Chloroacetic Acid → HCID 86639128, compound

Temperature

-78 °C

To a solution of 1,4-difluorobenzene (100 g, 876 mmol) in anhydrous THF (2.0 L) at −78° C. was added a solution of sec-butyllithium (1.4 M in cyclohexane, 626 mL, 876 mmol) dropwise, maintaining the reaction temperature below −60° C. The reaction mixture was allowed to stir at −78° C. for 30 minutes, and carbon disulfide (50.2 mL, 833 mmol) was then added dropwise. The reaction mixture was allowed to warm to room temperature over 30 minutes and then stirred at room temperature for 2 hours. Water (15 mL) was then added dropwise, and the mixture was then concentrated under reduced pressure. The crude brown semi-solid residue obtained was then suspended in water (600 mL) and treated with a solution of 2-chloroacetic acid (99.4 g, 1052 mmol) and sodium bicarbonate (73.6 g, 876 mmol) in water (200 mL). The mixture was stirred at room temperature for 14 hours and then acidified to pH 4 with 50% H2SO4. The mixture was extracted with CH2Cl2, and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude 2-(2,5-difluorophenylcarbonthioylthio)acetic acid (214 g) as red-brown syrup. This material was then suspended in a cooled (0° C.) solution of 0.5 M NaOH (1750 mL, 875 mmol), and hydrazine (54.0 mL, 1722 mmol) was then added dropwise. The reaction mixture was allowed to warm to room temperature and stir for 14 hours. The reaction mixture was then diluted with water and acidified to pH 4-5 using 1 N HCl. The mixture was then extracted with ethyl acetate and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude 2,5-difluorobenzothiohydrazide as a red-brown oil (162.5 g). This oil was suspended in ether (3.5 L) and filtered. The filtered solution was then treated with 2 M HCl in ether while stirring vigorously. The mixture was stirred at room temperature for 15 minutes. The precipitate that formed was isolated by filtration and dried under vacuum to afford 2,5-difluorobenzothiohydrazide hydrochloride (50 g, 26%) as a yellow solid.

1. temperaturemaintaining the reaction temperature below −60° C
2. temperatureto warm to room temperature over 30 minutes
3. stirringstirred at room temperature for 2 hours
4. concentrationthe mixture was then concentrated under reduced pressure
5. customThe crude brown semi-solid residue obtained
6. stirringThe mixture was stirred at room temperature for 14 hours
7. extractionThe mixture was extracted with CH2Cl2
8. washthe combined organics were washed with brine
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated

ORD record

ord-b7a6f17e1e024ad3a2c3ead47ecb39ed

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08324257B2