(2S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidyl)ethoxy]phenyl]-2H-chromen-7-ol synthesis

Yield:252555-01-4 276 mg

Reaction Conditions:

with hydrogenchloride in ethanol;water; for 1 h;

Steps:

1.I Synthesis of acolbifene ((S)-(+)-7-hydroxy-3-(4'-hydroxyphenyl)-4-methyl-2-(4"-(2'"-piperidinoethoxy)phenyl)-2H-1-benzopyran hydrochloride, EM-01538, (EM-652.HCl))

Synthesis of acolbifene ((S)-(+)-7-hydroxy-3-(4'-hydroxyphenyl)-4-methyl-2-(4"-(2'"-piperidinoethoxy)phenyl)-2H-1-benzopyran hydrochloride, EM-01538, (EM-652.HCl))
A suspension of compound 13 (EM-652-(+)-CSA salt, 500 mg, 0.726 mmol) in dimethylformamide (11 μL, 0.15 mmol) was treated with an 0.5 M aqueous sodium carbonate solution (7.0 mL, 3.6 mmol), and stirred for 15 min.
The suspension was treated with ethyl acetate (7.0 mL) and stirred during 4 h.
The organic phase was then washed with an aqueous saturated sodium carbonate solution (2*5 mL) and brine (1*5 mL) dried over magnesium sulfate, and concentrated.
A solution of the resulting pink foam (EM-652) in ethanol (2 mL) was treated with 2 N hydrochloric acid (400 μL, 0.80 mmol), stirred for 1 h, treated with distilled water (5 mL), and stirred during 30 min.
The resulting suspension was filtered, washed with distilled water (5 mL), dried in air and under high vacuum (65° C.) to give a creamy powder (276 mg, 77%): Fine off-white powder; Scanning calorimetry:
Melting peak onset at 219° C., ΔH=83 J/g; [α]²⁴_D=154° in methanol 10 mg/mL; ¹H NMR (300 MHz, CD₃OD) δ(ppm) 1.6 (broad, 2H, H-4'"), 1.85 (broad, 4H, H-3"" and 5""), 2.03 (s, 3H, CH₃), 3.0 and 3.45 (broad, 4H, H-2"" and 6""), 3.47 (t, J=4.9 Hz, 2H, H-3'"), 4.26 (t, J=4.9 Hz, 2H, H-2'"), 5.82 (s, 1H, H-2), 6.10 (d, J=2.3 Hz, 1H, H-8), 6.35 (dd, J=8.4, 2.43 Hz, 1H, H-6), 6.70 (d, J=8.6 Hz, 2H, H-3', and H-5'), 6.83 (d, J=8.7 Hz, 2H, H-3" and H-5"), 7.01 (d, J=8.5 Hz, 2H, H-2' and H-6'), 7.12 (d, J=8.4 Hz, 1H, H-5), 7.24 (d, J=8.6 Hz, 2H, H-2" and H-6"); ¹³C RMN (CD₃OD, 75 MHz) δ ppm 14.84, 22.50, 23.99, 54.78, 57.03, 62.97, 81.22, 104.38, 109.11, 115.35, 116.01, 118.68, 125.78, 126.33, 130.26, 130.72, 131.29, 131.59, 134.26, 154.42, 157.56, 158.96, 159.33.
Elemental Composition: C, H, N, Cl: Theory; 70.51, 6.53, 2.84, 7.18, %. Found: 70.31, 6.75, 2.65, 6.89%.

References:

US2015/250802,2015,A1 Location in patent:Paragraph 0228; 0230; 0235