Simple exploration of 11-(Piperazin-1-yl)dibenzo[b,f][1,4]thiazepine

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.

A toluene solution of ll-piperazin-l-yldibenzo[b,f][l,4]thiazepine (1500 mL, 0.686 mol) prepared by reaction of piperazine with ll-chloro-dibenzo[b,f][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 (32% w/w). The resulting mixture was heated to 70 0C and agitated for 45 min. Agitation was ceased and the mixture allowed to settle and phase separate for 30 min. The lower aqueous phase, containing the HCl salt of ll-piperazin-l-yldibenzo[b,fj[l,4]thiazepine was isolated. The aqueous phase was then treated with 1000 mL of toluene and 99 g of aqueous NaOH (47% w/w). The resulting mixture was heated to 70 C and agitated for 45 min. Agitation was ceased and the mixture allowed to settle and phase separate for 30 min. The lower aqueous phase was discarded and the upper organic phase retained to which 300 mL of deionized water was added. The resulting mixture was agitated for 15 min and then allowed to settle for 30 min. The aqueous phase was discarded and the organic phase retained. The organic phase was extracted once more with 300 mL of deionized water. About 750 mL of toluene from the organic phase was distilled out. The resulting concentrate was cooled to 60 C, then 200 mL of methyl-t-butyl ether (MTBE) was added. The resulting mixture was cooled to ambient temperature then seeded with Form A seed crystals. The seeded mixture was then cooled to 10 C and held at this temperature for 3 hours under slow agitation. The resulting solid was isolated under suction via a no. 3 sinter. The solid product was then washed with 170 mL of MTBE at ambient temperature and dried at 40 C under vacuum resulting in 175 g (86.4%) of crystalline product. Assay by NMR 95.1 % w/w.Solid ll-piperazin-l-yldibenzo[b,fj[l,4]thiazepine (30 g, 0.1016 mol) prepared as described above was slurried in isopropanol (120 mL). The resulting mixture was warmed to about 63-64 0C to completely dissolve the solid. The resulting solution was filtered through a preheated (about 55 0C) split Buchner funnel fitted with filter paper with a pore size of 6 Dm. The filtered solution was then adjusted to 55 C and seeded with seed crystals of Form A (0.024 g). The seeded solution was maintained at 55 0C for about 2 h then linearly cooled to 40 C over the course of 6 h, linearly cooled to 20 0C over the course of 2 h, and then linearly cooled to 0 0C over the course of 1 h. The resulting slurry was held at 0 0C for 12 h and the filtered to give a solid product cake (13 mm high x 68 mm diameter). The product cake was displacement washed with 30 niL isopropanol prechilled to 0 C and the cake allowed to deliquor. The product was then dried at 40 0C under vacuum yielding 24.9 g (83%) of Form A. Assay by NMR: 98.9% w/w., 5747-48-8

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Reference£º
Patent; ASTRAZENECA AB; WO2007/62337; (2007); A2;,
Piperazine – Wikipedia
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