Triethylamine → Ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfanyl)pyrimidine-5-carboxylate

HRID 917587Notes

Reaction equation

HRID 917587 reaction equation
[CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([Cl:15])[CH:17]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 800084-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl esterHCID 7380383-Chloro-4-methoxybenzylamine

Product 1

HCID 22025927Ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfanyl)pyrimidine-5-carboxylateYield 91.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
47.5 °C

Procedure

(1)-b) To a stirred suspension of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine (145.0 g, 0.62 mol) and (3-chloro-4-methoxyphenyl)methylamine (129.0 g, 0.62 mol) in dimethylformamide (435 ml) is added triethylamine (131.8 g, 1.30 mol) below 20° C. The mixture is stirred at the same temperature for about an hour. After the completion of the reaction, ethyl acetate (1450 ml) and water (870 ml) are added to the reaction mixture and stirred. The organic layer is separated and washed with water (870 ml) and a solution of sodium chloride (72.5 g) in water (290 ml), and dried over anhydrous magnesium sulfate (29.0 g). After removal of the drying agent by filtration and washed with ethyl acetate (145 ml), the filtrate and washings are combined and concentrated under reduced pressure. The resultant solid is suspended in 2-propanol (145 ml) and the mixture is concentrated under reduced pressure. The resultant solid is dissolved in hot 2-propanol (1450 ml) and the solution is seeded with 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine crystals at 55° C. The mixture is cooled down to 45-50° C. and continuously stirred at the same temperature for more than an hour. Then the mixture is cooled down below 10° C. and continuously stirred for more than 30 minutes. The precipated crystals are collected by filtration, washed with 2-propanol (145 ml) and dried at 50° C. for about 16 hours to produce 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine (209.2 g, 91%). mp. 86-88° C.

Workup

  1. additionare added to the reaction mixture
  2. stirringstirred
  3. customThe organic layer is separated
  4. washwashed with water (870 ml)
  5. dry with materiala solution of sodium chloride (72.5 g) in water (290 ml), and dried over anhydrous magnesium sulfate (29.0 g)
  6. customAfter removal of the drying agent
  7. filtrationby filtration
  8. washwashed with ethyl acetate (145 ml)
  9. concentrationconcentrated under reduced pressure
  10. concentrationthe mixture is concentrated under reduced pressure
  11. dissolutionThe resultant solid is dissolved in hot 2-propanol (1450 ml)
  12. customis seeded with 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine crystals at 55° C
  13. stirringcontinuously stirred at the same temperature for more than an hour
  14. temperatureThen the mixture is cooled down below 10° C.
  15. stirringcontinuously stirred for more than 30 minutes
  16. filtrationThe precipated crystals are collected by filtration
  17. washwashed with 2-propanol (145 ml)
  18. customdried at 50° C. for about 16 hours

Sources & evidence

ORD record
ord-023208cdbba0487083bbbdaf22d77878
Source dataset
uspto-grants-2007_09
Patent number
US07273868B2

Reaction notes

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