Hydrochloric Acid → (3-amino-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone

HRID 1773801노트

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HRID 1773801 반응식
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18](I)=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=[NH:93])(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:93][C:18]1[C:17]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[CH2:11][C:12]=12

참가 물질

10

반응물 5

HCID 313Hydrochloric AcidHCID 136809Benzophenone imineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 67958487(4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone

생성물 1

HCID 67960216(3-amino-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone수율 49.1%

시약·촉매·용매 4

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 1140Toluene용매HCID 10340Sodium Carbonate용매

실험 절차

Tris(dibenzylideneacetone)dipalladium(0) (9.6 mg, 0.01 mmol) was added to a stirred suspension of (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (50 mg, 0.1 mmol), sodium tert-butoxide (30 mg, 0.31 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19.6 mg, 0.031 mmol) in toluene (2 mL) in a sealed tube and under N2. The mixture was stirred at room temperature for 5 minutes and then benzophenone imine (0.035 mL, 0.21 mmol) was added. The mixture was stirred at 100° C. for 2.5 hours. Then a 1M aqueous solution of HCl (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with a saturated solution of Na2CO3 and water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 6/94). The desired fractions were collected and the solvents evaporated in vacuo. The desired product was triturated with diethyl ether to yield (3-amino-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone (18 mg, 47% yield) as a white solid. C20H19FN4O21H NMR (500 MHz, CDCl3) δ ppm 1.53 (s, 1H), 2.86 (br. s., 1H), 3.99 (br. s., 2H), 4.18 (br. s., 2H), 4.70 (br. s., 2H), 5.08 (s, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 2H), 7.15 (t, J=8.7 Hz, 2H), 7.30 (dd, J=8.4, 7.5 Hz, 2H), 7.49 (dd, J=8.5, 5.3 Hz, 2H).

후처리

  1. stirringThe mixture was stirred at 100° C. for 2.5 hours
  2. stirringthe mixture was stirred at room temperature for 16 hours
  3. extractionextracted with DCM
  4. customThe organic layer was separated
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. customthe solvents evaporated in vacuo
  8. customThe crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 6/94)
  9. customThe desired fractions were collected
  10. customthe solvents evaporated in vacuo
  11. customThe desired product was triturated with diethyl ether

출처 및 근거

ORD 기록
ord-a3c1718dc0f34330933dcf6ac82c88e8
출처 데이터셋
uspto-grants-2016_02
특허 번호
US09255103B2

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