Sodium Carbonate → (1R,2S)-5'-methoxy-2-(3-(4-(2-morpholinoethyl)styryl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

HRID 447526Notes

Reaction equation

HRID 447526 reaction equation
I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB(/[CH:33]=[CH:34]/[C:35]2[CH:48]=[CH:47][C:38]([CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH:33]=[CH:34][C:35]3[CH:36]=[CH:37][C:38]([CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:47][CH:48]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 66734102(E)-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenethyl)morpholineHCID 178487035HCID 178487035, compound

Product 1

HCID 67445618(1R,2S)-5'-methoxy-2-(3-(4-(2-morpholinoethyl)styryl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-oneYield 55.2%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 21863594Toluene ethanolSolvent

Procedure

To a mixture of (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (172 mg, 0.4 mmol) and (E)-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenethyl)morpholine (138 mg, 0.4 mmol) in PhCH3/EtOH (8 mL/4 mL) in a 20 mL microwave vial was added 1 M Na2CO3 (0.8 mL, 0.8 mmol), followed by Pd(PPh3)4 (23 mg, 0.02 mmol, 5 mol %). The resulting mixture was purged with argon, then microwaved for 2 h at 125° C. After cooling to rt, the mixture was diluted with H2O (20 mL), extracted with EtOAc (30 mL×2) and dried (Na2SO4). After removal of solvents, the residue was redissolved in DMF (4 mL) and purified by preparatory HPLC to give the title compound (TFA salt, 115 mg, 45%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.90 (d, J=8.4 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 7.43 (s, 1H), 7.37 (d, J=6.4 Hz, 2H), 7.28 (d, J=7.2 Hz, 2H), 6.95 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.06 (d, J=11.2 Hz, 2H), 3.80 (t, J=11.2 Hz, 2H), 3.56 (d, J=11.2 Hz, 2H), 3.38 (t, J=7.6 Hz, 2H), 3.27-3.12 (m, 5H), 3.07 (t, 2H), 2.20-2.10 (m, 2H); MS ESI 521.4 [M+H]+, calcd for [C32H32N4O3+H]+ 521.2.

Workup

  1. customThe resulting mixture was purged with argon
  2. custommicrowaved for 2 h at 125° C
  3. additionthe mixture was diluted with H2O (20 mL)
  4. extractionextracted with EtOAc (30 mL×2)
  5. dry with materialdried (Na2SO4)
  6. customAfter removal of solvents
  7. dissolutionthe residue was redissolved in DMF (4 mL)
  8. custompurified by preparatory HPLC

Sources & evidence

ORD record
ord-b791032252d34a7daa3276d3f3f6ab14
Source dataset
uspto-grants-2013_07
Patent number
US08481525B2

Reaction notes

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