HCID 59580411, compound → HCID 66644966, compound

HRID 1470424Notes

Reaction equation

HRID 1470424 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:22])C(=O)OC(C)(C)C)=[C:11](I)[N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:23]([Cu])#[N:24]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:14][CH3:22])=[C:11]([C:23]#[N:24])[N:12]=2)[CH:5]=[N:6][CH:7]=1

Participants

5

Reactant 2

HCID 59580411HCID 59580411, compoundHCID 178418546HCID 178418546, compound

Product 1

HCID 66644966HCID 66644966, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

To a nitrogen-purged solution of tert-butyl 2-(5-fluoropyridin-3-yl)-4-iodothiazol-5-yl(methyl)carbamate (1.0 g, 2.298 mmol) in DMF (8 mL) was added CuCN (288 mg, 3.22 mmol) and the mixture was heated in a microwave at 120° C. for 80 min. The mixture was diluted with ethyl acetate (75 mL) and successively washed with an aqueous solution (15 mL) of ethylene diamine (5% v/v), and brine, dried over MgSO4 filtered, and concentrated on a rotary evaporator under vacuum to give a yellow solid, 2-(5-fluoropyridin-3-yl)-5-(methylamino)thiazole-4-carbonitrile. The solid was used in the preparation of N-(4-cyano-2-(5-fluoropyridin-3-yl)thiazol-5-yl)-N-methyl-3-(methylthio)propanamide. To a solution of crude 2-(5-fluoropyridin-3-yl)-5-(methylamino)thiazole-4-carbonitrile (200 mg, 0.83 mmol) in CH2Cl2 (2 mL) were added K2CO3 (178 mg, 1.28 mmol) and 3-(methylthio)propanoyl chloride (130 mg, 0.94 mmol) followed by dimethylaminopyridine (21 mg, 0.17 mmol). The mixture was stirred at room temperature for 36 h and diluted with ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (5 mL). The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown gummy residue. This residue was purified by silica gel chromatography (6:4 hexane/ethyl acetate) to give N-(4-cyano-2-(5-fluoropyridin-3-yl)thiazol-5-yl)-N-methyl-3-(methylthio)propanamide as a pale yellow solid (164 mg, 57% yield): mp 97-98° C.; 1H NMR (300 MHz, CDCl3) δ 8.98 (bs, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.27 (dt, J=9.6, 1.8 Hz, 1H), 2.73 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.62, 2H), 2.09 (s, 3H), 2.03 (s, 3H): ESIMS m/z 337.2 (M+1).

Workup

  1. washsuccessively washed with an aqueous solution (15 mL) of ethylene diamine (5% v/v), and brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated on a rotary evaporator under vacuum

Sources & evidence

ORD record
ord-3846334b0f5d4a9691b1942f8814eb01
Source dataset
uspto-grants-2015_04
Patent number
US09006446B2

Reaction notes

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