WO2003066657A1 - Processus de preparation de bisulfate d'acide ursodeoxycholique et sels de ce compose repondant aux normes pharmaceutiques - Google Patents
Processus de preparation de bisulfate d'acide ursodeoxycholique et sels de ce compose repondant aux normes pharmaceutiques Download PDFInfo
- Publication number
- WO2003066657A1 WO2003066657A1 PCT/IB2003/000479 IB0300479W WO03066657A1 WO 2003066657 A1 WO2003066657 A1 WO 2003066657A1 IB 0300479 W IB0300479 W IB 0300479W WO 03066657 A1 WO03066657 A1 WO 03066657A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ursodeoxycholic acid
- acid
- disulphate
- sulphuric
- alkali metal
- Prior art date
Links
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229960001661 ursodiol Drugs 0.000 title claims abstract description 33
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](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)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 title claims abstract description 32
- 150000003839 salts Chemical class 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims abstract description 3
- 239000001117 sulphuric acid Substances 0.000 claims abstract description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- VFNGKCDDZUSWLR-UHFFFAOYSA-N disulfuric acid Chemical compound OS(=O)(=O)OS(O)(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- -1 alkali metal salts Chemical class 0.000 claims description 7
- 239000007795 chemical reaction product Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 2
- 229910021653 sulphate ion Inorganic materials 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000013019 agitation Methods 0.000 description 8
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010518 undesired secondary reaction Methods 0.000 description 1
- 125000001612 ursodeoxycholic acid group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
Definitions
- the present invention relates to a novel process for the preparation of ursodeoxycholic acid disulphate and its pharmaceutically acceptable salts, particularly the alkali metal salts.
- Ursodeoxycholic acid disulphate and its trisodium salt are described in EP-A-0 117 570; they are compounds derived from ursodeoxycholic acid which, unlike ursodeoxycholic acid, are very water-soluble and are therefore particularly useful in the preparation of liquid pharmaceutical formulations.
- the above-mentioned compounds have a therapeutic activity, similar to or in some cases better than that of ursodeoxycholic acid, especially in the treatment of qualitative or quantitative changes in the bile-forming function, including the forms with bile supersaturated with cholesterol, in combating the formation of cholesterol calculi or for creating conditions suitable for dissolving them.
- ursodeoxycholic acid disulphate (referred to hereinafter simply as "ursosulphate” ) can be prepared by reacting ursodeoxycholic acid in anhydrous pyridine with gaseous sulphuric anhydride; however, a preparation process that uses the pyridine-sulphuric anhydride complex as the sulphation agent is preferred.
- the ursodeoxycholic acid is dissolved in N,N-dimethylformamide and reacted with the pyridine-sulphuric anhydride complex in a molar ratio of 1.95-2.1 moles of the complex to 1 mole of ursodeoxycholic acid in a temperature range of from 0 to 100°C.
- the resulting oily residue constituted by free ursosulphate acid is neutralized using an aqueous, alcoholic or hydroalcoholic sodium hydroxide solution and the corresponding trisodium salt is precipitated in crystalline form by the addition of acetone.
- the addition of sodium hydroxide in aqueous methanolic or ethanolic solution to the reaction product in oily form involves, presumably owing to the highly exothermic acid-base reaction between soda and sulphuric pyridine (which is not completely eliminated during the evaporation of the solvent) , an increase in temperature with a high risk of decomposition of the desired end product .
- the object of the present invention is to provide an improved process suitable for obtaining ursodeoxycholic acid disulphate and its salts in a highly purified form and with high yields .
- the invention relates to a process for the preparation of ursodeoxycholic acid disulphate and its pharmaceutically acceptable salts, characterized in that it comprises the step of reacting ursodeoxycholic acid dissolved in a solvent, selected from the group consisting of dimethylformamide, pyridine, acetonitrile, dimethyl sulphoxide, octanoic acid, acetic anhydride and their mixtures, with a sulphation agent selected from sulphuric anhydride, sulphuric acid and complexes containing sulphuric anhydride in a molar ratio of sulphonic group to ursodeoxycholic acid of from 2.5 to 4.
- a solvent selected from the group consisting of dimethylformamide, pyridine, acetonitrile, dimethyl sulph
- the reaction is carried out at a temperature of from 0 to 100°C, preferably at an ambient temperature of approximately 20-30°C, preferably for a period of from 4 to 24 hours, under intense agitation.
- the reaction mixture is diluted with water in order to hydrate the sulphation agent ; the amount of water added is preferably equal to the amount necessary to bring the exothermic hydration reaction to completion.
- Alkali metal hydroxide in aqueous solution is then added to obtain a pH of preferably from 7 to 8, taking care that the temperature of the reaction mixture does not exceed 50°C, preferably 30°C.
- the solution is then concentrated, preferably under vacuum, keeping the temperature below 50°C, and the reaction product (constituted by the triple alkali metal salt of ursodeoxycholic acid disulphate) is precipitated by the addition of a solvent, which is preferably selected from acetone, alcohols or other alkanes, diethyl ether, tetrahydrofuran or dimethyl- formamide, and recovered.
- a solvent which is preferably selected from acetone, alcohols or other alkanes, diethyl ether, tetrahydrofuran or dimethyl- formamide, and recovered.
- the crude reaction product is further purified by crystallization in a water/methanol solution and precipitation in acetone.
- the process permits the manufacture of the alkali metal salt of ursodeoxycholic acid disulphate in a highly purified form with yields higher than 80% based on the ursodeoxycholic acid.
- the solution is then concentrated to half its volume under vacuum, keeping the temperature below 50°C (internal temperature) . While still maintaining the temperature at from 40 to 50°C, 2250 I of acetone are added and, when the addition of acetone is complete, the mixture is maintained at 50°C for 20 minutes and then cooled to 20°C.
