반응 #836449

반응 방정식

Dry ice

3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester

HONH2

KOH

HONH2.HCl

KOH

→

N-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}methyl)-phenyl]-(2E)-2-propenamide

수율 93.9%

용매

MeOH

MeOH

H2O

MeOH

MeOH

반응 조건

후처리

1. 1
   기타a precipitate results
2. 2
   여과After 15 minutes the mixture is filtered
3. 3
   세척the filter cake washed with MeOH
4. 4
   기타the filtrate evaporated under vacuum to approximately 75 mL
5. 5
   여과The mixture is filtered
6. 6
   기타is stored under N2 at −20° C.
7. 7
   기타up to 2 weeks
8. 8
   기타The liquid was decanted
9. 9
   workup.DISSOLUTIONthe solid was dissolved in MeOH
10. 10
    여과filtered
11. 11
    기타The filtrate is evaporated

실험 절차

A solution of 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (12.6 g, 37.7 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol), (i-Pr)2NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C. After 8 hours the mixture is partitioned with CH2Cl2/H2O. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel to produce 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (13.1 g). A solution of KOH (12.9 g (87% pure), 0.2 mol) in MeOH (100 mL) is added to a solution of HONH2.HCl (13.9 g, 0.2 mol) in MeOH (200 mL) and a precipitate results. After 15 minutes the mixture is filtered, the filter cake washed with MeOH and the filtrate evaporated under vacuum to approximately 75 mL. The mixture is filtered and the volume adjusted to 100 mL with MeOH. The resulting solution 2M HONH2 is stored under N2 at −20° C. for up to 2 weeks. Then 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (5.4 g, 11 mmol) is added to 2 M HONH2 in MeOH (90 mL, 180 mmol) followed by a solution of KOH (720 mg (87% pure), 11.2 mmol) in MeOH (5 mL) and the mixture stirred overnight. Dry ice is added to the reaction and the mixture diluted with H2O resulting in the formation of a precipitate. The liquid was decanted and the solid was dissolved in MeOH and filtered. The filtrate is evaporated to afford N-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}methyl)-phenyl]-(2E)-2-propenamide (5.1 g,) which is used without further purification. The hydroxamic acid (5.0 g, 13.3 mmol) is then dissolved in 95% TFA/H2O (59 mL) and heated to 40-50° C. for 4 hours. The mixture is evaporated and the residue purified by reverse phase HPLC to produce N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide as the trifluoroacetate salt (m/z 380 [MH+]).

출처