Triethylamine → 2,2-Difluoro-N-((1S,2R)-1-fluoromethyl-2-hydroxy-2-{4-[2-(methanesulfonylamino-methyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-ethyl)-acetamide

HRID 1487491Notes

Reaction equation

HRID 1487491 reaction equation
[NH2:1][C@H:2]([CH2:26][F:27])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[F:35][CH:36]([F:42])[C:37](OCC)=[O:38]>CO>[F:35][CH:36]([F:42])[C:37]([NH:1][C@H:2]([CH2:26][F:27])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)=[O:38]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 9961Ethyl difluoroacetateHCID 86695443N-{7-[4-((1R,2S)-2-Amino-3-fluoro-1-hydroxy-propyl)-phenyl]-imidazo[1,2-a]pyridin-2-ylmethyl}-methanesulfonamide

Product 1

HCID 866954442,2-Difluoro-N-((1S,2R)-1-fluoromethyl-2-hydroxy-2-{4-[2-(methanesulfonylamino-methyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-ethyl)-acetamideYield 3.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a stirred solution N-{7-[4-((1R,2S)-2-Amino-3-fluoro-1-hydroxy-propyl)-phenyl]imidazo[1,2-a]pyridin-2-ylmethyl}-methane sulfonamide (88 mg, crude) in methanol (1 mL) is added triethyl amine (0.05 mL, 0.346 mmol) followed by addition of ethyl difluoroacetate (0.02 mL, 0.208 mmol) at 0° C. then stirred at room temperature for 20 h. The reaction mixture is concentrated and purified by flash column chromatography eluting in 2.1% MeOH in CH2Cl2 followed by re-purification by preparative TLC to afford 5 mg and which is re-crystallized in Chloroform: hexane to afford 3 mg of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 2.94 (s, 3H), 4.31-4.35 (m, 3.5H), 4.41-4.45 (m, 0.5H), 4.54-4.57 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (t, J=3.96 Hz, 1H), 5.92 (d, J=4.52 Hz, 1H), 6.20 (t, J=53.8 Hz, 1H), 7.34 (d, J=6.16 Hz, 1H), 7.46 (d, J=8.24 Hz, 2H), 7.60 (t, J=6.12, 1H), 7.78-7.83 (m, 3H), 7.90 (s, 1H), 8.63 (d, J=7.16 Hz, 1H), 8.84 (d, J=8.8 Hz, 1H), 8.93 (bs, 1H). LC-MS (m/z): [M+H]=471.2.

Workup

  1. concentrationThe reaction mixture is concentrated
  2. custompurified by flash column chromatography
  3. washeluting in 2.1% MeOH in CH2Cl2
  4. customfollowed by re-purification by preparative TLC
  5. customto afford 5 mg and which
  6. customis re-crystallized in Chloroform

Sources & evidence

ORD record
ord-968999068acb4878ba948ca03b3c011a
Source dataset
uspto-grants-2016_08
Patent number
US09428528B2

Reaction notes

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