2-Dimethylaminopyridine → 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide

HRID 533331Notes

Reaction equation

HRID 533331 reaction equation
[CH3:1][S:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:6][C:7]=1[NH2:8].CN(C1C=CC=CN=1)C.[CH3:24][S:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl.O>[CH3:24][S:25][CH2:26][CH2:27][C:28]([NH:8][C:7]1[S:6][C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:3]=1[S:2][CH3:1])=[O:29]

Participants

6

Reactant 3

HCID 218852-DimethylaminopyridineHCID 129214403-(Methylthio)propionyl ChlorideHCID 134725544-(Methylthio)-2-(pyridin-3-yl)thiazol-5-amine

Product 1

HCID 595805513-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamideYield 22%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1 (M+1), 324.1 (M−1).

Workup

  1. customto remove residual acetic acid
  2. customThe crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification
  3. customto prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide
  4. customThe organic phase was separated
  5. washrinsed with brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated in vacuo
  8. customto give a yellow solid
  9. customThis solid was purified by silica gel chromatography (methylene chloride-methanol)

Sources & evidence

ORD record
ord-76e966fdac1c485584ac966a5642cfea
Source dataset
uspto-grants-2014_10
Patent number
US08853246B2

Reaction notes

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