Toluene → (R)-isopropyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

HRID 1693031Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1693031
C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34].C1(C)C=CC=CC=1>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH:36]([CH3:38])[CH3:37])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1

Komponenten

6

Edukt 4

HCID 1140TolueneHCID 7917Isopropyl chloroformateHCID 8471TriethylamineHCID 136121376(R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol

Produkt 1

HCID 135771842(R)-isopropyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamateAusbeute 38 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
-70 °C

Versuchsvorschrift

At RT under an N2 atmosphere, triethylamine (23 mL, 0.31 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg, 0.16 mmol) in THF (1.5 mL), and the reaction was cooled to −70° C. A 1.0 M solution of isopropyl chloroformate in toluene (133 μL, 0.15 mmol) was added, and the mixture was warmed to RT. The reaction was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were washed twice with H2O, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R)-isopropyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 12) (23 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J=8.1, 1.6 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=5.9 Hz, 1H), 7.38-7.32 (m, 2H), 6.94-6.90 (m, 2H), 4.81-4.74 (m, 1H), 4.25-4.11 (m, 3H), 4.06-4.01 (m, 1H), 3.85 (dd, J=11.1, 3.5 Hz, 1H), 2.49 (s, 3H), 2.25-2.17 (m, 1H), 2.05-1.99 (m, 1H), 1.20-1.15 (m, 6H) ppm. LC/MS: m/z 407.5 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).

Aufarbeitung

  1. temperaturethe mixture was warmed to RT
  2. customThe reaction was quenched with H2O
  3. extractionextracted with CH2Cl2
  4. washThe combined organic extracts were washed twice with H2O
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customPurification via silica gel chromatography
  8. additionin a 1:1 mixture of CH2Cl2 and hexanes

Quellen und Nachweise

ORD-Eintrag
ord-7e2ae1a4369043e1b1690650d964c39d
Quelldatensatz
uspto-grants-2012_04
Patentnummer
US08158637B2

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