Lithium Hexamethyldisilazide → HCID 178432536, compound

HRID 1812366Notes

Reaction equation

HRID 1812366 reaction equation
F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([Cl:31])=[N:29][CH:30]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:31][C:28]1[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:26][C:25]([NH:24][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][NH:12]4)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:30][N:29]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 595484686-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 71480920N-(5-amino-2-chloro-3-pyridinyl)methanesulfonamide

Product 1

HCID 178432536HCID 178432536, compoundYield 15%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Example 4, 0.0895 g, 0.286 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, Step 2, 0.0772 g, 0.348 mmol) in THF (1 mL) in 5 mL microwave vial, LiHMDS (1.14 mL, 1.14 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The reaction was quenched by adding saturated aqueous sodium chloride (0.2 mL). The reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with water (40 mL) and saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken into THF (5 mL) and 5 N HCl (1 mL) was added. The yellow mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The pure fractions were collected and lyophilized to afford N-(2-chloro-5-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (TFA salt, 0.0185 g, 11% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s., 1H) 9.79 (d, J=7.63 Hz, 1H) 9.67 (s, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.63 (s, 1H) 8.50 (d, J=2.54 Hz, 1H) 8.41 (dd, J=4.69, 1.96 Hz, 1H) 7.14 (dd, J=7.92, 4.79 Hz, 1H) 3.13-3.18 (m, 3H) 2.86-2.90 (m, 3H). Note: one proton was missing from the NMR spectrum. m/z (ESI, positive ion): 430.9 (M+H)+ as parent ion.

Workup

  1. customThe reaction was quenched
  2. additionby adding saturated aqueous sodium chloride (0.2 mL)
  3. customThe reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (30 mL) and EtOAc (30 mL)
  4. extractionThe aqueous phase was extracted with EtOAc (30 mL)
  5. washThe combined organic phases were washed with water (40 mL) and saturated aqueous sodium chloride (40 mL)
  6. dry with materialThe organic phase was dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. additionwas added
  10. stirringThe yellow mixture was stirred at room temperature for 30 min
  11. concentrationThe reaction mixture was concentrated
  12. customthe crude product was purified by preparative HPLC
  13. customC18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min)
  14. customThe pure fractions were collected

Sources & evidence

ORD record
ord-3d6f50d82ae9460c92bfb100c022b658
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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