Hydrochloric Acid → (1S,2S,3S) 2-hydroxymethyl-3-(4-methoxy-benzyloxymethyl)-cyclopropanecarboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide

HRID 1784057Notes

Reaction equation

HRID 1784057 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([CH2:32][O:33][CH2:34][C@@H:35]2[C@@H:40]3[C@H:36]2[CH2:37][O:38][C:39]3=[O:41])=[CH:30][CH:29]=1.Cl>C1COCC1.CCOC(C)=O>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:37]([C@@H:36]1[C@@H:35]([CH2:34][O:33][CH2:32][C:31]2[CH:42]=[CH:43][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C@@H:40]1[CH2:39][OH:41])=[O:38]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 2733832Lithium HexamethyldisilazideHCID 221815481-(4-Amino-3-fluorophenyl)pyridin-2-oneHCID 68853945(1R,5S,6S) 6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one

Product 1

HCID 86604993(1S,2S,3S) 2-hydroxymethyl-3-(4-methoxy-benzyloxymethyl)-cyclopropanecarboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amideYield 78%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
78 °C

Procedure

A solution of 850 mg (3.4 mmol) of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 80 ml of THF was cooled to −78° C., treated dropwise with 4.8 ml of a 1M lithium bis(trimethylsilyl)amide-solution in THF and stirred for 30 min at 78° C. To this solution were added 839 mg (4.8 mmol) of (1R,5S,6S) 6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one dissolved in 5 ml of THF. Stirring was continued at −78° C. for 1 hr and then for 3 hrs at RT. Pouring of the mixture into a 2M aqueous solution of HCl, extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration and evaporation of the solvent gave 1.2 g (77%) of (1S,2S,3S) 2-hydroxymethyl-3-(4-methoxy-benzyloxymethyl)-cyclopropanecarboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Yellow semisolid. 453 (M+H)+.

Workup

  1. stirringStirring
  2. waitwas continued at −78° C. for 1 hr
  3. waitfor 3 hrs at RT
  4. dry with materialdrying of the combined organic phases over Na2SO4, filtration and evaporation of the solvent

Sources & evidence

ORD record
ord-82455f92875a431cb285d19e454c5c5e
Source dataset
uspto-grants-2009_03
Patent number
US07501413B2

Reaction notes

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