Hydrochloric Acid → HCID 178498040, compound

HRID 1050470Notes

Reaction equation

HRID 1050470 reaction equation
CS([O:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23](O)[C:24]([CH3:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:16]([O:15][C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:23]2[C:24]([CH3:31])=[C:25]([CH:30]=[C:21]([Cl:20])[CH:22]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:7][CH2:8]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 70904667Methyl 5-chloro-3-hydroxy-2-methylbenzoateHCID 178454080HCID 178454080, compound

Product 1

HCID 178498040HCID 178498040, compoundYield 23.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a mixture of (cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (5.36 mL, 22.93 mmol), methyl 5-chloro-3-hydroxy-2-methylbenzoate (4.0 g, 19.94 mmol), and cesium carbonate (9.74 g, 29.9 mmol) was added N,N-dimethylformamide (DMF) (100 mL). The suspension was stirred at RT for 15 min, then heated at 65° C. under nitrogen septum for 3 days. The reaction was allowed to cool to RT and was poured into ice/saturated NH4Cl (500 mL). The mixture was neutralized with 1 M HCl and extracted with 1:1 EtOAc/ether (2×). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated. The resultant liquid was dried under high vacuum for 2 h. Purification of the residue by flash chromatography (200 gram Isco silica column, 4-50% ether/heptane) gave methyl 3-(((trans)-4-((tert -butoxycarbonyl)amino)cyclohexyl)oxy)-5-chloro-2-methylbenzoate (1.87 g, 4.70 mmol, 23.57% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.48 (m, 13 H) 1.80 (d, J=10.61Hz, 2 H) 1.98-2.07 (m, 2 H) 2.25 (s, 3 H) 3.23-3.33 (m, 1 H) 3.82 (s, 3 H) 4.30-4.45 (m, 1 H) 6.86 (d, J=7.58 Hz, 1 H) 7.28 (d, J=2.02 Hz, 1 H) 7.35 (d, J=2.02 Hz, 1 H). MS(ES) [M+H]+ 420.1 (Na adduct).

Workup

  1. temperatureheated at 65° C. under nitrogen septum for 3 days
  2. temperatureto cool to RT
  3. extractionextracted with 1:1 EtOAc/ether (2×)
  4. washThe combined organics were washed with brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated
  7. customThe resultant liquid was dried under high vacuum for 2 h
  8. customPurification of the residue by flash chromatography (200 gram Isco silica column, 4-50% ether/heptane)

Sources & evidence

ORD record
ord-7a07ec56089d4118b0f0fc0c2aec39c3
Source dataset
uspto-grants-2016_07
Patent number
US09382234B2

Reaction notes

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