Hydrochloric Acid → (1R,2S)-5'-methoxy-2-(3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

HRID 2281824노트

반응식

HRID 2281824 반응식
IC1C2C(=CC([C@H]3[C@@]4(C5C(=CC=C(OC)C=5)NC4=O)C3)=CC=2)NN=1.CN1CCC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)CC1.[ClH:47].[CH3:48][O:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54](=[O:59])[C@:53]12[CH2:61][C@H:60]1[C:62]1[CH:70]=[C:69]2[C:65]([C:66]([C:71]3[CH:76]=[CH:75][C:74]([CH:77]4[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]4)=[CH:73][CH:72]=3)=[N:67][NH:68]2)=[CH:64][CH:63]=1>CCOC(C)=O.O.C1COCC1>[ClH:47].[CH3:48][O:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54](=[O:59])[C@:53]12[CH2:61][C@H:60]1[C:62]1[CH:70]=[C:69]2[C:65]([C:66]([C:71]3[CH:76]=[CH:75][C:74]([CH:77]4[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]4)=[CH:73][CH:72]=3)=[N:67][NH:68]2)=[CH:64][CH:63]=1

참가 물질

8

반응물 4

HCID 313Hydrochloric AcidHCID 584862351-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidineHCID 58486259US9907800, Example A123HCID 178487035HCID 178487035, 화합물

생성물 1

HCID 67449499(1R,2S)-5'-methoxy-2-(3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride수율 17%

시약·촉매·용매 3

HCID 962Water용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

실험 절차

The title compound was synthesized according to the method of Example A51B, except reacting (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (195 mg, 0.45 mmol) with 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (150 mg, 0.50 mmol). The reaction was then allowed to cool to rt and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give an orange solid. The title compound was purified by silica gel chromatography (95:3:2 to 80:18:2 CH2Cl2/MeOH/NH3) to yield a yellow solid. HCl (1M in diethyl ether, 0.15 mL, 0.15 mmol) was added in a dropwise manner to a solution of (1R,2S)-5′-methoxy-2-(3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one in THF (2 mL). A brown precipitate formed and the solid was then filtered and freeze-dried to give the title compound as a white solid (43 mg, 17%). 1H NMR (400 MHz, CD3OD) δ 7.95-7.92 (m, 3H), 7.52 (s, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.5 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 5.61 (s, 1H), 3.67-3.64 (m, 2H),), 3.40-3.32 (m, 1H), 3.27 (s, 3H), 3.21 (t, J=12.8 Hz, 2H), 3.04-2.93 (m, 1H), 2.96 (s, 3H), 2.28-2.19 (m, 4H), 2.07-1.98 (m, 2H); MS ESI 479.4 [M+H]+, calcd for [C30H30N4O2+H]+ 479.24.

후처리

  1. customThe title compound was synthesized
  2. additionwas added
  3. extractionThe resulting mixture was extracted with EtOAc
  4. washthe combined organic extracts were washed with brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. customto give an orange solid
  8. customThe title compound was purified by silica gel chromatography (95:3:2 to 80:18:2 CH2Cl2/MeOH/NH3)
  9. customto yield a yellow solid
  10. customA brown precipitate formed
  11. filtrationthe solid was then filtered
  12. customfreeze-dried

출처 및 근거

ORD 기록
ord-da870aaed55e463bb7a2d8983c8b4b60
출처 데이터셋
uspto-grants-2015_09
특허 번호
US09139563B2

반응 노트

불러오는 중…