AcOAcO
AcOAcO
j—Br
j -
AcOAcO
AcOAcO
COOCH,COOCH,
RORO
OHOH
In den obigen Formeln bedeutet Ac Acetyl und R dung der obigen Formel nur unter großem Arbeitsentweder Wasserstoff oder die Acylgruppe. 50 aufwand und entsprechenden Kosten herstellen ließen.In the above formulas, Ac means acetyl and R means of the above formula only with great effort either Hydrogen or the acyl group. 50 outlay and corresponding costs.
Überraschenderweise wurde nun gefunden, daß 3/5 - Acetoxy - 5a - hydroxy - pregnan - 6,20 - dion eine Verbindung der FormelSurprisingly, it has now been found that 3/5 - acetoxy - 5a - hydroxy - pregnane - 6.20 - dione is a Compound of formula
CH3 CH 3
C = OC = O
Auf Grund ihrer Umständlichkeit ergab die über
6 Stufen verlaufende Synthese nur verhältnismäßig
geringe Ausbeuten, so daß sich bisher die Verbin-Due to its awkwardness, the over
6-stage synthesis only proportionally
low yields, so that so far the compounds
CH3CO · OCH 3 CO · O
OHOH
beim Behandeln mit N-Bromsuccinimid in Anwesenheit eines Peroxydkatalysators selektiv und beinahewhen treating with N-bromosuccinimide in the presence of a peroxide catalyst selectively and almost
ausschließlich am Kohlenstoffatom 17 bromiert wird. Das erwähnte Kohlenstoffatom befindet sich in α-Stellung zu der 20-ständigen Ketongruppe. überraschenderweise erfolgt hingegen keinerlei Bromierung am Kohlenstoffatom 7, das sich in α-Stellung zu der 6-ständigen Ketongruppe befindet.is brominated exclusively on carbon atom 17. The carbon atom mentioned is in the α-position to the 20-position ketone group. Surprisingly, however, there is no bromination at all Carbon atom 7, which is in the α-position to the 6-position ketone group.
Als Ergebnis dieser selektiven Bromierung von 3ß - Acetoxy - 5a - hydroxy - pregnan - 6,20 - dion in 17-Stellung erhält man eine neuartige, bisher nicht bekannte Verbindung, das 3^-Acetoxy-Sa-hydroxy-17a-brompregnan-6,20-dion. Diese Verbindung hat die FormelAs a result of this selective bromination of 3ß- acetoxy-5a-hydroxy-pregnane-6.20-dione in the 17-position, a new, previously unknown compound is obtained, 3 ^ -acetoxy-Sa-hydroxy-17a-bromopregnane-6 , 20-dione. This compound has the formula
CH,CH,
2020th
CH,COCH, CO
Das 3ß- Acetoxy - 5α - hydroxy -17α - brompregnan-6,20-dion
erleidet bei Behandlung mit einem Alkalidicarbonat im Methanol die »Favorski«-Umlagerung
in Übereinstimmung mit der beispielsweise von Rappe in Acta Chem. Scand., Bd. 17, (1963),
Nr. 10, beschriebenen Reaktion. Die Umlagerung führt zu S/^Sa-Dihydroxy-nu-m
oxyandrostan-6-on der FormelThe 3β- acetoxy-5α-hydroxy -17α-bromopregnane-6,20-dione undergoes the "Favorski" rearrangement in accordance with the, for example, von Rappe in Acta Chem. Scand., Vol. 17, when treated with an alkali metal carbonate in methanol. (1963) No. 10. The rearrangement leads to S / ^ Sa-dihydroxy-nu-m
oxyandrostan-6-one of the formula
COOCH,COOCH,
c-CH,c-CH,
IO HO IO HO
OHOH
in fast quantitativer Ausbeute.in almost quantitative yield.
