Piperidine → 4-Piperidine-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-(2,2-difluoro-ethoxy)-quinazolin-6-yl]-amide

HRID 467602Notes

Reaction equation

HRID 467602 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH:23]([F:25])[F:24])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)C(C)C)(C)C.Br[CH2:36][CH:37]=[CH:38][C:39](Cl)=[O:40].[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH:23]([F:25])[F:24])=[C:17]([NH:20][C:39](=[O:40])[CH:38]=[CH:37][CH2:36][N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

7

Reactant 4

HCID 8082Piperidine2×HCID 81531DiisopropylethylamineHCID 536352004-Bromo-but-2-enoyl chlorideHCID 86601522N4-(3-Chloro-4-fluoro-phenyl)-7-(2,2-difluoro-ethoxy)-quinazoline4,6-diamine

Product 1

HCID 730636304-Piperidine-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-(2,2-difluoro-ethoxy)-quinazolin-6-yl]-amide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

0.5 g N4-(3-Chloro-4-fluoro-phenyl)-7-(2,2-difluoro-ethoxy)-quinazoline-4,6-diamine was dissolved in 10 ml THF and 1.2 ml N,N-Diisopropyl-ethylamine (DIEA) and 0.48 g 4-Bromo-but-2-enoyl chloride were added and the mixture was stirred at room temperature for 2 hours. 0.27 ml piperidine was added and stirred at room temperature overnight. An additional 0.7 ml piperidine was added and the mixture heated to 70° C. After 3 hours the reaction mixture was poured into water, the solids were extracted with ethyl acetate, washed with water and brine, dried over NaSO4 and flash chromatographed under 0-4% methanol in chloroform to yield 0.2 g 4-Piperidine-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-(2,2-difluoro-ethoxy)-quinazolin-6-yl]-amide.

Workup

  1. stirringstirred at room temperature overnight
  2. temperaturethe mixture heated to 70° C
  3. extractionthe solids were extracted with ethyl acetate
  4. washwashed with water and brine
  5. dry with materialdried over NaSO4 and flash
  6. customchromatographed under 0-4% methanol in chloroform

Sources & evidence

ORD record
ord-18e9449a9f8b40f9bd9a08aece9335c4
Source dataset
uspto-grants-2014_01
Patent number
US08623883B2

Reaction notes

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