2,2-Dimethyl-1,3-dioxane-4,6-dione → 2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyridin-4-yl)benzoic acid

HRID 924647ノート

反応式

HRID 924647 の反応式
[CH3:1][N:2]1[CH:6]=[C:5]([C:7](=O)[CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:4]=[N:3]1.[CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([OH:27])[CH:18]=1)=O.[CH3:28][C:29]1(C)[O:36]C(=O)CC(=O)O1.C([O-])(C)=O.[NH4+:42]>CC(O)=O>[OH:27][C:19]1[CH:18]=[C:17]([CH:15]2[C:8]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[NH:42][C:29](=[O:36])[CH2:28]2)[CH:26]=[CH:25][C:20]=1[C:21]([OH:23])=[O:22]

参加物

6

反応物 4

HCID 162492,2-Dimethyl-1,3-dioxane-4,6-dioneHCID 517165Ammonium AcetateHCID 21626741Methyl 4-formyl-2-hydroxybenzoate2 回HCID 651957941-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone2 回

生成物 1

HCID 566444932-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyridin-4-yl)benzoic acid収率 8%

試薬・触媒・溶媒 1

HCID 176Acetic Acid溶媒

反応条件

温度
40 °C

実験手順

A mixture of 1-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone (Intermediate 3) (300 mg, 1.5 mmol), methyl 4-formyl-2-hydroxybenzoate (Intermediate 5) (315 mg, 1.7 mmol), meldrum's acid (245 mg, 1.7 mmol) and AcONH4 (130 mg, 1.7 mmol) in AcOH (3 mL) was refluxed under N2 atmosphere overnight. The mixture was concentrated under reduced pressure and taken up in MeOH (10 mL) and aq. NaOH (2 M, 10 mL). The reaction was stirred at 40° C. for 5 hours. The resulting mixture was cooled to room temperature, and then acidified with aq. HCl (2 M, 12 mL) to pH=5, followed by a standard aqueous/EtOAc workup. The residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound 9 as a gray solid (45 mg, 2-steps yield 8%). 1H NMR (DMSO-d6 400 MHz): δ 11.24 (brs, 1H), 9.41 (brs, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.38 (dd, J=4.8, 2.8 Hz, 1H), 7.08 (s, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.90-6.82 (m, 2H), 6.67 (d, J=5.2 Hz, 1H), 3.94 (d, J=6.4 Hz, 1H), 3.77 (s, 3H), 3.12 (dd, J=16.0, 7.6 Hz, 1H), 2.48-2.38 (m, 1H). MS (ESI): m/z 395.9 [M+1]+.

後処理

  1. temperaturewas refluxed under N2 atmosphere overnight
  2. concentrationThe mixture was concentrated under reduced pressure
  3. temperatureThe resulting mixture was cooled to room temperature
  4. customThe residue was purified by prep-HPLC (0.1% TFA as additive)

出典と根拠

ORDレコード
ord-28972b6cdee9406b9ef117212ea4be90
出典データセット
uspto-grants-2016_03
特許番号
US09283213B2

反応ノート

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