Hydrochloric Acid → HCID 69978605, compound

Temperature

0 °C

4-(Methoxy)benzenesulfonyl chloride was dissolved in CH2Cl2 and chilled in an ice bath to 0° C. To this solution was added the hydrochloride of Pro-Phe-OMe (1 eq.) and TEA (2.2 eq). The reaction was allowed to warm to room temperature and stirred overnight under a stream of N2. The reaction mixture was then concentrated and the residue taken up in EtOAc and H2O and the organic phase was washed with sat. NaHCO and brine, dried (MgSO4), filtered, concentrated to a tacky solid and used without further purification. The solid product was treated with with BBr3 (1 M in CH2Cl2, 3.0 eq., −78° C. for one hour then warmed to rt). The reaction was then chilled in an ice bath and quenched with water. Following concentration, the residue was taken-up in EtOAc and water. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to a foam. The product was esterified with MeOH and HCl gas (0° C. to rt, 16 hours) and purified by column chromatography. This product was then added to a chilled (0° C.) THF solution of triphenylphosphine (1.10 eq), 3-dimethylmino-1-propanol (1.0 eq) and diethyl azodicarboxylate (1.10 eq). The reaction temperature was held at 0° C. for 30 minutes and then allowed to warm to room tempetature and stirred overnight. The reaction mixture was concentrated and taken-up in EtOAc and washed with sat. NaHCO3. The product was than extracted with 0.2 N citric acid, and the aqueous phase washed with EtOAc. The aqueous phase was then made basic with solid NaHCO3 and the product extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The product was purified by preparative TLC. The hydrolysis was performed using Method 7 to yield the title compound as a mixture of diastereomers and was isolated as a white, hygroscopic solid.

1. temperatureto warm to room temperature
2. concentrationThe reaction mixture was then concentrated
3. washH2O and the organic phase was washed with sat. NaHCO and brine
4. dry with materialdried (MgSO4)
5. filtrationfiltered
6. concentrationconcentrated to a tacky solid
7. customused without further purification
8. additionThe solid product was treated with with BBr3 (1 M in CH2Cl2
9. temperature3.0 eq., −78° C. for one hour then warmed to rt)
10. temperatureThe reaction was then chilled in an ice bath
11. customquenched with water
12. concentrationconcentration
13. washThe organic phase was washed with brine
14. dry with materialdried (MgSO4)
15. filtrationfiltered
16. concentrationconcentrated to a foam
17. customwas esterified with MeOH and HCl gas (0° C. to rt, 16 hours)
18. custompurified by column chromatography
19. additionThis product was then added to
20. temperatureto warm to room tempetature
21. concentrationThe reaction mixture was concentrated and taken-up in EtOAc
22. washwashed with sat. NaHCO3
23. extractionthan extracted with 0.2 N citric acid
24. washthe aqueous phase washed with EtOAc
25. extractionthe product extracted with EtOAc
26. washThe organic phase was washed with brine
27. dry with materialdried (MgSO4)
28. filtrationfiltered
29. concentrationconcentrated
30. customThe product was purified by preparative TLC

ORD record

ord-b6162e3835174904845b8b942eb495e2

Source dataset

uspto-grants-2003_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06586602B2