1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 1-(benzo[d]oxazol-2-yl)-N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)cyclopropanecarboxamide

HRID 2241359Notes

Reaction equation

HRID 2241359 reaction equation
[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([OH:15])=O)[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[NH2:47][C:48]1[CH:81]=[CH:80][C:51]([O:52][C:53]2[CH:58]=[CH:57][N:56]=[C:55]3[N:59]([CH2:71][C:72]4[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=4)[N:60]=[C:61]([N:62]4[CH2:67][CH2:66][CH:65]([N:68]([CH3:70])[CH3:69])[CH2:64][CH2:63]4)[C:54]=23)=[C:50]([F:82])[CH:49]=1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([NH:47][C:48]2[CH:81]=[CH:80][C:51]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]4[N:59]([CH2:71][C:72]5[CH:73]=[CH:74][C:75]([O:78][CH3:79])=[CH:76][CH:77]=5)[N:60]=[C:61]([N:62]5[CH2:63][CH2:64][CH:65]([N:68]([CH3:70])[CH3:69])[CH2:66][CH2:67]5)[C:54]=34)=[C:50]([F:82])[CH:49]=2)=[O:15])[CH2:11][CH2:12]1

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 685133131-(Benzo[d]oxazol-2-yl)cyclopropanecarboxylic acidHCID 685138871-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine

Product 1

HCID 685161541-(benzo[d]oxazol-2-yl)-N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)cyclopropanecarboxamideYield 62%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a stirred solution of 1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylic acid (3.8 mg, 0.019 mmol) in 150 μL dichloromethane at room temperature under nitrogen was added DIEA (8 μL, 0.047 mmol) followed by EDCI (4.5 mg, 0.024 mmol) and HOBT-H2O (3.6 mg, 0.024 mmol). After 15 minutes, a solution of 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (7.7 mg, 0.016 mmol) (prepared in Example 93, Step A) in 150 μL dichloromethane was added. After stirring for 48 hours, the reaction was diluted to 30 mL with dichloromethane and washed with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with dichloromethane and eluted with a step gradient of dichloromethane (100 mL), 2.5/97.5 MeOH/dichloromethane (100 mL) and 5/95 MeOH/dichloromethane to provide the desired product as a white foam (6.6 mg, 62% yield).

Workup

  1. washwashed with 10% sodium carbonate solution
  2. dry with materialThe organics were dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. washeluted with a step gradient of dichloromethane (100 mL), 2.5/97.5 MeOH/dichloromethane (100 mL) and 5/95 MeOH/dichloromethane

Sources & evidence

ORD record
ord-db6205175ae44edca0b87b2112fca601
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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