Methyl iodide → HCID 17776997, compound

Temperature

-78 °C

Diisopropyl amine (478 g, 4.725 mol) and anhydrous THF (2.8 L) were charged to a 10 L 4-neck flask equipped with gas inlet, addition funnel, thermometer and mechanical stirrer. The solution was degassed with N2 for 5 min then cooled to −78° C. with dry ice acetone bath under N2 flow. A solution of n-BuLi in n-hexane (1.8 L, 2.5 M, 4.5 mol) was added to the stirring mixture at −20° C.˜−10° C. over 40 min. After the addition, the reaction was stirred at −20° C. for 40 min A solution of 5-fluoro-2-methoxybenzoic acid 60 (297.5 g, 1.75 mol) in anhydrous THF (1.3 L) was added to the reaction mixture at −55° C.—45° C. with stirring over 60 min. The resulting brown mixture was stirred at −15˜−25° C. for 3.5 h. The reaction mixture turned to red brown. Another para-reaction same with above reaction was set at same time. A 20 L four-neck flask equipped with gas inlet, addition funnel, thermometer and mechanical stirrer was charged with neat MeI (1500 g, 10.5 mol) and anhydrous THF (2.6 L). The mixture was degassed with N2 for 5 min and cooled to −20˜−15° C. with dry ice acetone bath under small N2 flow. The obtained solution from the above two para-reactions was transferred to the 20 L flask containing MeI at −15˜−5° C. with stirring over 20 min. The resulting cloudy mixture was stirred at −20˜−15° C. for 2 h and brought to ambient temperature over 1.5 h. The obtained brown suspension was stirred at 25-30° C. for 16 h. The reaction was then quenched with aqueous HCl (5.0 L, 2N) at 20-25° C. and diluted MTBE (3.0 L). After being stirred for 5 min at 20° C., the two phase mixture was separated, and the upper layer was concentrated to dryness under vacuum to give black oil. The aqueous layer was extracted with EtOAc (5×1.5 L) and all the organic layers were combined with the black oil. The resulting solution was washed with water (2×μL) and brine (3×1 L). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduce pressure to afford crude 3-fluoro-6-methoxy-2-methylbenzoic acid 61 (740 g, >100%) as brown crystal solid that was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=9.8, 8.5 Hz, 1H), 6.75 (dd, J=9.8, 3.7 Hz, 1H), 3.86 (s, 3H), 2.34 (d, J=2.4 Hz, 3H); MS (ESI) m/z 185.12 (M+H).

1. customequipped with gas inlet, addition funnel
2. customThe solution was degassed with N2 for 5 min
3. additionAfter the addition
4. additionwas added to the reaction mixture at −55° C.—45° C.
5. stirringThe resulting brown mixture was stirred at −15˜−25° C. for 3.5 h
6. customAnother para-reaction same with above reaction
7. customA 20 L four-neck flask equipped with gas inlet, addition funnel
8. customThe mixture was degassed with N2 for 5 min
9. temperaturecooled to −20˜−15° C. with dry ice acetone bath under small N2 flow
10. additioncontaining MeI at −15˜−5° C.
11. stirringwith stirring over 20 min
12. stirringThe resulting cloudy mixture was stirred at −20˜−15° C. for 2 h
13. waitbrought to ambient temperature over 1.5 h
14. stirringThe obtained brown suspension was stirred at 25-30° C. for 16 h
15. customThe reaction was then quenched with aqueous HCl (5.0 L, 2N) at 20-25° C.
16. stirringAfter being stirred for 5 min at 20° C.
17. customthe two phase mixture was separated
18. concentrationthe upper layer was concentrated to dryness under vacuum
19. customto give black oil
20. extractionThe aqueous layer was extracted with EtOAc (5×1.5 L) and all the organic layers
21. washThe resulting solution was washed with water (2×μL) and brine (3×1 L)
22. dry with materialThe organic layer was dried over Na2SO4
23. filtrationfiltered
24. concentrationThe filtrate was concentrated

ORD record

ord-5a3e6744e34e4010b4e15fbaa662a948

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09073829B2