Methyl Salicylate → (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester

HRID 458351Notes

Reaction equation

HRID 458351 reaction equation
Cl[C:2]([O:5]C(Cl)=O)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[F:19][C:20]1[CH:53]=[C:52]([F:54])[C:51]([F:55])=[CH:50][C:21]=1[CH2:22][O:23][CH2:24][C@@H:25]1[CH2:29][C@@H:28]([S:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][NH:26]1.[C:56]([O:65][CH3:66])(=[O:64])[C:57]1[C:58](=[CH:60][CH:61]=[CH:62][CH:63]=1)[OH:59].[H-].[Na+]>C(Cl)Cl>[CH3:66][O:65][C:56]([C:57]1[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=1[O:59][C:2]([N:26]1[CH2:27][C@H:28]([S:30][C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:29][C@H:25]1[CH2:24][O:23][CH2:22][C:21]1[CH:50]=[C:51]([F:55])[C:52]([F:54])=[CH:53][C:20]=1[F:19])=[O:5])=[O:64]

Participants

7

Reactant 5

HCID 4133Methyl SalicylateHCID 7047QuinolineHCID 10426DiphosgeneHCID 24758Sodium hydride2×HCID 11398267(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine

Product 1

HCID 11331466(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl esterYield 125.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of 0.07 ml (0.55 mmol) trichloromethyl-chloroformate in 7 ml CH2Cl2 was treated at 0° C. with 0.13 ml (1.1 mmol) quinoline and after 15 min with 0.52 g (1 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine in 7 ml CH2Cl2. After 2 h at 0° C. the CH2Cl2 was evaporated. The residue was dissolved in 15 ml THF, treated at 0° C. with 0.27 ml (2.1 mmol) methyl salicylate, 96 mg (2.4 mmol) of 55% NaH and 166 mg (1 mmol) of KI. The reaction was stirred at room temperature over night, cooled (0° C.) and after the addition of 44 mg (1 mmol) of 55% NaH refluxed for 3 h. The reaction was partitioned between aqueous 10% KHSO4/EtOAc (3×300). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography on silica gel (Hexane/EtOAc 9:1) gave 0.48 g (69%) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester, MS: 698 (MH+).

Workup

  1. customAfter 2 h at 0° C. the CH2Cl2 was evaporated
  2. dissolutionThe residue was dissolved in 15 ml THF
  3. temperaturecooled (0° C.)
  4. temperaturerefluxed for 3 h
  5. customThe reaction was partitioned between aqueous 10% KHSO4/EtOAc (3×300)
  6. washThe organic phases were washed with aqueous 10% NaCl
  7. dry with materialdried (Na2SO4)
  8. customevaporated

Sources & evidence

ORD record
ord-0be0adf144d54558bc24f684cd8360bb
Source dataset
uspto-grants-2007_03
Patent number
US07189756B2

Reaction notes

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