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

HRID 474147

反応式

HRID 474147 の反応式
[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

参加物

6

反応物 3

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

生成物 1

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

試薬・触媒・溶媒 2

HCID 178418476HCID 178418476、化合物触媒HCID 6342Acetonitrile溶媒

反応条件

温度
150 °C

実験手順

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.

後処理

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

出典と根拠

ORDレコード
ord-1aa7b41374224d2d9f72e230733a669f
出典データセット
uspto-grants-2014_01
特許番号
US08637513B2

関連ノート

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