Diisopropylethylamine → HCID 135771841, compound

HRID 2406186Notes

Reaction equation

HRID 2406186 reaction equation
C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:37].ClC([O-])=O>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 33521852,2-Dimethylpropyl carbonochloridateHCID 21226386CarbonochloridateHCID 136121403HCID 136121403, compound

Product 1

HCID 135771841HCID 135771841, compoundYield 95.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-60 °C

Procedure

At RT, diisopropyl ethylamine (273 μL, 1.57 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (266 mg, 0.79 mmol) in THF (15 mL), and the reaction was cooled to −60° C. Neopentyl chloroformate (116 μL in 2.0 mL THF, 0.79 mmol) was added dropwise over a period of 10 minutes. After addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to give (R)-neopentyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 11) (340 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.64-7.58 (m, 3H), 7.47 (q, J=7.8 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.87 (t, J=9.2 Hz, 1H), 4.28-3.99 (m, 5H), 3.71-3.64 (m, 2H), 2.56 (s, 3H), 2.23-2.14 (m, 1H), 2.07-1.92 (m, 1H), 0.89 (s, 9H) ppm. LC/MS: m/z 453.5 (M+H)+ at 2.66 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).

Workup

  1. temperaturethe reaction mixture was warmed to RT
  2. customquenched with H2O
  3. extractionextracted with CH2Cl2
  4. dry with materialThe organic phase was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified via silica gel chromatography
  8. additionin a 1:1 mixture of hexanes and CH2Cl2

Sources & evidence

ORD record
ord-487e797864c1459189ab34fd26e8f535
Source dataset
uspto-grants-2014_08
Patent number
US08809353B2

Reaction notes

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