Acetic Acid → HCID 70873606, compound

HRID 2208839Notes

Reaction equation

HRID 2208839 reaction equation
[Br:1][C:2]1[C:11]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:9]([Cl:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CCOC(C)=O.O>[Br:1][C:2]1[C:11]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:10][C:9]([Cl:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]

Participants

9

Reactant 5

HCID 176Acetic AcidHCID 177Acetaldehyde4×HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride4×HCID 70873931Benzoic acid, 2-bromo-5-chloro-3-[(tetrahydro-2H-pyran-4-yl)amino]-, methyl ester

Product 1

HCID 70873606HCID 70873606, compoundYield 38%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolvent2×HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of methyl 2-bromo-5-chloro-3-(oxan-4-ylamino)benzoate (300 mg, 0.86 mmol) in 1,2-dichloroethane (3 ml) at room temperature under nitrogen was added acetaldehyde (96 μl, 1.7 mmol) followed by acetic acid (0.3 ml, 5.16 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.55 g, 2.6 mmol) at room temperature with reaction monitoring by LCMS. After 22 h, further acetaldehyde (96 μl, 1.7 mmol) was added to the reaction mixture and this was stirred for 10 minutes before the addition of sodium triacetoxyborohydride (0.55 g, 2.6 mmol). After 3 days, the reaction mixture was diluted with 1,2-dichloroethane (5 ml). Acetaldehyde (962 μl, 17.2 mmol) was added to the reaction mixture and this was stirred for 10 minutes before the addition of sodium triacetoxyborohydride (1.82 g, 8.6 mmol). After 15 h, further acetaldehyde (960 μl, 17.2 mmol) was added to the reaction mixture and this was stirred for 10 minutes before the addition of sodium triacetoxyborohydride (1.82 g, 8.6 mmol). The reaction mixture was then stirred at room temperature for a further 22 hours before deionized water (25 ml) was added and the mixture was neutralised with solid NaHCO3. EtOAc (25 ml) was added and the phases were separated. The aqueous layer was then extracted with EtOAc (2×25 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 122 mg (38%) of the title compound as a colourless oil. LC-MS 85%, m/z=376.3/378.2/379.9, 1H NMR (500 MHz, Chloroform-d) δ 7.31 (d, J=2.5 Hz, 1H), 7.18 (d, 12.4 Hz, 1H), 3.98 (dd, J=8.7, 5.5 Hz, 2H), 3.94 (s, 3H), 3.35 (td, J=11.6, 5.5 Hz, 2H), 3.19 (t, J=7.1 Hz, 1H), 3.12 (q, J=7.1 Hz, 2H), 1.75 (td, J=10.1, 8.8, 3.9 Hz, 4H), 0.92 (t, J=7.1 Hz, 3H).

Workup

  1. waitAfter 3 days
  2. waitAfter 15 h
  3. additionwas added
  4. customthe phases were separated
  5. extractionThe aqueous layer was then extracted with EtOAc (2×25 ml)
  6. dry with materialthe combined organic extracts were dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 8:2 Heptane:EtOAc)

Sources & evidence

ORD record
ord-c9215d7bf8cc47d99a71e7856cd78070
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

Loading…