CH337841A - Process for the preparation of 1-dehydrocortisone acetate - Google Patents
Process for the preparation of 1-dehydrocortisone acetateInfo
- Publication number
- CH337841A CH337841A CH337841DA CH337841A CH 337841 A CH337841 A CH 337841A CH 337841D A CH337841D A CH 337841DA CH 337841 A CH337841 A CH 337841A
- Authority
- CH
- Switzerland
- Prior art keywords
- acetoxy
- sep
- trione
- dibromo
- pregnan
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 title description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229960004618 prednisone Drugs 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- -1 dibromo compound Chemical class 0.000 claims description 4
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 3
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 3
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 3
- KCJBSCPYEUJOIA-AHQXJJKUSA-N [2-[(8S,9S,10R,13S,14S,17R)-2,4-dibromo-17-hydroxy-10,13-dimethyl-3,11-dioxo-1,2,4,5,6,7,8,9,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound BrC1C(C(C2CC[C@H]3[C@@H]4CC[C@](C(COC(C)=O)=O)([C@]4(CC([C@@H]3[C@]2(C1)C)=O)C)O)Br)=O KCJBSCPYEUJOIA-AHQXJJKUSA-N 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- RBJWAERSBJWDSH-XAQLXDLTSA-N 2-[(8R,9S,10R,13S,14S,17S)-4-bromo-17-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethyl acetate Chemical compound BrC1C2CC[C@@H]3[C@H](CC[C@@]4([C@](CC[C@H]43)(CCOC(C)=O)O)C)[C@]2(CCC1)C RBJWAERSBJWDSH-XAQLXDLTSA-N 0.000 claims 1
- ZZKDGABMFBCSRP-UHFFFAOYSA-N 3-ethyl-2-methylpyridine Chemical compound CCC1=CC=CN=C1C ZZKDGABMFBCSRP-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 230000018044 dehydration Effects 0.000 claims 1
- 238000006297 dehydration reaction Methods 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 1
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Procédé pour la préparation de l'acétate de Z/J i-déhydrocortisone On conna?t la grande activité antiarthritique de deux nouveaux corticostéroïdes, la 0',4-prégnadiène- 17a,21-diol-3,11,20-trione (ou 4'-déhydrocortisone ou métacortandracine) et la 0',4-prégnadiène-110, 17a,21-triol-3,20-dione (ou 0'-déhydrocortisol ou métacortandralone) (Herzog et coll., Science, 1955, 121,
p. 176). La présente invention a pour objet un procédé pour la préparation de l'acétate de A'-déhydrocorti- sone (ou métacortandracine) ; ce procédé est caracté risé en ce qu'on oxyde et bromure la 3a,17a-dihydr- oxy-21-acétoxy-prégnane-11,20-dione pour obtenir la 2,4-dibromo-17a-hydroxy-21-acétoxy-prégnane- 3,11,
20-trione lévogyre et qu'on débromhydrate ce composé dibromé. L'invention est illustrée par le schéma réactionnel qui suit.
EMI0001.0027
Suivant un mode préféré de mise en oeuvre du procédé de l'invention, on fait agir sur le composé de départ I le N-bromo-succinimide en présence d'acide acétique, de dioxane et d'eau, et l'on ajoute directement au mélange réactionnel, sans isoler le composé II, la quantité nécessaire de brome, en pré sence de dioxane. Au lieu du brome, on peut aussi utiliser,
toujours en présence de dioxane, le N-bromo- succinimide en présence d'acide bromhydrique.
On peut débromhydrater la 2,4-dibromo-17cc- hydroxy-21-acétoxy-prégnane-3,11,20-trione lévo gyre soit à l'aide d'une base tertiaire, telle que la col- lidine ou la méthyl-éthyl-pyridine, soit par l'intermé diaire d'une dinitrophényl-hydrazone.
Le présent procédé permet de bifurquer à partir d'un terme intermédiaire de la synthèse de la corti sone vers la AI-déhydrocortisone et comporte comme unique différence la fixation stéréospécifique d'un deuxième atome de brome en position 2. On peut ainsi accéder à la AI-déhydrocortisone dans des con ditions particulièrement avantageuses au point de vue économique.
