Sodium Iodide → Formic acid 2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-N-(6-{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}-1H-indazol-4-yl)-1,3-thiazole-4-carboxamide

HRID 1695776Notes

Reaction equation

HRID 1695776 reaction equation
Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=3)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[CH3:42][C@H:43]1[O:48][C@@H:47]([CH3:49])[CH2:46][NH:45][CH2:44]1.CCN(C(C)C)C(C)C.[I-].[Na+].C[Si](C)(C)[O-].[K+]>CC#N.C1COCC1>[CH:32]([OH:31])=[O:48].[CH3:49][C@H:47]1[O:48][C@@H:43]([CH3:42])[CH2:44][N:45]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:46]1

Participants

8

Reactant 5

HCID 5238Sodium IodideHCID 81531DiisopropylethylamineHCID 6415002,6-Dimethylmorpholine, cis-HCID 23668039Potassium trimethylsilanolateHCID 582557402-(Chloromethyl)-N-[6-{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide

Product 1

HCID 67155589Formic acid 2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-N-(6-{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}-1H-indazol-4-yl)-1,3-thiazole-4-carboxamideYield 76.9%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

2-(Chloromethyl)-N-[6-{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.08 mmol) was dissolved in MeCN (0.5 ml). (2R,6S)-2,6-Dimethylmorpholine (23 mg, 0.1 mmol, available from Lancaster Synthesis) was dissolved in MeCN (0.3 ml) and added to the mixture, followed by DIPEA (0.026 ml, 0.15 mmol) and sodium iodide (0.012 g, 0.078 mmol) (heaped microspatula). The solution was stirred and heated to 70° C. for 18 hr. Potassium trimethylsilanolate (64 mg, 0.5 mmol) was dissolved in THF (0.4 ml) and added to the mixture which was then heated at 50° C. for 5 hrs. The solution was quenched with aqueous MeCN (50:50, 1 ml) and neutralised, then the solvents were removed in a blowdown unit. The residue was dissolved in DMSO 0.5 ml and purified by MDAP (Method D). The solvent was evaporated using the Genevac to give the title compound (19 mg).

Workup

  1. additionadded to the mixture
  2. additionadded to the mixture which
  3. temperaturewas then heated at 50° C. for 5 hrs
  4. customThe solution was quenched with aqueous MeCN (50:50, 1 ml)
  5. customneutralised, then the solvents were removed in a blowdown unit
  6. dissolutionThe residue was dissolved in DMSO 0.5 ml
  7. custompurified by MDAP (Method D)
  8. customThe solvent was evaporated

Sources & evidence

ORD record
ord-18f915daeaa64427894311e82d6439ef
Source dataset
uspto-grants-2012_04
Patent number
US08163743B2

Reaction notes

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