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1-Hydroxybenzotriazole → Tert-butyl 4-(7-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate

HRID 1676364
Notes
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Reaction equation

HRID 1676364 reaction equation
[NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[C:44](=[O:45])[C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=[N:40]2)=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:46]([C:43]2[C:44](=[O:45])[N:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[N:40]=[CH:41][CH:42]=2)=[O:47])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:15][C:8]=12
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 667671712-(4-Fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acidHCID 67346565Tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate

Product 1

HCID 67347399Tert-butyl 4-(7-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylateYield 40.62%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A round-bottomed flask was charged with tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (144.5 mg, 0.326 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (228.9 mg, 0.977 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (312.3 mg, 1.63 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (220.1 mg, 1.63 mmol), N-ethyl-N-isopropylpropan-2-amine (421.1 mg, 3.26 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (87.3 mg, 40.62%). LRMS (APCI pos): >95% purity, 254 nm, m/e 660 (M+1). 1H NMR (400 MHz, CD3Cl) δ 11.83 (s, 1H), 8.45 (d, 1H), 8.42 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.37-7.68 (m, 5H), 7.21-7.28 (m, 2H), 6.48 (d, 1H), 4.24 (m, 2H), 3.08 (m, 1H), 2.89 (m, 2H), 2.07 (m, 2H), 1.75 (m, 2H), 1.49 (s, 9H).

Workup

  1. customhad been consumed (overnight)
  2. customThen the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL)
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc (3×100 mL)
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto yield a crude product
  9. customThe crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1

Sources & evidence

ORD record
ord-9344b1e6185e48b282da4dddf5cb3089
Source dataset
uspto-grants-2011_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08003662B2

Reaction notes

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