Les points de fusion indiqués dans l'exemple qui suit correspondent à des fusion instantanées. <I>Exemple</I> On chauffe à 60,) C un mélange composé de 2 g de 3a,17a-dihydroxy-21-acétoxy-prégnane-11,20-di- one, 10 cm3 d'acide acétique, 5 cm3 de dioxane, 1,84g de N-bromo-succinimide et 0,15 cm3 d'eau distillée. Après vingt-cinq minutes, il n'y a plus de réaction au papier amidoioduré humide.
On ajoute alors 25 cm3 de dioxane, refroidit à 25 - 30o C et introduit 0,86 g de brome dissous dans 2 cm3 d'acide acétique. Lorsque tout le brome est absorbé, on ajoute 3 cm3 d'eau et agite pendant deux heures en viron à -I- 50 C. Le composé dibromé III cristallise lentement. On essore, lave au dioxane aqueux, puis à l'eau, essore et sèche sous vide. On obtient le composé III lévogyre brut avec un rendement de 25 0/a.
Par recristallisation dans l'acétone aqueuse, on obtient le produit pur, [0.120 = - 190 (c = 0,5 0/0, acétone).
EMI0002.0045
<I>Analyse <SEP> :</I> <SEP> C.z3H30O.Br., <SEP> = <SEP> 562,31
<tb> Calculé <SEP> : <SEP> C <SEP> 49,12 <SEP> % <SEP> H <SEP> 5,38 <SEP> 0/0 <SEP> Br <SEP> 28,43 <SEP> 0/0
<tb> Trouvé <SEP> : <SEP> C <SEP> 49,5 <SEP> % <SEP> H <SEP> 5,5 <SEP> 0/0 <SEP> Br <SEP> 28,4 <SEP> % Ce composé est nouveau.
On parvient au même résultat si, au lieu de fixer le deuxième atome de brome comme indiqué ci- dessus, on utilise à la place du brome le N-bromo- succinimide. Dans ce cas, après avoir introduit les 25 cm3 de dioxane et avoir refroidi à 25() C, on ajoute 1 cm3 d'une solution acétique d'acide brom hydrique sec (38,8 g d'acide bromhydrique pour 100 cm3) puis 0,9 g de N-bromo-succinimide. La bromuration est instantanée.
Après addition de 30 cm3 d'eau, on purifie comme précédemment.
2 g du composé dibromé 111 sont introduits dans 8 cm9 de collidine redistillée. On fait passer un cou rant d'azote et distille sous agitation en dix minutes environ 6 cm3 de collidine (E. 165 C). On laisse refroidir le résidu et le reprend par 20 cm2 du mé lange eau-glace et 6 cm3 d'acide chlorhydrique con centré. Le précipité formé est essoré et lavé à l'eau jusqu'à disparition de l'ion chlore.
On essore et sèche à 40() C. Le produit obtenu renferme 58 % d'acétate de AI-déhydrocortisone d'après le dosage fait par spectrographie dans 1'U. V. à 238 m#i. On l'isole par chromatographie sur alumine. Le produit montre les constantes de la littérature.
Process for the preparation of Z / J i-dehydrocortisone acetate The great antiarthritic activity of two new corticosteroids, 0 ', 4-pregnadiene-17a, 21-diol-3,11,20-trione ( or 4'-dehydrocortisone or metacortandracin) and 0 ', 4-pregnadiene-110, 17a, 21-triol-3,20-dione (or 0'-dehydrocortisol or metacortandralone) (Herzog et al., Science, 1955, 121 ,
p. 176). The present invention relates to a process for the preparation of A'-dehydrocortisone acetate (or metacortandracin); this process is characterized in that 3a, 17a-dihydr-oxy-21-acetoxy-pregnan-11,20-dione is oxidized and brominated to obtain 2,4-dibromo-17a-hydroxy-21-acetoxy- pregnane- 3,11,
20-trione levorotatory and dehydrated this dibrominated compound. The invention is illustrated by the reaction scheme which follows.
