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US 5,310,917 AGranted
Process for the preparation of 4-substituted-1,4-dihydropydrines
AssigneeMerck & Co., Inc.
InventorJoseph Auerbach
Life of this patent
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Abstract
4-Substituted-1,4-dihydropyridines are prepared by a cycloaddition reaction in which the cyclization is driven to completion, after thermal reaction, by addition of an acid. Felodipine, a vasodilator, is prepared by a cycloaddition reaction of ethyl 3-aminocrotonate with a suitably substituted dichlorobenzylidine under reaction conditions whereby the product crystallizes out of the reaction solution and may be directly isolated by filtration.
Claims24
A process for the preparation of a compound having the formula I:
- ##STR21## wherein Ar is selected from:
- ##STR22## R.sup.a is selected from:
- ##STR23## R.sup.1 and R.sup.2 are independently selected from:
- a) C.sub.1 -C.sub.8 -alkyl,
- b) C.sub.3 -C.sub.8 -cycloalkyl,
- c) C.sub.2 -C.sub.5 -alkenyl,
- d) C.sub.1 -C.sub.4 -aralkyl,
- e) C.sub.2 -C.sub.4 -aralkenyl
- f) -C.sub.1 -C.sub.5 -alkylNR.sup.8 R.sup.9,
- g) -C.sub.1 -C.sub.4 -alkyl-O-C.sub.1 -C.sub.4 -alkyl,
- h) -C.sub.1 -C.sub.4 -alkylONO.sub.2, ##STR24## wherein C.sub.1 -C.sub.4 aralkyl is selected from C.sub.1 -C.sub.4 -alkyl substituted one to two times with a group selected from phenyl and naphthyl;
- wherein C.sub.2 -C.sub.4 aralkenyl is selected from C.sub.2 -C.sub.4 -alkenyl substituted one to two times with a group selected from phenyl and naphthyl;
- R.sup.3 is selected from:
- a) C.sub.1 -C.sub.8 -alkyl,
- b) C.sub.3 -C.sub.8 -cycloalkyl,
- c) (CH.sub.2).sub.n --R.sup.12, and
- d) hydrogen;
- R.sup.4 is selected from:
- a) C.sub.1 -C.sub.8 -alkyl,
- b) C.sub.3 -C.sub.8 -cycloalkyl,
- c) (CH.sub.2).sub.n --R.sup.12, and
- d) hydrogen;
- R.sup.5, R.sup.6, and R.sup.7 are independently selected from:
- a) hydrogen,
- b) halogen,
- c) NO.sub.2, ##STR25## e) CF.sub.3, f) C.sub.1 -C.sub.8 -alkyl,
- g) C.sub.3 -C.sub.8 -cycloalkyl,
- h) ethynyl,
- i) --(CH.sub.2).sub.n --R.sup.12, ##STR26## k) --O--(CH.sub.2).sub.n --NH--CH.sub.2 --CH(OH)CH.sub.2 --O(C.sub.6 H.sub.5);
- R.sup.8 and R.sup.9 are independently selected from:
- a) C.sub.1 -C.sub.8 -alkyl,
- b) C.sub.3 -C.sub.8 -cycloalkyl,
- c) aralkyl as defined herein above, and
- d) hydrogen;
- R.sup.10 is selected from:
- a) hydrogen,
- b) C.sub.1 -C.sub.8 -alkyl,
- c) C.sub.3 -C.sub.8 -cycloalkyl, and
- d) C.sub.1 -C.sub.4 -aralkyl;
- R.sup.11 is selected from:
- a) hydrogen,
- b) C.sub.1 -C.sub.4 -aralkyl,
- c) dichlorophenyl, and
- d) C.sub.1 -C.sub.8 alkyl, and
- e) C.sub.3 -C.sub.8 -cycloalkyl;
- R.sup.12 is selected from:
- a) halogen,
- b) NR.sup.8 R.sup.9,
- c) NHC(O)-C.sub.1 -C.sub.8 -alkyl,
- d) SR.sup.8,
- e) SO.sub.2 -pyridyl,
- f) OR.sup.8, and
- g) CO.sub.2 R.sup.8 ;
- R.sup.15 is selected from:
- a) --NR.sup.8 R.sup.9, and
- b) -1-piperidinyl;
- X is O, S, or NR.sup.8 ;
- m is 0 to 2;
- and
- n is 0 to 3;
- comprising the step of:
- a) heating a mixture of a compound of the formula:
- ##STR27## wherein Ar, R.sup.2, and R.sup.3 are as defined hereinabove and a compound of the formula III:
- ##STR28## ` wherein R.sup.a and R.sup.4 are as defined hereinabove, in a solvent at an elevated temperature and for a length of time sufficiently long to consume the maximum amount of the starting materials but sufficiently short to allow only a minimum amount of the starting materials, intermediates or product to decompose
- with a strong acid, wherein the strong acid is added subsequent to heating to the elevated temperature;
- to form the compound of the formula I.
63 more elements
Dependencies are inferred from the claim text.