Pyrrolidine → HCID 22637163, compound

HRID 2416085Notes

Reaction equation

HRID 2416085 reaction equation
[CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:31][CH2:32][CH3:33])=[C:21]([NH:24][C:25](=[O:30])/[CH:26]=[CH:27]/[CH2:28]Cl)[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:34]#[N:35])=[CH:11][C:10]=1[Cl:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC(NC2C3C(=CC(OCC)=C([NH:62][C:63](=O)/[CH:64]=[CH:65]/[CH2:66]Br)C=3)N=CC=2C#N)=CC=1Cl)C1C=CC=CC=1.[NH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:31][CH2:32][CH3:33])=[C:21]([NH:24][C:25](=[O:30])[CH2:26][CH:27]([N:62]4[CH2:63][CH2:64][CH2:65][CH2:66]4)[CH2:28][N:77]4[CH2:81][CH2:80][CH2:79][CH2:78]4)[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:34]#[N:35])=[CH:11][C:10]=1[Cl:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 31268Pyrrolidine2×HCID 516892Sodium BicarbonateHCID 22637165HCID 22637165, compoundHCID 22637167HCID 22637167, compound

Product 1

HCID 22637163HCID 22637163, compoundYield 40%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
-50 °C

Procedure

An amount of 612 mg (1.1 mmol) of (E)-N-{4-[4-(benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-chloro-2-butenamide, and (E)-N-{4-[4-(benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-bromo-2-butenamide, were stirred in 6 mL of N,N-dimethylformamide and cooled to −50° C. Pyrrolidine (55 μL, 0.66 mmol), was added dropwise over a period of 30 min. After stirring for 2 hrs at −50° C., another 0.250 mL (3.0 mmol) of pyrrolidine was added dropwise over a period of 1.5 hrs, and the reaction mixture was warmed to room temperature for 16 hrs. A solution of saturated sodium bicarbonate was added, and the product was extracted with ethyl acetate and methylene chloride. Both organic layers were combined, dried over sodium sulfate, poured over a hydrous magnesium silicate plug, and evaporated to an oil. Purification was carried out by flash chromatography (40:4:2=ethyl acetate: methanol:ammonium hydroxide), and preparative thin layer chromatography (40:4:1=ethyl acetate:methanol:triethylamine), to give the title compound as an orange solid (284 mg, 40%), mp 85-87° C.; 1H NMR (DMSO-d6) δ10.59 (bs, 1H), 9.57 (s, 1H), 9.01 (s, 1H), 8.46 (s, 1H), 7.51-7.33 (m, 7H), 7.26-7.16 (m, 2H), 5.21 (s, 2H), 4.23 (q, 2H), 2.98 (bs, 1H), 2.71-2.60 (m, 8H), 2.49 (m, 2H) 1.74 (m, 5H), 1.64 (m, 5H), 1.43 (t, 3H); HRMS (ESI-FTMS) 653.29959 (M+1).

Workup

  1. temperaturethe reaction mixture was warmed to room temperature for 16 hrs
  2. extractionthe product was extracted with ethyl acetate and methylene chloride
  3. dry with materialdried over sodium sulfate
  4. additionpoured over a hydrous magnesium silicate plug
  5. customevaporated to an oil
  6. customPurification

Sources & evidence

ORD record
ord-8fc009ddb8ea4a42bd79c147810598ee
Source dataset
uspto-grants-2004_11
Patent number
US06821988B2

Reaction notes

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