FR2653127A1 - Process for the preparation of 12-oxocholanates - Google Patents
Process for the preparation of 12-oxocholanates Download PDFInfo
- Publication number
- FR2653127A1 FR2653127A1 FR8913570A FR8913570A FR2653127A1 FR 2653127 A1 FR2653127 A1 FR 2653127A1 FR 8913570 A FR8913570 A FR 8913570A FR 8913570 A FR8913570 A FR 8913570A FR 2653127 A1 FR2653127 A1 FR 2653127A1
- Authority
- FR
- France
- Prior art keywords
- methyl
- bromide
- alkaline
- sep
- hypochlorite
- 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.)
- Granted
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- RVGVSOKFBAOUCH-JDCDKZKASA-N (4r)-4-[(8r,9s,10s,13r,14s,17r)-10,13-dimethyl-12-oxo-1,2,3,4,5,6,7,8,9,11,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)C(=O)C2 RVGVSOKFBAOUCH-JDCDKZKASA-N 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title claims abstract description 4
- 238000000034 method Methods 0.000 title claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Inorganic materials Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 5
- BSYCBEFCUGMWAQ-YDCZHVRYSA-N (8S,9S,10R,13S,14S,17R)-16-hydroxy-13-methyl-17-[(2R)-pentan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-10-carboxylic acid Chemical compound C1CC2CCCC[C@]2(C(O)=O)[C@@H]2[C@@H]1[C@@H]1CC(O)[C@H]([C@H](C)CCC)[C@@]1(C)CC2 BSYCBEFCUGMWAQ-YDCZHVRYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- OBUOWZOYJNAMCZ-WNWGBCMMSA-N (4R)-4-[(8R,9S,10S,12S,13R,14S,17R)-12-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)[C@@H](O)C2 OBUOWZOYJNAMCZ-WNWGBCMMSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- -1 alkyl cholate Chemical compound 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 3
- 229910052783 alkali metal Inorganic materials 0.000 abstract 1
- 229910001513 alkali metal bromide Inorganic materials 0.000 abstract 1
- 229940099352 cholate Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BKPNMUHLOXZELU-AMSHGWJLSA-N 12alpha-Hydroxy-3alpha,7alpha-diacetoxy-5beta-cholansaeure-(24) Natural products C([C@H]1C[C@H]2OC(C)=O)[C@H](OC(C)=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BKPNMUHLOXZELU-AMSHGWJLSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
Description
La présente invention concerne un procédé pour l'oxydation d'hydroxycholanates par action d'un hypochlorite alcalin et de l'acide acétique. The present invention relates to a process for the oxidation of hydroxycholanates by the action of an alkaline hypochlorite and acetic acid.
Cette réaction, qui est connue en littérature et est conduite en utilisant un excès d'acide acétique, a l'inconvénient de libérer du chlore et de comporter ainsi des problèmes de contrôle pour éviter des dommages écologiques. This reaction, which is known in the literature and is conducted using an excess of acetic acid, has the disadvantage of releasing chlorine and thus containing control problems to avoid ecological damage.
On a maintenant trouvé que la réaction d'oxydation avec un hypochlorite alcalin peut être effectuée de façon efficace et sans problème de contrôle en utilisant la quantité stoechiométrique d'acide acétique et en opérant en présence d'un bromure alcalin à une température inférieure à 400C, de préférence inférieure à 10oC. It has now been found that the oxidation reaction with an alkaline hypochlorite can be carried out efficiently and without control problems using the stoichiometric amount of acetic acid and operating in the presence of an alkaline bromide at a temperature below 400C preferably less than 10oC.
Ainsi, la présente invention - concerne un procédé pour la préparation d'un 12-oxocholanate de formule
dans laquelle les-deux R et R' représentent l'hydrogène ou bien les deux R, identiques, représentent un groupe acétyle et R' représente méthyle, éthyle ou n-propyle, caractérisé en ce qu'on
in which the two R and R 'are hydrogen or the two R, identical, represent an acetyl group and R' represents methyl, ethyl or n-propyl, characterized in that
<tb> traite <SEP> un <SEP> 12a-hydroxycholanate <SEP> de <SEP> formule <SEP> : <SEP> COOL'
<tb> <SEP> OH
<tb> <SEP> CH <SEP> CCnD <SEP> < <SEP> O-COCH3
<tb> dans laquelle R' représente l'hydrogène ou un groupe méthyle1 éthyle ou n-propyle avec un hypochlorite alcalin et de l'acide acétique en quantités stoechiométriques en présence d'un bromure alcalin et à une température inférieure à 400C, et on saponifie éventuellement le produit ainsi obtenu.<tb> treats <SEP> a <SEP> 12a-hydroxycholanate <SEP> of <SEP> formula <SEP>: <SEP> COOL
<tb><SEP> OH
<tb><SEP> CH <SEP> CCND <SEP><SEP> O-COCH3
wherein R 'is hydrogen or methyl ethyl or n-propyl with alkaline hypochlorite and acetic acid in stoichiometric amounts in the presence of an alkaline bromide and at a temperature below 400C, and optionally saponifies the product thus obtained.
