Iodine → HCID 178422906, compound

Temperature

75 °C

A flask was charged with (2-formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-amino-3-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL). The mixture was stirred at 70-80° C. for 3 h. To the stirred, cooled (40-50° C.) mixture were added anhydrous potassium carbonate (16.6 g) and iodine (20.3 g). The batch was then stirred at 80° C. for at least 5 h or until HPLC analysis showed that the reaction had proceeded to greater the 98% completion. The cooled reaction mixture was filtered through a celite pad (8.8 g) and the filter cake was rinsed with MeOH (110 mL). The filtrate and rinse were diluted with toluene (90 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 20 wt % sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature. This mixture was extracted with CH2Cl2 (2×180 mL) and the separated organic layers were concentrated to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (10 mL) and loaded onto a Biotage KP-Sil SNAP cartridge (100 g) that had been pre-equilibrated with 300 mL 5% v/v triethylamine in hexane. A Biotage unit was used to elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure as quickly as possible to provide the title compound as a yellow solid (2.9 g 23% yield).

1. temperatureTo the stirred, cooled (40-50° C.) mixture
2. stirringThe batch was then stirred at 80° C. for at least 5 h or until HPLC analysis
3. customThe cooled reaction mixture
4. filtrationwas filtered through a celite pad (8.8 g)
5. washthe filter cake was rinsed with MeOH (110 mL)
6. washThe filtrate and rinse
7. additionwere diluted with toluene (90 mL)
8. concentrationconcentrated to dryness under reduced pressure
9. stirringThe residue was stirred with aqueous 20 wt % sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature
10. extractionThis mixture was extracted with CH2Cl2 (2×180 mL)
11. concentrationthe separated organic layers were concentrated to dryness in vacuo
12. concentrationThe concentrate (20 g)
13. dissolutionwas dissolved with methanol (10 mL)
14. washto elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%)
15. customClean fractions were collected
16. concentrationconcentrated to dryness under reduced pressure as quickly as possible

ORD record

ord-c16ec8d529f34387a4de3dca2d9bc37c

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09365575B2