Hydrochloric Acid → HCID 178456069, compound

HRID 243391Notes

Reaction equation

HRID 243391 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25](=O)[C@@H:26]([NH:29][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][N:34]3C2CCCCO2)[CH2:27][CH3:28])=[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:29][C:30]3[N:38]=[CH:37][N:36]=[C:35]4[C:31]=3[N:32]=[CH:33][NH:34]4)[CH2:27][CH3:28])[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 2

HCID 313Hydrochloric AcidHCID 681575322,2-dimethylpropionic acid 2-[(R)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]butyrylamino}phenylamino)piperidin-1-yl]ethyl ester

Product 1

HCID 178456069HCID 178456069, compoundYield 24.7%

Procedure

A solution of 2,2-dimethylpropionic acid 2-[(R)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]butyrylamino}phenylamino)piperidin-1-yl]ethyl ester (258 mg, 0.41 mmol), in aqueous 6M HCl (3 mL) was refluxed for 40 min. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (C18, gradient 2-30% 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 a colourless solid. The preparation was repeated on the same scale to give a combined yield of 44.4 mg of 259 (12%). LCMS (Method K): RT 2.07 min [M+H]+ 439.1. 1H NMR (CD3OD, 400 MHz): δ 8.28 (1H, s), 8.09 (1H, s), 7.59 (1H, dd, J=8.9, 5.0 Hz), 7.50 (1H, dd, J=9.6, 2.3 Hz), 7.00 (1H, dt, J=9.2, 2.3 Hz), 5.84 (1H, bs), 5.04-4.94 (1H, m), 3.68 (2H, t, J=5.8 Hz), 3.12-3.08 (1H, m), 3.00-2.93 (2H, m), 2.71-2.57 (2H, m), 2.33-2.16 (4H, m), 1.89-1.86 (1H, m), 1.82-1.77 (1H, m), 1.62-1.51 (1H, m), 1.09 (3H, t, J=7.4 Hz)

Workup

  1. customvolatiles were removed under reduced pressure
  2. customthe resulting residue purified by column chromatography (C18, gradient 2-30% 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)
  6. customafforded a colourless solid

Sources & evidence

ORD record
ord-b2dadcde47d940f8b217fe8af0a0ea47
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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