Thermal Ring Contraction of a 1,4-Diazepine; 6-Chloro-4-(o-chlorophenyl)-2-quinazoline carboxaldehyde
SyntheticPage 574
DOI:
10.1039/SP574
Submitted Nov 15, 2012, published Nov 15, 2012
Ramesha Ramakrishna (
ramesha63@hotmail.com)
A contribution from
ramesha
Chemicals Used
Lorazepam BP/EP grade purity 99.7%
Toluene commercial, 99%
Procedure
Lorazepam (10 g, 31.15 mmol) added to toluene (50 mL) in a 250 mL Dean Stark apparatus under nitrogen atmosphere. Reaction mixture was refluxed and the progress of the reaction was monitored by TLC. After 24 h the reaction mixture was cooled to 5-8 oC and the white crystals thus obtained were filtered and dried under vacuum for 6 hr at 70-75 oC to give the quinazoline aldehyde as white crystalline product (9.23 g, 98%) which is pure compound confirmed by NMR studies and does not require any further purification.
Author's Comments
1. The product is one of the pharmacopial impurity of Lorazepam and it is very difficult to prepare this in pure form by conventional method.
2. This is a clean method for the synthesis of 6-Chloro-4-(o-chlorophenyl)-2-quinazoline carboxaldehyde
3. The procedure does not requires any purification. The product is almost insoluble in the reaction medium and therefore it crystalizes out from the reaction medium.
Data
Melting pont : 176-178 oC
1H NMR (CDCl3, 300 MHz): δ δ 10.31 (s, 1H), 8.30 (d, J = 6.7 Hz,1H), 7.99 (dd, J = 6.6,1.6 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.52-7.48 (m, 4H)
13C NMR (CDCl3, 75 MHz): δ 191.3, 167.9, 155.3, 149.1, 136.6, 136.1, 134.8, 132.7, 131.7, 131.4, 130.9, 130.2, 127.3, 126.0, 124.8.
FTIR (KBr): 1721, 1385, 823 cm-1;
Lead Reference
Maravanahalli S. Siddegowda, Hemmige S. Yathirajan, Ramesha A. Ramakrishna. Indian Journal of Chemistry, Vol 51B, 2012, 1628-1632
Other References
1. Rutgers, J. G.; Shearer, C. M Analytical Profiles of Drug Substance, Vol 9, 1980, Edited by Florey K., Acedemic Press, 1980, 397-426. 2. Nudelman, A, McCaully, R. J, Bell, S. C. J. Pharm. Sci., 1974, 63, 1880-1884.
3. Sternbatch, L. H., Reder, E., Stempel, A., Rachlin, A. I. J. Org.Chem.,1964, 29, 332-336.
Supplementary Information
NMR-IR (Lorazepam rearrangement data files.docx)
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Get structure file (.cdx, .sk2, .mol)
Keywords: aldehydes, amides, aromatics/arenes, elimination, impurity, Lorazepam, quinazoline aldehyde, thermal, thermal rearrangement
