Synthesis and characterization of a novel ranitidine dimer

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 23, 1997, Pages 3045-3048

  Frutos, Rogelio P ^a   Roth, Gregory P ^a  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIMER; RANITIDINE; RANITIDINE DERIVATIVE;

ARTICLE; DRUG IMPURITY; DRUG PURIFICATION; DRUG SYNTHESIS; IN VITRO STUDY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; REACTION ANALYSIS;

EID: 0030721483     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)10132-9     Document Type: Article

References (13)

1. For a general description see: Hillier, K. Drugs of the Future 1979, Vol. IV, 9, 663; Daly, M. J.; Price, B. J. Prog. Med. Chem. 1983, 20, 337.
2. For a general description see: Hillier, K. Drugs of the Future 1979, Vol. IV, 9, 663; Daly, M. J.; Price, B. J. Prog. Med. Chem. 1983, 20, 337.
3. Madan, T.; Kakkar, A. P. Drug Dev. Ind. Pharm. 1994, 20, 1571; Crookes, D. L. US Patent 4,672,133, 1987; Crookes, D. L. FR Patent 2491067, 1982; Chem. Abstr. 1982, 97, 61014.
4. Madan, T.; Kakkar, A. P. Drug Dev. Ind. Pharm. 1994, 20, 1571; Crookes, D. L. US Patent 4,672,133, 1987; Crookes, D. L. FR Patent 2491067, 1982; Chem. Abstr. 1982, 97, 61014.
5. Madan, T.; Kakkar, A. P. Drug Dev. Ind. Pharm. 1994, 20, 1571; Crookes, D. L. US Patent 4,672,133, 1987; Crookes, D. L. FR Patent 2491067, 1982; Chem. Abstr. 1982, 97, 61014.
6. Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron Lett. 1988, 29, 2377.
7. Price, B. J.; Clitherow, J. W.; Bradshaw, J. US Patent 4,128,658, 1978, Chem. Abstr. 1978, 88, 190580.
8. 3) δ 6.10 (s, 2H), 3.70 (s, 2H), 3.40 (s, 2H), 3.21 (q, J = 6.3 Hz, 2H), 2.60 (t, J = 6.6 Hz, 2H), 2.23 (s, 6H), 1.43 (s, 9H).
9. +, 100).
10. 6-DMSO) δ 8.02 (br, 6H), 6.84 (d, J = 3.2 Hz, 2H), 6.49 (d, J = 3.2 Hz, 2H), 4 60 (s, 4H), 3.89 (s, 4H), 3.01 (q, J = 6.4 Hz, 4H), 2.93 (s, 6H), 2.70 (t, J = 7.4 Hz, 4H).
11. Preparation of Dimer 1 from 7: N-methyl-1-(methylthio)-2-nitroethenamine (754 mg, 5.09 mmol) was added to a stirred solution of crude salt 7 (1.81 mmol), diisopropylethylamine (1.6 mL, 9.18 mmol) and isopropanol (18 mL) at room temperature. The mixture was then refluxed for 18 h and concentrated under reduced pressure to afford a dark oil. Flash chromatography (neutral alumina, 3:1 ethyl acetate/methanol) afforded 614 mg (55%) of 1 as an amorphous yellow solid.
12. 2O: C, 45.82; H, 6.25; N, 15.58; Cl, 5.63. Found C, 45.89; H, 6.14; N, 15.39; Cl, 5.82.
13. It is proposed that the dimerization occurs via an intermediate oxonium ion generated by attack of acetyl chloride on one equivalent of the aminomethyl furan, subsequent attack by a second equivalent furnishes the desired ammonium salt. (figure presented)