2-Aminothiazole → 2-(6-Hydroxymethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile

HRID 1355518Notes

Reaction equation

HRID 1355518 reaction equation
C([SiH2][O:6][C:7](C)(C)[C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1.C1N=C(N)SC=1.NC1C=CC=CN=1>C1COCC1>[OH:6][CH2:7][C:8]1[N:13]=[C:12]([NH:14][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:11]=[CH:10][CH:9]=1

Participants

7

Reactant 5

HCID 21552-Aminothiazole2×HCID 104392-AminopyridineHCID 24758Sodium hydrideHCID 14852222-Chlorothiazole-5-carbonitrile2×HCID 1317239476-(2-Tert-butylsilyloxypropan-2-yl)pyridin-2-amine

Product 1

HCID 185069372-(6-Hydroxymethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

An oven dried flask was charged with 6-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (1.27 g, 5.33 mmol) and 10 ml anhydrous THF. The solution was cooled to 0° C. and NaH (60% dispersion, 0.43 g, 11 mmol) was added. The reaction was warmed to room temperature and 2-chloro-thiazole-5-carbonitrile (0.924 g, 6.39 mmol) was added. The reaction was heated to 50° C. for 4 h. An additional 0.200 g (1.38 mmol) 2-chloro-thiazole-5-carbonitrile was added and the reaction was heated overnight. After a total of 18 h the reaction was cooled and quenched with water. The pH was adjusted to 7 with 1M HCl. The resulting precipitate was filtered and washed with water. Purification in two batches by flash column chromatography (suspended material on 5 g silica, eluted DCM to 97:3 DCM/MeOH) afforded a mixture of the aminothiazole and starting aminopyridine. This aminothiazole (0.710 g, 2.05 mmol) was dissolved in 10 mL anhydrous THF and the resulting solution was cooled to 0° C. HF-pyr, 2.4 mL, was added and the reaction was allowed to warm to room temperature. After 1 h the reaction was quenched by the addition of sat NaHCO3 (aq) and the THF was removed in vacuo. The resulting precipitate was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ 12.18 (s, 1H), 8.22 (s, 1H), 7.78 (t, 1H, J=7.6 Hz), 7.10 (d, 1H, J=7.5 Hz), 6.96 (d, 1H, J=8.2 Hz), 5.45 (t, 1H, J=5.7 Hz), 4.59 (d, 2H, J=5.9 Hz).

Workup

  1. customAn oven dried flask
  2. temperatureThe reaction was warmed to room temperature
  3. temperatureThe reaction was heated to 50° C. for 4 h
  4. temperaturethe reaction was heated overnight
  5. temperatureAfter a total of 18 h the reaction was cooled
  6. customquenched with water
  7. filtrationThe resulting precipitate was filtered
  8. washwashed with water
  9. customPurification in two batches
  10. washby flash column chromatography (suspended material on 5 g silica, eluted DCM to 97:3 DCM/MeOH)
  11. customafforded
  12. temperaturethe resulting solution was cooled to 0° C
  13. additionHF-pyr, 2.4 mL, was added
  14. temperatureto warm to room temperature
  15. customAfter 1 h the reaction was quenched by the addition of sat NaHCO3 (aq)
  16. customthe THF was removed in vacuo
  17. filtrationThe resulting precipitate was filtered
  18. washwashed with water

Sources & evidence

ORD record
ord-4342587367c94a289b98f9fbe986dcfe
Source dataset
uspto-grants-2003_07
Patent number
US06586424B2

Reaction notes

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