Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-05-15
1992-05-12
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D21372
Patent
active
051129760
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. FIELD OF THE INVENTION
This invention relates to the preparation of 3-alkyl- or fluroalkyl-3-(4-pyridyl) piperidine-2, 6-diones of formula (1): ##STR2## wherein R represents an alkyl group having 2 to 10 carbon atoms or a fluoroalkyl group having 2 to 5 carbon atoms, and A represents hydrogen or an alkyl group having 1 to 4 carbon atoms, many of which are known compounds, useful in anti-cancer therapy, specifically the treatment of oestrogen-dependent breast tumours.
2. DESCRIPTION OF THE PRIOR ART
The compound of formula (1) wherein R is ethyl and X is hydrogen is 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione, conveniently called "pyridogluthethimide" for short, and is the subject of UK Pat. No. 2151226 B (NRDC). The same patent also covers derivatives thereof wherin A is alkyl of 1 to 4 carbon atoms. Analogues of pyridogluthethimide in which R is an alkyl group having 3 to 10 carbon atoms or a fluoroalkyl group having 2 to 5 carbon atoms are the subject of UK Pat. No. 2162177 B (NRDC).
In UK Pat. No. 2151226 B pyridoglutethimide is prepared by a 3-step process illustrated by Scheme 1 below: ##STR3## This method of preparation suffers from the disadvantage that the starting 4-pyridylacetonitrile is readily dialkylated, leading to a poor yield requiring a separation step.
In the final stage of Scheme 1, the reaction can be visualised as proceeding by a mechanism in which the cyano groups are hydrolysed to amido groups and then cyclised to single amido group with elimination of a molecule of ammonia. UK Pat. No. 2151226 B generalises on this reaction scheme as involving the cyclisation of a compound of formula (2): ##STR4## wherein at least one of Y and Z is cyano or amido and the other, if not also cyano or amido, can be a carboxylic acid group or a non-amide derivative thereof such as an ester. The preparation of compounds of formula (2) in which Y and Z are other than cyano is not described.
UK Pat. No. 2162177 B describes an improved method of carrying out the first step of Scheme 1, in which 4-pyridylacetronitrile is reacted with a primary alcohol, a trivalent rhodium salt and triphenylphosphine under mildly alkaline conditions. This gives the monoalkylated product, substantially free of dialkylated by-product. Other compounds were made using an alkyl bromide or fluoroalkyl iodide and caesium carbonate in the first step of Scheme 1. However, rhodium and caesium salts are relatively expensive reagents.
SUMMARY OF THE INVENTION
It has been found that pyridoglutethimide and its analogues can be prepared in good yield without the use of expensive inorganic salts or other esoteric reagents. In the process of the invention, it has been found possible to avoid production of a dialkylated intermediate and to carry out the whole process in only two reaction steps, which, under preferred conditions, can be carried out sequentially in the same reaction vessel.
The present invention provides a process for the preparation of 3-alkyl- or fluoroalkyl-3-(4-pyridyl)piperidine-2,6-diones of formula (1): ##STR5## wherein R represents an alkyl group having 2 to 10 carbon atoms or a fluoroalkyl group having 2 to 5 carbon atoms and A represents hydrogen or an alkyl group having 1 to 4 carbon atoms, said process comprising alkylating a 4-pyridylacetic acid alkyl ester, optionally substituted at the 2-position of the pyridine ring by an alkyl group having 1 to 4 carbon atoms, with an alkyl or fluoroalkyl halide of formula RX, X being iodo, bromo or chloro, in the presence of a sterically bulky base of a sodium, potassium or ammonium cation and reacting the product of said alkylation reaction, with acrylamide in the presence of a sodium or potassium branched chain alkoxide, until cyclisation occurs.
What is novel and inventive herein comprises: predominantly ionic, type of base in the alkylation reaction, so that excessive dialkylation is avoided, acrylonitrile and reaction with acrylamide. (This criticality is explained in more detail below.).
DESCRIPTION OF PREFERRED EMBODIMENTS
The process
REFERENCES:
patent: 2673205 (1954-03-01), Hoffmann et al.
patent: 2848455 (1958-08-01), Hoffmann et al.
Tet. Letts. (1985) 26 (10) 1311-1314 R. J. P. Corriu et al.
"Reagents for Organic Synthesis" vol. 1 (1967) L. F. Feiser et al. pp. 915-916 John Wiley & Sons. Inc. (New York, U.S.).
Journal of the Chemical Society. Perkin Transactions I (1981) pp. 2476-2482 M. P. Sammes et al.
Clissold Derek W.
Mann John
Thickitt Christopher P.
Ivy C. Warren
National Research Development Corporation
Scalzo Catherine
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