BE628304A - - Google Patents
Info
- Publication number
- BE628304A BE628304A BE628304DA BE628304A BE 628304 A BE628304 A BE 628304A BE 628304D A BE628304D A BE 628304DA BE 628304 A BE628304 A BE 628304A
- Authority
- BE
- Belgium
- Prior art keywords
- hydroxy
- keto
- tertiary
- alcohol
- steroids
- Prior art date
Links
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 4
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 claims description 4
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical group C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 229940072033 potash Drugs 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- -1 soda or potash Chemical class 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IATKKATWPOVYCC-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-2,3,6,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical class C1CC2=CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 IATKKATWPOVYCC-VMXHOPILSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- BQOIJSIMMIDHMO-FBPKJDBXSA-N 4-Hydroxytestosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1O BQOIJSIMMIDHMO-FBPKJDBXSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960004719 nandrolone Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 2
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 1
- 150000000315 19-norandrostanes Chemical class 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- XYGMEFJSKQEBTO-KUJXMBTLSA-N Clostebol acetate Chemical compound C1CC2=C(Cl)C(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)C)[C@@]1(C)CC2 XYGMEFJSKQEBTO-KUJXMBTLSA-N 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- GRXPVLPQNMUNNX-MHJRRCNVSA-N estrane Chemical compound C1CC2CCCC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 GRXPVLPQNMUNNX-MHJRRCNVSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical group [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Description
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BREVET DE PERFECTIONNEMENT L'invention a pour objet un perfectionnement à la
EMI1.1
synthèse des 4-hydroxy-3"céto-6 4 -stéroïdes des serves de l'androstane et du 19-norandrostane, Dans le brevet principal, on a décrit un procéda permettant d'obtenir des 4-hydroxy-
EMI1.2
'-3-céto-A -stéroïdes (III) de la série normale et de la série 19-nor, à partir des dérivés 4-chloro-correspondants (I) en faisant réagir ceux-ci sur l'oxygène en présence du sel de potassium d'un alcool aliphatique tertiaire comme le butoxyde tertiaire de potassium, puis en hydrogénant catalytiquement
EMI1.3
les Mhydroxy 3céto-.na..stêroïdes (II) ainsi obtenus.
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EMI2.1
EMI2.2
1 II III j alcali caustique aqueux alcool alipha :que tertiaire R-H ou CH 3
EMI2.3
On a trouvé malmenant que les 4-chloro-3-céto-A 4 -an- drostènes (1) de la série normale et de la série 19-nor, en réagissant sur un hydrcxyde alcalin dissous dans un alcool aliphatique tertiaire, sous atmosphère de gaz inerte, don-
EMI2.4
nent directement les 4-hydroxy-3-céto-A -androstènes (III).
Suivant la présente invention, on dissout ,dans un aleool aliphatique tertiaire comme l'alcool butylique tertiaire
EMI2.5
ou amylique tertiaire, les 4chloro-3ccto..I4stéro'ides des séries de l'androstane et du 19-norandrostane (préparés sui- vant les brevets belges n 549 701 du 19 juillet 1956, 562 152 et 552 153 du 27 octobre 1956,557 735 du 23 mai 1957) et on les fait réagir sur un excès d'hydroxyde alcalin aqueux, par exemple de soude ou de potasse, sous atmosphère de gaz inerte comme l'azote, et à chaud, de préférence au point d'ébullition de l'alcool utilisé, en un temps variant de quelques minutes a quelques heures.
Quand le traitement est terminé, on neutralise le mélange réactionnel au moyen d'acides comme l'acide acétique ou des acides minéraux dilués, puis on le dilue avec de l'eau. On isole le stérolde,
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de préférence en l'extrayant par un solvant organique non mis- cible à l'eau.
On peut purifier les produits bruts obtenus, c'est-à.
-dire les 4-hydroxy-3-céto-¯4-androstèbnes de la série normale et de la série 19-nor, soit en les cristallisant par un sol- vant organique, soit par chromatographie sur des adsorbants comme le "Florisil", puis par élution et cristallisation, ou bien on peut les transformer en dérivés acylés en acylant les groupes hydroxyle secondaires qu'ils contiennent au moyen d'un chlorure ou anhydride d'acide organique, facultativement en présence d'amines tertiaires, et en purifiant ensuite par les procédés usuels. Les 4-hydroxy-3-céto-6 4 -stéroïdes des séries de l'androstane et du 19-norandrostone sont utiles en théra- peutique comme agents anaboliques et androgènes.
