Water → 2-Isopropylaminothiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxyethoxy)phenyl]amide

HRID 1893696Notes

Reaction equation

HRID 1893696 reaction equation
[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].Br.[CH:20]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=1)([CH3:22])[CH3:21].P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[C:16]([C:3]1[C:2]([NH:1][C:29]([C:27]2[N:28]=[C:24]([NH:23][CH:20]([CH3:22])[CH3:21])[S:25][CH:26]=2)=[O:30])=[C:7]([Cl:8])[C:6]([O:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]

Participants

6

Reactant 4

HCID 962WaterHCID 24813Phosphorus oxychlorideHCID 119534892-(Isopropylamino)thiazole-4-carboxylic acid hydrobromideHCID 574451961-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone

Product 1

HCID 577850662-Isopropylaminothiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxyethoxy)phenyl]amideYield 85.7%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of 1-[2-amino-3-chloro-4-(2,2-dimethoxyethoxy)phenyl]ethanone (13 g, 47.5 mmol) and isopropylaminothiazole-4-carboxylic acid hydrobromide (prepared as described in Ivanov, V., et. al.; EP1881001A1, p. 62-63; 12.6 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at −40° C. The mixture was then stirred at 0° C. for 4 h. Upon completion of the reaction, H2O (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0° C. for another 15 min. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHCO3 aqueous solution. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH2Cl2, hexanes was added slowly to the solution, and a yellow solid started to crash out. More hexanes were added precipitation was complete to afford 2-isopropylaminothiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxyethoxy)phenyl]amide (18 g, 85% yield).

Workup

  1. customat −40° C
  2. additionwas added dropwise to the mixture
  3. stirringThe mixture was then stirred at 0° C. for another 15 min
  4. concentrationThe mixture was concentrated in vacuo
  5. additionThe residue was diluted with EtOAc
  6. washwashed with a sat. NaHCO3 aqueous solution
  7. dry with materialThe organic layer was dried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. dissolutionThe residue was dissolved in CH2Cl2
  10. additionhexanes was added slowly to the solution
  11. additionMore hexanes were added
  12. customprecipitation

Sources & evidence

ORD record
ord-bb650c1cc62c41f69ef806a2f0277212
Source dataset
uspto-grants-2013_08
Patent number
US08513186B2

Reaction notes

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