Acetic Acid → HCID 70873934, compound

HRID 2208891Notes

Reaction equation

HRID 2208891 reaction equation
[NH2:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[C:25]([O:24][C:23]([NH:22][CH:19]1[CH2:20][CH2:21][CH:16]([NH:1][C:2]2[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:18]1)=[O:29])([CH3:28])([CH3:26])[CH3:27]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 1512535tert-butyl N-(4-oxocyclohexyl)carbamate2×HCID 5049666Sodium triacetoxyborohydride2×HCID 86672668Methyl 3-amino-5-chloro-2-ethylbenzoate

Product 1

HCID 70873934HCID 70873934, compoundYield 89.2%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Procedure

To a stirred solution of methyl 3-amino-5-chloro-2-ethylbenzoate (365 mg, 1.7 mmol) in 1,2-dichloroethane (20 ml) under nitrogen, was added tert-butyl (4-oxocyclohexyl)carbamate (364 mg, 1.7 mmol) followed by acetic acid (587 μl, 10.3 mmol). The solution was stirred for 10 minutes before the portionwise addition of sodium triacetoxyborohydride (1.09 g, 5.1 mmol) over 1 hour. The resulting solution was stirred at room temperature for 17 hours, before treating with tert-butyl (4-oxocyclohexyl)carbamate (364 mg, 1.7 mmol). The reaction mixture was stirred for 30 minutes and then treated with sodium triacetoxyborohydride (1.09 g, 5.1 mmol) over 2.5 hours. The reaction mixture was stirred at room temperature for a further 26 hours before addition of deionized water (40 ml). The mixture was neutralised with solid NaHCO3 (2.95 g) and was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (35 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (25 g SNAP cartridge, Isolera, 0-18% EtOAc/Heptanes) to give as an oil the title compound (623 mg, 85%) as a mixture of cis/trans isomers. LC-MS 46.1%, 2.61 min (3.5 minute LC-MS method), m/z=411.1, 413.1 and 50.2%, 2.66 min (3.5 minute LC-MS method), m/z=411.1, 413.1; 1H NMR (500 MHz, Chloroform-d) d ppm 7.05 (dd, J=7.09, 2.05 Hz, 1H) 6.68 (t, J=2.36 Hz, 1H) 4.36-4.63 (m, 1H) 3.88 (d, J=3.31 Hz, 3H) 3.62-3.78 (m, 1H) 3.49 (br. s., 1H) 3.23 (br. s., 1H) 2.63-2.76 (m, 2H) 2.07-2.18 (m, 2H) 1.77-1.89 (m, 2H) 1.69 (br. s., 1H) 1.46 (s, 9H) 1.27 (m, 3H) 1.13-1.24 (m, 3H).

Workup

  1. stirringThe reaction mixture was stirred for 30 minutes
  2. extractionwas extracted with ethyl acetate (3×50 ml)
  3. washThe combined organic extracts were washed with brine (35 ml)
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated in-vacuo
  7. customThe crude residue was purified by column chromatography (25 g SNAP cartridge, Isolera, 0-18% EtOAc/Heptanes)

Sources & evidence

ORD record
ord-693fc394a5a045d28f1cbd63ddd4c5ec
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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