Les exemples suivants illustrent l'invention, sans la limiter.
Exemple 1.
4-hydroxytestostérone.
On chauffe au reflux 0,500 g d'acétate de 4-chlorotestos- térone pendant 15 minutes sous atmosphère d'azote avec 40 cm3 de butanol tertiaire (ou d'alcool amylique tertiaire), puis on ajoute une solution de 0,500 g de potasse (ou de soude) dans 10 cm3 d'eau. Une heure après l'addition, on neutralise la solution par l'acide acétique et on l'extrait par l'acétate d'éthyle. On lave l'extrait organique avec une solution aqueuse de soude à 5 %, puis avec de l'eau jusqu'à neutralité et on évapore le solvant sous vide. Le résidu présente un maximum d'absorption d'ultra-violet à 280 millimicrons ( @= 7000) et on le chromatographie sur du "Florisil".
Des fractions éluées pur le mélange de benzène et d'éther éthylique 1:1, on cristallise, par addition d'éther éthylique, la 4-hydroxy- testostérone, point de fusion 221-223 C.
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EMI4.1
Exemple 2.
EMI4.2
4-hydroxy-l7ar.méthyltestostérone.
En travaillant comme dans l'exemple 1, à partir de 0,500 g de 4¯chloro-i7a-métnyltestosté'ronâ, on obtient la 4hydroxy-l7ou-mthyltestostérone (point de fusion 170-1720c),
EMI4.3
Exemple 3.
EMI4.4
4-hydroxy-t 9-nortestostérone, En travaillant comme dans l'exemple 1, à partir de 1#5 g d'acétate de 4-chlorc-19-nortestostéronop on obtient la 4<'hydroxy'-19-nortest06térone (point de fusion 1 193 C), Exemple 4, 4-hydroxy-l7K"méthyl-19-nortestosterone* En opérant comme dans l'exemple 1, à partir de 1,5 g de 4-ehloro-17ct-mèthyl-19-nottestostdronop on obtient la 4-hydroxy-lioo--mthyll9nortestostérone (point de fusion 168- -17 onc).
EMI4.5
Exemple 5.
EMI4.6
4,11-dihydroxytestostrone.
En opérant comme dan l'exemple 1, à partir de 1,5 g de -.chloro-11-hydroxytéstostérone, on obtient la 4,11- -dihydroxytestostérone (point de fusion 210-212 C ).
EMI4.7
Exemple 6.
EMI4.8
4,11-dihydroxy-17omethyltestostérono.
En opérant comme dans l'exemple 1, à partir de 195 g de 4-chloro-11-hydroxy-17c6-mdthyltestostërone, on obtient la 4,11-dihydroxy-17 x-méthyltestostérone (point de fusion 183-185 C.
<Desc / Clms Page number 1>
IMPROVEMENT PATENT The object of the invention is to improve the
EMI1.1
synthesis of 4-hydroxy-3 "keto-6 4 -steroids from androstane and 19-norandrostane serves. In the main patent, a process has been described which makes it possible to obtain 4-hydroxy-
EMI1.2
'-3-keto-A -steroids (III) of the normal series and of the 19-nor series, from the corresponding 4-chloro-derivatives (I) by reacting these with oxygen in the presence of the salt potassium from a tertiary aliphatic alcohol such as tertiary potassium butoxide, followed by catalytically hydrogenating
EMI1.3
the Mhydroxy 3keto-.na..sterroids (II) thus obtained.
<Desc / Clms Page number 2>
EMI2.1
EMI2.2
1 II III j aqueous caustic alkali alcohol alipha: only tertiary R-H or CH 3
EMI2.3
It has been found inconvenient that the 4-chloro-3-keto-A 4 -androstenes (1) of the normal series and of the 19-nor series, when reacting with an alkali hydroxide dissolved in a tertiary aliphatic alcohol, under an atmosphere inert gas, don-
EMI2.4
directly originate the 4-hydroxy-3-keto-A -androstenes (III).
