2,2-dimethylpropionic acid 2-[(R)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester → HCID 178461945, compound

HRID 243389Notes

Reaction equation

HRID 243389 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 681580082,2-dimethylpropionic acid 2-[(R)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester

Product 1

HCID 178461945HCID 178461945, compoundYield 27%

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Procedure

A solution of 2,2-dimethylpropionic acid 2-[(R)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester (213 mg, 0.35 mmol), in aqueous 6M HCl (10 mL) was refluxed for 40 min. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 2-35% MeOH in 0.5% TFA/H2O) then 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, then 2M NH3/MeOH. Further purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM) afforded 256 as a pale yellow solid (40 mg, 27%). LCMS (Method K): RT 1.94 min [M+H]+ 425.1. 1H NMR (CD3OD, 400 MHz): δ 8.30 (1H, s), 8.08 (1H, s), 7.59 (1H, dd, J=8.9, 5.0 Hz), 7.49 (1H, dd, J=9.5, 2.3 Hz), 7.01 (1H, dt, J=9.2, 2.4 Hz), 6.03 (1H, bs), 3.67 (2H, t, J=5.8 Hz), 3.13-3.09 (1H, m), 2.98-2.92 (2H, m), 2.69-2.55 (2H, m), 2.28-2.14 (2H, m), 1.93-1.88 (1H, m), 1.82 (3H, d, J=7.0 Hz), 1.77-1.74 (1H, m), 1.51-1.41 (1H, m)

Workup

  1. customvolatiles were removed under reduced pressure
  2. customthe resulting residue was purified by column chromatography (C18, gradient 2-35% MeOH in 0.5% TFA/H2O)
  3. washThe cartridge was washed with dioxane/water (1:1)
  4. washdioxane and the product eluted with 10% 880 NH3 in dioxane
  5. customFurther purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM)

Sources & evidence

ORD record
ord-a601fe1f1bb94fc99ac738c9ce00db5d
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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