Dichloroacetyl chloride → 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(3-(methylsulfonamidomethyl)isoxazol-5-yl)phenyl)propan-2-yl)acetamide

HRID 1487549Notes

Reaction equation

[Cl-].[F:2][CH2:3][C@@H:4]([NH3+:24])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>CN(C)C=O>[Cl:34][CH:35]([Cl:39])[C:36]([NH:24][C@H:4]([CH2:3][F:2])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1)=[O:37]

Participants

Conditions

Temperature: 0 °C

Procedure

To a dimethylformamide (3 ml) solution of (1R,2S)-3-fluoro-1-hydroxy-1-(4-(3-(methylsulfonamidomethyl)isoxazol-5-yl)phenyl)propan-2-aminium chloride (150 mg, 0.40 mmol) is added diisopropylethylamine (0.255 g, 2 mmol). After cooling the reaction mixture to 0° C. dichloroacetyl chloride (62 mg, 0.42 mmol) is added. The reaction is stirred at 0° C. for twenty minutes then quenched by the addition of water (1 ml). The reaction mixture is concentrated to a volume of approximately two milliliters and subjected to reverse phase HPLC purification to give the title compound (95 mg): 1H NMR (400 MHz, CDCl3) 3.06 (s, 3H) 4.30-4.43 (m, 1H) 4.49 (d, J=6.32 Hz, 2H) 4.56-4.67 (m, 2H) 4.93 (m, br, 1H) 5.19-5.24 (m, 1H) 5.87 (s, 1H) 6.61 (s, 1H) 7.03 (d, J=9.09 Hz, 1H) 7.52 (d, J=8.08 Hz, 2H) 7.79 (d, J=8.59 Hz, 2H); m/z (CI) 454, 456, 458 ([M+H]+.

Workup

additionis added
customthen quenched by the addition of water (1 ml)
concentrationThe reaction mixture is concentrated to a volume of approximately two milliliters
customphase HPLC purification

Sources & evidence

ORD record: ord-7601849535fb4bb587cb2a358210ef31
Source dataset: uspto-grants-2016_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09428528B2

Reaction notes

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