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

HRID 2063481Notes

Reaction equation

HRID 2063481 reaction equation
ClC(Cl)(OC(=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.[N-:37]=[C:38]=[O:39].[Cl:40][C:41]1[CH:58]=[CH:57][C:44]([CH2:45][N:46]2[C:50]([C@H:51]3[CH2:55][CH2:54][CH2:53]N3)=[N:49][C:48]([CH3:56])=[N:47]2)=[CH:43][CH:42]=1>ClCCl>[Cl:40][C:41]1[CH:58]=[CH:57][C:44]([CH2:45][N:46]2[C:50]([C@H:51]3[CH2:55][CH2:54][CH2:53][N:37]3[C:38]([NH:25][C@@H:19]3[C:18]4[C:23](=[CH:24][C:15]([C:14]([F:13])([F:26])[F:27])=[CH:16][CH:17]=4)[O:22][CH2:21][CH2:20]3)=[O:39])=[N:49][C:48]([CH3:56])=[N:47]2)=[CH:43][CH:42]=1

Participants

7

Reactant 5

HCID 81531Diisopropylethylamine2×HCID 94429TriphosgeneHCID 105034IsocyanateHCID 46911908(S)-7-(trifluoromethyl)chroman-4-amineHCID 57650059(R)-1-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-1H-1,2,4-triazole

Product 1

HCID 57650243(R)-2-(2-(4-chlorobenzyl)-5-methyl-2H-1,2,4-triazol-3-yl)-N-((S)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl)pyrrolidine-1-carboxamideYield 15%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a stirring solution of triphosgene (18 mg, 0.06 mmol) in dichloromethane (3 ml) was slowly added dropwise via syringe a premixed solution of (S)-7-(trifluoromethyl)chroman-4-amine (39 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.069 ml) dissolved in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 30 minutes. The isocyanate thereby generated was then treated dropwise with a solution of (R)-1-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-1H-1,2,4-triazole (52 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.067 ml, 0.4 mmol) dissolved in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC yielded a clear oil (14 mg, 15%)

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 16 h
  2. customThe reaction mixture was evaporated to dryness
  3. additiondiluted with EtOAc
  4. washwashed with 5% aqueous NaHCO3 and brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification by preparative HPLC

Sources & evidence

ORD record
ord-fb594d5674e549a188718983c11056d9
Source dataset
uspto-grants-2012_10
Patent number
US08288371B2

Reaction notes

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