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

HRID 882001Notes

Reaction equation

HRID 882001 reaction equation
Cl.[Cl: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].N1C=CC=CC=1.[CH3:21][CH:22]([CH2:26][S:27][CH3:28])[C:23](Cl)=[O:24].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl: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[NH:8][C:23](=[O:24])[CH:22]([CH3:21])[CH2:26][S:27][CH3:28]

Participants

7

Reactant 4

HCID 962WaterHCID 1049PyridineHCID 758176512-Methyl-3-(methylthio)propanoyl chlorideHCID 867043434-Chloro-2-(pyridin-3-yl)-1,3-thiazol-5-amine hydrochloride

Product 1

HCID 59580564N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-2-methyl-3-(methylthio)propanamideYield 55%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
15 °C

Procedure

To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, addition funnel, and nitrogen inlet was charged 7.5 g (30.2 mmoles) of 4-chloro-2-(pyridine-3-yl)-1,3-thiazol-5-amine hydrochloride and 200 mLs of anhydrous methylene chloride. The resulting suspension was cooled to 15° C., and 5.98 g (76 mmoles) of pyridine was added at a rate that maintained the temperature below 20° C. 1.85 g (15.11 mmoles) of N,N-dimethylpyridin-4-amine was added in one portion and the resulting yellow solution was stirred at 5° C. for 10 minutes. A solution of 2-methyl-3-(methylthio)propanoyl chloride (5.54 g 36.3 mmoles) in 25 mLs of methylene chloride was added dropwise at a rate that maintained the temperature below 15° C. The reaction was stirred at ambient temperature for 12 hours, than poured into 200 mLs of water. The target was extracted with methylene chloride (3×100 mLs) and the combined methylene chloride extracts were washed with 0.5 N aqueous hydrochloric acid (100 mLs), water (100 mLs) and saturated aqueous sodium chloride solution (100 mLs). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 30 minutes to yield a yellow oil (5.4 g, 55%): 1H NMR (400 MHz, CDCl3) δ 9.12 (dd, J=2.3, 0.8 Hz, 1H), 9.00 (s, 1H), 8.64 (dd, J=4.8, 1.6 Hz, 1H), 8.17 (ddd, J=8.0, 2.3, 1.6 Hz, 1H), 7.37 (ddd, J=8.0, 4.9, 0.8 Hz, 1H), 3.00-2.57 (m, 3H), 2.17 (s, 3H), 1.38 (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.68, 155.24, 150.55, 146.75, 132.81, 129.26, 127.62, 124.99, 123.80, 40.85, 37.98, 17.46, 16.45.

Workup

  1. customTo a dry 500 ml round bottom flask equipped with magnetic stirrer
  2. additionthermometer, addition funnel, and nitrogen inlet
  3. temperaturemaintained the temperature below 20° C
  4. temperaturethat maintained the temperature below 15° C
  5. stirringThe reaction was stirred at ambient temperature for 12 hours
  6. extractionThe target was extracted with methylene chloride (3×100 mLs)
  7. washthe combined methylene chloride extracts were washed with 0.5 N aqueous hydrochloric acid (100 mLs), water (100 mLs) and saturated aqueous sodium chloride solution (100 mLs)
  8. extractionThe organic extract
  9. dry with materialwas dried over anhydrous magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under vacuum on a rotary evaporator
  12. customThe crude product was purified by silica gel flash chromatography
  13. washeluting with a gradient of 100% hexane to 100% ethyl acetate over 30 minutes

Sources & evidence

ORD record
ord-7f67006819fa480a888bf21ff7cf6491
Source dataset
uspto-grants-2015_03
Patent number
US08993769B2

Reaction notes

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