Diisopropylethylamine → (R)-2-(4-(4-chlorobenzyl)-5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)-N-((S)-7-(trifluoromethyl)chroman-4-yl)pyrrolidine-1-carboxamide

HRID 2063465Notes

Reaction equation

HRID 2063465 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.Cl.[Cl:38][C:39]1[CH:57]=[CH:56][C:42]([CH2:43][N:44]2[C:48]([C@H:49]3[CH2:53][CH2:52][CH2:51][NH:50]3)=[N:47][N:46]=[C:45]2[CH2:54][OH:55])=[CH:41][CH:40]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:38][C:39]1[CH:57]=[CH:56][C:42]([CH2:43][N:44]2[C:45]([CH2:54][OH:55])=[N:46][N:47]=[C:48]2[C@H:49]2[CH2:53][CH2:52][CH2:51][N:50]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:41][CH:40]=1

Participants

8

Reactant 5

HCID 81531Diisopropylethylamine2×HCID 94429TriphosgeneHCID 516892Sodium BicarbonateHCID 46911908(S)-7-(trifluoromethyl)chroman-4-amineHCID 68811325(R)-(4-(4-chlorobenzyl)-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole-3-yl)methanol HCl salt

Product 1

HCID 57650267(R)-2-(4-(4-chlorobenzyl)-5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)-N-((S)-7-(trifluoromethyl)chroman-4-yl)pyrrolidine-1-carboxamideYield 246.3%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
0 °C

Procedure

To a stirring solution of triphosgene (14.87 mg, 0.05 mmol) in 8 mL of CH2Cl2 at 0° C. was added dropwise a mixed solution of (S)-7-(trifluoromethyl)chroman-4-amine (32.58 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.07841 mL, 0.45 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at 0° C. for 30 minutes. Then to the mixture at 0° C. was added a solution of the (R)-(4-(4-chlorobenzyl)-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole-3-yl)methanol HCl salt (54.86 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.07841 mL, 0.45 mmol) in dichloromethane (2 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 gradient, 10-100% EtOAc with 10% MeOH) afforded the desired product as white solid (66 mg, 82.1%).

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% MeOH)

Sources & evidence

ORD record
ord-d129e0ff4e12416899010a663ecead5a
Source dataset
uspto-grants-2012_10
Patent number
US08288371B2

Reaction notes

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