1-(difluoromethyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole → tert-Butyl (1S,2R)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate

HRID 516059

반응식

HRID 516059 반응식
Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.[F:39][CH:40]([F:55])[N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][CH:40]([F:55])[N:41]1[CH:45]=[C:44]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=2)[CH:43]=[N:42]1

참가 물질

6

반응물 2

HCID 497579861-(difluoromethyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 86654712tert-Butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate

생성물 1

HCID 86654725tert-Butyl (1S,2R)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate수율 90%

시약·촉매·용매 3

HCID 178418476HCID 178418476, 화합물촉매HCID 10340Sodium Carbonate용매HCID 312751,4-Dioxane용매

실험 절차

A solution of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (35 mg, 0.064 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.67 mg, 0.076 mmol) and bis(triphenylphosphine)palladium chloride (44.7 mg, 0.064 mmol) in dioxane (500 μL) and saturated aq Na2CO3 (500 μL) was heated at 85° C. for 2 h. After filtering out the solids, the solvent was removed and the residue was dissolved in MeOH and DCM and purified by preparative HPLC. The fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (36 mg, 90%). [M+H] calc'd for C31H37F3N6O5, 631; found, 631.

후처리

  1. filtrationAfter filtering out the solids
  2. customthe solvent was removed
  3. dissolutionthe residue was dissolved in MeOH
  4. customDCM and purified by preparative HPLC
  5. customThe fractions were collected
  6. customACN was removed via rotary evaporation
  7. washwashed with EtOAc (2×200 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. customThe organic phase was stripped to dryness via rotary evaporation

출처 및 근거

ORD 기록
ord-fb4391d74b9f48bdacad5ae7a34b1e85
출처 데이터셋
uspto-grants-2015_08
특허 번호
US09108970B2

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