4-Chloro-2-isothiocyanato-1-methoxy-benzene → (+/-)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carbothioic acid N-(5-chloro-2-methoxy-phenyl)-amide

HRID 1914629Notes

Reaction equation

HRID 1914629 reaction equation
[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([N:38]=[C:39]=[S:40])[CH:31]=1>O1CCCC1.[Cl-].[NH4+].ClCCl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:39]([CH:15]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[N:8]=[C:9]23)=[S:40])[CH:31]=1

Participants

7

Reactant 3

HCID 7371654-Chloro-2-isothiocyanato-1-methoxy-benzeneHCID 2733832Lithium HexamethyldisilazideHCID 671776292-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one

Product 1

HCID 44594368(+/-)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carbothioic acid N-(5-chloro-2-methoxy-phenyl)-amideYield 31%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
-50 °C

Procedure

To a solution of 0.400 g (1.65 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one (step 1 of example 6) in 16 mL of dry tetrahydrofuran at −50° C., was added 1.82 mL (1.82 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The resulting mixture was stirred at −50° C. for 10 min. 0.494 g (2.48 mmol) of 4-chloro-2-isothiocyanato-1-methoxy-benzene dissolved in 2 mL of tetrahydrofuran was added at −50° C. the resulting mixture was stirred for 2 hours. The mixture was dissolved in a saturated solution of ammonium chloride and dichloromethane. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 99/1/0.1 to 98/2/0.2) to afford 0.224 g (31%) of a solid.

Workup

  1. additionwas added at −50° C. the resulting mixture
  2. stirringwas stirred for 2 hours
  3. washThe organic phases were washed with a saturated aqueous solution of sodium chloride
  4. dry with materialdried over sodium sulfate
  5. customevaporated to dryness
  6. customThe residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 99/1/0.1 to 98/2/0.2)

Sources & evidence

ORD record
ord-b6fb97a1d8ad40f5828449524a862fe5
Source dataset
uspto-grants-2013_12
Patent number
US08614219B2

Reaction notes

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