Norquetiapine

Pale-Yellow Solid

Preparation BA toluene solution of 1 l-piperazin-l-yldibenzo[b, fj[l, 4]thiazepine (1500 mL, 0.686 mol) prepared by reaction of piperazine with 1 l-chloro-dibenzo[b, fj[l, 4]-thiazepine in toluene (see, e.g., U. S. Pat. No. 4, 879, 288) was treated with 1500 mL deionized water and 90 mL of HCl (32percent w/w). The resulting mixture was heated to 70 Step 3 (E)-11-(Piperazin-1-yl)dibenzo[b, f][1, 4]thiazepine:; Methanol saturated with hydrochloric gas (45 mL) was added to a solution of (E)-tert-butyl 4-(dibenzo[b, f][1, 4]thiazepin-11-yl)piperazine-1-carboxylate (4.50 g, 11.38 mmol) in methanol (9 mL). The resulting mixture was stirred at ambient temperature for about 24 hours. The volatiles were removed in vacuo and the resulting residue was basified to pH 9 with a 10percent sodium carbonate solution. Standard extractive work up provided a viscous residue which upon trituration with petroleum ether gave the title product as a pale yellow sticky solid (2.70 g, 80percent). m.p. 66-69° C.; Into a 1000 mL round-bottom flask equipped with a magnetic stirring bar and reflux condenser with a nitrogen inlet was charged with 25.0 g (0.110 mol) of dibenzo[b, f][l, 4]thiazepine-ll(10-H)-one (made by the method of J. Schmutz et al. HeIv. CMm. Acta., 48: 336 (1965)), as a dry solid, followed by 310 mL POCl(b) (b) (b) (b) Preparation of 1 l-piperazin-l-yldibenzorTo a mixture of 10/-/-dibenzo-[b, /][1 , 4]thiazepin-11-one (II) (2 g, 8.8 mmol) and piperazine (2.27 g, 26.4 mmol) there was added titanium tetraisopropoxide (7.0 ml, 25.8 mmol) under an inert atmosphere. The resulting suspension was heated to 170

11-(Piperazin-1-yl)dibenzo[b,f][1,4]thiazepine is a metabolite of Quetiapine, a Benzothiazepine with mixed serotonin and dopamine receptor antagonistic properties used as an antipsychotic.