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Hydrochloric Acid → Ertiprotafib

HRID 1278825
Notes
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Reaction equation

HRID 1278825 reaction equation
C[O:2][C:3](=[O:37])[C@H:4]([O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[CH3:36])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+].Cl>O1CCCC1.CO.O>[Br:35][C:27]1[C:28]2[S:29][C:30]([CH3:34])=[C:31]([CH3:33])[C:32]=2[C:20]([C:16]2[CH:15]=[C:14]([CH3:36])[C:13]([O:12][C@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3]([OH:37])=[O:2])=[C:18]([CH3:19])[CH:17]=2)=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 70157633HCID 70157633, compound

Product 1

HCID 157049Ertiprotafib

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent
HCID 8028
Tetrahydrofuran
Solvent

Procedure

To a solution of (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid methyl ester (3.1 g, 5.4 mmol) in tetrahydrofuran (125 mL) and methanol (41 mL) at room temperature was added dropwise aqueous potassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol). After 1.5 h at room temperature the reaction mixture was placed in the freezer for 18 h. The reaction was removed from the freezer and allowed to stir at room temperature. More aqueous potassium hydroxide (19.5 mL of a 1N solution, 19.5 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 9.5 h. Concentration under reduced pressure gave a residue which was diluted with water (1 L). The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1, and extracted with diethyl ether (700 mL). The diethyl ether layer was washed twice with water (500 mL), and then dried (Na2SO4). Concentration under reduced pressure and chromatography on silica gel (treated with 2% phosphoric acid in methanol) with petroleum ether:ethyl acetate (90:10, then 86:14) gave the title compound as a white solid foam (1.9 g, 64%): Opt. Rot. [a]25/D=+33.380 (10.035 mg/mL, MeOH); NMR (DMSO-d6): δ 12.90 (broad singlet, 1H), 8.17 (d, 1H), 7.63 (ddd, 1H), 7.50-7.43 (m, 2H), 7.36-7.23 (m, 5H), 6.97 (s, 2H), 4.71 (t, 1H), 3.25 (d, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.54 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 558/560; Anal. Calc. for C31H27BrO3S: C, 66.55, H, 4.86, N, 0.00. Found: C, 65.91, H, 5.05, N, 0.09; Analytical HPLC indicates a major component (99.5%).

Workup

  1. customThe reaction was removed from the freezer
  2. additionMore aqueous potassium hydroxide (19.5 mL of a 1N solution, 19.5 mmol) was added
  3. stirringto stir at room temperature for 9.5 h
  4. concentrationConcentration under reduced pressure
  5. customgave a residue which
  6. extractionextracted with diethyl ether (700 mL)
  7. washThe diethyl ether layer was washed twice with water (500 mL)
  8. dry with materialdried (Na2SO4)
  9. concentrationConcentration under reduced pressure and chromatography on silica gel (treated with 2% phosphoric acid in methanol) with petroleum ether:ethyl acetate (90:10

Sources & evidence

ORD record
ord-0259d38b048c4e0c8fa615d912ac83a4
Source dataset
uspto-grants-2002_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06444670B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes