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An asymmetric synthesis of chiral dihydropyridine calcium channel blockers

Chen-Yu Cheng, and Mei-Jing Lee and Jy-Yih Chen

Institute of Pharmaceutical Sciences, National Taiwan University, 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan 10018

Introduction

4-Aryl-1,4-dihydropyridine-3,5-dicarboxylic diesters of the nifedipine type are the most effective of the calcium antagonists or calcium channel blockers, which are widely used in the treatment of hypertension and coronary heart diseases.1 Nifedipine, with symmetrical substituents on its dihydropyridine ring, is achiral; while second-generation derivatives, such as nimodipine, amlodipine, and nicardipine, with unsymmetrical substitution, are chiral, and demonstrate moderate to significant enantioselectivity in their pharmacological effects.2-6

Because of the importance of C-4 chirality in the pharmacological activity of 1,4-dihdropyridines, the availability of asymmetric synthesis of these compounds is desirable. The diastereoselective addition of aryllithium to position 4 of the chiral 3-dihydro-oxazolyl-5-methoxy-carbonyl pyridine (4 ) to give dihyropyridine 5 in diastereomeric excess (de) of 78-90% has been reported by Myers, et al.7,8 In this report, we describe our efforts to extend the above methodology to the synthesis of the pharmacologically more important dihydropyridines with methyl substituents in positions 2 and 6.

Results and discussion

In order to determine the effects of the 2,6-dimethyl substituents on the oxazoline-directed aryllithium addition to pyridine derivatives, we have prepared compound 6 and subjected it to the same reaction with PhLi as in Scheme 1. The nucleophilic attack occurred exclusively at the ester carbonyl carbon to give ketone 7 and carbinol 8; while the desired 1,4-addition was not observed, possibly due to the steric bulk and electron-donating effects of the 2,6-dimethyl substituents (Scheme 2 ).

We then prepared compound 9 the tert-butyl analogue of 6 in which the 5-carboxyl function is protected as its tert-butyl ester. Reaction of 9 with PhLi under the same condition as in Schemes 1 and 2 resulted in the desired 1,4-addition to give dihdropyridine 10 in 67% (Scheme 3).

Finally, we turned our attention to the chiral version of the above reaction. The key intermediate 1 was prepared as shown in Scheme 4. Phenyllithium (1.6 equiv. in hexane) was added to THF solution of 1 (0.02 M) during 20 min at -78 oC. The stirring was continued for 20 h, followed by quenching with ethyl chloroformate (5 equiv. ) at -78 oC. Aqueous work-up and CH2Cl2 extraction provided compounds 2 and 3 in a total yield 54% and a diastereoiosomeric ratio of 5 : 1, as determined by reverse-phase HPLC (65% CH3CN in H2O). (Scheme 4) Although the yield and stereoselectivity observed are not optimal, the above methodology can still be adopted for the preparation of pharmacologically active chiral dihydropyridines.

References
  1. F.Bossert, W Vater, Naturwissenschaften 58 (1971) 578.
  2. M. Ohtsuka, M. YoKota, I. Kodama, K. Yamada, S. Shibata, Gen. Pharmacol. 20 (1989) 539 - 556.
  3. S Kazda, R. Towart, Br. J. Pharmacol. 72 (1981) 582P - 583P.
  4. K. Tanaka, F. Gotoh, F Muramatsu, Y. Fukuuchi, H. Okayasu, N. Suzuki, M. Kobari, Azneim. Forsch. 32 (1982) 1529 - 1534.
  5. J. E. Arrowsmith, S. F. Campbell, P. E. Cross, J. K. Stubbs, Pharmacologist 27 (1985) 290.
  6. T. Takenaka, S. Usuda, T. Nomura, H. Maeno, T. Sado, Arzneim. Forsch. 26 (1976) 2172 - 2178.
  7. A. I. Meyers, T. Oppenlaender, J. Am. Chem. Soc. 108 (1986) 19899 - 1996.
  8. A. I. Meyers, T. Oppenlaender, J. Chem. Soc. Chem. Commun. 1986 920 - 921.
  9. Spectrum data for compound 2 and compound 3 : 1H NMR (400 MHz, CDCl3) 1.20 (t, J 7.1 Hz, 3H), 1.49 (s, 9H), 2.46 (s, 3H), 2.51 (s, 3H), 3.41 (s, 3H), 3.52 (dd, J 6.9, 9.6 Hz, 1H), 3.69 (dd, J 4.2, 10.5 Hz, 1H), 4.12 (q, J 7.0 Hz, 2H), 4.18-4.23 (m, 1H), 5.28 (s, 1H), 5.30 (s, 1H), 5.38 (d, J 6.6 Hz, 1H), 7.16-7.31 (m, 5H). Diastereotopic proton at 5.28 ppm and 5.30 ppm showed a ratio of 5:1, and determined by reverse-phase HPLC (65% CH3CN in H2O).13C NMR (100 MHz, CDCl3) d 14.27, 20.63, 21.22, 28.20, 42.64, 59.30, 62.35, 74.47, 81.28, 83.26, 120.06, 124.55, 125.33, 125.39, 126.38, 126.85, 127.06, 127.93, 128.24, 128.31, 128.60, 128.65, 141.05, 144.85, 148.37; MS (EI 70 eV) m/z calc for C32H38O6N2+: 546.3452, found 546.2724.