(Z)-2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic Acid → Aleglitazar

HRID 902457Notes

Reaction equation

HRID 902457 reaction equation
[CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[H][H]>>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]

Participants

3

Reactant 2

HCID 54578728(Z)-2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic AcidHCID 178418361HCID 178418361, compound

Product 1

HCID 10274777Aleglitazar

Procedure

In an analogous manner to Example 10, 2.5 g (5.74 mmol) of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid were asymmetrically hydrogenated in the presence of 3.22 mg of [Ru(OAc)2((S)-6-MeO-2-naphthyl)-MeOBIPHEP)] (S/C molar ratio 2000) at 40° C. under 15 bar of hydrogen for 24 h to reach 99.6% conversion. Rotary evaporation of the reaction mixture afforded quantitatively (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid of 75.8% ee with 98.5% purity (HPLC area). To a solution of 6.50 g (15.8 mmol) of crude product in 33 ml of tetrahydrofuran was added dropwise at reflux (63-65%° C.) under stirring a solution of 1.91 g (15.6 mmol) of (S)-phenyl ethylamine (commercially available from Fluka) in 3 ml of tetrahydrofuran. Addition of seed crystals and turning off the bath heating brought about the start of the crystallization. The crystallization was completed over night at room temperature, the white crystals were filtered off, washed with 20 ml of cold (−20° C.) tetrahydrofuran and dried to constant weight (50° C./10 mbar/6h) to afford 6.57 g (79.2%) of (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid as (S)-phenyl ethylamine salt of 96.3% ee with 99.9% purity (HPLC area), with a mp. of 157-159.5° C.

Workup

  1. customat 40° C.
  2. customfor 24 h
  3. customRotary evaporation of the reaction mixture

Sources & evidence

ORD record
ord-5ad16b08ff654b1d814303d3739171e3
Source dataset
uspto-grants-2008_04
Patent number
US07365207B2

Reaction notes

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