Pyridyl ethylation of lactam derivatives

Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...

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546193, 5462811, 5462814, G07D40106

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active

056866070

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/US94/10515, filed 16 Sep., 1994, which claims priority of U.S. Ser. No. 08/212,448 filed 14 Mar., 1994, now abandoned.


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 compounds of the formula ##STR4## wherein R is C.sub.1-4 alkyl or benzyl; and S--C.sub.1-4 alkyl; receptor antagonists described in U.S. Pat. No. 5,281,585, are prepared according to a three step process using commercially available starting materials.


SUMMARY OF THE INVENTION

The invention includes a process for preparing compounds having the formula ##STR5## wherein R is C.sub.1-4 alkyl or benzyl; and S--C.sub.1-4 alkyl;
a) dissolving a compound having the formula ##STR6## 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; and ##STR7##
b) decarboxylating the compound ##STR8## to form ##STR9##
c) alkylating iii to form ##STR10## wherein R is C.sub.1-4 alkyl or benzyl.
When R.sup.1 is not present, the compound identified in i is ##STR11##


DETAILED DESCRIPTION OF THE INVENTION

The invention includes a process for preparing compounds having the formula ##STR12## wherein R is C.sub.1-4 alkyl or benzyl; and S--C.sub.1-4 alkyl;
a) dissolving a compound having the formula ##STR13## wherein R.sup.8 is C.sub.1-4 alkyl, in an anhydrous alcohol solution comprising 4-vinylpyridine to form ##STR14##
b) decarboxylating the compound ##STR15## to form ##STR16##
c) alkylating iii to form ##STR17##
In one embodiment of the process, compound ii is decarboxylated in the presence of aqueous sodium hydroxide.
In another embodiment, compound iii is alkylated in the presence of a strong base, e.g. n-butyllithium.
In another embodiment, the process involves preparing a compound having the formula ##STR18## which comprises
a) dissolving a compound having the formula ##STR19## in an anhydrous alcohol solution comprising 4-vinylpyridine to form ##STR20##
b) decarboxylating the compound ##STR21## to form ##STR22##
c) alkylating iii to form ##STR23##
The process provides an efficient and chromatography-free means for introducing the piperidinyl or pyridinyl portion of compounds described in U.S. Pat. No. 5,281,585 to the lactam portion of those compounds.
Suitable starting materials ##STR24## include 3-carbethoxy-2-piperidone, commercially available from Aldrich Chemical Co., Inc., (Milwaukee, Wis.), and 3-carbethoxy-2-lactam derivatives prepared from 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 from substituted 2-pyrrolidinone, 2-piperidone, 2-oxohexamethyleneimine (e.g. substituted with OH, C.sub.1-3 alkyl, or benzyl).
iv may be saponified to form ##STR25## and then used to form any of a number of compounds which are useful for inhibiting the binding of fibrinogen to blood platelets. Such compounds, described in U.S. Pat. No. 5,281,585, have the general formula ##STR26## wherein X is ##STR27## R.sup.3 is hydrogen, groups selected from fluoro, chloro, bromo, iodo, hydroxyl, C.sub.1-5 alkylcarbonyl(C.sub.0-8 alkyl)amino, arylC.sub.1-5 alkylcarbonyl(C.sub.0-8 alkyl)amino, aryloxy, C.sub.1-10 alkoxy, C.sub.1-5 alkoxycarbonyl, C.sub.0-5 alkylaminocarbonyl, C.sub.1-5 alkylcarbonyloxy, C.sub.3-8 cycloalkyl, aryl, oxo, amino, C.sub.1-6 alkyl, C.sub.1-3 alkylamino, aminoC.sub.1-3 alkyl, arylC.sub.0-5 alkylaminocarbonyl, phenylC.sub.1-3 alkylamino

REFERENCES:
patent: 5281585 (1994-01-01), Duggan et al.
E.E. Mikhlina and M.V. Rubstov, Zh. Obshchei Khim., 1962, 32, 2177-84 (CA(58) 90246.
Shapiro et al., J. Org. Chem., 1962, 27, 174-8.
Leonard et al., J. Med. Chem., 1966, 9, 140.

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