反应详情

tert-Butyl (1S)-2-(cyclohexyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (225 mg, 0.84 mmol) was refluxed with m-bromobenzylamine (380 mg, 2.0 mmol) in 7 mL of isopropanol under nitrogen for 2 h, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. It was washed three times with small portions of 10% HCl, and the aqueous phases were back-extracted with ethyl acetate. The combined organic phases were washed with 1 N NaHCO3 and brine, dried over Na2SO4, and concentrated. The resulting oil (356 mg) was dissolved in 3 mL of dichloromethane and 2 mL of TFA and stirred for 1.5 h. It was concentrated, and by weight determined to contain 3 eq. of TFA. To this was added 2 mL of dry dimethylformamide (DMF) and 0.35 mL (3.2 mmol) of 4-methyl morpholine. To this was added a pre-mixed solution of 3-[(dipropylamino)carbonyl]-5-methylbenzoic acid (240 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 190 mg, 1 mmol), and 1-hydroxybenzotriazole hydrate (HOBT, 135 mg, 1 mmol) in 3 mL of dry DMF, which had been stirring together for 1.5 h. After 3 days the reaction was quenched with 1 N KH2PO4 and dissolved in ethyl acetate. The organic phase was washed with 1 N KH2PO4, 1 N NaHCO3 (2×) and brine, dried over Na2SO4, and concentrated. Chromatography over silica gel, eluting with 5% methanol (containing 1% NH4OH) in dichloromethane afforded 208 mg (0.32 mmnol) of N1-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(cyclohexylmethyl)-2-hydroxypropyl]-5-methyl-N3,N3-dipropylisophthalamide hydrochloride (EXAMPLE SP-257) after formation of the salt with ethereal HCl: CI MS m/z 600 [M+H]+.

1. customthe solvent was removed in vacuo
2. dissolutionthe residue was dissolved in ethyl acetate
3. washIt was washed three times with small portions of 10% HCl
4. extractionthe aqueous phases were back-extracted with ethyl acetate
5. washThe combined organic phases were washed with 1 N NaHCO3 and brine
6. dry with materialdried over Na2SO4
7. concentrationconcentrated
8. dissolutionThe resulting oil (356 mg) was dissolved in 3 mL of dichloromethane
9. concentrationIt was concentrated
10. stirringhad been stirring together for 1.5 h
11. customAfter 3 days the reaction was quenched with 1 N KH2PO4
12. dissolutiondissolved in ethyl acetate
13. washThe organic phase was washed with 1 N KH2PO4, 1 N NaHCO3 (2×) and brine
14. dry with materialdried over Na2SO4
15. concentrationconcentrated
16. washChromatography over silica gel, eluting with 5% methanol (containing 1% NH4OH) in dichloromethane