(+)-Tetrabenazine

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Example 10 Removal The Boc Protecting Group From First Intermediate 12 And Amino Cyclization Provide (+)-Tetrabenazine XVII

[0063] First intermediate 12 (1.0 eq) was dissolved in 10% Me₂S- dichloromethane to provide an 82 mM solution. The solution was cooled to 0 ⁰C and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0 ⁰C) was added to the reaction mixture to provide a final concentration of 41 mM. The reaction mixture was permitted to stir at 0 ⁰C for 1 h. Following the allotted time the reaction mixture was quenched at 0 ⁰C by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure to provide the crude product as a yellow solid. The crude product was recrystallized from 3.5% dimethoxyethane in hexanes. The resulting colorless crystals were washed with hexanes to provide pure (+)- tetrabenazine (XVII) 46%: mp 126.0 ⁰C (3.5% DME-hexanes) (a crystal polymorph was observed at 116 ⁰C);

[α]²⁶ _D +37.2 (c 0.41, CH₂Cl₂);  

¹H NMR (CD₂Cl₂) δ 0.89 (apparent t, J = 7.2 Hz, 6H), 0.98 (ddd, J = 12, 6.0, 4.0 Hz, IH), 1.59-1.68 (m, IH), 1.74 (ddd, J = 12, 5.9, 5.7 Hz, IH), 2.32 (apparent t, J = 11.7 Hz, IH), 2.46 (apparent t, J = 12.3 Hz, IH), 2.55 (ddd, J = 12, 10.0, 3.8 Hz, IH), 2.65-2.73 (m, 2H), 2.83 (dd, J = 5.5, 2.8Hz, IH), 2.97-3.07 (m, IH), 3.07-3.14 (m, IH), 3.25 (dd, J =9.7, 6.3 Hz, IH), 3.47 (apparent d, J = 12Hz, IH), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, IH), 6.60 (s, IH)  

¹³C NMR (CD₂Cl₂) δ 21.98, 23.02, 25.51, 29.46, 35.16, 47.47, 47.63, 50.47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72, 126.37, 128.96, 147.65, 147.98, 209.72;

HRMS-(ESI+) calcd for (C₁₉H₂₇NO₃ + H) ([M+H]⁺ 318.2069, found 318.2082.

 1H NMR PREDICT

 13C NMR PREDICT


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