Triphenylphosphine → 5-Chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[1-[(4-{[2-(dimethylamino)ethyl]oxy}phenyl)methyl]-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide

HRID 1874668Notes

Reaction equation

HRID 1874668 reaction equation
[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.ClCCl>[Cl:30][C:27]1[S:26][C:25]([S:22]([N:10]([S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][N:32]([CH3:31])[CH3:44])=[CH:41][CH:40]=3)[N:12]=2)(=[O:23])=[O:24])=[CH:29][CH:28]=1

Participants

7

Reactant 4

HCID 11776TriphenylphosphineHCID 97268Di-tert-butyl azodicarboxylateHCID 10176517{4-[2-(Dimethylamino)ethoxy]phenyl}methanolHCID 580544545-Chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide

Product 1

HCID 580545145-Chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[1-[(4-{[2-(dimethylamino)ethyl]oxy}phenyl)methyl]-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

A mixture of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (0.262 g, 0.5 mmol) and (4-{[2-(dimethylamino)ethyl]oxy}phenyl)methanol (98 mg, 0.5 mmol), triphenylphosphine (197 mg, 0.75 mmol) and di tert-butyl azodicarboxylate (230 mg, 1 mmol) in THF (30 mL) was heated to 65° C. for h. LCMS indicated complete reaction. The mixture was concentrated and the residue was dissolved in methanol and applied to an SCX-2 ion-exchange cartridge (50 g) eluting with methanol, followed by 10% aq. ammonia in methanol. The ammoniacal fractions were combined and evaporated in vacuo to give the crude product (400 mg) as a yellow gum. The mixture was loaded in dichloromethane on a silica cartridge (20 g) and purified by chromatography on Flashmaster using a gradient of 0-15% methanol (containing 1% Et3N)-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give impure product (167 mg) as a colourless gum. The sample was dissolved in 1:1 MeOH-DMSO (2 mL) and purified by MDAP on Xbridge column using acetonitrile water with an ammonium carbonate modifier Appropriate fractions were combined and the solvent was evaporated in vacuo to give the title compound (91 mg, 26%) LCMS (System C) (5 min run) RT=3.76 min, ES+ve m/z 701/703 (M+H)+.

Workup

  1. customreaction
  2. concentrationThe mixture was concentrated
  3. dissolutionthe residue was dissolved in methanol
  4. washeluting with methanol
  5. customevaporated in vacuo
  6. customto give the crude product (400 mg) as a yellow gum
  7. custompurified by chromatography on Flashmaster
  8. customover 40 min
  9. customevaporated in vacuo

Sources & evidence

ORD record
ord-b5da878397ed490a8339930f234154ae
Source dataset
uspto-grants-2012_11
Patent number
US08304446B2

Reaction notes

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