1,2-Dimethoxyethane → N-(4-(3-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine

HRID 911183Notes

Reaction equation

HRID 911183 reaction equation
[Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([O:31][C:32]4[C:37](B(O)O)=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:29][CH:28]=3)=[N:18][N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.COCCOC.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(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:37]2[C:32]([O:31][C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:19]4[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)=[N:17][N:18]=4)=[CH:42][CH:41]=3)=[N:33][CH:34]=[CH:35][CH:36]=2)[C:5]([F:9])=[CH:4][N:3]=1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2507052,4-Dichloro-5-fluoropyrimidineHCID 248560752-(4-(4-Phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid

Product 1

HCID 86614169N-(4-(3-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amineYield 93%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
85 °C

Procedure

Under an argon atmosphere, 2,4-dichloro-5-fluoropyrimidine (390 mg, 2.34 mmol) and 2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid (1.01 g, 2.34 mmol) were dissolved in 1,2-dimethoxyethane (15.6 ml, 2.34 mmol) in a screw capped test tube. Sodium carbonate (4.67 ml, 9.34 mmol) was added followed by Pd(PPh3)4 (0.270 g, 0.234 mmol). The tube was purged with argon, sealed, and heated to 85° C. After 3 h, LCMS showed mostly product, a small amount of starting material left. 100 mg of Dichlorofluoropyrimidine was added, and the reaction was stirred overnight. After 22 h, LCMS showed complete conversion to product. Water was added. The product was extracted with DCM. The organic phase was dried over MgSO4, filtered, and concentrated. Hexane was added to the residue. A tan solid precipitated and was filtered off with an aid of hexane. The product was purified using an ISCO column chromatography on silica gel eluting with 80:20 DCM:(90:10:1 DCM:MeOH:NHOH) and was obtained as a yellow solid, N-(4-(3-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine (1.13 g, 93% yield). MS Calcd for C29H18ClFN6O: [M]+=520. Found: [M+1]+=521.

Workup

  1. customcapped test tube
  2. customThe tube was purged with argon
  3. customsealed
  4. waita small amount of starting material left
  5. addition100 mg of Dichlorofluoropyrimidine was added
  6. waitAfter 22 h
  7. additionWater was added
  8. extractionThe product was extracted with DCM
  9. dry with materialThe organic phase was dried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. additionHexane was added to the residue
  13. customA tan solid precipitated
  14. filtrationwas filtered off with an aid of hexane
  15. customThe product was purified

Sources & evidence

ORD record
ord-43e379f9f70b489388cc4649ad9a6ac5
Source dataset
uspto-grants-2011_09
Patent number
US08022221B2

Reaction notes

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