Tetrahydrofuran → Methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate

HRID 525813Notes

Reaction equation

HRID 525813 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[F:36])=[O:27])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH:20]=O)=[O:16])[S:14][C:7]=12.Cl.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1.C(N(CC)CC)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[F:36])=[O:27])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:42]3[CH2:43][CH2:44][CH2:45][CH:41]3[C:40]([O:39][CH3:38])=[O:46])=[O:16])[S:14][C:7]=12

Participants

8

Reactant 5

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 2733200methyl L-prolinate hydrochlorideHCID 5003444Sodium cyanoborohydrideHCID 1176900397-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide

Product 1

HCID 86290798Methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide (150 mg, 0.29 mmol) in 10 ml of anhydrous DMF was added L-proline methyl ester hydrochloride (96 mg, 0.58 mmol) and triethylamine (58 mg, 0.58 mmol). The mixture was stirred at room temperature under nitrogen for one hour, and 1M solution of sodium cyanoborohydride in THF (0.60 ml, 0.60 mmol) was added. The mixture was stirred for another hour, and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude product, which was purified by silica gel chromatography eluting with 2˜3% of methanol in chloroform to afford methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate as white solid. Yield: 90 mg, 50%.

Workup

  1. stirringThe mixture was stirred for another hour
  2. filtrationThe precipitates were filtered
  3. washwashed with water
  4. customdried in vacuo
  5. customto give the crude product, which
  6. customwas purified by silica gel chromatography
  7. washeluting with 2˜3% of methanol in chloroform

Sources & evidence

ORD record
ord-839219c195414ba2a7d3aac76d274f96
Source dataset
uspto-grants-2016_05
Patent number
US09340555B2

Reaction notes

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