Chloroacetyl chloride → 2-Chloroacetyl-5-nitroisoindoline

Temperature

0 °C

To a suspension in which 42.8 g of 5-nitroisoindoline had been added to an aqueous potassium carbonate solution (108 g of potassium carbonate, 200 ml of water) was added dropwise 200 ml of an ethyl acetate solution containing 31.2 ml of chloroacetyl chloride at 0° C. over 1 hour. The mixture was further stirred at 0° C. for 45 minutes and precipitates were collected by filtration. The obtained solid was treated with activated carbon in ethyl acetate and recrystallized to obtain 2-chloroacetyl-5-nitroisoindoline. (2) In 10 ml of N,N-dimethylformamide were stirred 1.21 g of the compound obtained in the above (1), 1.07 g of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine and 1.39 g of potassium carbonate at room temperature for 20 hours. The reaction mixture was poured into water and precipitated solids were collected by filtration, washed with water, dried, and purified by silica gel column chromatography (solvent, chloroform-methanol=98:2 to 95:5) to obtain N-tert-butoxycarbonyl-trans-4-[(5-nitro-2-isoindolinyl)-carbonylmethylamino]cyclohexylamine. In 3 ml of trifluoroacetic acid was dissolved 284 mg of this compound and the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made basic by 10% sodium hydroxide and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain trans-4-[(5-nitro-2-isoindolinyl)carbonylmethylaminolcyclohexylamine (Reference Example 10-1 in Table 11).

1. customprecipitates
2. filtrationwere collected by filtration
3. additionThe obtained solid was treated with activated carbon in ethyl acetate
4. customrecrystallized

ORD record

ord-2788fd5a1c9943d8ba05ec429b13b1eb

Source dataset

uspto-grants-2008_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07332487B2