In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 16066-84-5 as follows. Recommanded Product: 16066-84-5
To a solution of tert-butyl-N-methylcarbamate (3.00 g, 22.9 mmol) in THF (50 mL) was added NaH (1 .37 g, 34.3 mmol) in portions at 0 C. The reaction mixture was stirred at 15 C for an hour. Then 81 (5.24 g, 22.9 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred at 15 C for 13 h. The reaction was quenched by ice water (10 mL) slowly and then extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified via silica gel columnchromatography (petroleum ether/ethyl acetate = 4:1) to give 82 (2.9 g, 45%) as a colorless oil.1H N R (400 MHz, CDCI3) 7.95-7.91 (m, 2H), 7.42-7.38 (m, 2H), 4.45 (s, 2H), 3.91 (s, 3H), 2.85 (s, 3H), 1 .48 (s, 9H). To a solution of 82 (2.8 g , 10 mmol) in THF (20 mL) was added LiAIH4(456 mg , 12.0 mmol) in portions at 0 C. The mixture was stirred at 15 C for 2 hours. The mixture was cooled to 0 C and quenched by saturated solution of potassium sodium tartrate (0.5 mL), the mixture was concentrated in vacuum (40C) to give 83 (1 .8 g, 71 %) as a colorless oil.1H NMR (400 MHz, CDCI3) 7.32-7.29 (m, 2H), 7.27-7.23 (m, 1 H), 7.15-7.14 (m, 1 H), 4.68 (s, 2H), 4.42 (s, 2H), 2.82 (s, 3H), 1 .48 (s, 9H). To a solution of 83 (1 .5 g, 6.0 mmol) in DCM (20 mL) was added A/-Fmoc-(S)-valine (2.23 g, 6.57 mmol), DCC (1 .6 g, 7.8 mmol) and DMAP (73 mg, 0.60 mmol). The mixture was stirred at 15 C for 12 h. Then DCM (10 mL) was added and the organic layer was washed with brine (10 mL x 3), dried over Na2S04and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 4: 1) to give 84 (1 .8 g, 53%) as a colorless oil.1H NMR (400 MHz, CDCI3) 7.70-7.80 (m, 2H), 7.54-7.62 (m, 2H), 7.35-7.42 (m, 2H), 7.23-7.33 (m, 4H), 7.19 (br s, 2H), 5.34-5.32 (m, 1 H), 5.29-5.14 (m, 2H), 4.43-4.41 (m, 4H), 4.40-4.14 (m, 4H), 2.83 (s, 3H), 2.12-2.23 (m, 1 H), 1 .47 (s, 9H), 0.86 (dd, J – 6.84, 2.87 Hz, 6H). To a solution of 84 (1 .00 g, 1 .75 mmol) in THF (6 mL) was added piperidine (298 mg, 3.50 mmol). The mixture was stirred at 15 C for 12 h . The mixture was concentrated in reduced pressure at 40 C. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1 :4) to give 85 (400 mg, 65%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) 7.37-7.35 (m, 1 H), 7.34-7.29 (m, 1 H), 7.27-7.22 (m, 1 H), 7.18-7.17 (m, 1 H), 5.16-5.06 (m, 2H), 4.37 (s, 2H), 3.15 (d, J – 4.0 Hz, 1 H), 2.74 (s, 3H), 1 .99-1 .84 (m, 1 H), 1 .42-1 .39 (m, 9H), 0.85 (d , J = 6.8 Hz, 3H), 0.79 (s, J = 6.4 Hz, 3H). To a solution of Acid-04 (164 mg, 0.856 mmol) in DMF (3 mL) was added HATU (390 mg, 1 .03 mmol) and TEA (260 mg, 2.57 mmol). The mixture was stirred at 20 C for 1 h. Then 85 (300 mg, 0.856 mmol) was added in one portion. The mixture was stirred at 20 C for 1 1 h. The reaction was quenched by water (10 mL) slowly at 0 C and then extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 1), dried over anhydrous Na2S04, filtered and then HCI/EtOAc (4 M, 4 mL) was added. The mixture was stirred at 20 C for 12 h. The mixture was concentrated in vacuo. The residue was purified by prep. HPLC (column: Luna C18 100 x 30 mm; liquid phase: 0.1 %TFA-ACN; B%: 10%-40%, 12 min). After prep. HPLC, 3N HCI (2 mL) was added before freeze drying. 6-122 (137 mg, 33%) was obtained as an off white solid.1H N R (400 MHz, DMSO-cfe) 9.21 (br s, 2H), 9.03 (s, 1 H), 8.59 (d, J – 8.0 Hz, 1 H), 7.55-7.51 (m, 2H), 7.46-7.45 (m, 2H), 7.35 (d, J – 8.0 Hz, 1 H), 7.24 (d, J – 8.0 Hz, 1 H), 5.19 (s, 2H), 4.97 (s, 2H), 4.37 (t, J – 8.0 Hz 1 H), 4.10 (s, 2H), 2.39 (s, 3H), 2.21 -2.16 (m, 1 H), 0.96 (d, J = 6.0 Hz, 6H); ESI-MS m/z 425 [M+H]+; HPLC purity: 94.93% (220 nm), 87.86% (254 nm).
According to the analysis of related databases, 16066-84-5, the application of this compound in the production field has become more and more popular.
Reference:
Patent; ANACOR PHARMACEUTICALS, INC.; AKAMA, Tsutomu; CARTER, David Scott; HALLADAY, Jason S.; JACOBS, Robert T.; LIU, Yang; PLATTNER, Jacob J.; ZHANG, Yong-Kang; WITTY, Michael John; (149 pag.)WO2017/195069; (2017); A1;,
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics