Methanol → HCID 67255609, compound

Temperature

0 °C

A solution of 2-amino-5-(1,4-dioxaspiro[4.5]dec-8-yl)-N-methylbenzamide (Compound 139B, 333 mg, 1.15 mmol) in THF (10 mL, 200 mmol) was treated with aqueous 3N HCl (2 mL) and allowed to stir at rt for 3.5 hours. The mixture was cooled to 0° C. and basified with dropwise addition of 50% aq. NaOH to pH˜10 and then was diluted with EtOAc (30 mL). The organic layer was separated, washed with brine (2×10 mL), dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure and the crude ketone was purified on the ISCO Combiflash eluting with 80-100% EtOAc in hexane then 5% DCM/MeOH to isolate the ketone intermediate as 235 mg of a white solid. MS (ES+): m/z=247.07 (100) [M+1]. LCMS: tR=2.29 min (ZQ3, polar—5 min). A solution of 2-amino-N-methyl-5-(4-oxocyclohexyl)benzamide in MeOH (7 mL, 200 mmol) was cooled to 0° C. and treated with sodium borohydride (43 mg, 1.1 mmol). The mixture was stirred at 0° C. for 1 hour then quenched with sat. aq. NH4Cl (1 mL). The crude residue obtained from concentrating the reaction mixture in vacuo was taken up in 1 mL H2O and EtOAc (30 m). The layers were separated. The aqueous layer was saturated with salt and washed again with ˜20 mL of EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude solid was taken up in DCM/MeOH, treated with silica and concentrated. This silica was loaded into an sample column and purified on an ISCO Combiflash (0-5% Then 10% MeOH/DCM) to isolate 201 mg of the desired product as an 80:20 mixture of cis/trans isomers. Major product (trans): MS (ES+): m/z=249.07 (100) {M+1]; HPLC: tR=2.10 min (ZQ3, polar—5 min). Minor product (cis): MS (ES+): m/z=249.10 (100) [M+1]; HPLC: tR=2.28 minutes (ZQ3, polar—5 min). The mixture was used in the next step.

1. custom5 min
2. customthen quenched with sat. aq. NH4Cl (1 mL)
3. customThe crude residue obtained
4. concentrationfrom concentrating the reaction mixture in vacuo
5. customThe layers were separated
6. washwashed again with ˜20 mL of EtOAc
7. washThe combined organic layers were washed with brine
8. dry with materialdried over anhydrous sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. additiontreated with silica
12. concentrationconcentrated
13. custompurified on an ISCO Combiflash (0-5%

ORD record

ord-67777f99ff67447ea824e2f328060bd1

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09096624B2