Zybrestat synthesis

Yield:404886-32-4 79%

Reaction Conditions:

in water;isopropyl alcohol at 16 - 25; for 1.75 h;

Steps:

Protocol - Preparation of CA4P-TRIS:; To the IPA solution of the cis form of the corresponding phosphoric acid (11.7g, 1 wt., corrected for IPA only) was added IPA (to a total of 102.3mL, 6.91 wt- eq. to 8.8 volumes). The solution was filtered through GF/F paper and the filtrate charged to a 3 necked round bottom flask equipped with a mechanical stirrer and dropping funnel. IPA (11.7mL, 1.0 volumes) was used as a line rinse (previously filtered through the filtration equipment used for the filtration of the cis CA4P solution).TRIS (3.63g, 0.3 lwt, leq) was charged to a separate 25OmL round bottom flask equipped with a magnetic stirrer. Water (102.3mL, 8.8 volumes) was charged to the flask at 16°C to 25°C and the reaction mixture was stirred for at least 15 minutes until complete dissolution was achieved. The aqueous solution of TRIS was filtered through glass fibre filter paper and the filtrate was then added to the solution described above over 45 minutes with rapid stirring. Water (11.7mL, 1.0 volumes) was used as a line rinse (previously filtered through the filtration equipment used for the filtration of the TRIS solution). The resulting off-white suspension was stirred at 16 to 25°C for 1 hour during which time crystallisation was noted. A further portion of filtered EPA (234mL, 20 volumes) was added over 15 minutes. The off white suspension was aged at 16°C to 25°C for 2 hours 15 minutes before being filtered under suction. The filter-cake was washed with filtered IPA (114.7mL, 9.8 volumes), pulled dry on the filter for at least 1 hour and then further dried at 75°C to 80⁰C under vacuum for 16 hours. Crude product was obtained as a pale yellow solid (12. Ig, 105%w/w, 79%: Yield based on the input value corrected for IPA only.) [111 to 128%w/w or 85% to 98% was the expected range]. The IPA content was less than l%w/w by ¹H NMR (D₂O).

References:

WO2008/103415,2008,A2 Location in patent:Page/Page column 15-16