Comme hydroxycholanate de départ préféré, on utilise 1' acide 3 a, 7 a-diacétoxy-12-hydroxy-5 cholanique (ou acide cholique 3,7-diacétate) ou son ester méthylique. As the preferred starting hydroxycholanate, there is used 3α, 7α-diacetoxy-12-hydroxy-5-cholanic acid (or cholic acid 3,7-diacetate) or its methyl ester.
La réaction peut être conduite dans un solvant organique ou organique-aqueux, le solvant organique étant un hydrocarbure halogéné, par exmeple le chlorure de méthylène ou le 1,2-dichloroéthane, l'acétate d'éthyle ou un éther, par exemple le diméthoxyéthane ou le tétrahydrofuranne. The reaction can be carried out in an organic or organic-aqueous solvent, the organic solvent being a halogenated hydrocarbon, for example methylene chloride or 1,2-dichloroethane, ethyl acetate or an ether, for example dimethoxyethane. or tetrahydrofuran.
Le bromure alcalin est avantageusement utilisé à raison de 0,34-1,15 mole par mole d'hydroxycholanate de départ, le cation étant de préférence celui de l'hypochlorite utilisé. De préférence, on utilise l'hypochlorite de sodium et le bromure de sodium. The alkaline bromide is advantageously used in a proportion of 0.34-1.15 mol per mole of starting hydroxycholanate, the cation being preferably that of the hypochlorite used. Preferably, sodium hypochlorite and sodium bromide are used.
La température de réaction doit être inférieure à 400C pour éviter la libération de chlore, mais il est avantageux de conduire l'oxydation au-dessous de 100C et, de préférence, au-dessous de OOC. The reaction temperature should be less than 400C to avoid the release of chlorine, but it is advantageous to conduct the oxidation below 100C and, preferably, below OOC.
En général, selon un mode opératoire préféré, la réaction est terminée après 16-24 heures à une température entre -10 et OOC et le produit final est isolé selon les techniques conventionnelles. In general, according to a preferred procedure, the reaction is terminated after 16-24 hours at a temperature between -10 and 0 ° C and the final product is isolated according to conventional techniques.
Par exemple, le produit ainsi obtenu peut être isolé sous forme cristalline en versant le mélange réactionnel dans l'eau, éventuellement en présence d'un sulfite alcalin qui sert à détruire l'excès d'agent oxydant encore présent, en éliminant la phase aqueuse et en évaporant le solvant. For example, the product thus obtained can be isolated in crystalline form by pouring the reaction mixture into water, optionally in the presence of an alkaline sulfite which serves to destroy the excess of oxidizing agent still present, by eliminating the aqueous phase. and evaporating the solvent.
On obtient ainsi un ester de l'acide 3a,7cc- diacétoxy-12-oxo-5ss-cholanique qui peut être saponifié en utilisant une solution aqueuse d'hydroxyde de sodium pour isoler l'acide 3a, 7a-dihydroxy-12-12-oxo-5 cholanique. A 3a, 7cc-diacetoxy-12-oxo-5ss-cholanic acid ester is thus obtained which can be saponified using an aqueous solution of sodium hydroxide to isolate 3a, 7a-dihydroxy-12-12 acid. -oxo-5 cholanic.
Les exemples suivants illustrent l'invention sans toutefois la limiter. The following examples illustrate the invention without limiting it.
Exemple 1
A une solution de 17kg de 3a,7a-diacétoxy-12a-hydroxy-5ss- cholanate de méthyle et 1,04 kg de bromure de sodium dans 46 kg d'acétate d'éthyle, 3,6 kg d'acide acétique et 3,4 kg d'eau, refroidie à -100C - OOC, on ajoute en 5 heures 18,48 1 d'une solution à 14,9 % poids/volume d'hypochlorite de sodium. On laisse le mélange réactionnel 16 heures à la même température, puis on ajoute 17 kg d'une solution de sulfite de sodium à 10% et on chauffe à 400C. On élimine la phase aqueuse, on neutralise avec une solution de bicarbonate ee sodium, on évapore le solvant sur un bain d'eau. Par refroidissement et filtration, on obtient 16,93 kg de 3a,7a-diacétoxy-12-oxo-5ss-cholanate de méthyle, identique à un échantillon authentique. Rendement quantitatif.Example 1
To a solution of 17 kg of methyl 3a, 7a-diacetoxy-12a-hydroxy-5ss-cholanate and 1.04 kg of sodium bromide in 46 kg of ethyl acetate, 3.6 kg of acetic acid and 3 4 kg of water, cooled to -100 ° C.-OOC, 18.48 liters of a 14.9% weight / volume solution of sodium hypochlorite are added over 5 hours. The reaction mixture is left for 16 hours at the same temperature, then 17 kg of a 10% sodium sulphite solution are added and heated to 400 ° C. The aqueous phase is removed, neutralized with sodium bicarbonate solution and the solvent is evaporated on a water bath. By cooling and filtration, 16.93 kg of methyl 3a, 7a-diacetoxy-12-oxo-5ss-cholanate are obtained, identical to an authentic sample. Quantitative yield.
