ChemSpider SyntheticPages

The Royal Society of Chemistry"

Thermal Ring Contraction of a 1,4-Diazepine

SyntheticPage 574

DOI: 

Submitted: November 15, 2012, published: November 15, 2012

Authors

Ramesha Ramakrishna (ramesha63@hotmail.com)

A contribution from 

Reaction Scheme

Chemicals

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 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.

Keywords

aldehydes, amides, aromatics/arenes, elimination, impurity, Lorazepam, quinazoline aldehyde, thermal, thermal rearrangement