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 447558Notes

Reaction equation

HRID 447558 reaction equation
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

Participants

8

Reactant 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, compound

Product 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 hydrochlorideYield 17%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

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. Optical Rotation: [α]22D=−127° (c 0.37, MeOH).

Workup

  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

Sources & evidence

ORD record
ord-4dec617eee6e4bbd9d20db4938ae0ff6
Source dataset
uspto-grants-2013_07
Patent number
US08481525B2

Reaction notes

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