1,2-Dichloroethane → 1-Cyclopropyl-3-(3-fluoro-4-(2-(5-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

HRID 1253583Notes

Reaction equation

HRID 1253583 reaction equation
[CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:48][N:49]1[CH2:54][CH2:53][N:52]([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:51][CH2:50]1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:58]6[CH2:57][CH2:56][CH:55]([N:52]7[CH2:51][CH2:50][N:49]([CH3:48])[CH2:54][CH2:53]7)[CH2:60][CH2:59]6)=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)=[O:33])[CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 7957071-Methyl-4-(piperidin-4-yl)piperazineHCID 674418286-(7-(4-(3-Cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)nicotinic acid

Product 1

HCID 534763961-Cyclopropyl-3-(3-fluoro-4-(2-(5-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureaYield 12.29%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a stirred solution of acid 225 (300 mg, 0.646 mmol) in DMF (10 mL) at 0° C. were added HOBT (198 mg, 1.292 mmol), EDC (248 mg, 1.292 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (118 mg, 0.646 mmol). The reaction mixture was stirred at room temperature overnight, diluted with NaHCO3 saturated solution, and extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified three times by Biotage (MeOH/EtOAc, 0-50%, 25 g column) followed by purification on Gilson [MeOH/H2O, 50-95%, HCOOH (0.05%)] to afford the title compound 234 (50 mg, 0.079 mmol, 12.29% yield) as a mono-formate salt. NMR (400 MHz, CD3OD) δ (ppm): 8.67 (dd, J1=0.8 Hz, J2=2.1 Hz, 1H,), 8.48 (s, 1H), 8.47 (s, 1H), 8.19 (dd, J1=0.8 Hz, J2=8.3 Hz, 1H), 8.16 (s, 1H), 7.97 (dd, J1=2.2 Hz, J2=8.2 Hz, 1H), 7.65 (dd, J1=2.4 Hz, J2=13.1 Hz, 1H), 7.29 (t, 1H, J=8.8 Hz, 1H), 7.20-7.18 (m, 1H), 6.65 (dd, J1=0.8 Hz, J2=5.5 Hz, 1H), 3.83 (br. s, 1H), 3.24 (br s, 1H), 3.01 (br. s, 6H), 2.85 (br. s, 3H), 2.76-2.70 (m, 2H), 2.67 (s, 3H), 2.61-2.57 (m, 1H), 2.02 (br. s, 1H), 1.91-1.85 (br. s, 1H), 1.56-1.49 (hr. s, 2H), 0.78-0.74 (m, 2H), 0.55-0.51 (m, 2H). MS: 630.4 (MH)+

Workup

  1. extractionextracted with EtOAc
  2. dry with materialThe extract was dried over anhydrous Na2SO4
  3. concentrationconcentrated in vacuum
  4. customThe residue was purified three times by Biotage (MeOH/EtOAc, 0-50%, 25 g column)
  5. customfollowed by purification on Gilson [MeOH/H2O, 50-95%, HCOOH (0.05%)]

Sources & evidence

ORD record
ord-90fe6e333e0549ea93d4059aed733a7a
Source dataset
uspto-grants-2013_06
Patent number
US08455484B2

Reaction notes

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