Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-29
2001-01-23
Dees, Jose′ G. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S114000, C540S119000, C540S116000
Reexamination Certificate
active
06177560
ABSTRACT:
Mometasone furoate is a well known (Shapiro and Grove, U.S. Pat. No. 4,472,393 and Kwok, Tsi, Tan and Fu; WO98/00437) and potent anti-inflammatory steroid having the structure:
U.S. Pat. No. 4,472,393 describes two processes for the production of mometasone furoate. In Example 12, Method I uses 9&bgr;,11&bgr;-epoxy-17&agr;,21-dihydroxy-16&agr;-methyl-1,4-pregnadien-3,20-dione as a starting material, whereas Method II uses 21-chloro-17&agr;-hydroxy-16&agr;-methyl-1,4,9(11)-pregnatriene-3,20-dione. WO98/00437 describes an improved process from 9&bgr;,11&bgr;-epoxy-17&agr;,21-dihydroxy-16&agr;-methyl-1,4-pregnadien-3,20-dione.
The present invention refers to a new process for the preparation of mometasone furoate carried out by esterifiication of the 17 hydroxy group of mometasone without prior protection of the 11 hydroxy group.
A great number of clinically useful steroids in which the 17 hydroxy group is esterified and in which the 11 hydroxy group exists in the free form are well known as clinically useful corticosteroids. Typically, the 17 ester function is introduced whilst no other hydroxyl group is present in the molecule, other free hydroxl groups being formed or unmasked later in the synthesis. When other hydroxyl groups, such as an 11 hydroxy function, are present indirect methods are used. It is possible to introduce the 17 ester group by hydrolysis of the 17,21-orthoesters or by carrying out the esterification after protection of the other hydroxyl groups in the molecule. For example, protecting a 11-hydroxy function as a trihaloacetate ester, as a trialkylsilyl ether or masked as a 9,11 epoxide have all been used to accomplish this.
Surprisingly it has been discovered in the present process that the 17 hydroxy group may be esterified without recourse to protection of the 11 hydroxy group or a masked 11 hydroxy group. In the prior art the introduction of the 17 furoate function has always been carried out with a 9,11 epoxide function present in the molecule which is later converted to the desired 9&agr;-chloro,11&bgr;-hydroxy derivative. Mometasone itself can be prepared by different methods as described in the prior art.
It has now been surprisingly found that when mometasone is reacted with 2-furoyl chloride in the presence of a tertiary amine in an inert solvent, mometasone 17-(2-furoate) is obtained in good yield. The 2-furoyl chloride should be used in excess, between 2.5 and 4 mole equivalents being preferred but quantities without this range are also acceptable. There is no limitations concerning the nature of the tertiary amine, whose function is to activate the 2-furoyl chloride and to neutralise the hydrochloric acid liberated during the reaction, although triethylamine is preferred. The tertiary base is used in an excess of 3 to 6 molar equivalents but more or less than these quantities can be used. The solvent is preferably a non polar, water inmiscible solvent and should be such that all the components of the reaction mixture, especially any activated form of the acylating agent, are maintained in solution during the reaction. Dichloromethane has been found to be a suitable solvent although others which meet the above criteria can be used. The reaction is carried out at low to moderate temperatures, typically 0 to 25° C., during several hours, although higher or lower temperatures can be used which may either shorten or extend the reaction time accordingly. When the reaction is carried out in dichloromethane at 10° C. and using triethylamine the reaction is typically complete within 10 to 15 hours.
During the reaction side products, such as the enol furoates at positions 3 and 20, may be formed. This is in no way detrimental to either the yield or the purity of the final product as these compounds are easily converted to mometasone furoate by a short treatment with dilute aqueous hydrochloric acid. Typically, after esterification is complete the reaction solution is treated with aqueous hydrochloric acid during several hours, after removal of excess base by a brief acid wash, to convert these side products to the desired mometasone furoate. This treatment can be carried out in a two phases system at a temperature of 10 to 25° C. although other temperatures may be used. In order to reduce reaction times intimate mixing and the use of a large volume of aqueous hydrochloric acid is preferred to ensure that a large surface area of the two phases are in contact. Alternatively, an organic solvent which is both miscible with water and the solvent of the reaction can be added to increase the concentration of the hydrochloric acid in the organic phase. For example, either ethanol or acetic acid can be used in the proportion 0.5 to 2 volumes for this purpose, in which case the reaction time at 25° C. is typically 3 to 5 hours.
The mometasone furoate can be isolated by standard procedures. Aqueous washes serve to remove water soluble materials, thereafter the dichloromethane is replaced by a lower molecular weight alcohol, such as methanol or ethanol, from which the product crystallises in a pure form and high yield. Further recrystallisations can be carried out from a number of solvents adequate for the purification of pharmaceutical products, such as acetone, methanol and ethanol.
REFERENCES:
patent: 4472393 (1984-09-01), Shapiro
patent: 5886200 (1999-03-01), Kwok et al.
patent: 9800437 (1998-01-01), None
Draper et al. (Ca 130:325286, abstract of Tetrahederon (1999), 55(11), 3355-3364, 1999.
Bandarra Joao
Heggie William
Dees Jose′ G.
Hovione Inter Ltd.
Ostrolenk Faber Gerb & Soffen, LLP
Qazi Sabiha
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