Chloroacetyl chloride → HCID 53416723, compound

Temperature

0 °C

To a 5 L 4-necked round bottom flask was charged 1,2-difluorobenzene (130.0 g) and dry THF (1.3 L). This solution was cooled to <−60 while stirring under nitrogen. To this was added n-hexyllithium (455 mL of 2.5 M/hexane) dropwise such that T<−60 (˜15 minute addition). The solution quickly turned into a stirrable slurry, which was aged for 1 hour cold. To this was added zinc chloride (2.3 L of 0.5 M/THF) such that T<−60 and the slurry quickly became a homogeneous solution. This was warmed to 0° C. followed by the addition of copper(I) chloride (11.3 g) and chloroacetyl chloride (142 g) such that T<5° C. The reaction was assayed after 20 minutes and judged complete by HPLC. The reaction was quenched with 1N HCl (2 L) and then the two phase system was transferred to a separatory funnel and diluted with IPAc (2 L). The aqueous was cut and the organic washed again with 1N HCl (2 L) followed by 1N NH4OH (2×2 L) and finally with water (2 L). The organic was concentrated to an oil. Assay yield=78%. The oil is then diluted with heptane (800 mL—does not all go into solution) and stirred while cooling to −30° C. During cooling the oil turns over to a crystalline solid. The slurry is aged 1 hour at −30° C., filtered and washed with cold heptane. Desired product isolated in 71% yield (154 g).

1. temperatureThis solution was cooled to <−60
2. additiondropwise such that T<−60 (˜15 minute addition)
3. waitThe reaction was assayed after 20 minutes
4. customThe reaction was quenched with 1N HCl (2 L)
5. customthe two phase system was transferred to a separatory funnel
6. additiondiluted with IPAc (2 L)
7. washthe organic washed again with 1N HCl (2 L)
8. concentrationThe organic was concentrated to an oil
9. additionThe oil is then diluted with heptane (800 mL—
10. stirringstirred
11. temperaturewhile cooling to −30° C
12. temperatureDuring cooling the oil
13. waitThe slurry is aged 1 hour at −30° C.
14. filtrationfiltered
15. washwashed with cold heptane

ORD record

ord-f5d87471c6144cc087922a0d354cdc61

Source dataset

uspto-grants-2010_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07829699B2