1H-Indole-4-boronic acid → 5-hydroxy-2-[2-(1H-indol-4-yl)pyridin-4-yl]-3-methylpyrimidin-4(3H)-one

HRID 869305Notes

Reaction equation

HRID 869305 reaction equation
Br[C:2]1[CH:7]=[C:6]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([OH:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:17]1[C:25]2[C:20](=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>C1COCC1.C([O-])([O-])=O.[Cs+].[Cs+].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:16][C:11]1[C:12](=[O:15])[N:13]([CH3:14])[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][NH:17]4)[CH:7]=2)=[N:9][CH:10]=1

Participants

6

Reactant 2

HCID 27631731H-Indole-4-boronic acidHCID 1357416812-(2-bromopyridin-4-yl)-5-hydroxy-3-methylpyrimidin-4(3H)-one

Product 1

HCID 1363429665-hydroxy-2-[2-(1H-indol-4-yl)pyridin-4-yl]-3-methylpyrimidin-4(3H)-oneYield 78.5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolventHCID 10796Cesium carbonateSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of 2-(2-bromopyridin-4-yl)-5-hydroxy-3-methylpyrimidin-4(3H)-one (30 mg, 0.106 mmol), 1H-indol-4-ylboronic acid (32 mg, 0.2 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichchloromethane complex (4 mg) in THF (2 mL) and 1 M aq Cs2CO3 (1 mL) was heated in a microwave at 160° C. for 10 min. After cooling to rt, the THF layer was separated and the aq. solution was extracted with THF (2 mL). The combined THF solution was treated with QuadraPure TU resin (Aldrich), filtered, and concentrated. The concentrated residue was purified by LCMS to give 5-hydroxy-2-[2-(1H-indol-4-yl)pyridin-4-yl]-3-methylpyrimidin-4(3H)-one (26.5 mg, TPA salt). 1H-NMR (499 MHz, d6-DMSO): δ 11.31 (s, 1H); 9.77 (s, 1H); 8.85 (d, J=5.0 Hz, 1H); 8.08 (s, 1H); 7.61-7.56 (m, 2H); 7.56-7.50 (m, 2H); 7.46 (t, H=2.7 Hz, 1H); 7.22 (t, J=7.7 Hz, 1H); 6.99-6.96 (m, 1H); 3.44 (s, 3H); HRMS calculated for (C18H14N4O2+H)+ 319.1190 found 319.1188. Assays The activity of the compounds in accordance with the present invention as COMT inhibitors may be readily determined without undue experimentation using a fluorescence or fluorescence polarization (FP) methodology that is well known in the art (Kurkela M et al., Anal Biochem (331) 2004, 198-200 and Graves, T L et al., Anal Biochem (373) 2008, 296-306). Assays utilized purified human COMT enzyme of the Val158 variant (membrane-bound MB-COMT or soluble S-COMT) containing a C-terminal 6 or 10-histidine tag. Compounds of the following examples had activity in reference assays by exhibiting the ability to inhibit the methylation of esculetin and/or inhibit the production of S-adenosyl-homocysteine (SAH). Any compound exhibiting an IC50 below 1 μM would be considered a COMT inhibitor as defined herein.

Workup

  1. temperatureAfter cooling to rt
  2. customthe THF layer was separated
  3. extractionthe aq. solution was extracted with THF (2 mL)
  4. additionThe combined THF solution was treated with QuadraPure TU resin (Aldrich)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe concentrated residue was purified by LCMS

Sources & evidence

ORD record
ord-e7cd8228be1e480f933e3eeb6d082378
Source dataset
uspto-grants-2015_03
Patent number
US08969364B2

Reaction notes

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