Hydrochloric Acid → Cobimetinib (R-enantiomer)

HRID 1808993Notes

Reaction equation

HRID 1808993 reaction equation
[F:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CO.Cl>O1CCOCC1>[F:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 887MethanolHCID 670516811-Piperidinecarboxylic acid, 2-[1-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl]-3-hydroxy-3-azetidinyl]-, 1,1-dimethylethyl ester, (2R)-

Product 1

HCID 16222097Cobimetinib (R-enantiomer)Yield 89.9%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

1,1-dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 0.12 mmol) was taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane (1 mL) and the solution was stirred at room temperature for one hour. The solution was then concentrated and the residue partitioned with chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using ethyl acetate then concentrated aqueous ammonia in chloroform and methanol (0.1:10:1) as eluents afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol (57.3 mg) as a colorless amorphous solid. The free base was taken into methanol (1 mL) then brought to about pH 1 by addition of 4 N HCl in dioxane and the solution concentrated. The residue was triturated with ethyl ether to afford a suspension. The solid was collected by filtration to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol hydrochloride salt (49 mg, 72% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3): 8.43-8.39 (d, 1H), 7.41-7.38 (dd, 1H), 7.33-7.31 (dt, 1H), 7.14-7.10 (m, 1H), 6.84-6.80 (m, 1H), 6.63-6.57 (m, 1H), 4.12-3.99 (m, 4H), 3.10-3.08 (d, 1H), 2.72-2.69 (d, 1H), 2.64-2.62 (m, 1H), 1.61-1.58 (m, 2H), 1.36-1.16 (m, 4H); MS (EI) for C21H21F3IN3O2: 532 (MH+).

Workup

  1. concentrationThe solution was then concentrated
  2. customthe residue partitioned with chloroform and saturated aqueous sodium bicarbonate
  3. washThe organic layer was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationthen filtered
  6. concentrationconcentrated
  7. customPurification of the residue by silica gel flash chromatography

Sources & evidence

ORD record
ord-738fbcc1d7b6430481d6ec82694bb36a
Source dataset
uspto-grants-2013_01
Patent number
US08362002B2

Reaction notes

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