Phosphorus oxychloride → HCID 90040707, compound

HRID 1485902Notes

Reaction equation

HRID 1485902 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:20]

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 796472,6-DifluoroanilineHCID 664088(3S)-2-((tert-butoxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

Product 1

HCID 90040707HCID 90040707, compoundYield 32.1%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a solution of (S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (200 mg, 721 μmol, Eq: 1.00) and 2,6-difluoroaniline (121 mg, 101 μL, 938 μmol, Eq: 1.3) in pyridine (2 mL) at 0° C. was added dropwise phosphorus oxychloride (166 mg, 101 μL, 1.08 mmol, Eq: 1.5). The cooling bath was removed and the reaction stirred at RT overnight. The reaction mixture was concentrated in vacuo and water was added to the residue. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with 0.1 M HCl, 0.1 M NaOH, and brine and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-tert-butyl 3-(2,6-difluorophenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a colorless oil (90 mg), m/z=411 (M+Na).

Workup

  1. customThe cooling bath was removed
  2. concentrationThe reaction mixture was concentrated in vacuo and water
  3. additionwas added to the residue
  4. extractionThe resulting mixture was extracted with EtOAc
  5. washthe combined organic layers were washed with 0.1 M HCl, 0.1 M NaOH, and brine
  6. concentrationconcentrated in vacuo
  7. customThe crude material was purified by flash chromatography

Sources & evidence

ORD record
ord-b7bca7e37b9e404a87465c45ff00a574
Source dataset
uspto-grants-2016_08
Patent number
US09422332B2

Reaction notes

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