Diisopropylethylamine → 5-(7-Acryloyl-2,7-diazaspiro[4.4]non-2-yl)-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide

HRID 1526273Notes

Reaction equation

HRID 1526273 reaction equation
Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].C(O[C:38]([N:40]1[CH2:44][CH2:43][C:42]2([CH2:48][CH2:47][NH:46][CH2:45]2)[CH2:41]1)=[O:39])(C)(C)C.[CH:49](N(C(C)C)CC)(C)[CH3:50].[N-]=C=O>CN(C)C=O.CN1CCCC1=O>[C:38]([N:40]1[CH2:44][CH2:43][C:42]2([CH2:45][N:46]([C:2]3[N:3]=[C:4]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([N:20]5[CH2:21][CH2:22][CH:23]([N:26]6[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]6)[CH2:24][CH2:25]5)=[CH:16][CH:15]=4)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=3[CH2:8][CH3:9])[CH2:47][CH2:48]2)[CH2:41]1)(=[O:39])[CH:49]=[CH2:50]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 105034IsocyanateHCID 23282813tert-Butyl 2,7-diazaspiro[4.4]nonane-2-carboxylateHCID 885697085-Chloro-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide

Product 1

HCID 1176671195-(7-Acryloyl-2,7-diazaspiro[4.4]non-2-yl)-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 5-chloro-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (21 mg), 2,7-diazaspiro[4.4]nonane-2-carboxylic acid-tert-butyl ester (41 mg), diisopropylethylamine (16 μL), and N-methylpyrrolidone (0.3 mL) was stirred at 140° C. for 2 hours and a half. To the reaction mixture was added PS-isocyanate (Biotage, 100 mg) at room temperature, N,N-dimethylformamide (1 mL) was added thereto, followed by stirring for 2 hours, and the insoluble matter was filtered. The filtrate was evaporated under reduced pressure and the obtained residue were added methanol (0.5 mL) and a 4 M hydrogen chloride-dioxane solution (0.45 mL), followed by stirring at room temperature for 8 hours. The solvent was evaporated under reduced pressure and the obtained residue were added tetrahydrofuran (0.9 mL) and a saturated aqueous sodium hydrogen carbonate solution (1 mL). Acryloyl chloride (8 μL) and tetrahydrofuran (0.1 mL) were added thereto at room temperature, followed by stirring for 4 hours. The reaction mixture was extracted with chloroform. The solvent of the organic phase was evaporated under reduced pressure and the obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 5-(7-acryloyl-2,7-diazaspiro[4.4]non-2-yl)-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (2 mg).

Workup

  1. stirringby stirring for 2 hours
  2. filtrationthe insoluble matter was filtered
  3. customThe filtrate was evaporated under reduced pressure
  4. additionthe obtained residue were added methanol (0.5 mL)
  5. stirringby stirring at room temperature for 8 hours
  6. customThe solvent was evaporated under reduced pressure
  7. additionthe obtained residue were added tetrahydrofuran (0.9 mL)
  8. additionAcryloyl chloride (8 μL) and tetrahydrofuran (0.1 mL) were added
  9. customat room temperature
  10. stirringby stirring for 4 hours
  11. extractionThe reaction mixture was extracted with chloroform
  12. customThe solvent of the organic phase was evaporated under reduced pressure
  13. customthe obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution)

Sources & evidence

ORD record
ord-c1b0138519de466eb123b00afb4b1384
Source dataset
uspto-grants-2015_07
Patent number
US09085540B2

Reaction notes

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