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

반응식

HRID 924647 반응식
[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]

참가 물질

6

반응물 4

HCID 162492,2-Dimethyl-1,3-dioxane-4,6-dioneHCID 517165Ammonium AcetateHCID 21626741Methyl 4-formyl-2-hydroxybenzoate2회HCID 651957941-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone2회

생성물 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 acid수율 8%

시약·촉매·용매 1

HCID 176Acetic Acid용매

반응 조건

온도
40 °C

실험 절차

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]+.

후처리

  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)

출처 및 근거

ORD 기록
ord-28972b6cdee9406b9ef117212ea4be90
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09283213B2

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