Acetic Acid → HCID 86691888, compound

Temperature

65 °C

To a solution of dimethyl(2-{1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}ethenyl)amine (may be prepared as described in Intermediate 4) (100 mg, 0.353 mmol) in ethanol (2 mL) was added (cis)-2,6-dimethylmorpholine (122 mg, 1.059 mmol, Alfa Aesar, Ward Hill, USA) and acetic acid (0.061 mL, 1.059 mmol). The reaction mixture was heated to 65° C. and stirred for 4 hours. The reaction mixture was cooled and the solvent removed under vacuum. The residue was dissolved in ethanol (2 mL) before the addition of further (cis)-2,6-dimethylmorpholine (122 mg, 1.059 mmol) and acetic acid (0.061 mL, 1.059 mmol). The reaction mixture was heated to 65° C. and stirred for 3 hours. The reaction mixture was cooled and the solvent removed under vacuum. The solid residue was partitioned between DCM (3 mL) and saturated aqueous NaHCO3 (2 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was dissolved in dry dichloromethane (DCM) (2 mL) before the addition of sodium triacetoxyborohydride (224 mg, 1.06 mmol). The reaction mixture was shaken at room temperature for 18 hours. The reaction mixture was partitioned between DCM (3 mL) and saturated aqueous NaHCO3 (2 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed. The residue was dissolved in methanol and passed through a 1 g SAX cartridge, eluting once with methanol. The methanol fractions were combined and the solvent removed to yield a yellow gum. The gum was dissolved in a minimum of methanol and 1N HCl in diethyl ether (2 mL) added. The solvent was removed under a stream of argon to yield a sticky orange gum. The product was partitioned between saturated aqueous NaHCO3 (1 mL) and DCM (1 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The product was further purified by silica chromatography (Biotage SP4 eluting a gradient from 50-100% EtOAc over 15 column volumes) to yield the title compound as a solid (12 mg).

1. temperatureThe reaction mixture was cooled
2. customthe solvent removed under vacuum
3. temperatureThe reaction mixture was heated to 65° C.
4. stirringstirred for 3 hours
5. temperatureThe reaction mixture was cooled
6. customthe solvent removed under vacuum
7. customThe solid residue was partitioned between DCM (3 mL) and saturated aqueous NaHCO3 (2 mL)
8. customThe organic layer was collected via a hydrophobic frit
9. customthe solvent removed under vacuum
10. stirringThe reaction mixture was shaken at room temperature for 18 hours
11. customThe reaction mixture was partitioned between DCM (3 mL) and saturated aqueous NaHCO3 (2 mL)
12. customThe organic layer was collected via a hydrophobic frit
13. customthe solvent removed under vacuum
14. customThe residue was purified by MDAP
15. additionFractions containing the desired product
16. customthe solvent removed
17. dissolutionThe residue was dissolved in methanol
18. washeluting once with methanol
19. customthe solvent removed
20. customto yield a yellow gum
21. additionadded
22. customThe solvent was removed under a stream of argon
23. customto yield a sticky orange gum
24. customThe product was partitioned between saturated aqueous NaHCO3 (1 mL) and DCM (1 mL)
25. customThe organic layer was collected via a hydrophobic frit
26. customthe solvent removed under vacuum
27. customThe product was further purified by silica chromatography (Biotage SP4
28. washeluting a gradient from 50-100% EtOAc over 15 column volumes)

ORD record

ord-93db5e319a6d4fd5be1e0442347bc503

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115132B2