Dichloromethane → (3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester

(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (4.9 g) was dissolved in 200 mL dry DCM and stirred on 0° C. bath. 100 mL 4N HCL in dioxane was added and the mixture stirred to rt over 3 h. The solvents were evaporated and the residue was evaporated from diethyl ether 4 times. 4 g of the residue was dissolved in 250 mL dry dioxane and 462 mg paraformaldehyde was added while stirring. Then 62.5 mL trifluoroacetic acid was added and the mixture was stirred 1.5 h. The solvents were then evaporated and the residue was dissolved in 250 mL EtOAc and 250 mL saturated aqueous NaHCO3, and 4.2 g di-t-butyl dicarbonate was added and stirred 18 h at rt. The layers were then separated and the organic layer was washed with brine, dried with Na2SO4, and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give 3.25 g after drying under vacuum. 1H NMR (400 MHz, acetone-d6): 7.72 (d, 1H), 7.61 (d, 1H), 7.51-7.42 (m, 3H), 7.12-7.07 (m, 2H), 0.680-6.70 (m, 2H), 5.20 (s, 2H), 5.13-5.07 (m, 1H), 5.02 and 4.76 (m, 1H), 4.66-4.52 (dd, 1H), 4.42 (d, 1H), 4.36-4.30 (m, 1H), 4.01 (m, 1H), 3.64 and 3.60 (s, 3H), 3.18-3.00 (m, 2H), 1.49 and 1.43 (s, 9H).

1. stirringthe mixture stirred to rt over 3 h
2. customThe solvents were evaporated
3. customthe residue was evaporated from diethyl ether 4 times
4. dissolution4 g of the residue was dissolved in 250 mL dry dioxane
5. addition462 mg paraformaldehyde was added
6. stirringwhile stirring
7. additionThen 62.5 mL trifluoroacetic acid was added
8. stirringthe mixture was stirred 1.5 h
9. customThe solvents were then evaporated
10. dissolutionthe residue was dissolved in 250 mL EtOAc
11. addition250 mL saturated aqueous NaHCO3, and 4.2 g di-t-butyl dicarbonate was added
12. stirringstirred 18 h at rt
13. customThe layers were then separated
14. washthe organic layer was washed with brine
15. dry with materialdried with Na2SO4
16. customevaporated
17. customThe residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc)
18. customto give 3.25 g
19. customafter drying under vacuum

ORDレコード

ord-592e32f022e047d2aded0e782d102a0e

出典データセット

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09175003B2