Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1996-08-29
1997-11-11
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
546193, 5462811, 5462814, G07D40106
Patent
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.
Chung John Y. L.
Mathre David J.
Zhao Dalian
Bond Robert T.
Merck & Co. , Inc.
Parr Richard S.
Winokur Melvin
LandOfFree
Pyridyl ethylation of lactam derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pyridyl ethylation of lactam derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyridyl ethylation of lactam derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1230419