Hydrochloric Acid → 5-(4-Chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)-2-methoxybenzoic acid

HRID 81058Notes

Reaction equation

HRID 81058 reaction equation
[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4](Cl)[CH:3]=1.B([C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33])(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4]([C:27]2[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=2)[C:32]([OH:34])=[O:33])[CH:3]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 62657Potassium Phosphate, TribasicHCID 441191545-Borono-2-methoxybenzoic acidHCID 866656924,6-Dichloro-2-(4-phenoxyphenyl)nicotinonitrile

Product 1

HCID 669269405-(4-Chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)-2-methoxybenzoic acidYield 98%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 12976736Bis(ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane);iron(2+)CatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 4,6-dichloro-2-(4-phenoxyphenyl)nicotinonitrile (41.2 mg, 0.121 mmol, from Step 3 of Example 152), 5-borono-2-methoxybenzoic acid (18.9 mg, 0.096 mmol), palladium(II) acetate (4 mg, 0.018 mmol), potassium phosphate (125.8 mg, 0.593 mmol) and 1,1′-bis(di-t-butylphosphino)ferrocene (8.3 mg, 0.017 mmol) in N,N-dimethylformamide (0.5 mL) was pumped and backfilled with nitrogen twice. The reaction vial was then sealed and heated to 85° C. for 3 h. The crude material was poured into a mixture of ethyl acetate (20 mL) and diluted HCl (1 mmol, 5 mL). The aqueous pH was tested as pH 5. The ethyl acetate phase was concentrated and purified by reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), to give impure 5-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)-2-methoxybenzoic acid (43 mg). This material was taken to next reaction without further purification. MS (ES+) m/z: 457 (M+H).

Workup

  1. customThe reaction vial was then sealed
  2. concentrationThe ethyl acetate phase was concentrated
  3. custompurified by reverse phase HPLC (Sunfire S10 30×250 mm column)
  4. washeluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA)

Sources & evidence

ORD record
ord-9559ccc0e2eb48ceb87a743b469e0d76
Source dataset
uspto-grants-2014_09
Patent number
US08846673B2

Reaction notes

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