Sodium Carbonate → 2-Chloro-5-fluoro-4-(7-{2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-benzo[b]thiophen-2-yl)-pyrimidine

HRID 558146Notes

Reaction equation

HRID 558146 reaction equation
[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[O:12][CH2:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:2]1=2.C(OB(OC(C)C)OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[Cl:47][C:48]1[N:53]=[C:52](Cl)[C:51]([F:55])=[CH:50][N:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(C)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:47][C:48]1[N:53]=[C:52]([C:5]2[S:1][C:2]3[C:9]([C:10]4[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=4[O:12][CH2:13][CH2:14][O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[C:51]([F:55])=[CH:50][N:49]=1

Participants

10

Reactant 5

HCID 10340Sodium CarbonateHCID 21531Triisopropyl borateHCID 2507052,4-Dichloro-5-fluoropyrimidineHCID 2724682Lithium diisopropylamideHCID 670000742-[2-(2-Benzo[b]thiophen-7-yl-phenoxy)-ethoxy]-tetrahydropyran

Product 1

HCID 866406622-Chloro-5-fluoro-4-(7-{2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-benzo[b]thiophen-2-yl)-pyrimidineYield 80.4%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 21906603Chloroform isopropyl alcoholSolvent

Procedure

In a 500-mL round bottom flask, cool a solution of 2-[2-(2-benzo[b]thiophen-7-yl-phenoxy)-ethoxy]-tetrahydropyran (500 mg, 1.41 mmol) and triisopropylborate (530 mg, 2.82 mmol) in THF (30 mL) to −70° C. under N2. To the solution, add lithium diisopropylamide (2 M in THF, 1.41 mL, 2.82 mmol) gradually over a period of 30 min. Stir the mixture continually for an additional 1 h in the cooling bath. Gradually transfer the mixture into a refluxing solution of 2,4-dichloro-5-fluoropyrimidine (353 mg, 2.12 mmol), Pd(dppf)Cl2 (57.6 g, 0.07 mmol) and sodium carbonate (2 M in water, 1.8 mL, 3.6 mmol) in THF (20 mL) over a period of 30 min. Reflux for an additional 1 h. Cool the mixture to RT and dilute with chloroform/IPA (3/1) and water. Wash the organic layer with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate in vacuo. Purify the residue by FCC (20% ethyl acetate in hexane) to give the title compound (550 mg, 80%). MS (ES) m/z 507 [M+Na]+.

Workup

  1. temperatureReflux for an additional 1 h
  2. washWash the organic layer with aqueous saturated sodium chloride
  3. dry with materialDry over sodium sulfate
  4. concentrationConcentrate in vacuo
  5. customPurify the residue by FCC (20% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-40e257fd33a04692aa83b4ac9e61ed7b
Source dataset
uspto-grants-2011_11
Patent number
US08063035B2

Reaction notes

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