Diethyl Ether → 4-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine hydrochloride

HRID 515131Notes

Reaction equation

HRID 515131 reaction equation
[CH2:1]([NH:3][C:4]1[S:8][C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:5]=1)[CH3:2].C(OCC)C.[Cl:20]NC(=O)CCC(N)=O>O1CCOCC1>[ClH:20].[Cl:20][C:5]1[N:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:8][C:4]=1[NH:3][CH2:1][CH3:2]

Participants

5

Reactant 3

HCID 3283Diethyl EtherHCID 15238416N-chlorosuccinamideHCID 86704351N-ethyl-2-(pyridin-3-yl)thiazol-5-amine

Product 1

HCID 666452174-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine hydrochloride

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
5 °C

Procedure

To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, and nitrogen inlet was charged N-ethyl-2-(pyridin-3-yl)thiazol-5-amine (5.1 g, 25 mmol), diethyl ether (200 mL) and dioxane (5 mL). The resulting suspension (not all solid dissolved) was cooled to 5° C., and N-chlorosuccinamide (3.65 g, 27.3 mmol) was added portionwise. After all of the chlorinating agent was added, a brown solid precipitated from solution. The reaction mixture was stirred at 5° C. for 60 minutes, then analyzed by HPLC(YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05% TFA over 20 Min @ 1.0 ml/min). HPLC analysis showed no starting material and one major product consistent with the desired chloride. The brown suspension was filtered through a pad of Celite®, and the Celite® pad rinsed with diethyl ether (˜20 mL). The filtrate was cooled to 5° C. and acidified with stirring by the addition of 6.5 ml of 4M HCl in dioxane. A yellow solid immediately formed. The solid was collected by vacuum filtration, rinsed with diethyl ether, and dried in vacuo at 40° C. for 2 hours. This gave 4-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine hydrochloride as a yellow solid (6.3 g, 92%): mp 180-182° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J=2.0 Hz, 1H), 8.70 (dd, J=5.4, 1.3 Hz, 1H), 8.59-8.42 (m, 1H), 7.86 (dd, J=8.2, 5.3 Hz, 1H), 5.27 (s, 5H), 3.20 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 148.10, 140.19, 138.58, 137.91, 137.01, 132.06, 127.30, 115.89, 43.43, 13.87; Anal. Calcd. for C10H11Cl2N3S: C, 43.49; H, 4.01; Cl, 25.67; N, 15.21; S, 11.61. Found: C, 43.42: H, 4.01; Cl, 25.55; N, 14.99; S, 11.46.

Workup

  1. customTo a dry 500 ml round bottom flask equipped with magnetic stirrer
  2. dissolutionThe resulting suspension (not all solid dissolved)
  3. additionAfter all of the chlorinating agent was added
  4. customa brown solid precipitated from solution
  5. filtrationThe brown suspension was filtered through a pad of Celite®
  6. washthe Celite® pad rinsed with diethyl ether (˜20 mL)
  7. temperatureThe filtrate was cooled to 5° C.
  8. stirringwith stirring by the addition of 6.5 ml of 4M HCl in dioxane
  9. customA yellow solid immediately formed
  10. filtrationThe solid was collected by vacuum filtration
  11. washrinsed with diethyl ether
  12. customdried in vacuo at 40° C. for 2 hours

Sources & evidence

ORD record
ord-2fe465fd5d8048c181af50ee8f09fa17
Source dataset
uspto-grants-2015_08
Patent number
US09108952B2

Reaction notes

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