Da die selektive Bromierung von 3ß-Acetoxy-5a-hydroxy-pregnan-6,20-dion unter Bedingungen erfolgt, bei welchen das Brom selektiv und beinahe ausschließlich am Kohlenstoffatom 17 eingeführt wird, ist eine neue und verbesserte Synthese möglich, bei der man ausgeht von dem Pregnenolonacetat und bei welcher das 30,5a - Dihydroxy -17a - methyl -1 Iß - carbomethoxyandrostan-6-on in hoher Ausbeute mit Hilfe einer Synthese erhalten werden, die nun nur noch 4 Stufen erfordert. Diese Vierstufensynthese, ausgehend von der Verbindung I, dem Pregnenolonacetat, kann durch folgendes Formelbild dargestellt werden:Since the selective bromination of 3ß-acetoxy-5a-hydroxy-pregnane-6,20-dione occurs under conditions in which the bromine is introduced selectively and almost exclusively at carbon atom 17, a new and improved synthesis is possible starting from of the pregnenolone acetate and in which the 30,5a-dihydroxy-17a-methyl -1 Iß- carbomethoxyandrostan-6-one can be obtained in high yield with the aid of a synthesis which now only requires 4 steps. This four-step synthesis, starting from compound I, the pregnenolone acetate, can be represented by the following formula:
CH.COCH.CO
CH3COCH 3 CO
CHXO · OCHXO · O
CH,CH,
C = OC = O
CH,CO · OCH, CO · O
R bedeutet Wasserstoff oder eine Acyl- bzw. Acetylgruppe. R denotes hydrogen or an acyl or acetyl group.
Wie erwähnt und aus dem Formelbild ersichtlich, geht diese Synthese von dem Pregnenolonacetat (Verbindung I) aus. Die Verbindung III ist das 3/1-Acetoxy - 5(/ - hydroxypregnan - 6,20 - dion, während die aus der selektiven Bromierung am Kohlenstoffatom 17 resultierende Verbindung IV die bisher nicht beschriebene neuartige Verbindung 3/J-Acetoxy-5u-hydroxy-17«-brom-pregnan-6,20-dion ist. Wie bereits erwähnt, geht diese Verbindung durch »Favorskk-Umlagerung in Verbindung V über, die. für die Synthese des oralaktiven Progestin 6,17«-Dimethyl - 4,6 - pregnadien - 3,20 - dions nach dem in der USA.-Patentschrift 31 70 936 beschriebenen Verfahren benutzt werden kann.As mentioned and can be seen from the formula, this synthesis starts from the pregnenolone acetate (compound I) off. The compound III is the 3/1-acetoxy - 5 (/ - hydroxypregnan - 6,20 - dione, while the Compound IV resulting from the selective bromination at carbon atom 17 has not yet been achieved described novel compound 3 / J-acetoxy-5u-hydroxy-17 "-bromo-pregnane-6,20-dione is. As already mentioned, this connection is converted into connection V by »Favorskk rearrangement, the. for the synthesis of the orally active progestin 6,17 «-dimethyl - 4,6 - pregnadiene - 3,20 - dione according to the method described in U.S. Pat. No. 3,170,936 can be used.
Die selektive Bromierung des 3/i-Acetoxy-5«-hydroxypregnan-6,20-dions wird durchgeführt durch Behandeln dieser Verbindung mit N-Bromsuccinimid oder N-Bromacetamid, zweckmäßig im Überschuß, in Anwesenheit eines Peroxydkatalysators, wie Benzoylperoxyd; man arbeitet innerhalb eines Temperaturbereiches, der von etwa 5O0C bis zum Siedepunkt des Lösungsmittels reicht. Die Umsetzung ergibt in guter Ausbeute das 17-Bromsteroid (Verbindung IV). Während der Bromierung wird in 7-Stellung kein Brom eingeführt, so daß keine unerwünschten Nebenprodukte gebildet werden. Die selektive Bromierung der Verbindung III kann praktisch so durchgeführt werden, daß man zu ■ einem Gemisch aus 3ß - Acetoxy - 5« - hydroxypregnan - 6,20 - dion (Verbindung III) und einem inerten Lösungsmittel, vorzugsweise Tetrachlorkohlenstoff, in Anwesenheit einer schwachen organischen Base, wie Pyridin, einen Peroxydkatalysator, wie Benzoylperoxyd, zufügt. Das Reaktionsgemisch wird erwärmt, vorzugsweise wird es etwa 1 Stunde unter Rückfluß gehalten. Arbeitet man bei niedriger Temperatur, beispielsweise bei 50° C, was grundsätzlich auch möglich ist, so verlängert sich selbstverständlich die Reaktionszeit entsprechend.The selective bromination of the 3 / i-acetoxy-5'-hydroxypregnane-6,20-dione is carried out by treating this compound with N-bromosuccinimide or N-bromoacetamide, advantageously in excess, in the presence of a peroxide catalyst such as benzoyl peroxide; is carried out within a temperature range ranging from about 5O 0 C to the boiling point of the solvent. The reaction gives the 17-bromo steroid (compound IV) in good yield. No bromine is introduced in the 7-position during the bromination, so that no undesired by-products are formed. The selective bromination of the compound III can practically be carried out by adding a mixture of 3β- acetoxy-5-hydroxypregnane-6.20-dione (compound III) and an inert solvent, preferably carbon tetrachloride, in the presence of a weak organic solvent Base such as pyridine, a peroxide catalyst such as benzoyl peroxide. The reaction mixture is heated, preferably it is refluxed for about 1 hour. If you work at a low temperature, for example at 50 ° C., which is also possible in principle, the reaction time is of course extended accordingly.
