Hydrochloric Acid → 649551-06-4

HRID 2376250Notes

Reaction equation

HRID 2376250 reaction equation
C([O:3][C:4](=[O:35])[CH:5]([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)C.Cl.CCOC(C)=O>P([O-])([O-])([O-])=O.CC(O)C.C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[N:9]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:8]=[C:7]([CH2:6][C@@H:5]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:4]([OH:35])=[O:3])[CH:11]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 8857Ethyl AcetateHCID 23568907HCID 23568907, compound

Product 1

HCID 11488979649551-06-4Yield 40.3%

Reagents, catalysts & solvents 2

HCID 1061PhosphateSolventHCID 21881414Toluene isopropyl alcoholSolvent

Procedure

To a stirred solution of the Altus catalyst #8 (10.0 g) in phosphate buffer (pH 7, 500 mL) was slowly added 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester from Example 508 (10.0 g, 0.0196 mol) in IPA/toluene (40 mL/15 mL) for over 30 min to form a slurried reaction mixture. The reaction was monitored at 2 day intervals using chiral HPLC. After 24 days, the reaction mixture was adjusted to pH 1-2 using 1 N HCl, and then EtOAc (300 mL) was added. The mixture was stirred vigorously for 1 h. The emulsion was filtered through a pad of CELITE®, washing with EtOAc (75 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to an oil. The crude oil was purified by filtration chromatography (silica gel column: 14 cm OD, 10 cm in height, 1% MeOH/20% EtOAc/hexanes). After the unreacted pyrazole ester (4:1 R/S) was recovered (6.0 g, 60%), the eluent was changed to 2-3% MeOH/50% EtOAc/hexanes to obtain the desired pyrazole acid (3.8 g, 40%) as an oil. Chiral HPLC (Method S): R1 (S enantiomer)=8.1 min. MS (ES+): mass calculated for C26H22Cl2N2O3, 480.10; m/z found, 480.8 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.31-7.09 (m, 8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H), 4.12-4.08 (dd, J=9.6, 5.8 Hz, 1H), 3.82 (s, 3H), 3.54-3.49 (dd, J=14.9, 9.6 Hz, 1H), 3.13-3.08 (dd, J=14.9, 5.8 Hz, 1H), 2.35 (s, 3H).

Workup

  1. customfor over 30 min
  2. customto form a slurried reaction mixture
  3. waitAfter 24 days
  4. filtrationThe emulsion was filtered through a pad of CELITE®
  5. washwashing with EtOAc (75 mL)
  6. customThe filtrate was transferred to a separatory funnel
  7. customthe layers were separated
  8. extractionThe aqueous layer was extracted with EtOAc (2×75 mL)
  9. dry with materialThe combined organic layers were dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated to an oil
  12. filtrationThe crude oil was purified by filtration chromatography (silica gel column: 14 cm OD, 10 cm in height, 1% MeOH/20% EtOAc/hexanes)
  13. customAfter the unreacted pyrazole ester (4:1 R/S) was recovered (6.0 g, 60%)

Sources & evidence

ORD record
ord-6f63b29d76ce443cb21cf5c1078014c4
Source dataset
uspto-grants-2008_12
Patent number
US07465808B2

Reaction notes

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