Process for preparing an antifungal azole with hydrazino and ami

Details Process for preparing an antifungal azole with hydrazino and ami Process for preparing an antifungal azole with hydrazino and ami

1997-04-09

1999-01-19

Richter, Johann

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

5482678, 5482692, C07D24908

Patent

active

058615164

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of international application PCT/GB95/01815, filed Aug. 1, 1995 which designated the U.S.
The present invention relates to a chemical process and to intermediates useful in such a process. In particular this invention relates to processes and intermediates for preparing a triazole having antifungal activity. ryl!-1H-1,2,4-triazol-1-yl!-3-(1H-1,2,4-triazol--1-yl)propan-2-ol is a very potent antifungal agent having a broad spectrum of activity. In particular this compound shows good activity against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. This compound is known in the literature by the code D0870 (more recently ZD0870) and has the structure of formula (I): ##STR1##
Representative references in the literature to the antifungal activity of D0870 include Yamada et al., Antimicrobial Agents and Chemotherapy 1993; 37(11): 2412-7; Mochizuki et al., Program and Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), New Orleans, 1993, 188 Abs. 377 and Edwards et al., Program and Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), New Orleans, 1993, 80 Abs. 143. The compound D0870 and pharmaceutically acceptable salts thereof are described and claimed in European Patent Application Publication no. 472392 and corresponding applications in other territories.
We have now discovered a new process for preparing D0870. This process is particularly suitable for operating on a large scale such as for preparing large quantities of compound for development activities and for sale. This new process avoids the problems associated with the processes disclosed in EPA 472392.
The processes disclosed in EPA 472392 comprise either the reaction of epoxide (A) with 1,2,4-triazole (B) in the presence of sodium hydride or the reaction of the alternative epoxide (C) with a substituted 1,2,4-triazole (D). These processes are depicted in Scheme I below. ##STR2##
These processes, as exemplified in EPA 472392, are satisfactory for the preparation of the compound of the formula (I) on the laboratory scale. However, they suffer from the problem of relatively poor selectivity leading to a mixture of regioisomers. These regioisomers have similar physical properties rendering isolation of the substantially pure product rather difficult, typically involving column chromatography on silica gel (see EPA 472392 Examples 16 and 19). Column chromatography is not attractive for the industrial scale preparation of the purified product. Therefore the present inventors have discovered a new, improved process which minimises the formation of regioisomers and which removes the need for column chromatography. This is of great significance in operating a practical, industrial scale process. Furthermore the novel process of the present invention provides improved yields. Again, this is of major significance for the economic production of large scale quantities of product.
Our present invention is directed to a new process for preparing D0870 from epoxide (C). In our new process the epoxide (C) is reacted with hydrazine or its equivalent to form a novel hydrazino alcohol intermediate. This novel intermediate is reacted with an iminoether to form a novel amidrazone intermediate which is then cyclised with an orthoformate to provide D0870. Our new process is depicted in Scheme II. ##STR3##
Accordingly the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof which comprises the steps of: ##STR4## with hydrazine or a chemical equivalent thereof to form a compound of the formula (II): ##STR5## ii) reacting the compound of the formula (II) with an iminoether of the formula (III) or a chemical equivalent thereof: ##STR6## wherein R.sup.1 is C.sub.1-6 alkyl or optionally substituted phenyl; to form a compound of the formula (IV): ##STR7## iii) reacting the compound of the formula (IV) with a compound of the formula (V): form a 1-6 compound of the f

REFERENCES:
Temple, Jr.: "Trizoles 1,2,4" (See IPER).
Boyle et al., "Synthesis and Structure Activity Relationships of a Novel Antifungal Agent, ICI 195,739", Annals of New York Academy of Science,1988, pp. 86-101.
Triazole Antifungal, Drugs of the Future, 1993, pp. 424-427.
Huisgen et al., "Additionen der Nitrilimine an Oxime, Azine und andere CN-Doppelbindungen", Chem. Ber., 1965, pp. 642-649.
Westermann et al., "Uber die Umsetzung des Benzloxycarbonylamino-acedtimidsaure-athylesters mit Alkyliden-und Arylhydrazinen", Chem. Ber., 1966, pp. 1111-1117.
Chemical Abstract 115:279925a (1991).

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