Die Beispiele dienen zur näheren Erläuterung der Erfindung.The examples serve to explain the invention in more detail.
Beispiel
a) 3/>'-Acetoxy-5,6-epoxypregnan-20-onexample
a) 3 />'- Acetoxy-5,6-epoxypregnan-20-one
Zur Herstellung des Ausgangsmaterials gibt man zu einem Gemisch aus 100 g Pregnenolonacetat und 10 g wasserfreiem Natriumacetat in 400 ml Benzol innerhalb 10 Minuten 100 ml 40%ige Peressigsäure hinzu. Nach lOminütigem Rühren wird das Gemisch mit Wasser gewaschen und die Benzolphase abgetrennt und zur Trockene eingedampft. Man erhält in fast quantitativer Ausbeute 100 g eines Gemisches aus 3/)' - Acetoxy - 5,6« - epoxypregnan - 20 - on und ^^OTo prepare the starting material, add to a mixture of 100 g of pregnenolone acetate and 10 g of anhydrous sodium acetate in 400 ml of benzene within 10 minutes 100 ml of 40% peracetic acid added. After stirring for 10 minutes, the mixture is washed with water and the benzene phase is separated off and evaporated to dryness. 100 g of a mixture are obtained in an almost quantitative yield from 3 /) '- acetoxy - 5,6 «- epoxypregnan - 20 - one and ^^ O
b) Sß-Acetoxy-Su-hydroxypregnan-o^O-dionb) Sβ-acetoxy-Su-hydroxypregnan-o ^ O-dione
Eine Lösung von 100 g des im Beispiel a) erhaltenen rohen Epoxysteroids in 1000 ml Aceton wird auf 2° C gekühlt und innerhalb 30 Minuten 125 ml einer 50%igen wäßrigen Chromsäurelösung zugefügt, wobei man die Temperatur unter 10°C hält. Das Reaktionsgemisch wird, nachdem die gesamte Chromsäure zugefügt ist, noch 10 Minuten weitergerührt, worauf man das entstandene Produkt mit Methylenchlorid aus dem Reaktionsgemisch extrahiert. Der Methylenchloridauszug wird mit Wasser gewaschen und zur Trockene eingedampft; man erhält 98 g S/i-Acetoxy-Su-hydroxypregnan-ö^O-dion.A solution of 100 g of the crude epoxy steroid obtained in example a) in 1000 ml of acetone is cooled to 2 ° C and 125 ml within 30 minutes a 50% aqueous chromic acid solution was added, the temperature being kept below 10 ° C. After all the chromic acid has been added, the reaction mixture is stirred for a further 10 minutes, whereupon the resulting product is extracted from the reaction mixture with methylene chloride. The methylene chloride extract is washed with water and evaporated to dryness; man receives 98 g of S / i-acetoxy-Su-hydroxypregnan-ö ^ O-dione.
