Cesium carbonate → methyl 2-(tert-butoxy)-2-(1-(3-fluoro-4-methylbenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate

HRID 1473239ノート

反応式

HRID 1473239 の反応式
[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[CH3:48])[CH2:43]Br>C(#N)C.O.Cl>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:43][C:42]3[CH:45]=[CH:46][C:47]([CH3:48])=[C:40]([F:39])[CH:41]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]

参加物

7

反応物 3

HCID 10796Cesium carbonateHCID 27746033-Fluoro-4-methylbenzyl bromideHCID 89462937methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate

生成物 1

HCID 89462853methyl 2-(tert-butoxy)-2-(1-(3-fluoro-4-methylbenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate収率 84%

試薬・触媒・溶媒 3

HCID 313Hydrochloric Acid溶媒HCID 962Water溶媒HCID 6342Acetonitrile溶媒

反応条件

温度
70 °C

実験手順

A solution of methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (20 mg, 0.046 mmol) in Acetonitrile (0.45 mL) was treated with Cs2CO3 (59.4 mg, 0.182 mmol), 3-fluoro-4-methylbenzyl bromide (13.89 mg, 0.068 mmol), and then stirred at 70° C. for 90 min. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-60% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(1-(3-fluoro-4-methylbenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (21.5 mg, 0.038 mmol, 84% yield) as clear oil: LCMS (m/z) ES+=561 (M+1). The intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with LiOH (0.100 mL, 0.200 mmol), and stirred overnight at 60° C. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (13.5 mg, 0.024 mmol, 64.7% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.36-7.29 (m, 0.4H), 7.12 (t, J=7.8 Hz, 1H), 7.04-6.87 (m, 3.6H), 6.80-6.66 (m, 1H), 5.97-5.59 (m, 3H), 5.46-5.40 (m, 0.4H), 5.21-5.11 (m, 0.6H), 4.27-4.10 (m, 2H), 3.71-3.61 (m, 3H), 2.77-2.58 (m, 2H), 2.27-2.19 (m, 3H), 2.16-2.05 (m, 2H), 2.02 (s, 2H), 1.94 (s, 1H), 1.19-1.11 (m, 6H), 1.05-0.99 (m, 3; LCMS (m/z) ES+=547 (M+1).

後処理

  1. temperatureThe reaction was cooled to rt
  2. extractionextracted with EtOAc
  3. washwashed Brine
  4. dry with materialdried with Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification with column chromatography (0-60% EtOAc/Hexane)

出典と根拠

ORDレコード
ord-1e1e179f32fd4c01a94388b676e24dfc
出典データセット
uspto-grants-2015_04
特許番号
US09012642B2

反応ノート

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