Sodium Carbonate → 2-(4-Quinazolin-8-ylphenyl)-n-{(1r)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide

HRID 474147

반응식

HRID 474147 반응식
[F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([NH:13][C:14](=[O:16])[CH3:15])[CH3:12])=[N:9][CH:10]=1.Br[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][N:26]=[CH:25]2.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][C:20]=2[C:20]2[CH:21]=[CH:22][C:23]([CH2:15][C:14]([NH:13][C@@H:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:18])=[CH:10][N:9]=3)[CH3:12])=[O:16])=[CH:24][CH:29]=2)[CH:25]=[N:26][CH:27]=1

참가 물질

6

반응물 3

HCID 10340Sodium CarbonateHCID 183178148-BromoquinazolineHCID 123785221N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide

생성물 1

HCID 426099612-(4-Quinazolin-8-ylphenyl)-n-{(1r)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide수율 75%

시약·촉매·용매 2

HCID 178418476HCID 178418476, 화합물촉매HCID 6342Acetonitrile용매

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온도
150 °C

실험 절차

To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethylamine bis-HCl (0.75 g, 2.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylacetic acid (0.67 g, 2.6 mmol), EDC (0.59 g, 3.1 mmol), and 1-hydroxy-7-azabenzotriazole (0.42 g, 3.1 mmol) in DMF (5 mL) was added diisopropylethylamine (1.8 mL, 10.2 mmol). After stirring for 90 min at room temperature, the reaction mixture was loaded directly onto a silica gel column and purified by normal phase chromatography (20-80% EtOAc/hexanes) to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (0.77 g, 65%) as a viscous oil that slowly solidified to a white solid. MS (Electrospray): m/z 465.1 (M+H). To a microwave vial containing 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (50 mg, 0.11 mmol), 8-bromoquinazoline (25 mg, 0.12 mmol), and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) in acetonitrile (1 mL) was added aqueous 1M sodium carbonate (1 mL, 1.0 mmol) and the mixture was heated in a microwave at 150° C. for 10 min. The top organic layer was removed, loaded onto a silica gel column and purified by normal phase chromatography (30-100% EtOAc/hexanes) to give 2-(4-quinazolin-8-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (21 mg, 38%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 9.37 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.96 (m, 2H), 7.75 (m, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.22 (m, 2H), 6.79 (d, J=7.2 Hz, 1H), 5.16 (m, 1H), 4.37 (q, J=8.0 Hz, 2H), 3.68 (s, 2H), 1.44 (d, J=6.8 Hz, 3H); MS (Electrospray): m/z 467.1 (M+H). FLIPR alpha1I IP=19 nM.

후처리

  1. customThe top organic layer was removed
  2. custompurified by normal phase chromatography (30-100% EtOAc/hexanes)

출처 및 근거

ORD 기록
ord-1aa7b41374224d2d9f72e230733a669f
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08637513B2

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