2-Mercaptobenzoic Acid → 4-((alpha-s)-alpha-((2s,5r)-2,5-Dimethyl-1-piperazinyl)benzyl)-n,n-diethylbenzamide

A solution of bis(dibenzylidineacetone)palladium (1.438 g, 2.5 mmol, Acros Organics) and 1,4-bis(diphenylphosphino)butane (1.066 g, 2.5 mmol, Acros Organics) in tetrahydrofuran (20 mL) was stirred under nitrogen at room temperature for 15 min, then added via syringe to a stirred solution under nitrogen of 4-((alpha-S)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (20.98 g, 50 mmol) and thiosalicylic acid (9.25 g, 60 mmol) in anhydrous tetrahydrofuran (100 mL). The reaction mixture was stirred under nitrogen for 2 h at room temperature, evaporated to dryness, the residue dissolved in ethyl acetate (120 mL) and diluted with ether (300 mL). The solution was washed with dilute sodium carbonate solution (saturated:H2O, 1:3, 3×200 mL). The organic solution was diluted with pentane (800 mL) and extracted with 3M hydrochloric acid (5×40 mL), followed by 1 M hydrochloric acid (3×50 mL, alternating with water (3×50 mL)). The combined aqueous extracts were filtered to remove a small amount of suspended solid and the pH adjusted to 12 with 5 M NaOH. The resulting oily suspension was extracted with methylene chloride (3×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness to yield 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a very pale yellow solid (18.07 g, 97.8%) The product showed a single spot on thin layer chromatography (silica gel, EM60F254, 4% NH4OH/10% EtOH in ethyl acetate, Rf=0.25). and was used without further purification. Calc. for C24H33N3O 0.2 H2O: C, 75.24; H, 8.79; N, 10.97. Found C, 75.24; H, 8.87; N, 10.86%. 1H NMR (CDCl3, 600 MHz); δ 0.93 (d, J=6.3 Hz, 3H); 1.12 (br m, 3H); 1.20 (d, J=6.1 Hz, 3H); 1.24 (br m, 3H); 1.55 (dd, J=9.7, 11.3 Hz, 1H, partially obscured by br m, 2H); 2.33 (m, 1H); 2.68 (m, 2H); 2.89 (m, 1H); 2.92 (dd, J=12.1, 3.1 Hz, 1H); 3.29 (br m, 2H); 3.54 (br m, 2H); 5.38 (s, 1H); 7.14 (m, 2H); 7.30 (m, 3H); 7.35 (m, 2H); 7.46 (d, J=7.8 Hz, 2H).

1. customevaporated to dryness
2. dissolutionthe residue dissolved in ethyl acetate (120 mL)
3. additiondiluted with ether (300 mL)
4. washThe solution was washed with dilute sodium carbonate solution (saturated:H2O, 1:3, 3×200 mL)
5. additionThe organic solution was diluted with pentane (800 mL)
6. extractionextracted with 3M hydrochloric acid (5×40 mL)
7. filtrationThe combined aqueous extracts were filtered
8. customto remove a small amount of suspended solid
9. extractionThe resulting oily suspension was extracted with methylene chloride (3×150 mL)
10. dry with materialThe combined organic extracts were dried over anhydrous sodium sulfate
11. customevaporated to dryness

ORD record

ord-ca50069ac5594fadb1d5833bdce7738f

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08476280B2