According to the present invention, is dissolved in a tertiary aliphatic aleool such as tertiary butyl alcohol
EMI2.5
or tertiary amyl, the 4chloro-3ccto..I4steroids of the androstane and 19-norandrostane series (prepared according to Belgian patents n.549,701 of July 19, 1956, 562,152 and 552,153 of October 27, 1956, 557 735 of May 23, 1957) and reacted with an excess of aqueous alkali hydroxide, for example soda or potash, under an inert gas atmosphere such as nitrogen, and hot, preferably at the boiling point of the alcohol used, in a time varying from a few minutes to a few hours.
When the work-up is finished, the reaction mixture is neutralized with acids such as acetic acid or dilute mineral acids, and then diluted with water. We isolate the steroid,
<Desc / Clms Page number 3>
preferably by extracting it with a non-target organic solvent with water.
One can purify the crude products obtained, that is.
- say the 4-hydroxy-3-keto-¯4-androstèbnes of the normal series and of the 19-nor series, either by crystallizing them with an organic solvent, or by chromatography on adsorbents such as "Florisil", then by elution and crystallization, or they can be transformed into acylated derivatives by acylating the secondary hydroxyl groups they contain with an organic acid chloride or anhydride, optionally in the presence of tertiary amines, and then purifying by the usual methods. The 4-hydroxy-3-keto-6 4-steroids of the androstane and 19-norandrostone series are useful therapeutically as anabolic and androgenic agents.
The following examples illustrate the invention without limiting it.
Example 1.
4-hydroxytestosterone.
0.500 g of 4-chlorotestosterone acetate is refluxed for 15 minutes under a nitrogen atmosphere with 40 cm3 of tertiary butanol (or tertiary amyl alcohol), then a solution of 0.500 g of potassium hydroxide (or of soda) in 10 cm3 of water. One hour after the addition, the solution is neutralized with acetic acid and extracted with ethyl acetate. The organic extract is washed with a 5% aqueous sodium hydroxide solution, then with water until neutral and the solvent is evaporated off in vacuo. The residue shows an ultraviolet absorption maximum at 280 millimicrons (@ = 7000) and is chromatographed on "Florisil".
From the fractions eluted pure the mixture of benzene and ethyl ether 1: 1, crystallized, by addition of ethyl ether, 4-hydroxy-testosterone, mp 221-223 C.
<Desc / Clms Page number 4>
EMI4.1
Example 2.
EMI4.2
4-hydroxy-17ar.methyltestosterone.
Working as in Example 1, from 0.500 g of 4¯chloro-i7a-métnyltestosté'ronâ, 4hydroxy-l7ou-mthyltestosterone (melting point 170-1720c) is obtained,
EMI4.3
Example 3.
EMI4.4
4-hydroxy-t 9-nortestosterone, Working as in example 1, from 1 # 5 g of 4-chlorc-19-nortestosteronop acetate, 4 <'hydroxy'-19-nortest06terone is obtained (point of fusion 1 193 C), Example 4, 4-hydroxy-17K "methyl-19-nortestosterone * Working as in Example 1, from 1.5 g of 4-ehloro-17ct-methyl-19-nottestostdronop 4-hydroxy-lioo-mthyll9nortestosterone (melting point 168- -17 ounc) is obtained.
EMI4.5
Example 5.
EMI4.6
4,11-dihydroxytestostrone.
By operating as in Example 1, from 1.5 g of -.chloro-11-hydroxytestosterone, 4.11- -dihydroxytestosterone (melting point 210-212 C) is obtained.
EMI4.7
Example 6.
EMI4.8
4,11-dihydroxy-17omethyltestosterono.
By operating as in Example 1, from 195 g of 4-chloro-11-hydroxy-17c6-mdthyltestosterone, 4,11-dihydroxy-17x-methyltestosterone is obtained (melting point 183-185 C.
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BE628304A true BE628304A (en) |
Family
ID=198248
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BE628304D BE628304A (en) |
Country Status (1)
| Country | Link |
|---|---|
| BE (1) | BE628304A (en) |
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0
- BE BE628304D patent/BE628304A/fr unknown
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