Thiophosgene → (R)-2-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrrolidine-1-carbothioamide

HRID 2063499Notes

Reaction equation

HRID 2063499 reaction equation
[C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[N:7]=1.C(N(CC)C(C)C)(C)C.Cl.[Cl:27][C:28]1[CH:46]=[CH:45][C:31]([CH2:32][N:33]2[C:37]([C@H:38]3[CH2:42][CH2:41][CH2:40][NH:39]3)=[N:36][N:35]=[C:34]2[CH2:43]C)=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:27][C:28]1[CH:46]=[CH:45][C:31]([CH2:32][N:33]2[C:34]([CH3:43])=[N:35][N:36]=[C:37]2[C@H:38]2[CH2:42][CH2:41][CH2:40][N:39]2[C:1](=[S:2])[NH:12][C:11]2[C:6]([CH3:5])=[N:7][C:8]([C:13]([F:14])([F:16])[F:15])=[CH:9][CH:10]=2)=[CH:30][CH:29]=1

Participants

8

Reactant 5

HCID 10040ThiophosgeneHCID 81531Diisopropylethylamine2×HCID 516892Sodium BicarbonateHCID 35218502-methyl-6-(trifluoromethyl)pyridin-3-amineHCID 68811647(R)-4-(4-chlorobenzyl)-3-ethyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole HCl salt

Product 1

HCID 57650139(R)-2-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrrolidine-1-carbothioamideYield 26.9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
0 °C

Procedure

To a stirring solution of thiophosgene (0.23 mL, 3 mmol) in 50 mL of CH2Cl2 at 0° C. was added dropwise a mixed solution of 2-methyl-6-(trifluoromethyl)pyridin-3-amine (0.528 g, 3 mmol) and N,N-diisopropylethylamine (0.522 mL, 3 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 0° C., warming up to room temperature within an hour. Then the mixture was cooled at 0° C. and to it was added a solution of the (R)-4-(4-chlorobenzyl)-3-ethyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole HCl salt (1.05 g, 3 mmol) and N,N-diisopropylethylamine (1.044 mL, 6 mmol) in dichloromethane (10 mL) slowly. The resulting mixture was stirred 0° C. for 30 minutes, then at room temperature overnight. The reaction mixture was treated with sat. aqueous NaHCO3 (10 mL) and brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification (Hex/EtOAc with 10% of MeOH) afforded the desired product as yellow solid (0.4 g, 26.9%).

Workup

  1. temperaturewarming up to room temperature within an hour
  2. temperatureThen the mixture was cooled at 0° C. and to it
  3. stirringThe resulting mixture was stirred 0° C. for 30 minutes
  4. customat room temperature
  5. customovernight
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customFlash chromatography purification (Hex/EtOAc with 10% of MeOH)

Sources & evidence

ORD record
ord-463794765f4c4cf28c6f671ddfc22ad9
Source dataset
uspto-grants-2012_10
Patent number
US08288371B2

Reaction notes

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