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 1621233

Reaktionsgleichung

Reaktionsgleichung von HRID 1621233
[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]

Komponenten

6

Edukt 3

HCID 101863Phosphorochloridic acid, dimethyl ester2×HCID 21584119Ethylacetate methanolHCID 57594136(S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide

Produkt 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 phosphateAusbeute 77,1 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 142844-(Dimethylamino)pyridineKatalysator2×HCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

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.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-27cfc9cac8314468918504df0df0d58c
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08772507B2

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