Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Utility Patent
1998-04-28
2001-01-02
Badio, Barbara (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Utility Patent
active
06169178
ABSTRACT:
FIELD OF INVENTION
The present invention regards a new process for the preparation of 16,17 acetals of pregnane derivatives, in particular of budesonide [16,17-butylidenebis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione], a glucocorticoid having an anti-inflammatory activity.
Budesonide and other structurally correlated glucocorticoids were described for the first time in the patent application GB 1.429.922 and in the patents of the same family in the name of Bofors. Owing to the presence of the acetal carbon atom C-22, budesonide and its structural analogues exist in the form of epimers at the C-22 position. The epimer C-22 R, sometimes also referred to as epimer B, is for budesonide, and more in general for its structural analogues, the more active from a pharmacological standpoint.
The present invention regards, in particular, a process for the preparation of budesonide and of 16,17 acetals of pregnane derivatives structurally correlated thereto, comprising treating with aldehydes 16,17-diols, or of 16,17-ketals or cyclic acetals, in the presence of aqueous hydrobromic acid or hydriodic acid, used as reaction catalysts and solvents.
Unexpectedly, when operating in aqueous HBr or HI, it is possible to control as desired the epimeric ratio at the C-22 position, obtaining high yields both of R epimer-enriched mixtures and of mixtures containing the epimers R and S in approximately equal amounts.
TECHNICAL PROBLEM
From the standpoint of the pharmacological activity, it is undoubtedly important to have available processes for the preparation of budesonide and of the glucocorticoids with anti-inflammatory activity structurally correlated thereto, that prevalently lead to the production of the R epimer, which is pharmacologically the more active.
However, from a practical point of view, it is useful to have available processes of synthesis that allow to control the epimeric ratio as desired, so as to be able synthesize, even mixtures with R/S epimeric ratios of between 60/40 and 50/50 in high yields and using industrial methods. In the case of budesonide, in fact, these mixtures are of considerable interest from the commercial standpoint, in so far as they are the ones for which, in various countries, health registration has been obtained and is still valid.
PRIOR ART
The patent application GB 1,429,922 describes the synthesis of budesonide and its structural analogues by treatment of the corresponding 16&agr;,17&agr; diols of 11&bgr;,21-dihydroxy-pregna-1,4-diene-3,20-diones with aldehydes, in dioxane, in the presence of perchloric acid. This method yields mixtures of epimers at the C-22 position, the separation of which is difficult and may be obtained only using far from practical techniques from the industrial standpoint, such as the molecular-exclusion chromatography described in U.S. Pat. No. 3,928,326.
The ketalization in dioxane and perchloric acid does not allow the ratio between the R and S epimers to be controlled, this ratio varying very little even if the reaction temperature is changed, and moreover depending upon the substrate used. In fact, as illustrated by the comparative data of the applicant given later in the present text, in order to obtain mixtures of 22R and 22S epimers in approximately equal quantities, it is necessary the presence on the pregnane nucleus of a free hydroxyl group both in the position 11&bgr; and in the position 21. In the absence of just one of these free hydroxyl groups, mixtures of epimeric acetals are obtained in which the diastereoisomer S, which is less active pharmacologically, prevails.
WO 91/04984 describes the preparation of budesonide as a mixture of 22R epimers: 22S epimers in the ratio of approximately 1:1 by treatment of 16-&agr;-hydroxy-prednisolone with butyraldehyde, in acetonitrile, in the presence of para-toluenesulphonic acid.
EP-A-164636 describes the preparation of budesonide and of structurally correlated 16,17 pregnane acetals in the form of mixtures in which the R epimer prevails, by transketalization with butyraldehyde in aqueous HF of the corresponding 16-&agr;,17-&agr; acetonides (or 16,17-diols) of 16-&agr;-hydroxyprednisolone.
The use of HF, which is notably corrosive, presents the drawback of requiring special equipment, with the consequent increase in industrial costs of production, and moreover is not suitable for obtaining mixtures of 22R and 22S epimers in approximately equal quantities, in so far as it does not enable to obtain at the same time the complete conversion into the desired acetals, stopping at the desired R/S epimeric ratio. In fact, as shown by Examples 1 and 3 of EP-A-164.636, when operating in aqueous HF, it is possible to obtain the 22R and 22S epimers in approximately equal quantities only at extremely low temperatures (of about −78° C.), which it is practically impossible to be obtained in industrial systems. Furthermore, at such temperatures, even after prolonged reaction times, high quantities (approximately 40%) of non-reacted starting product are found. The conversion of unreacted 16,17-acetonide in the desired acetal calls for the use of higher temperatures (approximately of from −10° C. to 0° C.), at which temperatures, however, mixtures are isolated that are markedly enriched in R epimer (approximately 90%), without it being possible to obtain 22R/22S mixtures in ratios of from 60/40 to 50/50. Similar problems are encountered when operating in aqueous HCl, where in addition the reaction product is obtained in a less pure form.
EP-A-262,108 describes a method for controlling the epimeric distribution of 11&bgr;-OH 16,17-acetals of pregnane derivatives by reacting the corresponding 16,17-diols or 16,17-acetonides with carbonyl compounds in the presence of acid catalysts, preferably perchloric acid, in hydrocarbon or halogenated hydrocarbon solvent, such as chloroform or methylene chloride (somewhat toxic solvents, the use of which is preferably to be avoided or at least limited), possibly in the presence of dimethyl formamide or dimethyl sulphoxide as regulators of the epimeric distribution (these latter solvents are difficult to be removed from the end product owing to their high boiling point).
EP-A-262,108 moreover describes a method for obtaining prevalently the 22R epimer by treatment of 16,17-diols or acetonides with aldehydes in a hydrocarbon solvent in the presence of perchloric acid and of high quantities (about 20 times by weight with respect to the organic substrate) of granular material (e.g., sand or ceramic material) in finely subdivided form.
In any case, the formation of acetals according to EP-A-262,108 is always conducted in organic solvent.
The methods for the preparation of budesonide and of its structural analogues above recalled are based on the acetalization of 16,17-diols or transketalization of having a free hydroxyl group at the 11&bgr; position.
EP-A-508,900 describes the preparation of budesonide by transketalization with butyraldehyde of of 11&bgr;-formyloxy or 9-halo-11&bgr;-formyloxy derivative of 21-acetoxy-16-&agr;,17-&agr;-dihydroxy-pregna-1,4-diene-3,20-dione, 16,17-acetonides in halogenated solvent, in the presence of perchloric acid, followed by alkaline solvolysis of the formyl group. The R epimer is prevalently obtained.
GB 1,469,575 describes the preparation of acetals or ketals of 16,17 dihydroxy pregnane derivatives by treatment with aldehydes or ketones of the corresponding 9&bgr;-11&bgr;-epoxides in aqueous hydrogen halides, in particular aqueous HF or HCl, to yield the corresponding 9-halo,11-hydroxy 16,17 acetals. This document does not provide any teaching regarding the epimeric control at the C-22 position of budesonide or of acetals structurally correlated thereto.
There is therefore felt the need to find new processes enabling a control of the ratio between the 22R and 22S epimers of budesonide and its structural analogues, so overcoming the drawbacks of the known methods.
SUMMARY
Now the applicant has surprisingly found that it is possible to control as desired the ratio between the 22R and 22S epimers of b
La Loggia Filippo
Petacchi Paolo
Badio Barbara
Farmabios S.r.l.
Hedman, Gibson & Costigan, P.C.
LandOfFree
Process for the preparation of 16,17 acetals of pregnane... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of 16,17 acetals of pregnane..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of 16,17 acetals of pregnane... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2502833