Downstream synthetic route of 5747-48-8

As the paragraph descriping shows that 5747-48-8 is playing an increasingly important role.

With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.5747-48-8,11-(Piperazin-1-yl)dibenzo[b,f][1,4]thiazepine,as a common compound, the synthetic route is as follows.

5747-48-8, A 1 liter round bottom flask equipped with stirring rod, thermo pocket, water condenser was charged with solution of l l-piperazinyldibenzo[b,fj [l,4]thiazepine in toluene 350 cc [63.0 g (0.22 moles)] and the mixture was stirred for 15 min 25- 30C, to which, was added sodium carbonate [41.0 gm (0.39 moles)], tetra butyl ammonium bromide [16.0 gm (0.05 mole)] and 2-(2-chloroethoxy) ethanol [32.0 gm ( 0.257 moles)] at room temperature. The reaction mixture was heated to reflux at 110- 112C. The reaction mixture was maintained at reflux for 10-12 hrs. The reaction mixture was analyzed by HPLC (to check for absence of compound IV) and was cooled to at 25C to 30C,and was added 150 cc DM water, the reaction mixture was stirred for 30 min at 25-30C. The layers were separated and the aqueous layer extracted with 50 cc toluene. The extract and the organic layer were combined, and the pH was adjusted to 2-3 using IN HCl solution in DM water, the reaction mixture was stirred for 30 min at 25-3O0C. The layers were separated and the aqueous layer washed with 100 cc toluene twice. To the aqueous layer was added 250 cc toluene, and the pH was adjusted to 8-10 using sodium carbonate, the reaction mixture was stirred for 30 min at 25-30C. The layers were separated and the aqueous layer extract with 125 cc toluene. The extract and the organic layer were combined, and washed with DM water 300 cc twice. The organic layer was distilled off under vacuum below 500C leaving 50-60 cc toluene with product. Purity of 2-(2-(4- dibenzo[b,f]-[l,4] thiazepine- l l-yl-l-piperazinyl)ethoxy) ethanol in toluene was 99.0% (area % by HPLC). To this solution 1000 cc absolute ethanol was added with activated carbon 5.0 gm and heated to reflux for 90 min. The resulting solution was cooled to 50-550C and filtered. The resulting solution was added 12.5 gm (0.5 moles) fumaric acid at 500C. The reaction mixture was heated to reflux for 2 hrs and was slowly cooled to room temperature and maintained for 2 hrs at room temperature. The reaction mass was filtered and washed with 200 cc absolute ethanol. The wet material obtained was dried under vacuum at 50-55C to afford quetiapine fumarate. Dry weight of quetiapine fumarate is 60-65 gm. Purity of quetiapine fumarate was 99.5% (area % by HPLC).

As the paragraph descriping shows that 5747-48-8 is playing an increasingly important role.

Reference£º
Patent; TEVA PHARMACEUTICAL INDUSTRIES LTD.; TEVA PHARMACEUTICALS USA, INC.; WO2008/121415; (2008); A2;,
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