Proton sponge → Monomethyl auristatin E intermediate-9

HRID 2282801

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HRID 2282801 반응식
[CH2:1]([O:8][C:9]([N:11]([CH3:27])[C@@H:12]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:13]([OH:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>ClCCCl>[CH2:1]([O:8][C:9]([N:11]([CH3:27])[C@@H:12]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:13]([O:22][CH3:28])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

참가 물질

5

반응물 3

HCID 88675Proton spongeHCID 2735153Oxonium, trimethyl-, tetrafluoroborate(1-) (1:1)HCID 10022629tert-butyl (3R,4S,5S)-4-{[(benzyloxy)carbonyl](methyl)amino}-3-hydroxy-5-methylheptanoate

생성물 1

HCID 10249994Monomethyl auristatin E intermediate-9

시약·촉매·용매 1

HCID 111,2-Dichloroethane용매

실험 절차

To a solution of #3 (8.4 g, 22 mmol, 1 eq.) in 1,2-dichloroethane (25 mL, 0.88 M) were added molecular sieves (4 Å, 0.7 g) and Proton sponge (1,8-bis(dimethylamino)naphthalene) (13.4 g, 59.2 mmol, 2.7 eq.), followed by trimethyloxonium tetrafluoroborate (9.10 g, 61.6 mmol, 2.8 eq.). After stirring overnight, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 40% 1:1 acetone:ethyl acetate in heptane) to give #@2 (8.7 g, 68%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.28-7.40 (m, 5H), 5.01-5.13 (m, 2H), 3.89-4.08 (br m, 1H), 3.70-3.82 (m, 1H), 3.18 and 3.26 (2 s, total 3H), 2.66 and 2.71 (2 br s, total 3H), 2.44-2.53 (m, 1H, assumed; partially obscured by solvent peak), 2.17-2.24 (m, 1H), 1.71-1.86 (br m, 1H), 1.39 and 1.39 (2 s, total 9H), 1.31-1.40 (m, 1H), 0.94-1.08 (m, 1H), 0.76-0.91 (m, 6H).

후처리

  1. filtrationthe reaction mixture was filtered through Celite
  2. concentrationThe filtrate was concentrated in vacuo
  3. customthe residue was purified by silica gel chromatography (Gradient: 0% to 40% 1:1 acetone:ethyl acetate in heptane)
  4. customto give #@2 (8.7 g, 68%) as a colorless oil
  5. additiona mixture of rotamers
  6. customδ 7.28-7.40 (m, 5H), 5.01-5.13 (m, 2H), 3.89-4.08 (br m, 1H), 3.70-3.82 (m, 1H), 3.18 and 3.26 (2 s, total 3H), 2.66 and 2.71 (2 br s, total 3H), 2.44-2.53
  7. custom2.17-2.24 (m, 1H), 1.71-1.86 (br m, 1H), 1.39 and 1.39 (2 s, total 9H), 1.31-1.40 (m, 1H), 0.94-1.08 (m, 1H), 0.76-0.91 (m, 6H)

출처 및 근거

ORD 기록
ord-ee0c18f2ac6b434bb088645cad01a63d
출처 데이터셋
uspto-grants-2015_09
특허 번호
US09138486B2

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