Approaches to combinatorial synthesis of heterocycles: A solid-phase synthesis of 1,4-dihydropyridines

Journal of Organic Chemistry

Volumn 61, Issue 3, 1996, Pages 924-928

  Gordeev, Mikhail F ^a   Patel, Dinesh V ^a   Gordon, Eric M ^a  

^a AFFYMAX RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 DIHYDROPYRIDINE DERIVATIVE; NIFEDIPINE; NIMODIPINE; NITRENDIPINE;

ARTICLE; DRUG SYNTHESIS; INFRARED SPECTROPHOTOMETRY; NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS; STEREOCHEMISTRY; TECHNIQUE;

EID: 0030038838     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo951706s     Document Type: Article

References (72)

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28. For early ground-breaking reviews on solid-phase synthesis of organic molecules, see (a) Crowley, J. I.; Rapoport, H. J. Org. Chem. 1976, 9, 135. (b) Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327. (e) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (d) Mathur, N. G.; Narang, C. K. Polymers as Aids in Organic Synthesis; Academic Press: New York, 1980. (e) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (f) Akelah, A.; Sherrington, D. C. Chem. Rev. 1981, 81, 557. For some early examples of organic syntheses using polymeric support, see also: (g) Patchornik, A.; Kraus, M. A. J. Am. Chem. Soc. 1970, 92, 7587. (h) Camps, F.; Castells, M. J.; Ferrando, M. J.; Font, J. Tetrahedron Lett. 1971, 12, 1713
29. For early ground-breaking reviews on solid-phase synthesis of organic molecules, see (a) Crowley, J. I.; Rapoport, H. J. Org. Chem. 1976, 9, 135. (b) Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327. (e) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (d) Mathur, N. G.; Narang, C. K. Polymers as Aids in Organic Synthesis; Academic Press: New York, 1980. (e) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (f) Akelah, A.; Sherrington, D. C. Chem. Rev. 1981, 81, 557. For some early examples of organic syntheses using polymeric support, see also: (g) Patchornik, A.; Kraus, M. A. J. Am. Chem. Soc. 1970, 92, 7587. (h) Camps, F.; Castells, M. J.; Ferrando, M. J.; Font, J. Tetrahedron Lett. 1971, 12, 1713
30. For early ground-breaking reviews on solid-phase synthesis of organic molecules, see (a) Crowley, J. I.; Rapoport, H. J. Org. Chem. 1976, 9, 135. (b) Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327. (e) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (d) Mathur, N. G.; Narang, C. K. Polymers as Aids in Organic Synthesis; Academic Press: New York, 1980. (e) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (f) Akelah, A.; Sherrington, D. C. Chem. Rev. 1981, 81, 557. For some early examples of organic syntheses using polymeric support, see also: (g) Patchornik, A.; Kraus, M. A. J. Am. Chem. Soc. 1970, 92, 7587. (h) Camps, F.; Castells, M. J.; Ferrando, M. J.; Font, J. Tetrahedron Lett. 1971, 12, 1713
31. For early ground-breaking reviews on solid-phase synthesis of organic molecules, see (a) Crowley, J. I.; Rapoport, H. J. Org. Chem. 1976, 9, 135. (b) Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327. (e) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (d) Mathur, N. G.; Narang, C. K. Polymers as Aids in Organic Synthesis; Academic Press: New York, 1980. (e) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (f) Akelah, A.; Sherrington, D. C. Chem. Rev. 1981, 81, 557. For some early examples of organic syntheses using polymeric support, see also: (g) Patchornik, A.; Kraus, M. A. J. Am. Chem. Soc. 1970, 92, 7587. (h) Camps, F.; Castells, M. J.; Ferrando, M. J.; Font, J. Tetrahedron Lett. 1971, 12, 1713
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33. For reviews, see e.g.: (a) Godfraind, T.; Miller, R.; Wibo, M. Pharmacol. Rev. 1986, 38, 321. (b) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug Res. 1987, 16, 309. (c) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269. (d) Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery 1992, 8, 273. (e) Mannhold, R.; Jablonka, B.; Voigdt, W.; Schoenafinger, K.; Schraven, E. J. Med. Chem. 1992, 27, 229. (f) Gaudio, A. C.; Korolkovas, A.; Takahata, Y. J. Pharm. Sci. 1994, 83, 1110.
34. For reviews, see e.g.: (a) Godfraind, T.; Miller, R.; Wibo, M. Pharmacol. Rev. 1986, 38, 321. (b) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug Res. 1987, 16, 309. (c) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269. (d) Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery 1992, 8, 273. (e) Mannhold, R.; Jablonka, B.; Voigdt, W.; Schoenafinger, K.; Schraven, E. J. Med. Chem. 1992, 27, 229. (f) Gaudio, A. C.; Korolkovas, A.; Takahata, Y. J. Pharm. Sci. 1994, 83, 1110.
35. For reviews, see e.g.: (a) Godfraind, T.; Miller, R.; Wibo, M. Pharmacol. Rev. 1986, 38, 321. (b) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug Res. 1987, 16, 309. (c) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269. (d) Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery 1992, 8, 273. (e) Mannhold, R.; Jablonka, B.; Voigdt, W.; Schoenafinger, K.; Schraven, E. J. Med. Chem. 1992, 27, 229. (f) Gaudio, A. C.; Korolkovas, A.; Takahata, Y. J. Pharm. Sci. 1994, 83, 1110.
36. For reviews, see e.g.: (a) Godfraind, T.; Miller, R.; Wibo, M. Pharmacol. Rev. 1986, 38, 321. (b) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug Res. 1987, 16, 309. (c) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269. (d) Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery 1992, 8, 273. (e) Mannhold, R.; Jablonka, B.; Voigdt, W.; Schoenafinger, K.; Schraven, E. J. Med. Chem. 1992, 27, 229. (f) Gaudio, A. C.; Korolkovas, A.; Takahata, Y. J. Pharm. Sci. 1994, 83, 1110.
37. For reviews, see e.g.: (a) Godfraind, T.; Miller, R.; Wibo, M. Pharmacol. Rev. 1986, 38, 321. (b) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug Res. 1987, 16, 309. (c) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269. (d) Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery 1992, 8, 273. (e) Mannhold, R.; Jablonka, B.; Voigdt, W.; Schoenafinger, K.; Schraven, E. J. Med. Chem. 1992, 27, 229. (f) Gaudio, A. C.; Korolkovas, A.; Takahata, Y. J. Pharm. Sci. 1994, 83, 1110.
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57. Reverse phase HPLC purity of the crude Nifedipine thus obtained was ca. 70-80% (detection at 220 nM).
58. 4 = Ph (Me)].
59. 2, or TsOH also afforded predominantly compound 8, and no Nifedipine was obtained from transformation in the presence of DIEA in DMF.
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61. Three-component condensations of an aldehyde, β-keto ester, and benzylamine hydrochloride in Py at ca. 100 °C were previously reported to afford DHP derivatives in low to moderate yields, and no possible mechanism of the py action in these transformations has been discussed: (a) Bossert, F.; Elberfeld, W.; Vater, W. U.S. Patent 3,647,807, March 7, 1972. (b) Funer, A. V.; Strehl, P.; Schubel-Hopf, U.; Ebbinghaus, D ; Finck, D. German Patent 2,908,738, March 6, 1979.
62. 13a-d
63. 13a-d
64. 13a-d
65. 13a-d
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