Organic compounds -- part of the class 532-570 series – Organic compounds – 9,10-seco-cyclopentanohydrophenanthrene ring system or...
Patent
1995-04-17
1998-03-10
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
9,10-seco-cyclopentanohydrophenanthrene ring system or...
C07C40100
Patent
active
057263302
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a process for producing 22-oxavitamin D derivatives that have the potential for use as pharmaceuticals. The invention also relates to highly crystalline 22-oxavitamin D derivatives produced by that process.
BACKGROUND OF THE INVENTION
Heretofore, 22-oxavitamin D derivatives have been produced by several methods, one of which is described in Japanese Laid-open Patent Publication No. 61-267550. However, the 22-oxavitamin D derivatives produced by the conventional methods have the disadvantage that their crystallinity is low enough to cause variations in purity. This defect is inherent in 22-oxavitamin D derivatives and absent from the manufacture of ordinary vitamin D derivatives.
SUMMARY OF THE INVENTION
An object, therefore, of the invention is to provide novel vitamin D derivatives having high crystallinity.
Another object of the invention is to provide a process that overcomes the aforementioned drawback of the prior art to enable the production of highly pure 22-oxavitamin D derivatives.
The present inventors conducted intensive studies with a view to attaining these objects and found that 22-oxavitamin D derivatives having the hydroxy group in 1- and 3-positions protected with an acyl group had high crystallinity and that 22-oxavitamin D.sub.3 derivatives produced by hydrolyzing those compounds had a very high purity.
Thus, in its first aspect, the present invention relates to novel 22-oxavitamin D derivatives represented by the general formula (I): ##STR2## where R.sub.1 is a straight or branched C.sub.4 -C.sub.9 alkyl group optionally having a hydroxyl group; R.sub.2 and R.sub.3 which may be the same or different are each an acyl group.
In its second aspect, the invention relates to a process in which the compounds defined above are hydrolyzed to produce 22-oxavitamin D.sub.3 derivatives represented by the general formula (II): ##STR3## where R.sub.1 is a straight or branched C.sub.4 -C.sub.9 alkyl group optionally having a hydroxyl group.
The compounds represented by the general formula (I) include but are not limited to: na-5,7,10(19)-triene; regna-5,7,10(19)-triene; gna-5,7,10(19)-triene; and gna-5,7,10(19)-triene.
The invention embraces the crystals of these compounds. The crystals may be separated by conventional procedures such as column chromatography and high-performance liquid chromatography, followed by recrystallization from appropriate solvents such as n-hexane. Thus, the invention provides 1.alpha.,3.beta.-diacetyloxy-20S-(3-hydroxy-3-methylbutyloxy)-9,10-secopre gna-5,7,10(19)-triene in the form of a crystal of X-ray diffraction compatible quality.
The compounds of the invention can be produced by acylating, in the usual manner, the hydroxyl group in the 1- and 3-positions of 22-oxavitamin D derivatives that are prepared typically by the method described in Japanese Laid-open Patent Publication No. 61-267550, supra.
The compounds of the invention can also be produced by acylating, in the usual manner, the 1- and 3-positions of 22-oxaprovitamin D derivatives described in the above Patent Publication, followed by irradiating the acylated derivatives with light and subjecting the thus obtained compounds to thermal isomerization reaction.
Acylation in these reaction can be performed in the usual manner by reaction with acid anhydrides or acid halides in basic solvents. Preferred basic solvents include pyridine, collidine, triethylamine, etc. Exemplary reactant acid anhydrides include acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, etc. Exemplary reactant acid halides include acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, etc.
Hydrolysis for producing the compounds of the general formula (II) is performed in solvents under basic conditions using alkali metal hydroxides. Any inert solvents may be used and preferred examples are alcoholic solvents such as methanol and ethanol. Exemplary alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, etc; thes
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A. Brown et al, Kidney International (Supplement 29), vol. 38, 1990, pp. S-22-S-27.
N. Kubodera et al, Chemical and Pharmaceutical Bulletin, vol. 40, No. 6, Jun. 1992, pp. 1494-1499.
Morrison & Boyd, Organic Chemistry, 4th ed. (1983), pp. 830-836.
Greene, Protective Groups in Organic Synthesis 2nd ed., 1991, pp. 10-14, 77-83 & 88-92.
Chugai Seiyaku Kabushiki Kaisha
Raymond Richard L.
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