Chloroacetyl chloride → HCID 67442872, compound

HRID 1400953Notes

Reaction equation

HRID 1400953 reaction equation
[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:46][C:47](Cl)=[O:48].[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54]>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([C:47](=[O:48])[CH2:46][NH:54][CH2:53][CH2:52][N:51]([CH3:55])[CH3:50])[CH2:35][CH2:36]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 6577Chloroacetyl chlorideHCID 8471TriethylamineHCID 66053N,N-DimethylethylenediamineHCID 674423881-Cyclopropyl-3-(3-fluoro-4-(2-(5-(piperazin-1-ylmethyl)pyridin-2-yl)thieno[3,2-b]-pyridin-7-yloxy)phenyl)urea

Product 1

HCID 67442872HCID 67442872, compoundYield 10.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 49 (100 mg, 0.19 mmol) and triethylamine (107 μl, 0.77 mmol) in DCM (10 ml) under nitrogen was added chloroacetyl chloride (19 μl, 0.23 mmol), and the reaction mixture was stirred at rt for 25 min. N,N-Dimethylethylene diamine (134 μl, 1.16 mmol) was added, and the reaction mixture was stirred at rt overnight, heated at 40° C. for 5 h, then at rt. The reaction mixture was concentrated, diluted with water and few drops of 1N NaOH and sonicated. The resulting gel was collected by filtration, rinsed with water and air-dried. The crude product was purified three times by Biotage [Snap 30 g cartridge KP-C18-HS (reverse phase) ×2: MeOH/water (Millipore): 20/80 to 95/05 over 40 CV; Analogix SF 25-40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 50/50 over 60 CV], to afford the desired compound 549 (13 mg, 0.02 mmol, 10% yield) as a pale yellow sticky solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.75 (s, 1H), 8.56 (bd, J=1.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.2, 1.9 Hz, 1H), 7.72 (dd, J=13.6, 2.4 Hz, 1H), 7.37 (t, J=9.1 Hz, 1H), 7.20 (bd, J=8.9 Hz, 1H), 6.64 (d, J=5.4 Hz, 1H), 6.61 (bd, J=1.9 Hz, 1H), 3.58 (s, 2H), 3.50-3.36 (m, 4H), 3.33 (s, 2H), 2.59-2.51 (m, 1H), 2.52 (t, J=6.3 Hz, 2H), 2.43-2.31 (m, 4H), 2.27 (t, J=6.3 Hz, 2H), 2.10 (s, 6H), 0.70-0.58 (m, 2H), 0.47-0.37 (m, 2H), one NH secondary amine is missing. MS (m/z): 647.6 (M+H).

Workup

  1. stirringthe reaction mixture was stirred at rt overnight
  2. temperatureheated at 40° C. for 5 h
  3. customat rt
  4. concentrationThe reaction mixture was concentrated
  5. additiondiluted with water and few drops of 1N NaOH
  6. customsonicated
  7. filtrationThe resulting gel was collected by filtration
  8. washrinsed with water
  9. customair-dried
  10. customThe crude product was purified three times by Biotage [Snap 30 g cartridge KP-C18-HS (reverse phase) ×2: MeOH/water (Millipore): 20/80 to 95/05 over 40 CV; Analogix SF 25-40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 50/50 over 60 CV]

Sources & evidence

ORD record
ord-aba2d000896740a5b9124cba7b743313
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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