Diisopropylethylamine → (3R,5R)-1-(((S)-7-(trifluoromethyl)chroman-4-yl)carbamoyl)-5-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-3-yl acetate

HRID 2063471Notes

Reaction equation

HRID 2063471 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.[C:41]([O:44][C@@H:45]1[CH2:49][C@H:48]([C:50]2[N:54]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=3)[C:53]([CH3:63])=[N:52][N:51]=2)N[CH2:46]1)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:44][C@@H:45]1[CH2:49][C@H:48]([C:50]2[N:54]([CH2:55][C:56]3[CH:57]=[CH:58][C:59]([Cl:62])=[CH:60][CH:61]=3)[C:53]([CH3:63])=[N:52][N:51]=2)[N:37]([C:38](=[O:39])[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)[CH2:46]1)(=[O:43])[CH3:42]

Participants

7

Reactant 5

HCID 81531Diisopropylethylamine2×HCID 94429TriphosgeneHCID 105034IsocyanateHCID 46911908(S)-7-(trifluoromethyl)chroman-4-amineHCID 68813707(3R,5R)-5-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-3-yl acetate hydrochloride

Product 1

HCID 68811435(3R,5R)-1-(((S)-7-(trifluoromethyl)chroman-4-yl)carbamoyl)-5-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-3-yl acetateYield 100%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a stirring solution of triphosgene (23 mg, 0.078 mmol) in dichloromethane (0.5 ml) was slowly added dropwise via syringe a premixed solution of (S)-7-(trifluoromethyl)chroman-4-amine (45 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.073 ml, 0.42 mmol) dissolved in dichloromethane (0.8 ml). The reaction mixture was stirred at room temperature for 15 minutes. The isocyanate thereby generated was then treated dropwise with a solution of (3R,5R)-5-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-3-yl acetate hydrochloride from Step E (70 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.073 ml, 0.42 mmol) dissolved in dichloromethane (0.8 ml). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 10% aqueous KHSO4, 5% aqueous NaHCO3, and brine, dried (Na2SO4), filtered and concentrated to yield an oil (120 mg, 100%) which was used without further purification in the next reaction.

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 10% aqueous KHSO4, 5% aqueous NaHCO3, and brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-ecb59bfe7c9c462da7d72f365d4fa897
Source dataset
uspto-grants-2012_10
Patent number
US08288371B2

Reaction notes

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