Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-08-29
1997-09-09
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540531, 546194, 5462784, C07D21176, C07D22310, C07D40106
Patent
active
056658826
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/US94/12671 filed on Nov. 7, 1994.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,281,585, describes fibrinogen receptor antagonists. According to the procedure described in U.S. Pat. No. 5,281,585, the compound: ##STR2## is prepared according to a 17-step procedure which requires the use of expensive reagents and numerous chromatography steps, and gives a <3% overall yield (see columns 63 to 67).
The preparation described in U.S. Pat. No. 5,281,585 involves use of 4-piperidineethanol as a starting material, and a nine step procedure leading to the intermediate ##STR3## which is thereafter modified to produce various fibrinogen receptor antagonists.
According to the present invention, an important new class of compounds, ##STR4## useful as intermediates for preparing numerous fibrinogen receptor antagonists described in U.S. Pat. No. 5,281,585 is prepared according to a two step process using commercially available starting materials.
SUMMARY OF THE INVENTION
The invention includes new compounds having the formula: ##STR5## wherein
R is C.sub.1-4 alkyl or benzyl; and
R.sup.1, when present, is C.sub.1-4 alkyl, OH, O--C.sub.1-4 alkyl, or S--C.sub.1-4 alkyl; ##STR6## to form ##STR7## b) dissolving the substituted lactam ##STR8## in a non-aqueous solvent solution comprising a non-aqueous solvent and a tertiary amine base, ##STR9##
When R.sup.1 is not present, the lactam identified in i is ##STR10##
Preferably, the solution of (b) is cooled to about 0.degree. C. and stirred for about 1-2 hours prior to addition of the silyl derivative. Also, if the silyl derivative of step c) is not an iodo silyl derivative (e.g. chlorotriethylsilane), the non-aqueous solvent system of step b) further comprises sodium iodide.
DETAILED DESCRIPTION OF THE INVENTION
The new intermediate compounds are prepared according to a process which uses a rapid, simple, and selective silyl-mediated conjugate addition of 4-vinylpyridine to a lactam.
According to the process, a lactam having the structure ##STR11## wherein
R.sup.1, when present, is C.sub.1-4 alkyl, OH, O--C.sub.1-4 alkyl, or S--C.sub.1-4 alkyl; ##STR12## wherein
R is C.sub.1-4 alkyl or benzyl. ##STR13## to form ##STR14##
To effect conjugation, the ester ii is dissolved in a non-aqueous solvent solution, which includes a non-aqueous solvent and a tertiary amine base, and cooled to about (-10).degree. C. to about (+10).degree. C. (e.g. about 0.degree. C.). A silyl derivative is added, at a temperature between about the cooled temperature and about 20.degree. C., and the mixture is stirred for 1-2 hours.
If the silyl derivative is not an iodo silyl derivative (e.g. chlorotriethylsilane), the non-aqueous solvent system further comprises sodium iodide. Inclusion of sodium iodide in the non-aqueous solvent system provides in situ formation of an iodo silyl derivative.
4-vinylpyridine is then added to the resulting mixture at about (-5).degree. C. to about 0.degree. C. for about 1-2 hours. ##STR15##
Suitable lactams useful as starting materials for the process of the present invention include 5-, 6-, and 7-membered lactams, including 2-pyrrolidinone, 2-piperidone, 2-oxohexamethyleneimine (caprolactam), all commercially available from Aldrich Chemical Co., Inc., (Milwaukee, Wis.) and substituted 2-pyrrolidinone, 2-piperidone, 2-oxohexamethyleneimine (e.g. substituted with OH, C.sub.1-3 alkyl, or benzyl).
The suitable non-aqueous solvent solution comprises a non-aqueous solvent and a tertiary amine base. If the silyl derivative used for silyl-mediated conjugation of 4-vinylpyridine to ii is not an iodo silyl derivative, the non-aqueous solvent system further comprises sodium iodide.
Suitable non-aqueous solvents include, but are not limited to, acetonitrile, dochloromethane, toluene, diethyl ether, dipropyl ether, and t-butylmethyl ether.
Suitable tertiary amine bases include, but are not limited to, triethylamine, trimethylamine, ethyldimethylamine, and cyclic amines such as N-methyl piperidine and N-methylmorpholine.
Suitable sily
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Chung John Y. L.
Hughes David L.
McNamara James M.
Zhao Dalian
Huang Evelyn
Ivy C. Warren
Merck & Co. , Inc.
Parr Richard S.
Winokur Melvin
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