1-Methylpiperazine → n-(3-(4-(1h-Indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)-quinazolin-2-yl)phenyl) butyramide di-hydrochloride salt

HRID 61682Notes

Reaction equation

HRID 61682 reaction equation
[C:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29](C(OC(C)(C)C)=O)[N:28]=[CH:27]4)[C:20]3[C:15](=[CH:16][C:17]([O:44][CH3:45])=[C:18]([O:40][CH2:41][CH2:42][Cl:43])[CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CS(C)=O>[ClH:43].[ClH:43].[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:20]4[C:15](=[CH:16][C:17]([O:44][CH3:45])=[C:18]([O:40][CH2:41][CH2:42][N:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH:19]=4)[N:14]=[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:12]=[CH:11][CH:10]=4)[N:22]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1

Participants

4

Reactant 2

HCID 531671-MethylpiperazineHCID 59361971tert-butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate

Product 1

HCID 66826237n-(3-(4-(1h-Indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)-quinazolin-2-yl)phenyl) butyramide di-hydrochloride saltYield 43%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.170 g, 0.299 mmol) in DMSO (2 mL) was added 1-methylpiperazine (0.5 mL). The subsequent mixture was heated at 85° C. for 2.5 h upon which it was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried under vacuum. The precipitate was purified via preparative TLC (SiO2, CH2Cl2:MeOH:NH4OH 9:1:0.1). The purified compound was taken up in CH2Cl2 (2 mL) and HCl (4M in 1,4 dioxane, 10 mL) and stirred at RT for 4 h. The volatiles were removed in vacuo and the residue was triturated with Et2O, filtered and dried under vacuum to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)-quinazolin-2-yl)phenyl) butyramide di-hydrochloride salt (0.085 g, 0.128 mmol, 43% over two steps). MS 595 (M+1). HPLC retention time 4.337 mins.

Workup

  1. temperatureto cool to RT
  2. customA precipitate formed which
  3. filtrationwas collected via filtration and it
  4. customwas dried under vacuum
  5. customThe precipitate was purified via preparative TLC (SiO2, CH2Cl2:MeOH:NH4OH 9:1:0.1)
  6. customThe volatiles were removed in vacuo
  7. customthe residue was triturated with Et2O
  8. filtrationfiltered
  9. customdried under vacuum

Sources & evidence

ORD record
ord-f63f4ba206f34b6dbab88047aa440e61
Source dataset
uspto-grants-2016_09
Patent number
US09440961B2

Reaction notes

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