Hexamethyldisilazane → 2-(3-Chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester

Temperature

-78 °C

In a round bottom flask was placed tetrahydrofuran (20 mL) and 1,1,1,3,3,3-hexamethyldisilazane (0.97 mL, 4.66 mmol) and it was cooled to −78° C. in a dry ice/acetone bath. To this cooled solution was then added n-butyl lithium (2.5 M solution in hexanes, 1.75 mL, 4.37 mmol) and it was stirred for 15 min at −78° C. To this was then added a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in PCT WO 2003/095438 A1, Example 4, 0.96 g, 4.16 mmol) in tetrahydrofuran (6 mL) dropwise. The reaction was then stirred for 15 min at −78° C. then at 0° C. for 1 h which resulted in a yellow solution. After such time, the reaction was cooled back to −78° C. and a solution of 3-iodomethyl-tetrahydro-furan (1.32 g, 6.23 mmol) in tetrahydrofuran (6 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL, 6.24 mmol) was added dropwise at −78° C. The reaction was stirred at −78° C. for 15 min, at 0° C. for 2.5 h and then was stored in a freezer overnight. After such time, the reaction was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated sodium chloride solution wash. The organics were dried over sodium sulfate, filtered and then concentrated in vacuo. Purification on an AnaLogix Intelliflash system (120 g column, 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester (1.0 g, 77%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.42-1.62 (m, 1H, CH of CH2), 1.79-1.94 (m, 1H, CH of CH2), 1.94-2.21 (m, 3H, CH and CH2), 2.47 (s, 3H, SCH3), 3.26-3.38 (m, 1H, OCH of OCH2), 3.45-3.52 (m, 1H, ArCH), 3.65-3.75 (m, 1H, OCH of OCH2), 3.67 (s, 3H, OCH3), 3.76-3.94 (m, 2H, 2×OCH of OCH2), 7.11 (d, Jo=8.2 Hz, 1H, Ar), 7.19 (dd, Jo=8.2 Hz, Jm=1.7 Hz, 1H, Ar), 7.30 (d, Jm=1.7 Hz, 1H, Ar).

1. customIn a round bottom flask was placed
2. customat 0° C. for 1 h which resulted in a yellow solution
3. temperatureAfter such time, the reaction was cooled back to −78° C.
4. stirringThe reaction was stirred at −78° C. for 15 min, at 0° C. for 2.5 h
5. waitwas stored in a freezer overnight
6. washwashed with a saturated aqueous ammonium chloride solution
7. washwash
8. dry with materialThe organics were dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customPurification on an AnaLogix Intelliflash system (120 g column, 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes)

ORD record

ord-f1beb4c28b654cefad96a2820f87645c

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935699B2