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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 PDF

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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
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.)
Ceased
Application number
PCT/IB2003/000479
Other languages
English (en)
Inventor
Alberto Giraudi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ABC INTERNATIONAL PHARMA Srl
Original Assignee
ABC INTERNATIONAL PHARMA Srl
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ABC INTERNATIONAL PHARMA Srl filed Critical ABC INTERNATIONAL PHARMA Srl
Priority to BR0303067-9A priority Critical patent/BR0303067A/pt
Priority to AU2003244517A priority patent/AU2003244517A1/en
Publication of WO2003066657A1 publication Critical patent/WO2003066657A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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.

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  • 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
PCT/IB2003/000479 2002-02-06 2003-02-06 Processus de preparation de bisulfate d'acide ursodeoxycholique et sels de ce compose repondant aux normes pharmaceutiques Ceased WO2003066657A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BR0303067-9A BR0303067A (pt) 2002-02-06 2003-02-06 Processo de preparação de dissulfato de ácido ursodesoxicólico e seus sais farmacêuticamente aceitáveis
AU2003244517A AU2003244517A1 (en) 2002-02-06 2003-02-06 A process for preparing ursodeoxycholic acid dusulphate and pharmaceutically acceptable salts thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITTO2002A000102 2002-02-06
IT2002TO000102A ITTO20020102A1 (it) 2002-02-06 2002-02-06 Procedimento per la preparazione dell'acido ursodesossicolico disolfato e suoi sali farmaceuticamente accettabili.

Publications (1)

Publication Number Publication Date
WO2003066657A1 true WO2003066657A1 (fr) 2003-08-14

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2003/000479 Ceased 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 (3)

* Cited by examiner, † Cited by third party
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
US12419897B2 (en) 2018-12-04 2025-09-23 President And Fellows Of Harvard College Synthetic derivatives of cholic acid 7-sulfate and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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 (3)

* Cited by examiner, † Cited by third party
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
US12419897B2 (en) 2018-12-04 2025-09-23 President And Fellows Of Harvard College Synthetic derivatives of cholic acid 7-sulfate and uses thereof

Also Published As

Publication number Publication date
BR0303067A (pt) 2004-03-09
ITTO20020102A1 (it) 2003-08-06
ITTO20020102A0 (it) 2002-02-06
AU2003244517A1 (en) 2003-09-02

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