反应详情

温度

22.5 °C

To a suspension of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (7.50 kg, 12.30 mmol) and methyl 5-formylthiophene-3-carboxylate (2.2 kg, 13.10 mol) was added triethylamine (2.08 kg, 20.60 mol) at 20-25° C. The mixture was stirred to a clear solution, to which acetic acid (1.24 kg, 20.60 mol) was added. The resulting mixture was stirred at 20-25° C. for 1 hour and then cooled to 15° C. Solid sodium triacetoxyborohydride (1.31 kg, 6.17 mol) was added and the reaction mixture was stirred for 0.5 hours. The addition of sodium triacetoxyborohydride was repeated three more times. At the end, a total of 5.22 kg (24.7 mol) sodium triacetoxyborohydride was added in 2 hours. The reaction mixture was stirred at 20-25° C. for 16 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, TBME (48.1 L) was added to the resulting jelly reaction mixture. The mixture was washed with saturated sodium hydrogen carbonate solution (60.0 L×3). The combined aqueous phase was extracted with TBME (48.1 L). All organic layers were combined, washed with brine (48.1 L) and concentrated in vacuum to a volume of 10.6 L. Isopropanol (192.3 L) was added to the residue and the resulting oil precipitates were dissolved upon warming up to 70-75° C. The solvent volume was reduced to 160.0 L by distillation at 70-75° C. Concentrated HCl (1.5 L) was added at 75° C. in 10 minutes followed by the addition of seed crystals. Crystallization occurred upon cooling to 20-25° C. in 16 hours. The mixture was filtered. The cake was washed with isopropanol (9.6 L×2) and dried at maximum 40° C. to a constant weight. 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid methyl ester hydrochloride salt (6.57 kg, 88.0%) was obtained as white crystalline solid. mp=204-207° C. 1H NMR (CDCl3): 14.22 (1H, b), 8.18 (1H, d, J=0.9 Hz), 7.86 (1H, m), 7.67 (2H, d, J=8.1 Hz), 7.24 (1H, m), 7.23 (2H, d, J=8.1 Hz), 6.67 (2H, m), 4.76 (2H, m), 4.46 (1H, m), 4.16 (1H, m), 4.02 (2H, m), 3.86 (3H, s), 3.75 (1H, m), 3.38 (3H, s). 13C NMR (CDCl3): 18 Carbons (171.24, 162.32, 152.98, 136.05, 135.27, 134.03, 132.83, 131.94, 130.46, 128.85, 128.56, 123.92, 117.52, 113.43, 71.13, 52.43, 52.22, 46.73). Anal. Calcd for C27H23Cl3N4O4S: C, 53.52; H, 3.83; N, 9.25; S, 5.29; Cl, 17.55. Found: C, 53.07; H, 3.69; N, 9.08; S, 5.23; Cl, 17.20.

1. additionwas added
2. temperaturecooled to 15° C
3. stirringthe reaction mixture was stirred for 0.5 hours
4. stirringThe reaction mixture was stirred at 20-25° C. for 16 hours
5. additionwas added to the resulting jelly reaction mixture
6. washThe mixture was washed with saturated sodium hydrogen carbonate solution (60.0 L×3)
7. extractionThe combined aqueous phase was extracted with TBME (48.1 L)
8. washwashed with brine (48.1 L)
9. concentrationconcentrated in vacuum to a volume of 10.6 L
10. additionIsopropanol (192.3 L) was added to the residue
11. customthe resulting oil precipitates
12. dissolutionwere dissolved
13. temperatureupon warming up to 70-75° C
14. distillationThe solvent volume was reduced to 160.0 L by distillation at 70-75° C
15. additionConcentrated HCl (1.5 L) was added at 75° C. in 10 minutes
16. additionfollowed by the addition of seed crystals
17. customCrystallization
18. temperatureupon cooling to 20-25° C. in 16 hours
19. filtrationThe mixture was filtered
20. washThe cake was washed with isopropanol (9.6 L×2)
21. customdried at maximum 40° C. to a constant weight