Tetrahydrofuran → isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

HRID 2062348Notes

Reaction equation

HRID 2062348 reaction equation
[NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C1COCC1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1)[CH:43]([CH3:45])[CH3:44]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 1361213492-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol

Product 1

HCID 136121450isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateYield 70.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.6 mmol), THF (6.0 mL), and CH2Cl2 was stirred under an N2 atmosphere. Triethylamine (0.166 mL, 1.2 mmol) was added, and the reaction was cooled in an ice bath. To this was added 1 M isobutyl chloroformate solution (78 μL in 600 μL THF, 0.6 mmol). After allowing the reaction mixture to warm to room temperature, CH2Cl2 was added, and the organic solution washed twice with water, then dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2/hexanes (1:1) gave isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (183 mg, 70%). LC/MS: m/z 435.5 (M+H)+ at 2.63 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). LC/MS: m/z 435 (M+H)+ at 2.63 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=8.2, 1.8 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.42-7.31 (m, 3H), 6.93-6.89 (m, 2H), 4.17-3.91 (m, 3H), 3.80-3.69 (m, 3H), 3.34-3.30 (m, 1H), 3.21-3.07 (m, 2H), 2.49 (s, 3H), 2.16-2.08 (m, 1H), 1.88-1.74 (m, 2H), 0.88 (d, J=6.7 Hz, 6H).

Workup

  1. temperaturethe reaction was cooled in an ice bath
  2. washthe organic solution washed twice with water
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification via silica gel chromatography

Sources & evidence

ORD record
ord-ae33ed00ec8c4506ab31945d96ba667b
Source dataset
uspto-grants-2012_10
Patent number
US08283354B2

Reaction notes

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