Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-20
2002-07-09
Coleman, Brenda (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06417350
ABSTRACT:
The present invention refers to a new process for preparing the compound of formula I
i.e. (11&bgr;,16&bgr;)-21-(3-carboxy-1-oxopropoxy)-11-hydroxy-2′-methyl-5′H-pregna-1,4-dieno(17,16-d)oxazole-3,20-dione.
The above compound is a water soluble ester of deflazacort (INN—International Nonproprietary Name), wherein the acetate moiety on the C-21 of deflazacort is substituted by an hemisuccinate moiety.
Deflazacort is a compound employed in therapy since some years as a calcium-sparing corticoid agent.
These compounds belong 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.
EP-B-322630 discloses a fermentation process for preparing the (11&bgr;,16&bgr;)-11,21-dihydroxy-2′-metyl-5′H-pregna-1,4-dieno(17,16-d)oxazole-3,20-dione, which corresponds to the compound of formula I bearing a hydroxy group in place of the hemisuccinate moiety at the position 21. This compound is referred to in the above patent as 11&bgr;-21-dihydroxy-2′methyl-5′&bgr;H-pregna-1,4-dieno(17,16-d)oxazoline-3,20-dione and can be represented by the following formula II:
U.S. Pat. No. 4,440,764 discloses the compound of formula I, with the name 11&bgr;-21-dihydroxy-2′-methyl-5′&bgr;H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione 21-hemisuccinate, and a process for its preparation, which comprises reacting the compound of formula II with a molar excess of succinic anhydride (from 0.1 to 5 times) in an organic solvent and in the presence of a basic catalyst.
Among the cited organic solvents are halogenated lower aliphatic hydrocarbons, acetone, ethyl acetate, dimethylformamide and acetonitrile; as the basic catalyst, 4-(N,N-diethylamino)pyridine is specifically mentioned; alternatively, organic solvents may be employed which act both as reaction solvents and basic catalysts, such as pyridine, collidine, picoline and mixtures thereof. The product can be recovered by washing the reaction mixture with an acidic solution and then crystallizing the end product from a suitable solvent.
In particular, methylene chloride can be employed as the organic solvent and 4-(N,N-diethylamino)pyridine as the catalyst; after the reaction is completed, the reaction mixture is then washed with aqueous 1 HCl and water and then diluted with toluene. The reaction solvent is distilled off and the product crystallizes in toluene upon cooling.
It has now been found that, by using a (C
1
-C
4
) alkyl ester of a (C
1
-C
4
) carboxylic acid as the reaction solvent, the same reaction solvent can surprisingly be used also for the crystallization of the end-product. The main advantages are a simplification of the preparation procedure and higher yields with respect to the prior art. Furthermore, these solvents, particularly ethyl acetate, are solvents widely accepted in industrial preparations, for what concerns the security, industrial hygiene and environment protection.
Although all of the other solvents known in the art are good reaction solvents, allowing the quantitative conversion of the compound of formula II into the compound of formula I, none of them is suitable also for crystallizing the final product. For instance, the compound of formula I is too soluble in halogenated lower aliphatic hydrocarbons (such as methylene chloride) and thus may not be crystallized from those solvents. Likewise, direct crystallization from solvents like dimethylformamide or acetonitrile is not possible, due to the high solubility of the above compound in these solvents. On the other side, the direct crystallization from acetone gives very poor yields, while a considerable amount of impurities co-crystallize with the desired product.
Thus, the process of the invention comprises reacting the compound of formula II with succinic anhydride in a (C
1
-C
4
)alkyl ester of a (C
1
-C
4
) carboxylic acid in the presence of a basic catalyst.
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&agr;, 16&agr;-d-]oxazolinyl-3,20-dione is contacted with a sequentially growing mixed culture of a Curvularia strain and an Arthrobacter strain.
REFERENCES:
patent: 4440764 (1984-04-01), Nathansohn et al.
Cancellieri Calogero
Forte Luigi
Aventis Bulk S.p.A.
Coleman Brenda
Knight Julie Anne
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