Organic compounds -- part of the class 532-570 series – Organic compounds – 9,10-seco-cyclopentanohydrophenanthrene ring system or...
Reexamination Certificate
1998-12-09
2002-09-10
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
9,10-seco-cyclopentanohydrophenanthrene ring system or...
Reexamination Certificate
active
06448421
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel crystals of a vitamin D derivative and, more specifically, to novel crystals of a vitamin D derivative which are obtained by purifying the vitamin D derivative through a reverse phase chromatography and then crystallizing the purified derivative from an organic solvent. The present invention also relates to a method for purifying a vitamin D derivative which comprises a crystallization step.
BACKGROUND ART
A variety of vitamin D derivatives are known to have useful physiological activities. For example, JP 6-23185 B/1994 discloses that a 1 &agr;-hydroxyvitamin D
3
derivative represented by the following general formula:
wherein R
1
denotes an amino group or the formula OR′ where R′ denotes a lower alkyl group having 1 to 7 carbon atoms which is unsubstituted or substituted by a hydroxyl group, a halogen atom, a cyano group or an acylamino group, and R
2
denotes a hydrogen atom or a hydroxyl group, is useful as a therapeutic agent for diseases caused by calcium dysbolism or as an anti-tumor agent.
1&agr;,25-dihydroxy-2&bgr;-(3-hydroxypropoxy)vitamin D
3
(also called as ED-71) which is one of the compounds covered by the above general formula is an active form of a vitamin D derivative having a bone forming action and thus is in a way to be developed as a therapeutic agent for osteoporosis.
Once such a vitamin D derivative is established as a therapeutic agent, it should be highly purified and be supplied in bulk and steadily. Therefore, it is desired to establish a method for manufacturing a vitamin D derivative as soon as possible.
In particular, ED-71 has been obtained only in an amorphous form and there is no reported isolation of ED-71 in a crystalline form.
DISCLOSURE OF THE INVENTION
An object of the present invention is to establish a method for preparing a highly purified vitamin D derivative, especially ED-71, which makes it possible to supply the product in bulk and steadily.
Another object of this invention is to provide crystals of a vitamin D derivative which may be obtained by purifying a crude or preliminarily purified product of the vitamin D derivative.
Another object of this invention is to provide a method for purifying a vitamin D derivative which comprises a crystallization step.
A further object of this invention is to provide a method for purifying the pre form compound of ED-71, which comprises a crystallization step, and to provide a purified pre form compound obtained by the method.
A still further object of this invention is to provide novel compounds which are secondarily formed during the synthesis and purification of a vitamin D derivative.
We have conducted extensive research on the following points which are issued during the synthesis and purification of ED-71 from its provitamin D derivative (pro form): (1) the effect of impurities in the pro form on the HPLC preparative purification of ED-71; (2) the stability of ED-71 and its previtamin D derivative (pre form) to heat, light and oxygen; (3) the handling of ED-71 which exhibits a high physiological action even in a extremely small dose; and (4) the possibility of the purification of ED-71 by crystallization. As a result of the research, we have found that crystals of ED-71 can be obtained in gram order by recrystallizing the pro form from methanol, subjecting the recrystallized pro form to a photo-reaction at a low temperature and then a thermal isomerization reaction, purifying the isomerized product by a reverse phase HPLC, concentrating the eluate, and then crystallizing the residue from ethyl acetate, and have completed the present invention. Further, we have determined the structure of by-products which are originally contained in the pro form or formed during the photo-reaction and found that some compounds of them are novel.
According to one aspect of the present invention, crystals of the compound represented by formula (I):
are provided.
According to another aspect of the present invention, crystals of a vitamin D derivative which are obtained by purifying a crude or preliminarily purified product of the vitamin D derivative through a reverse phase chromatography and then crystallizing the purified derivative from an organic solvent, are provided.
According to a further aspect of the present invention, a method for purifying a vitamin D derivative which comprises subjecting the vitamin D derivative to a reverse phase chromatography is provided.
According to a further aspect of the present invention, a method for purifying a vitamin D derivative which comprises crystallizing the vitamin D derivative from an organic solvent is provided.
According to a further aspect of the present invention, a method for purifying a vitamin D derivative which comprises purifying a crude or preliminarily purified product of the vitamin D derivative through a reverse phase chromatography and then crystallizing the purified derivative from an organic solvent is provided.
According to a further aspect of the present invention, a method for purifying the compound represented by formula (II):
which comprises recrystallizing a crude or preliminarily purified product of the compound represented by formula (II) from an alcohol is provided.
According to a further aspect of the present invention, a purified product of the compound represented by formula (II):
which is obtained by recrystallizing a crude or preliminarily purified product of the compound represented by formula (II) from an alcohol is provided.
According to a further aspect of the present invention, a method for preparing a purified product of the vitamin D derivative represented by formula (I):
which comprises recrystallizing a crude or preliminarily purified product of the compound represented by formula (II):
from an alcohol, subjecting the recrystallized compound of formula (II) to an ultraviolet light radiation and then a thermal isomerization reaction to give a vitamin D derivative represented by formula (I), purifying the crude or preliminarily purified vitamin D derivative of formula (I) through a reverse phase chromatography, and crystallizing the vitamin D derivative of formula (I) from an organic solvent, is provided.
According to a still further aspect of the present invention, the compound represented by formula (III):
and the compound represented by formula (IV):
are provided. These compounds are contained in the reaction mixture obtained by the ultraviolet light radiation and the subsequent thermal isomerization reaction of the pro form of ED-71.
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XP-002102281, Derwent Publication Ltd., 1995.*
Posner et al., J. Org. Chem., vol. 59, pp. 7855-7861, 1994.*
Chemical Abstracts, vol. 124, No. 7, p. 225, (1996).
Miyamoto et al., “Synthetic Studies of Vitamin D Analogues. XIV. Synthesis and Calcium Regulating Acitivity of Vitamin D Analogues Bearing a Hydroxyalkoxy Group at 2B-Position”,Chem Pharm. Bull, vol. 41, No. 6, pp1111-1113, (1993).
Posner et al., “Stereocontrolled Total Synthesis of Calcitriol Derivatives: 1,25-Dihydroxy-2-(4-hydroxybuty) vitamin D Analogs of an Osteoporosis Drug”,J. Qrg. Chem, vol. 59, pp. 7855-7861, (1994).
Barner et al., “87. Zur Konfiguration des Vitamin-D-Metabiliten 25,26-Dihydroxycholecaciferol: Synthese von (25S,26)-und (25R,26)-Dihydroxycholecalciferol”,Helvetica Chimica Acta, vol. 64, pp. 915-938, (1981).
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XP-002102281, Derwent Publication Ltd.,
Badio Barbara P.
Browdy and Neimark
Chugai Seiyaku Kabushiki Kaisha
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