Dexniguldipine hydrochloride, (R)-Niguldipine hydrochloride

Dexniguldipine hydrochloride, (R)-Niguldipine hydrochloride

BY-935, B8509-035, B-844-39(racemate), B-859-34 [(-)-(S)-isomer], B-859-35

(R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5-[3-(4,4-diphenyl-1-piperidinyl)propyl] diester hydrochloride

113145-70-3, 113165-32-5 ((-)-enantiomer, free base), 120054-86-6 (free base), 102993-22-6 (undefined isomer, free base)

CAS No.	189624-85-9
Chemical Name:	(R)-(-)-NIGULDIPINE HYDROCHLORIDE
Synonyms:	By 935;B859-35;(S)-Ae0047;Dexniguldipine hydrochloride;(R)-Nigaldipine hydrochloride; (-)-Nigaldipine hydrochloride;(R)-(-)-NIGULDIPINE HYDROCHLORIDE; (S)-(+)-Watanidipine hydrochloride,; (R)-1,4-DIHYDRO-2,6-DIMETHYL-4-(3-NITROPHENYL)-3,5-PYRIDINEDICARBOXYLIC ACID,  3-(4,4-DIPHENYL-1-PIPERIDINYL)PROPYL METHYL ESTER HYDROCHLORIDE; R(-)-1,4-DIHYDRO-2,6-DIMETHYL-4-(3-NITROPHENYL)- 3,5-PYRIDINE-DICARBOXYLIC ACID 3-(4,4-DIPHENYL-1-PIPERIDINYL)- PROPYL METHYL ESTER HYDROCHLORIDE
Molecular Formula:	C36H39N3O6
Formula Weight:	609.71

Altana Pharma (Originator)

Modulators of the Therapeutic Activity of Antineoplastic Agents, Multidrug Resistance Modulators, ONCOLYTIC DRUGS

Phase II

The reaction of diketene (I) with 2-bromoethanol (II) by means of dimethylaminopyridine (DMAP) in dichloromethane gives acetoacetic acid 2-bromoethyl ester (III), which is condensed with 3-nitrobenzaldehyde (IV) by means of piperidine acetate in isopropanol yielding the corresponding 3-nitrobenzylidene derivative (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) by heating at 80  affords 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-bromoethyl) 5-methyl diester (VII), which is condensed with chloromethyl ethyl ether (VIII) by means of NaH in THF to afford the corresponding 1-ethoxymethyl derivative (IX). The reaction of diester (IX) with NaCN and tetrabutylammonium cyanide or sodium p-toluenesulfonate and benzyltriethylammonium chloride (BTEACl) in DMF gives 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylic acid monomethyl ester (X). The optical resolution of (X) through the cinchonidine salt yields, after crystallization, the cinchonidine salt of the (R)-enantiomer (XI) (1), which is treated with HCl to eliminate the cinchonidine, and esterified with 1,3-dibromopropane and K2CO3 in acetone to afford (R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(3-bromopropyl) 5-methyl diester (XII). Finally, this compound is condensed with 4,4-diphenylpiperidine (XIII) by means of K2CO3 in DMF at 100 

 References
1. Amschler, H., Flockerzi, D., Klemm, K. et al. (Byk Gulden Lomberg Chem. Fabrik GmbH). 1,4-Dihydropyridine enantiomers. AU 8816264, EP 296316, EP 343193, WO 8807525.

2. Klemm, K., Ulrich, W.-R., Flockerzi, D., Sanders, K., Beller, K.-D. (Gyk Gulden Lomberg Chem. Fabrik GmbH). Optically pure (R)-(-)-niguldipine and its derivs. for treating tumor diseases. WO 8907443.