Triethylamine → HCID 135771828, compound

HRID 1693001Notes

Reaction equation

HRID 1693001 reaction equation
[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[OH:25])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>C1COCC1>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:25])[C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 694002-Methoxyethyl chloroformateHCID 136121403HCID 136121403, compound

Product 1

HCID 135771828HCID 135771828, compoundYield 50%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-50 °C

Procedure

To a mixture of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (200 mg, 0.59 mmol) and THF (6 mL) was added triethylamine (165 μL, 1.18 mmol) to form a clear solution. The mixture was cooled to −50° C. external temperature, and a 1:1 mixture of 2-methoxyethyl chloroformate (65 μL) and THF (65 μL) was added dropwise. After complete addition, the reaction was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 gave (R)-2-methoxyethyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 1) (130 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=8.7 Hz, 1H), 7.71 (d, J=6.1 Hz, 1H), 7.58 (s, 1H), 7.33 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.69 (m, 1H), 4.22 (m, 1H), 4.04 (m, 5H), 3.84 (m, 1H), 3.48 (t, J=4.6 Hz, 2H), 3.23 (s, 3H), 2.52 (s, 3H), 2.20 (m, 1H), 2.02 (m, 1H) ppm. LC/MS: m/z 441.5 (M+H)+ at 2.10 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).

Workup

  1. customto form a clear solution
  2. additionwas added dropwise
  3. additionAfter complete addition
  4. customthe reaction was quenched with H2O
  5. extractionextracted with CH2Cl2
  6. dry with materialThe combined organic extracts were dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification via silica gel chromatography
  10. additionin a 1:1 mixture of hexanes and CH2Cl2

Sources & evidence

ORD record
ord-1385f028b2b2421784ad5abb0fafcc8b
Source dataset
uspto-grants-2012_04
Patent number
US08158637B2

Reaction notes

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