1H-BenziMidazole, 2-(6-fluoro-3-pyridinyl)-6-(trifluoroMethyl)- synthesis
- Product Name:1H-BenziMidazole, 2-(6-fluoro-3-pyridinyl)-6-(trifluoroMethyl)-
- CAS Number:947144-28-7
- Molecular formula:C9H8F3NO4
- Molecular Weight:251.16
947144-30-1
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Yield:-
Reaction Conditions:
Stage #1:3-(2-ethoxycarbonylacetylamino)-4,4,4-trifluorobut-2-enoic acid ethyl ester with potassium tert-butylate in ethanol at 60 - 80; for 4 h;
Stage #2: with citric acid in water
Steps:
1
To dissolve 3-Amino-4,4,4-trifluorocrotonic acid ethyl ester(100 g/546 mmol) in dichloromethane (600 ml_) was added pyridine (53 mU660 mmol). Placed under nitrogen and cooled to 5°C by suspending in an ice-bath. Ethyl malonyl chloride was added dropwise over approx 1 hr such that temperature did not exceed 20°C. Resulting pale brown solution was stirred at 5°C for 3 hrs then allowed to warm to room temperature overnight to give a dark green solution. Washed with 1M HCI(aq) (200 ml_) then saturated NaHCO3(aq) (250 ml_). Aqueous washings sequentially re- extracted with further dichloromethane (2x250ml_). Organics combined, dried over Na2SO4, filtered and concentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl- acetylamino)-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175 g). A portion of the crude (120 g) was dissolved in ethanol (300 ml.) and placed under nitrogen. Potassium tert- butoxide (54 g/480 mmol) was added in several portions such that temperature did not exceed 60°C resulting in a purple solution. Heated at 70°C for 3 hrs. Added ethanol (100 ml_) to reduce viscosity and heated at 80°C for a further hour. Allowed to cool and concentrated in vacuoXo a red solid. Dissolved in water (500 ml_) and added citric acid (180 g) causing precipitation. Added ethyl acetate (600 ml_). Poured into separating funnel and ran off aqueous. The organic layer containing much undissolved solid was filtered to give the title compound (46.5 g) as a white solid. Concentration of the organic filtrate and trituration with methanol afforded 2,4-dihydroxy-6-trifluoromethyl- nicotinic acid ethyl ester (15.3 g) as a white solid.
References:
PFIZER PRODUCTS INC. WO2008/47201, 2008, A2 Location in patent:Page/Page column 31