Acetonitrile → HCID 90413833, compound

HRID 1746072Notes

Reaction equation

HRID 1746072 reaction equation
[CH2:1]1[C:9]2[C:4](=[CH:5][C:6](B3OC(C)(C)C(C)(C)O3)=[CH:7][CH:8]=2)[CH2:3][O:2]1.[NH2:19][C:20]1[C:25]([F:26])=[C:24](Cl)[N:23]=[C:22]([C:28]([O:30][CH3:31])=[O:29])[C:21]=1[Cl:32].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>O.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:19][C:20]1[C:25]([F:26])=[C:24]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][O:2][CH2:3]3)[N:23]=[C:22]([C:28]([O:30][CH3:31])=[O:29])[C:21]=1[Cl:32]

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 10340Sodium CarbonateHCID 22677265Methyl 4-amino-3,6-dichloro-5-fluoropicolinateHCID 796621981,3-Dihydroisobenzofuran-5-boronic Acid Pinacol Ester

Product 1

HCID 90413833HCID 90413833, compoundYield 22.1%

Reagents, catalysts & solvents 2

HCID 178418903HCID 178418903, compoundCatalystHCID 962WaterSolvent2×

Conditions

Temperature
85 °C

Procedure

To the crude 2-(1,3-dihydroisobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (estimated to be 570 mg, 2.3 mmol, 1.1 equiv) was added methyl 4-amino-3,6-dichloro-5-fluoropicolinate (500 mg, 2.1 mmol, 1.0 equiv), dichloro[bis(triphenylphosphino)]-palladium(II) (150 mg, 0.21 mmol, 0.10 equiv), and sodium carbonate (240 mg, 2.3 mmol, 1.1 equiv) followed by a 1:1 mixture of water:acetonitrile (7.0 mL) at 23° C. The resulting dark orange/brown mixture was heated to 85° C. and stirred for 4 h. The cooled reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (4×70 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to yield the title compound as an orange powder (150 mg, 22%): mp 153-156° C.; IR (neat film) 3468 (m), 3334 (s), 3205 (m), 2952 (m), 2856 (m), 1735 (s), 1623 (s), 1579 (w) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.81-7.86 (m, 2H), 7.33 (d, J=8 Hz, 1H), 5.16 (br d, J=4 Hz, 1H), 4.89 (br s, 2H), 3.97 (s, 3H); ESIMS m/z 323 [(M+H)+].

Workup

  1. customat 23° C
  2. customThe cooled reaction mixture
  3. extractionextracted with dichloromethane (4×70 mL)
  4. dry with materialThe combined organic layers were dried (magnesium sulfate), gravity
  5. filtrationfiltered
  6. concentrationconcentrated by rotary evaporation
  7. customThe residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient)

Sources & evidence

ORD record
ord-b6a37671d41a452d9957dbf77dc47fd8
Source dataset
uspto-grants-2015_10
Patent number
US09149038B2

Reaction notes

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