Lithium Hydroxide → 3-(4-((3-(4-Ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid

HRID 2177239Notes

Reaction equation

HRID 2177239 reaction equation
[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[CH:18][C:17]=3[F:30])=[C:12]([C:31]([F:34])([F:33])[F:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C2C(CO)=C(C(F)(F)F)SN=2)=CC=1)C.FC1C=C(CC(C)C(OCC)=O)C=CC=1O.[Li+].[OH-]>O.O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[CH:18][C:17]=3[F:30])=[C:12]([C:31]([F:32])([F:34])[F:33])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 70640794Ethyl 3-(3-fluoro-4-hydroxyphenyl)-2-methylpropanoateHCID 90418304HCID 90418304, compoundHCID 90418374Ethyl 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3-fluorophenyl)-2-methylpropanoate

Product 1

HCID 904181263-(4-((3-(4-Ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Into a 50-mL round-bottom flask, was placed ethyl 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3-fluorophenyl)-2-methylpropanoate (74 mg, 0.15 mmol, 1.00 equiv) (prepared according to the procedure of Example 1 step 5 by coupling (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and ethyl 3-(3-fluoro-4-hydroxy phenyl)-2-methylpropanoate), tetrahydrofuran (1.5 mL). This was followed by the addition of a solution of LiOH (74 mg, 3.09 mmol, 20.69 equiv) in water (1.5 mL) dropwise with stirring. The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. Hydrogen chloride (2N) was employed to adjust the pH to 1. The solids were collected by filtration. The crude product (35 mg) was purified by Prep-HPLC with the following conditions (1# water 2767-16): Column, SunFire Prep C18 Sum, 19*150 nm; mobile phase, water with 0.05% trifluoroacetic acid and CH3CN. (70% CH3CN up to 90% in 7.0 min, up to 100% in 2.0 min, down to 70% in 2.0 min); Detector, 254 nm. This resulted in 3.4 mg (5%) of 3-(4-((3-(4-ethylphenyl)-5-(trifluoro methyl)isothiazol-4-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid as a white solid. 1H NMR (300 Hz, CD3OD): 7.64 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 6.92-7.03 (m, 3H), 5.14 (s, 2H), 2.89-2.97 (m, 1H), 2.62-2.75 (m, 4H), 1.27 (t, J=7.8 Hz, 3H), 1.16 (d, J=3.3 Hz, 3H). 19F NMR (300 Hz, CD3OD): δ−56.57, −76.95, −135.59. Mass spectrum (ESI, m/z): Calcd. for C24H21.5F5.5NO4S, 468.1 (M-0.5CF3COOH+H). found 468.1.

Workup

  1. customInto a 50-mL round-bottom flask, was placed
  2. stirringThe resulting solution was stirred overnight at 25° C
  3. concentrationThe resulting mixture was concentrated under vacuum
  4. filtrationThe solids were collected by filtration
  5. customThe crude product (35 mg) was purified by Prep-HPLC with the following conditions (1# water 2767-16)
  6. waitup to 100% in 2.0 min
  7. waitdown to 70% in 2.0 min)
  8. customThis resulted in 3.4 mg (5%) of 3-(4-((3-(4-ethylphenyl)-5-(trifluoro methyl)isothiazol-4-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid as a white solid

Sources & evidence

ORD record
ord-332fe71c240e47cba048137b000731bc
Source dataset
uspto-grants-2015_06
Patent number
US09067898B1

Reaction notes

Loading…