Methanesulfonic Acid → (R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid (2-chloro-ethyl)-amide

温度

0 °C

The title compound was prepared as follows. (R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1 (1.95 g, 7.47 mmol) was dissolved in EtOAc (25 mL) and cooled to 0° C. Diphenyl chlorophosphate (1.71 mL, 8.23 mmol) was added followed by TEA (1.14 mL, 8.23 mmol). The reaction was stirred at 0° C. for 1 h, and treated with (S)-Cyclohex-2-enylamine (0.8 g, 8.23 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between 1N HCl (25 mL) and EtOAc (30 mL). The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a yellow oil. The resulting oil (2.54 g, 7.47 mmol) was dissolved in EtOAc (30 mL) and then cooled to 0° C. Methanesulfonic acid (2.27 mL, 33.62 mmol) was added and the solution was stirred at 0° C. for 15 minutes, then at room temperature for 4 h. The mixture was re-cooled to 0° C. and quenched with 10% Na2CO3 (30 mL) then extracted with EtOAc (30 mL). Organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a yellow oil 3. The resulting yellow oil (1.86 g, 7.74 mmol) was dissolved in EtOAc (77 mL). BOC-AHPBA 4 (2.29 g, 7.74 mmol) was added followed by HOBt (1.05 g, 7.74 mmol). The mixture was stirred at room temperature 1 h, then cooled to 0° C. DCC (1.60 g, 7.74 mmol) was slowly added as solution in EtOAc (30 mL). The mixture was allowed to gradually warm to room temperature and stirred overnight. The mixture was filtered and the filtrate was washed with 1N HCl (40 mL), saturated NaHCO3 (40 mL), brine (40 mL), dried over Na2SO4 and concentrated to give a crude white solid (contaminated with DCU). The DCU was removed by flash chromatography (30% to 50% EtOAc in hexanes) to provide a white solid (4 g, 7.73 mmol), which was dissolved in EtOAc (30 mL) and then cooled to 0° C. Methanesulfonic acid (2.35 mL, 34.76 mmol) was added and the solution was stirred at 0° C. for 15 minutes, then at room temperature for 3 h. The mixture was re-cooled to 0° C. and quenched with 10% Na2CO3 (35 mL) then extracted with EtOAc (30 mL). Organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a material which was recrystalized from 60% EtOAc in hexanes to provide B1 (2.41 g, 80%) as a white solid. 1H NMR (DMSO-d6) δ 8.21 (d, J=8.1, 1H), 7.31–7.17 (m, 5H), 5.80 (d, J=5.6, 1H), 5.52–5.48 (m, 2H), 5.30–5.25 (m, 2H), 4.89 (s, 2H), 4.26 (s, 1H), 4.21–4.00 (m, 3H), 3.15–2.70 (m, 2H), 2.50–2.00 (m, 2H), 2.00–1.00 (m, 4H), 1.49 (s, 3H), 1.31 (s, 3H); Anal. Calcd for C22H31N3O3S: C, 63.28; H, 7.48; N, 10.06. Found: C, 63.40; H, 7.20; N, 9.98.

1. stirringThe reaction mixture was stirred at room temperature overnight
2. custompartitioned between 1N HCl (25 mL) and EtOAc (30 mL)
3. washThe organic layer was washed with saturated NaHCO3, brine
4. dry with materialdried over Na2SO4
5. concentrationconcentrated to a yellow oil
6. temperaturecooled to 0° C
7. stirringthe solution was stirred at 0° C. for 15 minutes
8. waitat room temperature for 4 h
9. temperatureThe mixture was re-cooled to 0° C.
10. customquenched with 10% Na2CO3 (30 mL)
11. extractionthen extracted with EtOAc (30 mL)
12. washOrganic layer was washed with brine
13. dry with materialdried over Na2SO4
14. concentrationconcentrated in vacuo

ORDレコード

ord-f95d46d5137142fabbbcce6cfc995bcd

出典データセット

uspto-grants-2006_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07094909B2