(3aα-4α α,7a )-2-(4-Bromo-3-methvIphenyl)tetrahvdro-4.7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione

 




Example 1
(3aα-4α α,7a )-2-(4-Bromo-3-methvIphenyl)tetrahvdro-4.7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione (lC)

A. 4-(tert-Butyldimethylsiloxy)-2H-thiopyran (1A)

2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.14 mol, synthesized as described in Richards et al, J. Org. Chem. 46, 4836-4842 (1981)) was dissolved in CH₂C1₂ (130 mL) and triethylamine (5.47 mL, 39.41 mmol) was added. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.62 mL, 15.77 mmol) was then added. After 10 minutes, the volatiles were removed by rotary evaporator at 25°C. The resulting yellow oil was passed through a short column of SiO₂ eluting with 3% TEA in hexanes to yield 1.82 g of compound 1A as an orange oil.
B. l-[4-bromo-3-methylphenyl]-lH-pyrrole-2,5-dione (IB)

4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898 g, 9.16 mmol) were dissolved in acetic acid (10 mL) and heated at 115 °C for 12 h. The reaction was then cooled to 25°C and the acetic acid was removed in vacuo. The resulting residue was suspended in 5% K₂CO₃ (100 mL), stirred for 25 minutes and followed by filtering and rinsing with water. The material was then dried in vacuo to give compound IB as a light brown solid (1.65 g). HPLC: 100% at 2.96 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
C. (3 a ,4α,7α,7aα)-2-(4-Bromo-3-methylphenyl)tetrahydro-4,7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione (IC)
Compound 1A (0.313 g, 1.41 mmol) and compound IB (0.250 g, 0.94 mmol) were dissolved in toluene and heated to reflux for 5 h. The toluene was then removed by passing a stream of argon through the reaction flask. The residue was then purified by flash chromatography on SiO₂ eluting with 20% hexane in chloroform. This gave 0.168 g ofthe enol ether intermediate as a yellow solid. The enol ether intermediate was dissolved in dichloroethane (2.0 mL) and TFA (0.25 mL) was added. After 0.5 h, the reaction was quenched with saturated aqueous NaHCO₃ and extracted with CH₂C1₂ (2 x 30 mL). The organics were dried over anhydrous sodium sulfate and evaporated to give 0.079 g of compound IC as a white solid. HPLC: 99% at 3.010 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90%) aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS (ES): m z 396.9 [M+ NH₄]⁺.














/////////////////WO2002024702A1







.....


DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter     

Join me on google plus Googleplus

 amcrasto@gmail.com