反应详情

温度

10 °C

To a solution of 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 (20.00 g, 33.00 mmol) and 1,2-propanediol (5.0 g) in tetrahydrofuran (200 mL) and water (100 mL) was added slowly potassium hydroxide solution (0.85M, 116 mL) at 8-12° C. in 0.5 hours. The resulting biphasic mixture was stirred at 8-12° C. for 20-27 hours until the reaction was complete. The reaction mixture was washed with n-heptane (200 mL). The pH was adjusted to 6.5 with addition of water (100 mL) and acetic acid (2.5 mL). Tetrahydrofuran was removed under reduced pressure at internal temperature <40° C. The pH was adjusted to 4.5 with addition of isopropyl acetate (400 mL) and acetic acid (11 mL). After 10 minutes of stirring, the aqueous layer was separated and was extracted with isopropylacetate (200 mL). The organic layers were combined, washed with water (100 mL) and concentrated under reduced pressure to a volume of 190 mL at bath temperature <40° C. Crystallization occurred during concentration. The crystal slurry was stirred at 20-25° C. for 16 hours and was then filtered. The cake was washed with cold isopropylacetate (15 mL×3) and dried in vacuum at 35-40° 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 (14.35 g, 78.3%) was obtained as white and sandy crystalline solid. mp=209-230° C. 1H NMR (Acetone-d6): 8.19 (1H, d, J=1.3 Hz), 7.76 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.2 Hz), 7.43 (1H, d, J=1.0 Hz), 7.41 (1H, t, J=1.9 Hz), 6.87 (2H, d, J=1.9 Hz), 4.16 (1H, dd, J1=13.9 Hz J2=0.8 Hz), 4.10 (1H, dd, J1=11.7 Hz, J2=6.2 Hz), 3.99 (1H, d, J=14.0 Hz), 3.48(1H, d, J=10.6 Hz), 3.47 (1H, dd, J1=9.6 Hz, J2=6.2 Hz), 3.25 (3H, s), 3.24 (1H, dd, J1=9.6 Hz, J2=11.7 Hz), 3.01 (1H, d, J=11.3 Hz). 13C NMR (Acetone-d6): 22 Carbons (172.69, 163.7, 153.98, 144.55, 142.23, 135.26, 135.09, 134.41, 133.89, 132.96, 130.33, 128.27, 126.98, 125.18, 119.07, 112.44, 74.28, 59.09, 56.45, 54.33, 50.73, 25.75). Anal. Calcd for C26H20Cl2N4O4S: C, 56.22; H, 3.62; N, 10.08; S, 5.77; Cl, 12.76. Found: C, 56.27; H, 3.20; N, 9.97; S, 5.65; Cl, 12.68.

1. washThe reaction mixture was washed with n-heptane (200 mL)
2. additionThe pH was adjusted to 6.5 with addition of water (100 mL) and acetic acid (2.5 mL)
3. customTetrahydrofuran was removed under reduced pressure at internal temperature <40° C
4. additionThe pH was adjusted to 4.5 with addition of isopropyl acetate (400 mL) and acetic acid (11 mL)
5. stirringAfter 10 minutes of stirring
6. customthe aqueous layer was separated
7. extractionwas extracted with isopropylacetate (200 mL)
8. washwashed with water (100 mL)
9. concentrationconcentrated under reduced pressure to a volume of 190 mL at bath temperature <40° C
10. customCrystallization
11. concentrationoccurred during concentration
12. stirringThe crystal slurry was stirred at 20-25° C. for 16 hours
13. filtrationwas then filtered
14. washThe cake was washed with cold isopropylacetate (15 mL×3)
15. customdried in vacuum at 35-40° C. to a constant weight