Triethylamine → HCID 22280146, compound

Temperature

90 °C

Preparation of [5-Methoxy-2-methyl-4-(2′,4′,6′-trimethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 5A) 2-Bromo-1,3,5-trimethyl-benzene (396 mg, 2mmol), 4-hydroxymethylphenylboronic acid (334 mg, 2.2 mmol), cesium carbonate (1.3 g, 4 mmol), and PdCl2(dppf) (82 mg, 0.1 mmol) were added to 5 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90° C. for 1 h. The reaction was cooled, poured into diethyl ether and washed with water (2×10 ml), brine (1×10 ml) and dried over anhydrous sodium sulfate. The organic solution was filtered through silica gel, eluted with diethyl ether, and concentrated. The crude product was dissolved in 10 ml dichloromethane. Added to this solution were triethylamine (202 mg, 2 mmol) then methanesulfonyl chloride (184 mg, 1.6 mmol) and allowed to stir at ambient temperature for 18 h. The reaction was poured into water and extracted with methylene chloride. The organic solution was dried over anhydrous sodium sulfate, decanted and concentrated to provide the crude alkyl chloride. The product from Example 1D (387 mg, 1.6 mmol), the crude 4′-chloromethyl-2,4,6-trimethyl-biphenyl, and cesium carbonate (1 g, 3.06 mmol) were stirred in 10 ml acetonitrile for 3 h, filtered, concentrated, and purified by normal phase chromatography to afford the title product. MS m/z 451 (M+1). Step 2. Preparation of [5-Methoxy-2-methyl-4-(2′,4′,6′-trimethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid The title compound was prepared in the manner analogous to Example 1 using 5A. mp 141° C.; 400 MHz 1H NMR (DMSO-d6) δ 12.81 (br(s), 1H), 7.04 (d, 2H, J=8.4 Hz), 6.77 (m, 3H), 6.69 (s, 2H), 6.36 (s, 1H), 4.43 (s, 2H), 3.82 (s, 2H), 3.58 (s, 3H), 2.03 (s, 3H), 1.82 (s, 3H), 1.67 (s, 6H). MS m/z 437 (M+1).

1. customThe reaction was flushed with nitrogen
2. temperatureThe reaction was cooled
3. additionpoured into diethyl ether
4. washwashed with water (2×10 ml), brine (1×10 ml)
5. dry with materialdried over anhydrous sodium sulfate
6. filtrationThe organic solution was filtered through silica gel
7. washeluted with diethyl ether
8. concentrationconcentrated
9. dissolutionThe crude product was dissolved in 10 ml dichloromethane
10. additionAdded to this solution
11. extractionextracted with methylene chloride
12. dry with materialThe organic solution was dried over anhydrous sodium sulfate
13. customdecanted
14. concentrationconcentrated
15. customto provide the crude alkyl chloride
16. filtrationfiltered
17. concentrationconcentrated
18. custompurified by normal phase chromatography

ORD record

ord-b8e8b83b639d47218389b4bc9ee2190f

Source dataset

uspto-grants-2007_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

USRE039916E1