Morpholine → (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amine

HRID 74886Notes

Reaction equation

HRID 74886 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:24])=[CH:14][N:13]=3)=[CH:10][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCNC4)C(F)=CN=3)=CN([S:58]([C:61]3C=CC(C)=CC=3)(=[O:60])=[O:59])C2=NC=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.N1CCOCC1>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][N:21]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:20]4)[C:15]([F:24])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1

Participants

7

Reactant 5

HCID 8083MorpholineHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 672853922-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-pyrrolidin-3-yl]pyrimidin-4-amine hydrochlorideHCID 672853932-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-pyrrolidin-3-yl]pyrimidin-4-amine

Product 1

HCID 68008525(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amineYield 37%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a stirred suspension of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-pyrrolidin-3-yl]pyrimidin-4-amine hydrochloride, 7c, (0.05 g, 0.10 mmol) in THF (1 mL) was added iPr2NEt (0.10 mL, 0.57 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.57 mmol). The resulting homogenous light yellow mixture was heated at 50° C. for one hour at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube until LCMS showed reaction was complete. The resulting solution was quenched with aqueous saturated NH4Cl (0.5 mL) then evaporated to dryness. The residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 15.8 mg (37% yield) of 398, as a solid.

Workup

  1. customreaction
  2. customthe solution evaporated to dryness
  3. dissolutionThe resulting residue was dissolved in methanol (2 mL)
  4. additionthen treated with 25% sodium methoxide/methanol (0.5 mL)
  5. temperatureheated at 60° C. in sealed tube until LCMS
  6. customreaction
  7. customThe resulting solution was quenched with aqueous saturated NH4Cl (0.5 mL)
  8. customthen evaporated to dryness
  9. dissolutionThe residue was dissolved in DMSO
  10. custompurified by reverse phase HPLC (ammonium formate buffer)

Sources & evidence

ORD record
ord-667ead7ed66b4b86bb5e6c2b6c76b89f
Source dataset
uspto-grants-2014_09
Patent number
US08829007B2

Reaction notes

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