Hydrochloric Acid → 3-(5-Chloro-8-fluoroisoquinolin-3-yl)-5-[2-(4-methylpiperazin-1-yl)-thiazol-5-yl]-pyridin-2-ylamine trihydrochloride

HRID 1926307노트

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HRID 1926307 반응식
Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[N:4][CH:3]=1.[Cl:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[CH:17]=[C:18]([C:26]1[C:27]([NH2:41])=[N:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=1)[N:19]=[CH:20]2.C(=O)([O-])[O-].[K+].[K+].[ClH:48]>C(Cl)Cl.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[ClH:14].[ClH:48].[ClH:14].[Cl:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[CH:17]=[C:18]([C:26]1[C:27]([NH2:41])=[N:28][CH:29]=[C:30]([C:2]3[S:6][C:5]([N:7]4[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]4)=[N:4][CH:3]=3)[CH:31]=1)[N:19]=[CH:20]2

참가 물질

9

반응물 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 457875521-(5-Bromo-1,3-thiazol-2-yl)-4-methylpiperazineHCID 67520645HCID 67520645, 화합물

생성물 1

HCID 675203853-(5-Chloro-8-fluoroisoquinolin-3-yl)-5-[2-(4-methylpiperazin-1-yl)-thiazol-5-yl]-pyridin-2-ylamine trihydrochloride

시약·촉매·용매 4

HCID 178418397HCID 178418397, 화합물촉매HCID 3283Diethyl Ether용매HCID 6344Dichloromethane용매HCID 18180031Water 1,2-dimethoxyethane용매

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온도
100 °C

실험 절차

A solution of 1-(5-bromothiazol-2-yl)-4-methylpiperazine (45 mg, 0.17 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB5) (89.2 mg, 0.223 mmol), potassium carbonate (71.2 mg, 0.515 mmol), and Pd(PPh3)4 (11.9 mg, 0.0103 mmol) in previously degassed DME/Water (4:1) (3.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×), and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3] resulting in a pure yellow solid. This sample was then dissolved in a minimum of DCM then charged with 3 equiv of 1M HCl in ether and the reaction mixture was concentrated in vacuo resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.83 (d, J=4.0 Hz, 3H), 3.13-3.28 (m, 2H), 3.45-3.60 (m, 4H), 4.07 (d, J=14.3 Hz, 2H), 7.67 (t, J=8.0 Hz, 1H), 7.84 (s, 1H), 8.11 (dd, J=8.4, 4.8 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H), 8.54 (s, 1H), 8.61 (s, 1H), 9.67 (s, 1H), 11.05 (br. s., 1H). MS (ES+): m/z=455.07/457.08 (76/24) [MH+]. HPLC: tR=1.99 min (ZQ2, polar—5 min).

후처리

  1. customevacuated
  2. additioncharged with N2 (2×)
  3. customThe reaction mixture was partitioned between CHCl3 and H2O
  4. customthe layers were separated
  5. extractionThe aqueous layer was re-extracted with CHCl3 (3×)
  6. washthe combined organic fractions were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3]
  11. customresulting in a pure yellow solid
  12. concentrationthe reaction mixture was concentrated in vacuo

출처 및 근거

ORD 기록
ord-32a7bf9811e74261889386c6103b33e4
출처 데이터셋
uspto-grants-2012_05
특허 번호
US08178668B2

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