Diisopropylethylamine → (R)-2-(4-(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl)-N-((S)-7-(trifluoromethyl)chroman-4-yl)pyrrolidine-1-carboxamide

HRID 2063458Notes

Reaction equation

HRID 2063458 reaction equation
Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:24]=[C:23]2[C:18]([C@@H:19]([NH2:25])[CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.[Cl:44][C:45]1[CH:61]=[CH:60][C:48]([CH2:49][N:50]2[CH:54]=[N:53][N:52]=[C:51]2[C@H:55]2[CH2:59][CH2:58][CH2:57][NH:56]2)=[CH:47][CH:46]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:44][C:45]1[CH:61]=[CH:60][C:48]([CH2:49][N:50]2[CH:54]=[N:53][N:52]=[C:51]2[C@H:55]2[CH2:59][CH2:58][CH2:57][N:56]2[C:2]([NH:25][C@@H:19]2[C:18]3[C:23](=[CH:24][C:15]([C:14]([F:13])([F:26])[F:27])=[CH:16][CH:17]=3)[O:22][CH2:21][CH2:20]2)=[O:4])=[CH:47][CH:46]=1

Participants

8

Reactant 5

HCID 81531Diisopropylethylamine2×HCID 94429TriphosgeneHCID 516892Sodium BicarbonateHCID 46911908(S)-7-(trifluoromethyl)chroman-4-amineHCID 86629195(R)-4-(4-chlorobenzyl)-3-(pyrrolidin-2-yl)-4H-1,2,4-triazole TFA salt

Product 1

HCID 57650035(R)-2-(4-(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl)-N-((S)-7-(trifluoromethyl)chroman-4-yl)pyrrolidine-1-carboxamideYield 52.6%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
0 °C

Procedure

To a stirring solution of triphosgene (0.0205 g, 0.691 mmol) in 8 mL of CH2Cl2 at 0° C. was added dropwise a mixed solution of (S)-7-(trifluoromethyl)chroman-4-amine (44.91 mg, 0.2068 mmol) and N,N-diisopropylethylamine (0.108 mL, 0.620 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at 0° C. for 30 minutes. Then to the mixture at 0° C. was slowly added a solution of the (R)-4-(4-chlorobenzyl)-3-(pyrrolidin-2-yl)-4H-1,2,4-triazole TFA salt (0.125 g, 0.2068 mmol) and N,N-diisopropylethylamine (0.108 mL, 0.620 mmol) in dichloromethane (2 mL). 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 gradient, 10-100% EtOAc with 10% of MeOH) afforded the desired product (55 mg, 52.6%).

Workup

  1. stirringThe resulting mixture was stirred 0° C. for 30 minutes
  2. customat room temperature
  3. customovernight
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customFlash chromatography purification (Hex/EtOAc gradient, 10-100% EtOAc with 10% of MeOH)

Sources & evidence

ORD record
ord-bd40fc2f7c7d4283a8813b0103b154fb
Source dataset
uspto-grants-2012_10
Patent number
US08288371B2

Reaction notes

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