1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-(4-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(2-morpholinoethyl)amino)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 2241439Notes

Reaction equation

HRID 2241439 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:48][O:49][C:50]1[CH:82]=[CH:81][C:53]([CH2:54][N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([N:64]([CH2:73][CH2:74][N:75]4[CH2:80][CH2:79][O:78][CH2:77][CH2:76]4)[C:65]4[CH:70]=[CH:69][C:68]([NH2:71])=[CH:67][C:66]=4[F:72])=[C:58]3[CH:57]=[N:56]2)=[CH:52][CH:51]=1>CN(C=O)C>[CH3:48][O:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([N:64]([CH2:73][CH2:74][N:75]4[CH2:80][CH2:79][O:78][CH2:77][CH2:76]4)[C:65]4[CH:70]=[CH:69][C:68]([NH:71][C:15]([C:12]5[C:13](=[O:14])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]=[CH:10][CH:11]=5)=[O:17])=[CH:67][C:66]=4[F:72])=[C:58]3[CH:57]=[N:56]2)=[CH:81][CH:82]=1

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 667671712-(4-Fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acidHCID 68514133N1-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-fluoro-N1-(2-morpholinoethyl)benzene-1,4-diamine

Product 1

HCID 68516410N-(4-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(2-morpholinoethyl)amino)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 51.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.0310 g, 0.132 mmol) (prepared according to the procedure of Example 19, Step C) was taken up in DMF (1 mL). EDCI (0.0422 g, 0.220 mmol), HOBt (0.0298 g, 0.220 mmol), and DIEA (0.0384 ml, 0.220 mmol) were then added. After stirring under N2 for 15 minutes, N1-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-fluoro-N1-(2-morpholinoethyl)benzene-1,4-diamine (0.021 g, 0.0441 mmol) was added in DMF (1 mL). After stirring for 5.5 hours, DCM was removed. The product was taken up into EtOAc and washed with diluted NaHCO3 and brine. The product was dried over Na2SO4, filtered and concentrated. Purification via Flash Si 5 g eluting with 1-5% MeOH/DCM with NH4OH to obtain 15.7 mg (51%) of product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 8.41 (d, 1H), 8.24 (m, 2H), 7.93 (dd, 1H), 7.63 (m, 2H), 7.43 (m, 1H), 7.35 (m, 1H), 7.27 (m, 4H), 6.80 (m, 2H), 6.61 (br s, 1H), 6.31 (d, 1H), 5.48 (s, 2H), 3.94 (t, 2H), 3.75 (s, 3H), 3.65 (t, 3H), 2.88 (s, 1H), 2.75 (t, 2H), 2.47 (t, 4H); 19F NMR (376 MHz, CDCl3) −111.41 (s, 1F), −117.59 (s, 1F); LRMS (apci pos): 693.3 (M+H)+.

Workup

  1. stirringAfter stirring for 5.5 hours
  2. customDCM was removed
  3. washwashed with diluted NaHCO3 and brine
  4. dry with materialThe product was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification via Flash Si 5 g
  8. washeluting with 1-5% MeOH/DCM with NH4OH

Sources & evidence

ORD record
ord-cfbeb5763bef417dbded994df600721f
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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