Hydrochloric Acid → Cobimetinib (R-enantiomer)

HRID 1717588노트

반응식

HRID 1717588 반응식
[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]

참가 물질

5

반응물 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)-

생성물 1

HCID 16222097Cobimetinib (R-enantiomer)수율 89.9%

시약·촉매·용매 1

HCID 312751,4-Dioxane용매

실험 절차

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+).

후처리

  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

출처 및 근거

ORD 기록
ord-757e171089cd4a119551a620f5782dcd
출처 데이터셋
uspto-grants-2010_09
특허 번호
US07803839B2

반응 노트

불러오는 중…