1-Hydroxybenzotriazole → N-(4-(2-(1,4-dioxaspiro[4.5]decan-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 1676375Notes

Reaction equation

HRID 1676375 reaction equation
[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=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>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH:25][C:43]([C:40]5[C:41](=[O:42])[N:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)[N:37]=[CH:38][CH:39]=5)=[O:44])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1

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 67347550HCID 67347550, compound

Product 1

HCID 67347914N-(4-(2-(1,4-dioxaspiro[4.5]decan-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 67.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A 100 mL, single-neck, round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]decan-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (12.8 mg, 0.032 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 22.5 mg, 0.096 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (30.6 mg, 0.160 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21.6 mg, 0.160 mmol), N-ethyl-N-isopropylpropan-2-amine (41.3 mg, 0.320 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that 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 50/1 to 10/1, v/v) to afford product (13.3 mg, 67.5%). LRMS (APCI pos): m/e 617 (M+1).

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 50/1 to 10/1

Sources & evidence

ORD record
ord-6fde97ae7810462fb583d0a11407d6b5
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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