1-Hydroxybenzotriazole → 1-[[(3-Ethoxy-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid

633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 482 mg (3.1 mmol) of 1-hydroxybenzotriazole, 517 mg (3 mmol) of 3-ethoxy-2-thiophenecarboxylic acid and 1.16 g (9 mmol) of diisopropylethylamine in 10 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and the mixture was stirred overnight, followed by collecting of the crystal by filtration. Then, the obtained crystal was dissolved in 3 ml of tetrahydrofuran solution, 2.8 ml of 2N aqueous NaOH solution was added thereto, and the mixture was heated under reflux for 3 hours. Ether was added to the reaction solution to separate the aqueous layer. After the separated aqueous layer was neutralized by concentrated hydrochloric acid, it was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 656 mg (73%) of the title compound.

1. temperaturecooling
2. concentrationthe reaction solution was concentrated under reduced pressure, ethyl acetate
3. additionwas added
4. washthe mixture was washed with water
5. dry with materialby drying with anhydrous sodium sulfate
6. distillationAfter the solvent was distilled off under reduced pressure, diisopropyl ether
7. additionwas added to the residue
8. stirringthe mixture was stirred overnight
9. filtrationby collecting of the crystal by filtration
10. dissolutionThen, the obtained crystal was dissolved in 3 ml of tetrahydrofuran solution
11. addition2.8 ml of 2N aqueous NaOH solution was added
12. temperaturethe mixture was heated
13. temperatureunder reflux for 3 hours
14. additionEther was added to the reaction solution
15. customto separate the aqueous layer
16. extractionwas extracted with ethyl acetate
17. washAfter the obtained organic layer was washed with saturated brine, it
18. dry with materialwas dried with anhydrous sodium sulfate
19. distillationThe solvent was distilled off under reduced pressure

ORD-Eintrag

ord-5e41933cbfa6455487821e88b72cad93

Quelldatensatz

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08829209B2