- the crude trisodium salt of the ursodeoxycholic acid disulphate precipitates from the reaction medium and is recovered by centrifuging and dried at 40°C for 12 hours to give 330 kg of crude product.
- the 330 kg of the trisodium salt so obtained are placed in a 4000 I , reactor where 1700 I of methanol and 900 i of water are added thereto. The whole is maintained under agitation for 30 minutes at ambient temperature.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
La présente invention concerne un processus de préparation de bisulfate d'acide ursodéoxycholique ou de sels de ce composé répondant aux normes pharmaceutiques. Ce processus comprend la réaction de cet acide ursodéoxycholique dissout dans un solvant sélectionné dans le groupe constitué de diméthyl-formamide, pyridine, acétonitrile, diméthyle sulfoxyde, acide caprylique, anhydride acétique et de mélanges de ces composés, avec un agent de sulfatation sélectionné dans le groupe constitué d'anhydride sulfurique, d'acide sulfurique et de complexes contenant un anhydride sulfurique dans un rapport molaire de groupes sulfoniques sur acide ursodéoxycholique compris entre 2,5/1 et 4/1
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003244517A AU2003244517A1 (en) | 2002-02-06 | 2003-02-06 | A process for preparing ursodeoxycholic acid dusulphate and pharmaceutically acceptable salts thereof |
| BR0303067-9A BR0303067A (pt) | 2002-02-06 | 2003-02-06 | Processo de preparação de dissulfato de ácido ursodesoxicólico e seus sais farmacêuticamente aceitáveis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2002TO000102A ITTO20020102A1 (it) | 2002-02-06 | 2002-02-06 | Procedimento per la preparazione dell'acido ursodesossicolico disolfato e suoi sali farmaceuticamente accettabili. |
| ITTO2002A000102 | 2002-02-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003066657A1 true WO2003066657A1 (fr) | 2003-08-14 |
Family
ID=27638823
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2003/000479 WO2003066657A1 (fr) | 2002-02-06 | 2003-02-06 | Processus de preparation de bisulfate d'acide ursodeoxycholique et sels de ce compose repondant aux normes pharmaceutiques |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU2003244517A1 (fr) |
| BR (1) | BR0303067A (fr) |
| IT (1) | ITTO20020102A1 (fr) |
| WO (1) | WO2003066657A1 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2221313A1 (fr) | 2009-02-19 | 2010-08-25 | Prodotti Chimici E Alimentari Spa | Procédé de préparation d'acide ursodeoxycholique, 3,7-disulfate di-sodique |
| US12186329B2 (en) | 2018-08-23 | 2025-01-07 | President And Fellows Of Harvard College | Compositions and methods related to cholic acid 7-sulfate as a treatment for diabetes |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0117570A1 (fr) * | 1983-02-24 | 1984-09-05 | ISTITUTO BIOLOGICO CHEMIOTERAPICO "ABC" S.p.A. | Sel de sodium du sulfate d'acide ursodésoxycholique |
| WO1997018816A2 (fr) * | 1995-11-21 | 1997-05-29 | Children's Hospital Medical Center | Conjugues du type sulfates de l'acide ursodesoxycholique et leur utilisation pour traiter avec succes des troubles inflammatoires et similaire |
-
2002
- 2002-02-06 IT IT2002TO000102A patent/ITTO20020102A1/it unknown
-
2003
- 2003-02-06 WO PCT/IB2003/000479 patent/WO2003066657A1/fr not_active Application Discontinuation
- 2003-02-06 BR BR0303067-9A patent/BR0303067A/pt not_active IP Right Cessation
- 2003-02-06 AU AU2003244517A patent/AU2003244517A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0117570A1 (fr) * | 1983-02-24 | 1984-09-05 | ISTITUTO BIOLOGICO CHEMIOTERAPICO "ABC" S.p.A. | Sel de sodium du sulfate d'acide ursodésoxycholique |
| WO1997018816A2 (fr) * | 1995-11-21 | 1997-05-29 | Children's Hospital Medical Center | Conjugues du type sulfates de l'acide ursodesoxycholique et leur utilisation pour traiter avec succes des troubles inflammatoires et similaire |
Non-Patent Citations (2)
| Title |
|---|
| BANDIERA T ET AL: "A CONVENIENT PROCEDURE FOR THE SYNTHESIS OF URSODEOXYCHOLIC ACID SULFATED DERIVATIVES", SYNTHETIC COMMUNICATIONS, MARCEL DEKKER, INC., BASEL, CH, vol. 17, no. 9, 1987, pages 1111 - 1117, XP000564355, ISSN: 0039-7911 * |
| GOTO, J. ET AL.: "Synthesis of Disulfates of Unconjugated and Conjugated Bile Acids", CHEM. PHARM. BULL., vol. 35, no. 11, 1987, pages 4562 - 4567, XP001157455 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2221313A1 (fr) | 2009-02-19 | 2010-08-25 | Prodotti Chimici E Alimentari Spa | Procédé de préparation d'acide ursodeoxycholique, 3,7-disulfate di-sodique |
| US12186329B2 (en) | 2018-08-23 | 2025-01-07 | President And Fellows Of Harvard College | Compositions and methods related to cholic acid 7-sulfate as a treatment for diabetes |
Also Published As
| Publication number | Publication date |
|---|---|
| BR0303067A (pt) | 2004-03-09 |
| ITTO20020102A1 (it) | 2003-08-06 |
| AU2003244517A1 (en) | 2003-09-02 |
| ITTO20020102A0 (it) | 2002-02-06 |
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