Title:
METHOD FOR THE PRODUCTION OF CRYSTALLINE (6RS)-N(5)-FORMYL-5,6,7,8-TETRAHYDROFOLIC ACID
Document Type and Number:
WIPO Patent Application WO2005080395
Kind Code:
A3
Abstract:
The inventive method for the production of crystalline (6RS)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid or amorphic (6S)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid is characterized in that an aqueous solution of (6RS)- or (6S)-calcium folinate, which has a temperature of 40 °C to 50 °C, and an aqueous solution of hydrochloric acid or acetic acid are added to stirred water having a temperature of 2 °C to 12 °C, such that the temperature is kept at 2 °C to 12 °C in the mixture thus obtained when the two above-mentioned solutions are added and the pH value is kept at 2,5 to 3,5, the solid thus arising is isolated by means of filtration or centrifugation, the solid is initially washed with cold water and then with an aqueous organic solvent, and the washed solid, i.e. crystalline (6RS)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid or amorphous (6S)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid is dried at reduced pressure and obtained.
Inventors:
GIANCARLO FRANCESE (CH)
MOROSOLI MORENO (CH)
MOROSOLI MORENO (CH)
Application Number:
PCT/CH2005/000092
Publication Date:
February 16, 2006
Filing Date:
February 18, 2005
Export Citation:
Assignee:
CERBIOS PHARMA SA (CH)
GIANCARLO FRANCESE (CH)
MOROSOLI MORENO (CH)
GIANCARLO FRANCESE (CH)
MOROSOLI MORENO (CH)
International Classes:
C07D475/04; (IPC1-7): C07D475/04; A61K31/522; A61P35/00
Domestic Patent References:
| WO1993017022A1 | 1993-09-02 | |||
| WO1995026963A1 | 1995-10-12 |
Foreign References:
| EP0293029A1 | 1988-11-30 | |||
| EP0495204A1 | 1992-07-22 | |||
| EP0667159A2 | 1995-08-16 | |||
| US4148999A | 1979-04-10 | |||
| EP0401895A1 | 1990-12-12 |
Other References:
EDWIN H. FLYNN: "A Synthetic Compound with Folinic Acid Activity", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 73, 1951, USAMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., pages 1979 - 1982, XP002287843
BARBARA ROTH: "Synthesis of Leucovorin", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 74, 1952, USAMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., pages 3247 - 3252, XP002287844
TEMPLE C ET AL: "PREPARATION AND PURIFICATION OF L-(PLUS OR MINUS)-5-FORMYL-5,6,7,8-TE TRAHYDROFOLIC ACID", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 22, no. 6, 1 June 1979 (1979-06-01), pages 731 - 734, XP002074295, ISSN: 0022-2623
FEENEY ET AL.: "Hydrogen-1 Nuclear Magnetic Resonance Study of the Complexes of Two Diastereoisomers of Folinic Acid with Dihydrofolate Reductase", BIOCHEMISTRY., vol. 20, 1981, USAMERICAN CHEMICAL SOCIETY. EASTON, PA., pages 1837 - 1842, XP002352951
KHALIFA ET AL, HELVETICA CHIMICA ACTA., vol. 63, 1980, CHVERLAG HELVETICA CHIMICA ACTA. BASEL., pages 2554 - 2558, XP002352952
BARBARA ROTH: "Synthesis of Leucovorin", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 74, 1952, USAMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., pages 3247 - 3252, XP002287844
TEMPLE C ET AL: "PREPARATION AND PURIFICATION OF L-(PLUS OR MINUS)-5-FORMYL-5,6,7,8-TE TRAHYDROFOLIC ACID", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 22, no. 6, 1 June 1979 (1979-06-01), pages 731 - 734, XP002074295, ISSN: 0022-2623
FEENEY ET AL.: "Hydrogen-1 Nuclear Magnetic Resonance Study of the Complexes of Two Diastereoisomers of Folinic Acid with Dihydrofolate Reductase", BIOCHEMISTRY., vol. 20, 1981, USAMERICAN CHEMICAL SOCIETY. EASTON, PA., pages 1837 - 1842, XP002352951
KHALIFA ET AL, HELVETICA CHIMICA ACTA., vol. 63, 1980, CHVERLAG HELVETICA CHIMICA ACTA. BASEL., pages 2554 - 2558, XP002352952
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