Hydrochloric Acid → (S)-1-[3-(2',4'-difluoro-biphenyl-4-yloxymethyl)-benzoyl]-pyrrolidine-2-carboxylic acid

HRID 1665250Notes

Reaction equation

HRID 1665250 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20](O)=[O:21])=[CH:11][CH:10]=1.S(Cl)(Cl)=O.[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33].C([O-])([O-])=O.[Na+].[Na+].Cl>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([N:30]2[CH2:37][CH2:36][CH2:35][C@H:31]2[C:32]([OH:34])=[O:33])=[O:21])=[CH:13][CH:14]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 24386Thionyl ChlorideHCID 145742L-ProlineHCID 582711993-(2',4'-Difluoro-biphenyl-4-yloxymethyl)-benzoic acid

Product 1

HCID 46926372(S)-1-[3-(2',4'-difluoro-biphenyl-4-yloxymethyl)-benzoyl]-pyrrolidine-2-carboxylic acidYield 90.8%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

3-(2′,4′-Difluoro-biphenyl-4-yloxymethyl)-benzoic acid (4.0 g, 11.76 mmol) in 125 mL toluene was treated with thionyl chloride (8.28 mL, 117.6 mmol) and DMF (200 uL) was heated to 80-90° C. for 3 hrs. The reaction mixture was cooled, evaporated and re-evaporated from toluene 4 times to give a yellow oil that crystallized by pumping under high vacuum. This acid chloride was dissolved in 160 mL acetonitrile to which was added a solution of L-proline (2.62 g, 22.8 mmol) in 33 mL H2O and 1N Na2CO3 (22.8 mL, 22.8 mmol). The reaction mixture was stirred at RT for 45 min, diluted with 300 mL H2O and 450 mL ethyl acetate. The mixture was acidified to pH 2 with 1N HCl. The ethyl acetate layer was separated, washed with H2O, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography with a 0-90% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in hexanes to yield 4.67 g (90.8%) of (S)-1-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-benzoyl]-pyrrolidine-2-carboxylic acid as a white solid. LC-MS (ES) calculated for C25H21F2NO4, 437.45; found m/z 438.1 [M+H]+.

Workup

  1. temperatureThe reaction mixture was cooled
  2. customevaporated
  3. customre-evaporated from toluene 4 times
  4. customto give a yellow oil
  5. customthat crystallized
  6. dissolutionThis acid chloride was dissolved in 160 mL acetonitrile to which
  7. customThe ethyl acetate layer was separated
  8. washwashed with H2O
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated in vacuo
  11. customThe crude product was purified by flash chromatography with a 0-90% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in hexanes

Sources & evidence

ORD record
ord-46be9ad0468048c7817b53ac5adedc17
Source dataset
uspto-grants-2011_10
Patent number
US08039495B2

Reaction notes

Loading…