Gamma-Aminobutyric Acid → 1-Cyclopropyl-3-(3-fluoro-4-(2-(6-((2-oxopyrrolidin-1-yl)methyl)pyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

HRID 1400901Notes

Reaction equation

HRID 1400901 reaction equation
[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:25]=[N:26][C:27]([CH:30]=O)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CC(O)=O.[NH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:25]=[N:26][C:27]([CH2:30][N:37]6[CH2:38][CH2:39][CH2:40][C:41]6=[O:43])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 119Gamma-Aminobutyric AcidHCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 866585971-Cyclopropyl-3-(3-fluoro-4-(2-(6-formylpyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

Product 1

HCID 674414791-Cyclopropyl-3-(3-fluoro-4-(2-(6-((2-oxopyrrolidin-1-yl)methyl)pyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureaYield 3.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of aldehyde 282 (0.5 g, 1.115 mmol) and AcOH (128 μl, 2.23 mmol) in DMF (10 mL) was added 4-aminobutyric acid (345 mg, 3.34 mmol). After 40 min, sodium triacetoxyborohydride (945 mg, 4.46 mmol) was added and the reaction was stirred at RT for 22 h. The reaction mixture was then diluted with water to form a precipitate that was collected by filtration, dried under vacuum and purified by Biotage (SNAP 50 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV) and by Gilson (Phenomenex, Luna 15 μl, C18(2) 100A, 250×50.0 mm, 15 μm; 0.05% of formic acid in both MeOH/water:30/80 to 95/5 over 60 min, flow; 30 mL/min), to afford the title compound 283 (20 mg, 0.04 mmol, 3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.28 (s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.42 (bs, 1H), 8.26 (dd, J=2.4 and 8.0 Hz, 1H), 8.25 (s, 1H), 7.74 (dd, J=2.0 and 13.6 Hz, 1H), 7.41-7.34 (m, 2H), 7.24-7.20 (m, 1H), 7.08 (bs, 1H), 6.62 (d, J=5.6 Hz, 1H), 4.53 (s, 2H), 2.58-2.51 (m, 1H), 2.32 (t, J=8.0 Hz, 2H), 1.98 (quin, J=7.2 Hz, 2H), 0.65-0.60 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 518.5 (M+H).

Workup

  1. customto form a precipitate that
  2. filtrationwas collected by filtration
  3. customdried under vacuum
  4. custompurified by Biotage (SNAP 50 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV) and by Gilson (Phenomenex, Luna 15 μl, C18(2) 100A, 250×50.0 mm, 15 μm
  5. wait0.05% of formic acid in both MeOH/water:30/80 to 95/5 over 60 min

Sources & evidence

ORD record
ord-c81bb38ef55e4a0caad9d282bb89a8c5
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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