Exemple 2
On opère comme décrit ci-dessus jusqu'à l'évaporation du solvant de la solution contenant le 3a-,7a-diacétoxy-12-oxo-St3- cholanate de méthyle, puis on ajoute 4 équivalents d'hydroxyde de sodium à 40% et on chauffe au reflux jusqu'à ce que la saponification soit complète. Par acidification avec de l'acide chlorhydrique, on obtient l'acide 3a,7a-dihydroxy-12-oxo-5ss- cholanique ayant un titre supérieur à 99% par rapport à un échantillon authentique. Rendement quantitatif. Example 2
The operation is carried out as described above until the solvent is evaporated from the solution containing methyl 3α, 7α-diacetoxy-12-oxo-3-cholanate and then 4 equivalents of 40% sodium hydroxide are added. and refluxing until saponification is complete. Acidification with hydrochloric acid gives 3a, 7a-dihydroxy-12-oxo-5ss-cholanic acid having a titer greater than 99% with respect to an authentic sample. Quantitative yield.
Claims (4)
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8913570A FR2653127B1 (en) | 1989-10-17 | 1989-10-17 | PROCESS FOR THE PREPARATION OF 12-OXOCHOLANATES. |
| ES90402879T ES2086388T3 (en) | 1989-10-17 | 1990-10-16 | PROCEDURE FOR THE PRODUCTION OF CHENODESOXICOLIC ACID. |
| DE69025449T DE69025449T2 (en) | 1989-10-17 | 1990-10-16 | Process for the preparation of chenodeoxycholic acids |
| AT90402879T ATE134378T1 (en) | 1989-10-17 | 1990-10-16 | METHOD FOR PRODUCING CHENODESOXYCHOLIC ACIDS |
| EP90402879A EP0424232B1 (en) | 1989-10-17 | 1990-10-16 | Process for the production of chenodesoxycholic |
| DK90402879.2T DK0424232T3 (en) | 1989-10-17 | 1990-10-16 | Process for the preparation of chenodesoxycholic acid |
| IE370190A IE73449B1 (en) | 1989-10-17 | 1990-10-16 | Process for the production of chenodeoxycholic |
| GR960401242T GR3019857T3 (en) | 1989-10-17 | 1996-05-07 | Process for the production of chenodesoxycholic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8913570A FR2653127B1 (en) | 1989-10-17 | 1989-10-17 | PROCESS FOR THE PREPARATION OF 12-OXOCHOLANATES. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2653127A1 true FR2653127A1 (en) | 1991-04-19 |
| FR2653127B1 FR2653127B1 (en) | 1994-12-09 |
Family
ID=9386488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8913570A Expired - Fee Related FR2653127B1 (en) | 1989-10-17 | 1989-10-17 | PROCESS FOR THE PREPARATION OF 12-OXOCHOLANATES. |
Country Status (1)
| Country | Link |
|---|---|
| FR (1) | FR2653127B1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0063106A1 (en) * | 1981-04-14 | 1982-10-20 | ERREGIERRE S.p.A. | Process for preparing high purity ursodeoxycholic acid |
| EP0072293A2 (en) * | 1981-08-07 | 1983-02-16 | Roussel-Uclaf | Process for the preparation of ursodeoxycholic acid starting from 3-alpha, 7-beta, 12-alpha-trihydroxy cholanic acid, and intermediates used |
| EP0088637A2 (en) * | 1982-03-09 | 1983-09-14 | Kabushiki Kaisha Yakult Honsha | A method for producing ursodeoxycholic acid |
-
1989
- 1989-10-17 FR FR8913570A patent/FR2653127B1/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0063106A1 (en) * | 1981-04-14 | 1982-10-20 | ERREGIERRE S.p.A. | Process for preparing high purity ursodeoxycholic acid |
| EP0072293A2 (en) * | 1981-08-07 | 1983-02-16 | Roussel-Uclaf | Process for the preparation of ursodeoxycholic acid starting from 3-alpha, 7-beta, 12-alpha-trihydroxy cholanic acid, and intermediates used |
| EP0088637A2 (en) * | 1982-03-09 | 1983-09-14 | Kabushiki Kaisha Yakult Honsha | A method for producing ursodeoxycholic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2653127B1 (en) | 1994-12-09 |
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