Hydrochloric Acid → Ethyl 2-(3-chloro-5-fluorophenylhydrazino)propionate

Temperature

0 °C

To a suspension of 3-chloro-5-fluoroaniline (8.0 g) in a 6 N aqueous hydrochloric acid solution (28 ml) was added a solution of sodium nitrite (4.17 g) in H2O (5.2 ml) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The resultant mixture was added to a solution of potassium hydroxide (17.0 g), sodium acetate (17.0 g) and ethyl 2-methylacetoacetate (8.72 g) in H2O (80 ml) and ethyl alcohol (64 ml) at 0° C., and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was extracted with ethyl acetate twice, and the combined organic layer was evaporated under reduced pressure. The residue was dissolved in water and ethyl acetate, and the insoluble materials were filtered off. The filtrate was separated, and the organic layer was washed with brine and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residual solid was triturated with hexane to give ethyl 2-(3-chloro-5-fluorophenylhydrazino)propionate (4.0 g) as a pale brown solid. APCI-Mass m/Z 259/261 (M+H). (2) The above compound was treated in a manner similar to Reference Example 3-(2), (3), (4) and (5) to give the titled compound, 4-chloro-6-fluoroindoline as colorless oil. APCI-Mass m/Z172/174 (M+H). 1H-NMR (DMSO-d6) δ 2.90 (t, J=9.3 Hz, 2H), 3.52 (t, J=8.7 Hz, 2H), 6.16 (s, 1H), 6.19 (dd, J=10.1, 1.9 Hz, 1H), 6.35 (dd, J=9.5, 1.9 Hz, 1H). Pharmacological Experiments 1. Assay for SGLT2 Inhibition Test Compounds:

1. stirringthe mixture was stirred at the same temperature for 2 hours
2. extractionThe reaction mixture was extracted with ethyl acetate twice
3. customthe combined organic layer was evaporated under reduced pressure
4. dissolutionThe residue was dissolved in water
5. filtrationethyl acetate, and the insoluble materials were filtered off
6. customThe filtrate was separated
7. washthe organic layer was washed with brine
8. dry with materialdried over magnesium sulfate
9. filtrationThe insoluble materials were filtered off
10. customthe filtrate was evaporated under reduced pressure
11. customThe residual solid was triturated with hexane

ORD record

ord-152d01b3dc084a188ee6f9d5d0c28bc5

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07851617B2