Water → HCID 59506393, compound

HRID 1798909Notes

Reaction equation

HRID 1798909 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[C:19]([C:20]([O-:22])=O)=[C:18]([N:23]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:17]=[C:16]([S:41][CH3:42])[N:15]=1.O>O1CCCC1>[Cl:13][C:14]1[C:19]2[C:20](=[O:22])[CH:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34][CH2:33][N:23]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:18]=2[N:17]=[C:16]([S:41][CH3:42])[N:15]=1

Participants

6

Reactant 4

HCID 962WaterHCID 7912DiisopropylamineHCID 86645840HCID 86645840, compoundHCID 178418339Butyllithium

Product 1

HCID 59506393HCID 59506393, compoundYield 89.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To an ice-cooled solution of diisopropylamine (28.16 mL, 198.96 mmol) in tetrahydrofuran (400 mL) was added n-BuLi (15% in hexane, 82.5 mL, 192.93 mmol) dropwise and the mixture was then stirred at the 0° C. for 45 min. The reaction mixture was cooled to -78° C. and 4-chloro-6-((4-ethoxy-4-oxobutyl)(4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (29.0 g, 60.17 mmol) in tetrahydrofuran (300 mL) was added to the mixture dropwise over 45 min. and the reaction mixture was stirred at −78° C. for 15 min and ice cooled water (1 L) was added to the reaction mixture at same temperature. The reaction mixture was then warmed to room temperature and extracted with EtOAc (500 mL×2). The combined organic layer was washed with water (1 L), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford ethyl 4-chloro-9-(4-methoxybenzyl)-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepine-6-carboxylate (23.5 g); which was used in the next step without any purification. 1HNMR (400 MHz, CDCl3): δ 7.19 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.17 (d, J=14.8 Hz, 2H), 4.23-4.16 (d, J=14.8 Hz, 2H), 4.12-4.06 (m, 1H), 3.85-3.83 (m, 1H), 3.80 (s, 3H), 3.45-3.33 (m, 2H), 2.72-2.64 (m, 1H), 2.47 (s, 3H), 2.29-2.22 (m, 1H), 1.17 (t, J=7.2 Hz, 3H). LCMS [M+H]: 436

Workup

  1. temperatureThe reaction mixture was cooled to -78° C.
  2. stirringthe reaction mixture was stirred at −78° C. for 15 min
  3. additionwas added to the reaction mixture at same temperature
  4. temperatureThe reaction mixture was then warmed to room temperature
  5. extractionextracted with EtOAc (500 mL×2)
  6. washThe combined organic layer was washed with water (1 L)
  7. dry with materialdried over anhydrous sodium sulphate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-70178c77c041439f8663b4a0274650f6
Source dataset
uspto-grants-2013_01
Patent number
US08343983B2

Reaction notes

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