Methanol → (R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acid

HRID 546188Notes

Reaction equation

HRID 546188 reaction equation
[CH3:1][OH:2].[Na].Cl[C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:16](NC2C=CN(CCC(=O)N(C)C)N=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12].[OH2:37]>CS(C)=O>[CH:32]1([CH2:31][C@H:15]([C:7]2[CH:8]=[CH:9][C:10]([S:11]([CH3:14])(=[O:12])=[O:13])=[C:5]([O:2][CH3:1])[CH:6]=2)[C:16]([OH:17])=[O:37])[CH2:33][CH2:34][CH2:35][CH2:36]1

Participants

6

Reactant 4

HCID 887MethanolHCID 962WaterHCID 5360545SodiumHCID 671884802(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-dimethylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide

Product 1

HCID 67191012(R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acidYield 44%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
25 °C

Procedure

In a round bottom flask under argon was placed methanol (50 mL) and to it was added in small portions sodium metal (1.15 g, 45.35 mmol). This was stirred at 25° C. for 1 h. It was then concentrated in vacuo and azeotroped with acetonitrile. To this solid residue under argon was then added 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO200058293, Example 12, 3.00 g, 9.07 mmol) in dimethylsulfoxide (25 mL). This was then stirred and heated at 75° C. for 1 h. Let the solution cool back to 25° C. and then diluted it with water (120 mL). The solution was then filtered through celite and washed with water. The pH of the filterate was then adjusted pH=2 using a 1 N aqueous hydrochloric acid solution. It was then extracted with ethyl acetate (200 mL) and dried using sodium sulfate. The solution was filtered and concentrated in vacuo. The crude racemic material was then separated into the chiral components by supercritical fluid chromatography (SFC) on a Berger MultiGram II Supercritical Fluid Chromatography (SFC) system (Mettler-Toledo AutoChem Berger Instruments, Newark, Del.) (Chiral column: Daicel OJ-H, 250 mm×30 mm i.d., 5 μm-particle size, temperature: 35° C., flow rate of 70 mL/min, and 100 bar back pressure, 12% of a 1:1 ethanol/acetonitrile as mobile phase modifier and UV Detection: 220 nm) to afford (R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acid (second compound to elute, 1.31 g, 44%) as a white foam: [α]31589=−47.4° (c=0.23, methanol); ES-HRMS m/e calcd for C16H22O5S (M+H)+ 327.1261, observed 327.1262; 1H NMR (300 MHz, DMSO-d6) δ 1.10 (m, 2H, CH2), 1.36-1.81 (m, 8H, 4×CH2), 2.00 (m, 1H, CH), 3.22 (s, 3H, SO2CH3), 3.66 (t, J=7.7 Hz, 1H, ArCHCO), 3.95 (s, 3H, OCH3), 7.10 (dd, Jm=1.4 Hz, Jo=8.1 Hz, 1H, Ar), 7.22 (d, Jm=1.4 Hz, 1H, Ar), 7.74 (d, Jo=8.1 Hz, 1H, Ar), 12.56 (s, 1H, CO2H).

Workup

  1. customIn a round bottom flask under argon was placed
  2. concentrationIt was then concentrated in vacuo
  3. customazeotroped with acetonitrile
  4. stirringThis was then stirred
  5. temperatureheated at 75° C. for 1 h
  6. temperaturecool back to 25° C.
  7. filtrationThe solution was then filtered through celite
  8. washwashed with water
  9. extractionIt was then extracted with ethyl acetate (200 mL)
  10. customdried
  11. filtrationThe solution was filtered
  12. concentrationconcentrated in vacuo
  13. customThe crude racemic material was then separated into the chiral components by supercritical fluid chromatography (SFC) on a Berger MultiGram II Supercritical Fluid Chromatography (SFC) system (Mettler-Toledo AutoChem Berger Instruments, Newark, Del.) (Chiral column

Sources & evidence

ORD record
ord-dfdaa308d1114bf6a5328696cfd012f6
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

Loading…