Molbank 2005, M454

http://www.mdpi.net/molbank/

 

Synthesis of 8-chloro-11-(4-(3-(p-tolyloxy)propyl)piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

 

Ben Capuano*, Ian T. Crosby, Sean E. K. Lim & Edward J. Lloyd

 

Department of Medicinal Chemistry,

Victorian College of Pharmacy, Monash University,

381 Royal Parade, Parkville, Victoria,

3052, Australia.

Tel. +61 3 9903 9556; Fax +61 3 9903 9582 e-mail: [email protected]

 

Received: 24 November 2005 / Accepted: 7 December 2005 / Published: 12 December 2005

 

Keywords: clozapine, amidine, p-tolyloxypropyl analogue, dibenzodiazepine.

 

As part of our ongoing research programme in the area of anti-schizophrenia therapeutics, we have synthesized the title compound based on the structural hybridization of the two prominent antipsychotic drugs, clozapine and haloperidol. The starting tricyclic lactam, 1, was synthesized according to previously described literature procedures [1, 2, 3]. Subsequent treatment of 1 with the titanium-amine complex [4] formed from the addition of titanium tetrachloride to the monosubstituted piperazine, 2, furnished the title compound 3 in respectable yield.

 

 

To a solution of 1‑(3‑(p‑tolyloxy)propyl)piperazine (2) (1.20 g, 5.14 mmol) in anhydrous anisole (5 mL) under nitrogen was added a solution of titanium tetrachloride in toluene (1.0 M, 1.10 mL, 1.10 mmol). The mixture was warmed to 50-55oC and a hot solution of 8‑chloro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one (1) (250 mg, 1.02 mmol) in anhydrous anisole (10 mL) was then added via syringe. The mixture was heated at reflux for 4 h after which time it was cooled and then evaporated to dryness in vacuo. The brown coloured residue was partitioned between ethyl acetate (50 mL) and aqueous sodium hydroxide (2 M, 30 mL), the mixture filtered under vacuum and the residue washed with ethyl acetate (20 mL). The organic layer was separated and the aqueous phase extracted with ethyl acetate (2 ´ 50 mL). The organic fractions were combined, washed with water (2 ´ 30 mL), dried (anhydrous sodium sulfate), evaporated to dryness and the resulting residue purified using flash column chromatography (silica gel 230-400 mesh, ethyl acetate:hexane, 4:1). The fractions corresponding to the major product were pooled and evaporated to dryness producing a yellow oily residue. Recrystallisation from a methanol-water gave the title compound 3 as bright yellow prisms (252 mg, 53%).

 

Melting Point: 154.4–156.8ēC

 

TLC: Rf (silica; ethyl acetate:hexane, 4:1) 0.30.

 

Elemental Analysis:       Calculated for C27H29ClN4O: C, 70.34%; H, 6.34%; N, 12.15%. Found: C, 70.36%; H, 6.36%; N, 12.24%.

 

IR (KBr, cm-1): 3292, 2920, 2852, 1598, 1558.

 

UV ((EtOH; λmax  nm; log10e): 217 (4.54), 225 (4.55), 261 (4.26), 297 (4.08).

 

1H-NMR (300 MHz, d6-acetone): d= 7.36–7.26 (m, 2 H); 7.08–6.99 (m, 4 H); 6.96 (m, 1 H); 6.88–6.75 (m, 4 H); 6.52 (s, 1 H, H5); 4.02 (t, J = 6.5 Hz, 2 H, H3''); 3.41 (m, 4 H, H2', H6'); 2.60–2.50 (m, 6 H, H1'', H3', H5'); 2.23 (s, 3 H, CH3); 1.93 (m, J = 6.5 Hz, 2 H, H2'').

 

13C-NMR (75 MHz, d6-acetone): d= 164.0 (Cq); 158.1 (Cq); 154.9 (Cq); 143.4 (Cq); 142.9 (Cq); 132.7 (CH); 130.9 (CH); 130.6 (CH); 130.1 (Cq); 128.5 (Cq); 126.9 (CH); 124.6 (Cq); 123.40 (CH); 123.35 (CH); 121.3 (CH); 121.1 (CH); 115.2 (CH); 66.8 (CH2); 55.7 (CH2); 53.8 (CH2); 48.2 (CH2); 27.6 (CH2); 20.5 (CH3).

 

MS ESI (m/z, %): 463.3 (M[37Cl]H+, 36%); 461.3 (M[35Cl]H+, 100%).

 

Acknowledgment

The authors gratefully acknowledge financial support from Monash University and the assistance of Ms Anna Podloucka and Mr James Shin.

 

References:

1. Capuano, B.; Crosby, I. T.; Lloyd, E. J.; Taylor D. A. Aust. J. Chem. 2002, 55, 565.

2. Burton, B; Gibson, C. S. J. Chem. Soc. 1924, 125, 2501.

3. Hunziker, F.; Lauener, H.; Schmutz, J. Arzneimittelforschung 1963, 13, 324.

4. Schneider, J. Neues verfahren zur ilerstellung von organischen verbindungen. Ger. Patent No. 2 316 438, 1973, 23 pp.

 

Sample Availability: Available from the author.

 

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