Diisopropylethylamine → 1-(4-(2-(5-((4-(2-(1H-tetrazol-5-yl)ethyl)piperazin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-cyclopropylurea

HRID 1400947Notes

Reaction equation

HRID 1400947 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.CCN(C(C)C)C(C)C.Cl[CH2:48][CH2:49][C:50]1[NH:54][N:53]=[N:52][N:51]=1.CO.O>CS(C)=O.O>[NH:51]1[C:50]([CH2:49][CH2:48][N:34]2[CH2:33][CH2:32][N:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([C:22]4[S:23][C:16]5[C:17](=[N:18][CH:19]=[CH:20][C:15]=5[O:14][C:11]5[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]6[CH2:3][CH2:2]6)=[O:6])=[CH:9][C:10]=5[F:37])[CH:21]=4)=[N:25][CH:26]=3)[CH2:36][CH2:35]2)=[N:54][N:53]=[N:52]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 22242641Methanol--water (1/1)HCID 674423881-Cyclopropyl-3-(3-fluoro-4-(2-(5-(piperazin-1-ylmethyl)pyridin-2-yl)thieno[3,2-b]-pyridin-7-yloxy)phenyl)ureaHCID 178478456HCID 178478456, compound2×

Product 1

HCID 1785222271-(4-(2-(5-((4-(2-(1H-tetrazol-5-yl)ethyl)piperazin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-cyclopropylureaYield 3.9%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Procedure

To a stirred suspension of 49 (300 mg, 0.578 mmol, scheme 15) and DIPEA (303 μl, 1.74 mmol) in DMSO (5 ml) under nitrogen at rt was added 5-(2-chloroethyl)-1H-tetrazole (137 mg, 1.03 mmol), and the reaction mixture was stirred at rt for 1 h, heated at 60° C. overnight, then at rt. More 5-(2-chloroethyl)-1H-tetrazole (300 mg, 2.27 mmol) was added and the reaction mixture was heated at 60-65° C. for 24 h, then rt. The reaction mixture was diluted with water, and sonicated. The solid was collected by filtration, rinsed with water and air-dried. The crude material was purified three times by Biotage (Snap 25 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 5/95 to 25/75 over 20 CV, then 25/75 to 50/50 over 20 CV; Silia Sep HP 12 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 10/90 to 30/70 over 20 CV, then 30/70 to 40/60 over 20 CV; Snap 30 g KP-C18-HS (reverse phase): MeOH/water (millipore): 20/80 to 95/05 over 40 CV), to afford the desired product 512 (14 mg, 0.02 mmol, 3.9% yield) as a beige sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): one NH is missing, 8.74 (s, 1H), 8.54 (bd, J=1.6 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (dd, J=9.0, 1.4 Hz, 1H), 6.64 (dd, J=5.4, 0.7 Hz, 1H), 6.60 (bd, J=2.5 Hz, 1H), 3.55 (s, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.59-2.32 (m, 9H), 0.72-0.58 (m, 2H), 0.50-0.37 (m, 2H). MS (m/z): 615.7 (M+H).

Workup

  1. temperatureheated at 60° C. overnight
  2. customat rt
  3. temperaturethe reaction mixture was heated at 60-65° C. for 24 h
  4. customrt
  5. customsonicated
  6. filtrationThe solid was collected by filtration
  7. washrinsed with water
  8. customair-dried
  9. customThe crude material was purified three times by Biotage (Snap 25 g cartridge

Sources & evidence

ORD record
ord-f9b9debde8a74cb98a18c3b6e22c47ee
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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