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 222902

Reaction equation

HRID 222902 reaction equation
[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]

Participants

6

Reactant 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

Product 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 phosphateYield 77.1%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalyst2×HCID 6344DichloromethaneSolvent

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-ef25b8a74d9947e5ae475d6ffcea2e4f
Source dataset
uspto-grants-2012_06
Patent number
US08207340B2

Linked notes

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