2-Methoxyethanol → 2-(5,6-dimethoxypyridin-3-yl)-7-(2-methoxyethoxy)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

HRID 1259349Notes

Reaction equation

HRID 1259349 reaction equation
Cl[C:2]1[N:7]=[C:6]2[CH:8](Cl)[N:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:48][O:49][CH2:50][CH2:51][OH:52]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][O:31][C:30]1[CH:29]=[C:28]([C:2]2[N:7]=[C:6]3[CH:8]([O:52][CH2:51][CH2:50][O:49][CH3:48])[N:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=4)[C:10](=[O:11])[C:5]3=[CH:4][CH:3]=2)[CH:27]=[N:26][C:25]=1[O:24][CH3:23]

Participants

7

Reactant 4

HCID 80192-MethoxyethanolHCID 10340Sodium CarbonateHCID 453617702,3-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine2×HCID 866619702,7-dichloro-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Product 1

HCID 667425332-(5,6-dimethoxypyridin-3-yl)-7-(2-methoxyethoxy)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneYield 21.7%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

As shown in step 18-ii of Scheme 18, to Compound 2060 (180 mg, 0.5127 mmol) in DMF (6 mL) was added 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound 2021, 163 mg, 0.62 mmol), Na2CO3 (217 mg, 2.05 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), and 2-methoxyethanol (1.5 mL, 19.0 mmol). The reaction vessel was evacuated, placed under an atmosphere of nitrogen, then warmed to 100° C. (sand bath). After 16 hours, the reaction mixture was partitioned between EtOAc and water (100 mL each). The organics were concentrated under reduced pressure and the residue dissolved in DMSO (5 mL) and purified by reversed-phase HPLC (10-90% aqueous MeCN with 0.1% TFA buffer) to give 2-(5,6-dimethoxypyridin-3-yl)-7-(2-methoxyethoxy)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 336, 55 mg) as a white lyophilizate: ESMS (M+H) 494.39; 1H NMR (CD3OD, 300 MHz) δ 8.50 (d, J=3 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J=9 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 8.08 (d, J=3 Hz, 1H), 8.00 (s, 1H), 6.29 (s, 1H), 4.99 (q, J=9 Hz, 2H), 4.03 (s, 3H), 3.97 (s, 3H), 3.66 (m, 1H), 3.53 (m, 3H), 3.29 (s, 3H).

Workup

  1. customThe reaction vessel was evacuated
  2. customthe reaction mixture was partitioned between EtOAc and water (100 mL each)
  3. concentrationThe organics were concentrated under reduced pressure
  4. dissolutionthe residue dissolved in DMSO (5 mL)
  5. custompurified by reversed-phase HPLC (10-90% aqueous MeCN with 0.1% TFA buffer)

Sources & evidence

ORD record
ord-55fce80ea3394e69a37e6ca0bbe1141c
Source dataset
uspto-grants-2013_06
Patent number
US08466288B2

Reaction notes

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