Pyridine → HCID 86292589, compound

HRID 873937Notes

Reaction equation

HRID 873937 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.N1C=CC=CC=1>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([C:33]4[C:28]([CH3:27])=[N:29][CH:30]=[CH:31][CH:32]=4)[C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 1049PyridineHCID 201116472-Methylpyridine-3-boronic acid2×HCID 178434165HCID 178434165, compound

Product 1

HCID 86292589HCID 86292589, compoundYield 4.4%

Reagents, catalysts & solvents 2

HCID 8895Cupric acetateCatalystHCID 180504Ceric ammonium nitrateSolvent

Conditions

Temperature
65 °C

Procedure

To a stirred solution of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 81.1) (200 mg, 0.542 mmol) in CAN (4 mL) with molecular sieves (4 g) under Ar were added 2-methylpyridine-3-boronic acid (166 mg, 1.085 mmol), pyridine (0.088 mL, 1.085 mmol) and copper(II) acetate (148 mg, 0.813 mmol) and the reaction mixture was stirred 10 min at 65° C. 2-methylpyridine-3-boronic acid (1.485 g, 10.85 mmol) was added portionwise over a period of 1 hr. The reaction mixture was concentrated under reduced pressure, quenched with a saturated aq. NaHCO3 solution and the aq. layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 1.5-5%). followed by preparative achiral SFC (column 4-Ethyl-pyridine, gradient 13-18% in 6 min_total 11 min) and triturated in Hexane/Et2O (1:1) to afford the title product (11 mg, 0.024 mmol, 4% yield). tR: 3.20 min (HPLC 1); tR: 0.87 min (LC-MS 2); ESI-MS: 460 [M+H]+ (LC-MS 2); Rf=0.53 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6)6 ppm 1.89 (s, 3H) 1.93 (s, 3H) 2.18 (s, 3H) 3.37 (s, 3H) 6.23 (s, 1H) 7.28-7.49 (m, 6H) 7.77 (d, J=2.7 Hz, 1H) 7.88 (dd, J=7.8, 1.56 Hz, 1H) 8.63 (dd, J=4.9, 1.4 Hz, 1H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customquenched with a saturated aq. NaHCO3 solution
  3. extractionthe aq. layer was extracted with CH2Cl2
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 1.5-5%)
  7. customfollowed by preparative achiral SFC (column 4-Ethyl-pyridine, gradient 13-18% in 6 min_total 11 min)
  8. customtriturated in Hexane/Et2O (1:1)

Sources & evidence

ORD record
ord-20484108d396449c9587e6ea10d13ff8
Source dataset
uspto-grants-2015_03
Patent number
US08975417B2

Reaction notes

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