반응 #42555

반응 방정식

3-[(dipropylamino)carbonyl]-5-methylbenzoic acid

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

1-hydroxybenzotriazole hydrate

4-methyl morpholine

tert-Butyl (1S)-2-(cyclohexyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate

m-bromobenzylamine

TFA

→

N1-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(cyclohexylmethyl)-2-hydroxypropyl]-5-methyl-N3,N3-dipropylisophthalamide hydrochloride

수율 38.9%

용매

DMF

dimethylformamide

isopropanol

반응 조건

후처리

1. 1
   기타the solvent was removed in vacuo
2. 2
   workup.DISSOLUTIONthe residue was dissolved in ethyl acetate
3. 3
   세척It was washed three times with small portions of 10% HCl
4. 4
   추출the aqueous phases were back-extracted with ethyl acetate
5. 5
   세척The combined organic phases were washed with 1 N NaHCO3 and brine
6. 6
   건조dried over Na2SO4
7. 7
   농축concentrated
8. 8
   workup.DISSOLUTIONThe resulting oil (356 mg) was dissolved in 3 mL of dichloromethane
9. 9
   농축It was concentrated
10. 10
    workup.STIRRINGhad been stirring together for 1.5 h
11. 11
    기타After 3 days the reaction was quenched with 1 N KH2PO4
12. 12
    workup.DISSOLUTIONdissolved in ethyl acetate
13. 13
    세척The organic phase was washed with 1 N KH2PO4, 1 N NaHCO3 (2×) and brine
14. 14
    건조dried over Na2SO4
15. 15
    농축concentrated
16. 16
    세척Chromatography over silica gel, eluting with 5% methanol (containing 1% NH4OH) in dichloromethane

실험 절차

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]+.

출처