Hydrochloric Acid → Aleglitazar

HRID 2098337Notes

Reaction equation

O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H].Cl>C(OCC)(=O)C.O.O1CCCC1.CO>[CH3:3][O:4][C@@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]

Participants

Conditions

Temperature: 55 °C

Procedure

In a glove box (O2 content≦2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 2.70 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0023 mmol, S/C 2,000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run under 30 bar of hydrogen at 60° C. for 20 h and subsequently at 80° C. for 2 h. Then the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 89.9% (>99.9% conversion) and an enantiomeric purity of 99.8%. The crude product was dissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2M aqueous HCl were added and the biphasic mixture was stirred at 55° C. for 15 min. The organic layer was separated, the aqueous layer extracted with 20 ml of ethyl acetate and the combined organic layers stirred over 0.5 g of carcoal (Darko KB) at r.t. for 2 h. After filtration over celite, the colorless solution was dried over 3 g of sodium sulfate and evaporated to dryness (40° C./10 mbar). The crude product was dissolved in 50 ml of isopropyl acetate at reflux (oil bath temp. 100° C.) and allowed to cool to room temperature whereby crystallization started spontaneously. The formed crystals were filtered off, washed with 10 ml of isopropyl acetate and dried at 75° C./500 mbar for 4 h to yield 1.60 g (79%) of pure (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white crystals with a chemical purity of 99.6% and an enantiomeric purity of 99.8% ee.

Workup

customThe autoclave was sealed
customthe yellowish solution was rotary evaporated to dryness (50° C./5 mbar)
customto afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 89.9% (>99.9% conversion)
customThe organic layer was separated
extractionthe aqueous layer extracted with 20 ml of ethyl acetate
stirringthe combined organic layers stirred over 0.5 g of carcoal (Darko KB) at r.t. for 2 h
filtrationAfter filtration over celite
dry with materialthe colorless solution was dried over 3 g of sodium sulfate
customevaporated to dryness (40° C./10 mbar)
dissolutionThe crude product was dissolved in 50 ml of isopropyl acetate
temperatureat reflux (oil bath temp. 100° C.)
temperatureto cool to room temperature
customwhereby crystallization
filtrationThe formed crystals were filtered off
washwashed with 10 ml of isopropyl acetate
customdried at 75° C./500 mbar for 4 h

Sources & evidence

ORD record: ord-5bc82a8ef475440bbcae600ad756a203
Source dataset: uspto-grants-2013_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08450496B2

Reaction notes

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