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 447412ノート

反応式

HRID 447412 の反応式
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

参加物

8

反応物 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、化合物

生成物 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 hydrochloride収率 17%

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-68541b47a98c488382f32ae7144ec3c0
出典データセット
uspto-grants-2013_07
特許番号
US08481533B2

反応ノート

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