2,2-Dimethylpropionic acid 2-[(S)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester → HCID 178461946, compound

HRID 243404Notes

Reaction equation

HRID 243404 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25](=O)[C@@H:26]([NH:28][C:29]2[N:37]=[CH:36][N:35]=[C:34]3[C:30]=2[N:31]=[CH:32][N:33]3C2CCCCO2)[CH3:27])=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17]C(=O)C(C)(C)C)[CH2:10]2)[CH:7]=1>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:24]=[C:25]([C@@H:26]([NH:28][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:27])[N:8]([C@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[C:6]=2[CH:7]=1

Participants

3

Reactant 1

HCID 681578182,2-Dimethylpropionic acid 2-[(S)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester

Product 1

HCID 178461946HCID 178461946, compoundYield 21.3%

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Procedure

A solution of 2,2-dimethylpropionic acid 2-[(S)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester (583 mg, 0.95 mmol), in aqueous 6M HCl (20 mL) was refluxed for 30 min. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue loaded in dioxane/water (1:1) onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane/water (1:1), then dioxane and the product eluted with 10% 880 NH3 in dioxane. The fractions containing product were purified by column chromatography (C18, gradient 2-40% MeOH in 0.5% TFA/H2O) then loaded in dioxane onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane then the product eluted with 10% 880 NH3 in dioxane. Further purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM) afforded 278 as a colourless solid (85.8 mg, 21%). LCMS (Method K): RT 2.05 min [M+H]+ 425.1. 1H NMR (CD3OD, 400 MHz): δ 8.29 (1H, s), 8.09 (1H, s), 7.58 (1H, dd, J=9.0, 5.0 Hz), 7.50 (1H, dd, J=9.6, 2.3 Hz), 7.00 (1H, dt, J=9.3, 2.3 Hz), 5.97 (1H, bs), 4.80-4.71 (1H, m), 3.41-3.39 (2H, m), 3.15-3.10 (1H, m), 2.92 (1H, bd, J=11.3 Hz), 2.81 (1H, t, J=11.0 Hz), 2.53-2.21 (4H, m), 2.01-1.97 (1H, m), 1.92-1.86 (1H, m), 1.80 (3H, d, J=6.9 Hz), 1.78-1.70 (1H, m)

Workup

  1. customvolatiles were removed under reduced pressure
  2. washThe cartridge was washed with dioxane/water (1:1)
  3. washdioxane and the product eluted with 10% 880 NH3 in dioxane
  4. additionThe fractions containing product
  5. customwere purified by column chromatography (C18, gradient 2-40% MeOH in 0.5% TFA/H2O)
  6. washThe cartridge was washed with dioxane
  7. washthe product eluted with 10% 880 NH3 in dioxane
  8. customFurther purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM)

Sources & evidence

ORD record
ord-8afc9f3d68c5432e8f0f46cb804cabfc
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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