4-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester → Ethyl 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylate

HRID 2280779Notes

Reaction equation

HRID 2280779 reaction equation
Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[C:16]12([NH2:21])[CH2:20][CH:18]([CH2:19]1)[CH2:17]2.CCN(C(C)C)C(C)C>C(O)C.O>[C:16]12([NH:21][C:2]3[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=3)[CH2:20][CH:18]([CH2:19]1)[CH2:17]2

Participants

6

Reactant 3

HCID 800084-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl esterHCID 81531DiisopropylethylamineHCID 54589873Bicyclo[1.1.1]pentan-1-amine hydrochloride

Product 1

HCID 71237071Ethyl 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylateYield 96.5%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Procedure

A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (200 g, 0.86 mol), bicyclo[1.1.1]pentan-1-amine hydrochloride (171 g, 1.11 mol; prepared according to Org. Lett., 13(17): 4746-4748 (2011)) and DIEA (278 g, 2.15 mol) in ethanol (2.4 L) was stirred overnight at room temperature. After completion of the reaction, the solvents were concentrated under reduced pressure to give the crude product, which was diluted with water (1 L). The aqueous layer was extracted with chloroform (2×1 L) and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvents afforded the desired compound (231 g, 0.83 mol, 96% yield) as a pale brown oil which was contaminated with trace amounts of DIEA. This product was used in the next reaction without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 8.61 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 2.54 (s, 3H), 2.51 (s, 1H), 2.20 (s, 6H), 1.35 (t, J=7.2 Hz, 3H).

Workup

  1. customAfter completion of the reaction
  2. concentrationthe solvents were concentrated under reduced pressure
  3. customto give the crude product, which
  4. extractionThe aqueous layer was extracted with chloroform (2×1 L)
  5. washthe combined organic layers were washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. customEvaporation of the solvents

Sources & evidence

ORD record
ord-a71a876a1c794f69a85f4beb3027df5f
Source dataset
uspto-grants-2015_09
Patent number
US09139534B2

Reaction notes

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