Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-05
2000-08-15
Ford, Johm M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07J 7100
Patent
active
061038954
DESCRIPTION:
BRIEF SUMMARY
This application is a national stage entry under 35 U.S.C. .sctn. 371 of an International Application No. PCT/EP96/05390, filed Dec. 4, 1996, which claims the benefit of priority of EP application 95119626.0, filed Dec. 13, 1995.
The present invention refers to a new process for preparing the compound (11.beta.16.beta.)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4-dien o[17,16-d] oxazole-3,20-dione, also known, and hereinafter referred to, with the INN (International Nonproprietary Name) deflazacort. Deflazacort is represented by the following formula I ##STR1##
Deflazacort is employed in therapy since some years as a calcium-sparing corticoid agent.
This compound belongs to the more general class of pregneno-oxazolines, for which anti-inflammatory, glucocorticoid and hormone-like pharmacological activities are reported. Examples of compounds of the above class, comprising deflazacort, are disclosed in U.S. Pat. No. 3,413,286, where deflazacort is referred to as 11.beta.-21-dihydroxy-2'-methyl-5'.beta.H-pregna-1,4-dieno[17,16-d]oxazole -3,20-dione 21-acetate.
According to the process disclosed by U.S. Pat. No. 3,413,286, deflazacort is obtained from 5-pregnane-3.beta.-ol-11,20-dione-2'-methyloxazoline by 2,4-dibromination with Br.sub.2 -dioxane, heating the product in the presence of LiBr-LiCO.sub.3 for obtaining the 1,4-diene, and converting this latter into the 21-iodo and then into the desired 21-acetyloxy compound. By hydrolysis of deflazacort, the 11.beta.-21-dihydroxy-2'-methyl-5'.beta.H-pregna-1,4-dieno[l7,16-d-]oxazol ine-3,20-dione of formula II is obtained: ##STR2##
The compound of formula II is preferably obtained according to a fermentation process disclosed in EP-B-322630; in said patent, the compound of formula II is referred to as 11.beta.-21-dihydroxy-2'-methyl-5'.beta.H-pregna-1,4-dieno[17,16-d-]oxazol ine-3,20-dione.
The present invention provides a new advantageous single-step process for obtaining deflazacort, by acetylation of the compound of formula II.
More in detail, the process of the present invention comprises reacting the compound of formula II with acetic anhydride in a suitable organic solvent in the presence of a basic catalyst and water.
The starting material of formula II is obtained according to the procedures known in the art, for instance according to the fermentation process disclosed in the above cited EP-B-322630, here incorporated by reference. Said patent discloses a fermentation process for obtaining the compound of formula II, wherein a 2'-methyl-4-pregnen-21-ol-[17.alpha.16.alpha.-d-]oxazolinyl-3,20-dione is contacted with a sequentially growing mixed culture of a Curvularia strain and an Arthrobacter strain. More in particular, according to a preferred embodiment, the above compound is added to a growing culture of C. lunata NRRL 2380 in a suitable fermentation medium after 12-24 hours from inoculum, and, after 48-72 hours from inoculum, a growing culture of A. simplex ATCC 6946 of 18-36 hours is added to the mixture and further cultivated for 40-55 hours; the fermentation is carried out under submerged conditions, temperature is kept between 27.degree. C. and 32.degree. C. and pH between 6 and 8; the fermentation product of formula II is recovered according to procedures known in the art.
Organic solvents suitable for the process of the present invention are those which are able to at least partially solubilize the starting materials, without negatively affecting the reaction course. Examples of suitable organic solvents are halogenated (C.sub.1 -C.sub.4)hydrocarbons, (C.sub.1 -C.sub.4)alkyl esters of (C.sub.1 -C.sub.4) carboxylic acids, dimethylformamide, acetonitrile, acetone and the like. Preferred solvents are the (C.sub.1 -C.sub.4)alkyl esters of (C.sub.1 -C.sub.4) carboxylic acids, such as methyl, ethyl, propyl, iso-propyl, butyl, 2-methylpropyl or t-butyl formiate; methyl, ethyl, propyl, iso-propyl, butyl, 2-methylpropyl or t-butyl acetate; methyl, ethyl, propyl, iso-propyl, butyl, 2-methylpropyl or t-butyl propionate; methyl, ethyl, propyl, iso-pr
REFERENCES:
Ed. W. Gerhartz & Y. S. Yamamoto, Ullamann's Encyclopedia of Industrial Chemistry, vol. A1, pp. 65-66, 1985.
Cancellieri Calogero
Forte Luigi
Coleman Brenda
Ford Johm M.
Gruppo Lepetit S.p.A.
Gupta Balarm
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