1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (R)-N-(3-fluoro-4-(2-(4-(3-hydroxypyrrolidine-1-carbonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 1676369Notes

Reaction equation

HRID 1676369 reaction equation
[F:1][C:2]1[CH:26]=[C:25]([NH:27][C:28]([C:30]2[C:35](=[O:36])[N:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:33]=[CH:32][CH:31]=2)=[O:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[S:13][C:6]=12.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[NH:66]1[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:1][C:2]1[CH:26]=[C:25]([NH:27][C:28]([C:30]2[C:35](=[O:36])[N:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[N:33]=[CH:32][CH:31]=2)=[O:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:66]4[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]4)=[O:20])=[CH:21][CH:22]=3)[S:13][C:6]=12

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 2759337(R)-3-PyrrolidinolHCID 27960291-Hydroxybenzotriazole hydrateHCID 673452974-(7-(2-Fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzoic acid

Product 1

HCID 58949446(R)-N-(3-fluoro-4-(2-(4-(3-hydroxypyrrolidine-1-carbonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 55.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A capped vial was charged with 4-(7-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzoic acid (0.100 g, 0.168 mmol), HOBT-H2O (0.103 g, 0.671 mmol), EDCI (0.129 g, 0.671 mmol), and DMF (2 mL). After stirring for 45 minutes, (R)-pyrrolidin-3-ol (0.0584 g, 0.671 mmol) and Hunig's base (0.175 ml, 1.01 mmol) were added. After stirring for 18 hours, water (20 mL) was added. The formed precipitate was isolated by filtration. After drying, (62 mg, 55%) of product was isolated as orange solid. LRMS (esi+) 666 m/z (M+1) detected. 1H NMR (CDCl3, 400 MHz) δ 11.84 (s, 1H), 8.47 (s, 1H), 8.39 (d, J=4 Hz, 1H), 8.22 (d, J=4 Hz, 1H), 7.97 (m, 1H), 7.76 (m, 3H), 7.62 (m, 4H), 7.39 (d, J=9 Hz, 1H), 7.26 (m, 3H), 6.52 (d, J=6 Hz, 1H), 4.50 (br s, 1H), 3.72 (m, 5H), 2.07 (m, 2H).

Workup

  1. stirringAfter stirring for 18 hours
  2. customThe formed precipitate was isolated by filtration
  3. customAfter drying

Sources & evidence

ORD record
ord-12b2d4f226cc423099a7a359a47deaa5
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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