EMI0001.0027
According to a preferred embodiment of the process of the invention, the starting compound I is allowed to act on N-bromo-succinimide in the presence of acetic acid, dioxane and water, and one adds directly in the reaction mixture, without isolating compound II, the necessary quantity of bromine, in the presence of dioxane. Instead of bromine, one can also use,
always in the presence of dioxane, N-bromosuccinimide in the presence of hydrobromic acid.
2,4-Dibromo-17cc-hydroxy-21-acetoxy-pregnan-3,11,20-trione levogyre can be dehydrated either with the aid of a tertiary base, such as collidin or methyl-. ethyl-pyridine, or through the intermediary of a dinitrophenyl-hydrazone.
The present process makes it possible to bifurcate from an intermediate term in the synthesis of cortisone towards Al-dehydrocortisone and has as the only difference the stereospecific fixation of a second bromine atom in position 2. It is thus possible to access the Al-dehydrocortisone under conditions which are particularly advantageous from the economic point of view.
The melting points indicated in the example which follows correspond to instantaneous melts. <I> Example </I> A mixture composed of 2 g of 3a, 17a-dihydroxy-21-acetoxy-pregnan-11,20-di-one, 10 cm3 of acetic acid, 5 cm3 of dioxane, 1.84g of N-bromo-succinimide and 0.15 cm3 of distilled water. After twenty-five minutes, there is no further reaction to the wet starchy paper.
Then added 25 cm3 of dioxane, cooled to 25-30o C and introduced 0.86 g of bromine dissolved in 2 cm3 of acetic acid. When all the bromine has been absorbed, 3 cm3 of water are added and the mixture is stirred for about two hours at -I- 50 C. The dibromo compound III slowly crystallizes. It is filtered off, washed with aqueous dioxane, then with water, filtered off and dried under vacuum. The crude levorotatory compound III is obtained with a yield of 25 0 / a.
By recrystallization from aqueous acetone, the pure product is obtained, [0.120 = -190 (c = 0.5 0/0, acetone).
EMI0002.0045
<I> Analysis <SEP>: </I> <SEP> C.z3H30O.Br., <SEP> = <SEP> 562.31
<tb> Calculated <SEP>: <SEP> C <SEP> 49.12 <SEP>% <SEP> H <SEP> 5.38 <SEP> 0/0 <SEP> Br <SEP> 28.43 <SEP > 0/0
<tb> Found <SEP>: <SEP> C <SEP> 49.5 <SEP>% <SEP> H <SEP> 5.5 <SEP> 0/0 <SEP> Br <SEP> 28.4 <SEP >% This compound is new.
The same result is achieved if, instead of fixing the second bromine atom as indicated above, instead of bromine is used N-bromosuccinimide. In this case, after having introduced the 25 cm3 of dioxane and having cooled to 25 () C, 1 cm3 of an acetic solution of dry hydrobromic acid (38.8 g of hydrobromic acid per 100 cm3) is added then 0.9 g of N-bromo-succinimide. Bromination is instantaneous.
After addition of 30 cm3 of water, it is purified as above.
2 g of the dibromo compound 111 are introduced into 8 cm9 of redistilled collidine. Is passed a stream of nitrogen and distilled with stirring in ten minutes about 6 cm3 of collidine (E. 165 C). The residue is allowed to cool and is taken up in 20 cm2 of the water-ice mixture and 6 cm3 of concentrated hydrochloric acid. The precipitate formed is filtered off and washed with water until the chlorine ion has disappeared.
It is filtered off and dried at 40 ° C. The product obtained contains 58% of Al-dehydrocortisone acetate according to the assay made by spectrography in 1'U. V. at 238 m # i. It is isolated by chromatography on alumina. The product shows the constants of the literature.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR337841X | 1955-04-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH337841A true CH337841A (en) | 1959-04-30 |
Family
ID=8891512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH337841D CH337841A (en) | 1955-04-15 | 1956-04-06 | Process for the preparation of 1-dehydrocortisone acetate |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH337841A (en) |
-
1956
- 1956-04-06 CH CH337841D patent/CH337841A/en unknown
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