Pyridine → Methyl 5-chloro-1-((4-(hydroxymethyl)thiazol-2-yl)carbamoyl)spiro[indoline-3,3'-pyrrolidine]-1'-carboxylate

Methyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (100 mg, 0.37 mmol) was dissolved in N,N′-dimethylformamide (0.5 mL). Thereafter, 4-nitrophenyl chloroformate (75 mg, 0.37 mmol) and pyridine (30 μL, 0.37 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 13 hours. Thereafter, the (2-aminothiazol-4-yl)methyl acetate (65 mg, 0.37 mmol) synthesized by a method described in the known methods (International Publication WO2006/011631 etc.) or a method similar thereto was dissolved in N,N′-dimethylformamide (1.4 mL), and the obtained solution was then added to the reaction solution. The obtained mixture was stirred at room temperature for 24 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was successively washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo, to obtain a residue. The obtained residue was dissolved in methanol (1 mL), and thereafter, potassium carbonate (51 mg, 0.37 mmol) was added to the mixed solution at room temperature. The obtained mixture was stirred for 2 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with chloroform. The resultant was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0→10:1) to obtain the captioned compound (26.5 mg, 17%) in the form of a light yellow amorphous product.

1. additionthe obtained solution was then added to the reaction solution
2. stirringThe obtained mixture was stirred at room temperature for 24 hours
3. extractionwas then extracted with ethyl acetate
4. washThe organic layer was successively washed with a saturated aqueous solution of sodium hydrogen carbonate and brine
5. dry with materialwas then dried over anhydrous sodium sulfate
6. concentrationfollowed by concentration in vacuo
7. customto obtain a residue
8. stirringThe obtained mixture was stirred for 2 hours
9. extractionwas then extracted with chloroform
10. dry with materialThe resultant was dried over anhydrous sodium sulfate
11. concentrationwas then concentrated in vacuo
12. customThe obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0→10:1)

ORD record

ord-efa5cda937eb4f0582831960348ba20b

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08921576B2