Pyridine → N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-2-methyl-3-(methylthio)propanamide

HRID 1803460Notes

Reaction equation

HRID 1803460 reaction equation
Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[NH:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH3:23][CH:24]([CH2:28][S:29][CH3:30])[C:25](Cl)=[O:26]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[N:8]([CH2:9][CH3:10])[C:25](=[O:26])[CH:24]([CH3:23])[CH2:28][S:29][CH3:30]

Participants

6

Reactant 3

HCID 1049PyridineHCID 666452174-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine hydrochlorideHCID 758176512-Methyl-3-(methylthio)propanoyl chloride

Product 1

HCID 49805426N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-2-methyl-3-(methylthio)propanamideYield 90%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
35 °C

Procedure

Into a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, reflux condensor, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-amine hydrochloride (20.0 g, 72.4 mmol green solid) and dichloromethane (150 mL). To this suspension was added pyridine (14.32 g, 181 mmol, 2.5 eq) (portionwise over 1 min to form a dark green-black solution. To this solution was added DMAP (4.4 g, 36 mmol) followed by 2-methyl-3-methylthiopropanoyl chloride (16.5 g, 108.6 mmol), which was added portionwise over 1 minute. The reaction exotherm went from 20° C. to 31° C. during the addition of the acid chloride. The reaction was heated to 35° C. for 10 hours then cooled to 25° C. for 14 h. To the dark brown reaction mixture was added dichloromethane (200 mL) and the solution was transferred to a 500 mL separatory funnel. The solution was washed with water (100 mL) and the layers were separated. The brown aqueous layers was extracted with dichloromethane (50 mL) and the dark brown dichloromethane extracts combined, washed with brine (100 mL), dried (MgSO4), filtered and rotary evaporated. This gave 30.49 g (74% pure by HPLC at 254 nm) of a crude black oil. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a beige solid (23.2 g, 89%): mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.7 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.27-8.13 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.90 (bs, 1H), 3.69 (bs, 1H), 2.80 (bs, 2H), 2.47 (bs, 1H), 2.02 (s, 3H), 1.21 (q, J=7.3 Hz, 6H); ESIMS m/z 356 (M+1).

Workup

  1. customInto a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer
  2. temperaturereflux condensor, and nitrogen inlet
  3. customto form a dark green-black solution
  4. additionwas added portionwise over 1 minute
  5. temperaturethen cooled to 25° C. for 14 h
  6. customthe solution was transferred to a 500 mL separatory funnel
  7. washThe solution was washed with water (100 mL)
  8. customthe layers were separated
  9. extractionThe brown aqueous layers was extracted with dichloromethane (50 mL)
  10. washwashed with brine (100 mL)
  11. dry with materialdried (MgSO4)
  12. filtrationfiltered
  13. customThe crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-d1d9a31221424b5b9af9421455fe91ff
Source dataset
uspto-grants-2013_01
Patent number
US08350044B2

Reaction notes

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