Isobutyl chloroformate → tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

To a mixture of (2S)-1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (1.16 g), triethylamine (1.42 mL) and tetrahydrofuran (12 mL) was added 2-methylpropyl chlorocarbonate (0.662 mL) with stirring at room temperature. After 1 hr, 3-amino-5-bromothiophene-2-carboxamide (752 mg) produced in Example 1, step D, was added, and the mixture was stirred in a microwave reactor at 100° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL), 2M aqueous sodium hydroxide solution (10.2 mL) was added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was ice-cooled, and 6M hydrochloric acid (3.33 mL) was added dropwise. The reaction mixture was poured into brine, and extracted with 3:1 ethyl acetate/tetrahydrofuran mixture. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (851 mg) as a white solid. The optical purity was 51.1% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK IC (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm).

1. stirringthe mixture was stirred in a microwave reactor at 100° C. for 2 hr
2. temperatureto cool to room temperature
3. extractionThe mixture was extracted with ethyl acetate
4. dry with materialthe extract was dried over anhydrous magnesium sulfate
5. customInsoluble material was removed by filtration
6. concentrationthe filtrate was concentrated under reduced pressure
7. dissolutionThe residue was dissolved in ethanol (10 mL)
8. addition2M aqueous sodium hydroxide solution (10.2 mL) was added
9. stirringthe mixture was stirred at 90° C. for 2 hr
10. temperaturecooled
11. addition6M hydrochloric acid (3.33 mL) was added dropwise
12. additionThe reaction mixture was poured into brine
13. extractionextracted with 3:1 ethyl acetate/tetrahydrofuran mixture
14. dry with materialThe extract was dried over anhydrous magnesium sulfate
15. customInsoluble material was removed by filtration
16. concentrationthe filtrate was concentrated under reduced pressure
17. customThe residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate)

ORD record

ord-7b7c9d33565a4de28d4e529e38e7fdec

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09388195B2