Acetonitrile → LP533401

HRID 469879Notes

Reaction equation

HRID 469879 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.[C:28]([O-:31])([O-])=[O:29].[Na+].[Na+].[C:34](#[N:36])[CH3:35]>Cl[Pd](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.O>[NH2:36][C@@H:34]([CH2:35][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=2)=[CH:16][CH:15]=1)[C:28]([OH:31])=[O:29]

Participants

6

Reactant 3

HCID 6342AcetonitrileHCID 10340Sodium CarbonateHCID 585161494-Chloro-6-(2,2,2-trifluoro-1-(3'-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine

Product 1

HCID 44560455LP533401

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
150 °C

Procedure

4-Chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (0.75 g, 1.89 mmol), L-p-boronophenylalanine (0.47 g, 2.26 mmol), Pd(PPh3)2Cl2 (79 mgs, 0.113 mmol), Na2CO3 (0.44 g, 4.15 mmol), acetonitrile (10 mls), and H2O (10 mls) were combined in a 20 ml microwave reactor and heated in the microwave at 150° C. for 7 minutes. The reaction was complete by LCMS (Sunfire, neutral). The mixture was concentrated, dissolved in NaOH (20 m is 0.5 N), filtered, extracted with ether three times, and cooled to 0° C. At 0° C., 1.0 N HCl was added slowly until a pH of 6.5 was attained. The mixture was stirred at 0° C. for 30 minutes and the product was filtered, dried in air, treated with excess 2.0 N HCl in ether, concentrated, then triturated with CH2Cl2 to give 1.12 g, 99% (95.5% purity). 385 mgs were purified via prep HPLC (Sunfire, TFA), concentrated, treated with excess 1.0 N HCl (aq.), concentrated to a small volume and lyophilized to afford 240 mgs of the captioned compound. M+1=527; 1H NMR 6 (CD3OD) 7.86 (d, 2H), 7.64 (s, 4H), 7.49 (d, 2H), 7.36 (m, 2H), 7.28 (m, 1H), 7.02 (m, 1H), 6.95 (s, 1H), 6.75 (q, 1H), 4.26 (t, 1H), 3.32 (m, 1H), 3.21 (m, 1H).

Workup

  1. concentrationThe mixture was concentrated
  2. dissolutiondissolved in NaOH (20 m is 0.5 N)
  3. filtrationfiltered
  4. extractionextracted with ether three times
  5. temperaturecooled to 0° C
  6. additionAt 0° C., 1.0 N HCl was added slowly until a pH of 6.5
  7. filtrationthe product was filtered
  8. customdried in air
  9. additiontreated with excess 2.0 N HCl in ether
  10. concentrationconcentrated
  11. customtriturated with CH2Cl2
  12. customto give 1.12 g, 99% (95.5% purity)
  13. custom385 mgs were purified via prep HPLC (Sunfire, TFA)
  14. concentrationconcentrated
  15. additiontreated with excess 1.0 N HCl (aq.)
  16. concentrationconcentrated to a small volume

Sources & evidence

ORD record
ord-38976c6e8e2a40b0bd657b85cdd9994e
Source dataset
uspto-grants-2014_01
Patent number
US08629156B2

Reaction notes

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