Toluene → HCID 66599389, compound

HRID 2410713Notes

Reaction equation

HRID 2410713 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:29]=[CH:28][C:12]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=2)=[C:4]([C:30]#[N:31])[CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CO>[C:30]([C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:33]([F:32])[CH:34]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:29]=[CH:28][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)#[N:31]

Participants

7

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 27821943-Fluoro-4-methoxyphenylboronic acidHCID 66599441HCID 66599441, compound

Product 1

HCID 66599389HCID 66599389, compoundYield 96.1%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolvent

Conditions

Temperature
105 °C

Procedure

A 125 ml pressure flask was loaded with tert-butyl 4-(4-(4-bromo-2-cyanophenylamino)benzoyl)piperazine-1-carboxylate (6.55 g, 13.49 mmol), 3-fluoro-4-methoxyphenylboronic acid (2.75 g, 16.19 mmol) and Pd(Ph3P)4 (0.43 g, 0.372 mmol). Toluene (45 mL), MeOH (22.50 mL) and a 2 molar solution of Na2CO3 (16.87 mL, 33.7 mmol) were added, the flask flushed with nitrogen, sealed and heated to 105° C. for 5 hours. The reaction mixture was poured into a separating funnel loaded with water and dichloromethane, the layers separated and the aqueous layer extracted one more time with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica. Gradient from 100% CH2Cl2 to 67% CH2Cl2+33 ethyl acetate. Product containing fractions were combined and concentrated in vacuum. 6.88 g tert-butyl 4-(4-(3-cyano-3′-fluoro-4′-methoxybiphenyl-4-ylamino)benzoyl)-piperazine-1-carboxylate were isolated as a pale yellow foam of ˜80% purity. The material was used in then next step without further purification. MS (ESI) m/z 529 (M−H).

Workup

  1. customthe flask flushed with nitrogen
  2. customsealed
  3. additionThe reaction mixture was poured into a separating funnel
  4. customthe layers separated
  5. extractionthe aqueous layer extracted one more time with dichloromethane
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuum
  10. customThe crude product was purified by column chromatography on silica
  11. additionProduct containing fractions
  12. concentrationconcentrated in vacuum

Sources & evidence

ORD record
ord-dfd94cf0cd4349d69a31ac0ac63f8390
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

Loading…