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

Reaction equation

HRID 924647 reaction equation
[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]

Participants

6

Reactant 4

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

Product 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 acidYield 8%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
40 °C

Procedure

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]+.

Workup

  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)

Sources & evidence

ORD record
ord-28972b6cdee9406b9ef117212ea4be90
Source dataset
uspto-grants-2016_03
Patent number
US09283213B2

Linked notes

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