c) 3/i-Acetoxy-5fi-hydroxy-l 7a-brompregnan-6,20-dion c) 3 / i-acetoxy-5fi-hydroxy-l 7a-bromopregnane-6,20-dione
Erfindungsgemäß wird ein Gemisch aus 98 g 3/1 - Acetoxy - 5« - hydroxypregnan - 6,20 - dion, (wird erhalten nach Beispiel b), 82 g N-Bromsuccinimid, 27 ml Pyridin und 2000 ml Tetrachlorkohlenstoff zum Sieden gebracht. Dem siedenden Gemisch fügt man 6,8 g Benzoylperoxyd zu, und nach 40 Minuten Sieden unter Rückfluß wird der Niederschlag abfiltriert und das Filtrat mit wäßrigem Natriumbisulfit und Wasser gewaschen. Beim Eindampfen zur Trokkene erhält man 100 g 3ß - Acetoxy - 5« - hydroxy-17«-brompregnan-6,20-dion, Fp. 195° C, vmax (CHCl3) 3580, 3440, 1710, 1040, 1028 cm-1; NMR (CDCl3) δ 0,76, 0,84, 2,02, 2,4, 3,5, 5,05 ppm; m/e 470, 468, 410, 408 und 43.According to the invention, a mixture of 98 g of 3/1-acetoxy-5'-hydroxypregnane-6.20-dione (obtained according to Example b), 82 g of N-bromosuccinimide, 27 ml of pyridine and 2000 ml of carbon tetrachloride is brought to the boil. 6.8 g of benzoyl peroxide are added to the boiling mixture and, after refluxing for 40 minutes, the precipitate is filtered off and the filtrate is washed with aqueous sodium bisulfite and water. Evaporation to dryness gives 100 g of 3β- acetoxy-5 "- hydroxy-17" -bromopregnane-6,20-dione, melting point 195 ° C., v max (CHCl 3 ) 3580, 3440, 1710, 1040, 1028 cm - 1 ; NMR (CDCl 3 ) δ 0.76, 0.84, 2.02, 2.4, 3.5, 5.05 ppm; m / e 470, 468, 410, 408 and 43.
d) 3/?,5a-Dihydroxy-17a-methyl-17/?-carbomethoxyandrostan-6-on d) 3 / ?, 5a-dihydroxy-17a-methyl-17 /? - carbomethoxyandrostan-6-one
Einer unter Rückfluß siedenden Lösung von 100 g des im Beispiel c) erhaltenen rohen 3ß-Acetoxy-5rt-hydroxy-17-brompregnan-6,20-dions in 1200 ml Methanol fügt man eine Lösung von 27 g Kaliumbicarbonat in 112 ml Wasser hinzu. Das Sieden unter Rückfluß wird fortgesetzt, wobei etwa 3/4 des Methanols abdestilliert werden. Der Rückstand wird dann mit 1 1 Wasser verdünnt, der sich abscheidende Niederschlag abfiltriert und mit 50 ml Methanol digeriert; man erhält 65 g gereinigtes 3/S,5a-Dihydroxy - 17a - methyl - I] β - carbomethoxyandrostan-6-on, Fp. 279 bis 28 Γ C.A solution of 27 g of potassium bicarbonate in 112 ml of water is added to a refluxing solution of 100 g of the crude 3β-acetoxy-5rt-hydroxy-17-bromopregnane-6,20-dione obtained in example c) in 1200 ml of methanol. The boiling under reflux is continued, with about 3/4 of the methanol is distilled off. The residue is then diluted with 1 liter of water, the precipitate which separates out is filtered off and digested with 50 ml of methanol; 65 g of purified 3 / S, 5a-dihydroxy-17a-methyl- I] β -carbomethoxyandrostan-6-one, melting point 279 to 28 ° C. are obtained.
609 620/37609 620/37
Claims (5)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51069765 | 1965-11-30 | ||
| US510697A US3351641A (en) | 1965-11-30 | 1965-11-30 | 3beta-acetoxy-5alpha-hydroxy-17alpha-bromo-pregnane-6, 20-dione |
| DEA0054202 | 1966-11-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1568052A1 DE1568052A1 (en) | 1970-02-05 |
| DE1568052B2 DE1568052B2 (en) | 1975-09-11 |
| DE1568052C3 true DE1568052C3 (en) | 1976-05-13 |
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