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Phosphorochloridic acid, dimethyl ester → (3S)-4-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-3-[([3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]butyl dimethyl phosphate

HRID 1436186
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HRID 1436186 반응식
[C:1]([C:4]1[N:5]([CH3:34])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=3)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=2)[N:8]=1)(=[O:3])[CH3:2].[P:35](Cl)([O:39][CH3:40])([O:37][CH3:38])=[O:36].CCOC(C)=O.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:35]([O:39][CH3:40])([O:37][CH3:38])([O:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:30])[CH3:31])=[C:24]([Cl:32])[CH:23]=1)=[O:33])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]([CH3:34])[CH:6]=2)=[CH:10][CH:11]=1)=[O:36]
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참가 물질

6

반응물 3

HCID 101863Phosphorochloridic acid, dimethyl ester2회HCID 21584119Ethylacetate methanolHCID 57594136(S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide

생성물 1

HCID 57594157(3S)-4-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-3-[([3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]butyl dimethyl phosphate수율 77.1%

시약·촉매·용매 2

HCID 142844-(Dimethylamino)pyridine촉매2회HCID 6344Dichloromethane용매

실험 절차

To a solution of N-((1S)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide (500 mg, 1.04 mmol) in dry CH2Cl2 (10 mL) under N2, was added dimethyl chlorophosphate (748 mg, 5.18 mmol) followed by DMAP (660 mg, 5.41 mmol) at rt. After 30 min, TLC (95:5 EtOAc/MeOH) showed ˜50% conversion, so an additional portion of dimethyl chlorophosphate (748 mg, 5.18 mmol) and DMAP (660 mg, 5.41 mmol) were added. After an additional 30 min, the reaction was quenched with saturated aqueous NH4Cl and diluted with CH2Cl2. The aqueous layer was back-extracted with CH2Cl2 and the combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% EtOAc; isocratic on Analogix) to give 475 mg (77%) of the title compound as a pale yellow oil. LC/MS (ES) m/e 592.4 (M+H)+. Note that the product was contaminated with ˜1 eq of the starting dimethyl chlorophosphate/dimethyl hydrogenphosphate reagent and carried on as is.

후처리

  1. waitAfter an additional 30 min
  2. customthe reaction was quenched with saturated aqueous NH4Cl
  3. additiondiluted with CH2Cl2
  4. extractionThe aqueous layer was back-extracted with CH2Cl2
  5. dry with materialthe combined organics were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography (100% EtOAc; isocratic on Analogix)

출처 및 근거

ORD 기록
ord-adf6a6e5e2f44d0280618c6ba5059a36
출처 데이터셋
uspto-grants-2009_11
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US07618981B2

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