Chloromethyl Methyl Ether → 6-(N-(3-Chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

HRID 1424882Notes

Reaction equation

HRID 1424882 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:11])[CH:9]=[CH2:10].CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51]Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([C:17]2[C:36]([CH:37]3[CH2:38][CH2:39]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([O:11][CH2:49][O:50][CH3:51])[CH:9]=[CH2:10]

Participants

6

Reactant 3

HCID 7864Chloromethyl Methyl EtherHCID 81531Diisopropylethylamine2×HCID 1317323286-(N-(3-Chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Product 1

HCID 1317323296-(N-(3-Chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideYield 77.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 6-(N-(3-chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (210 mg, 0.37 mmol) in THF (7 mL) was added DIEA (0.084 mL, 0.48 mmol) and chloromethyl methyl ether (0.16 mL, 2.12 mmol). The reaction mixture was heated at 50° overnight. Another portion of DIEA (0.32 mL, 1.85 mmol) was added and heating was continued for another 5 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine (1×), dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes) afforded the title compound (175 mg, 77%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (q, 1H), 8.10 (s, 1H), 7.93-8.00 (m, 2H), 7.36-7.53 (m, 5H), 7.19 (s, 1H), 5.88 (ddd, 1H), 5.38 (d, 1H), 5.18-5.30 (m, 2H), 4.66 (d, 1H), 4.53 (d, 1H), 3.38-3.46 (m, 3H), 3.23 (s, 3H), 2.83 (d, 3H), 2.08-2.17 (m, 1H), 0.92-1.06 (m, 1H), 0.75-0.91 (m, 2H), 0.39-0.51 (m, 1H). LCMS (m/z, ES+)=613 (M+H+).

Workup

  1. temperatureThe reaction mixture was heated at 50° overnight
  2. temperatureheating
  3. extractionextracted with EtOAc (2×)
  4. washThe combined organic layers were washed with brine (1×)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customPurification by flash chromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes)

Sources & evidence

ORD record
ord-3ba43c8681184cc58cfb15cf13f0e169
Source dataset
uspto-grants-2015_01
Patent number
US08927593B2

Reaction notes

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