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Hydrochloric Acid → N-(3-{[2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-6-yl]oxy}phenyl)-4-[2-(morpholin-4-yl)ethoxy]benzamide

HRID 1986402
Notes
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Reaction equation

HRID 1986402 reaction equation
Cl.[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([O:33][C:34]2[N:39]=[CH:38][C:37]3[N:40]=[C:41]([C:45]4[C:46]([NH2:50])=[N:47][O:48][N:49]=4)[N:42]([CH2:43][CH3:44])[C:36]=3[CH:35]=2)[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[NH2:50][C:46]1[C:45]([C:41]2[N:42]([CH2:43][CH3:44])[C:36]3[CH:35]=[C:34]([O:33][C:29]4[CH:28]=[C:27]([NH:26][C:15](=[O:17])[C:14]5[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:2]6[CH2:3][CH2:4][O:5][CH2:6][CH2:7]6)=[CH:19][CH:18]=5)[CH:32]=[CH:31][CH:30]=4)[N:39]=[CH:38][C:37]=3[N:40]=2)=[N:49][O:48][N:47]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 65578Oxalyl chlorideHCID 65042324-(2-Morpholin-4-yl-ethoxy)-benzoic acidHCID 11404963HCID 11404963, compound

Product 1

HCID 16095342N-(3-{[2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-6-yl]oxy}phenyl)-4-[2-(morpholin-4-yl)ethoxy]benzamideYield 83%

Reagents, catalysts & solvents 3

HCID 1049PyridineSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

Under argon, to a suspension of the HCl salt of 4-{[2-(4-morpholinyl)ethyl]oxy}benzoic acid (3.98 g, 13.8 mmol) in CH2Cl2 (100 ml) was added DMF (40 μl), followed with oxalylchloride (3.6 ml, 41.4 mmol). This mixture was then heated to reflux until a clear solution resulted. The reaction mixture was then concentrated, added CH2Cl2 (20 mL) and reconcentrated. A suspension of the above product in CH2Cl2 (100 mL), was added to a suspension of the product of Example 3 (3.96 g, 11.7 mmol) in pyridine (30 mL). This mixture was then heated to 70° C., the CH2Cl2 was distilled off, then stirred for 1 h. CH2Cl2 (200 mL) was added to the cooled reaction mixture, stirred for 15 min and then filtered to provide a first crop of product (crop 1). The filtrate was concentrated in vacuo and the residue taken up in EtOAc, washed with water (4×), brine, dried over Na2SO4, filtered and concentrated to provide Crop 2. Crops 1 and 2 were combined and recrystallized from MeOH to afforded a off white solid (5.54 g, 83%). 1H NMR (400 MHz, DMSO) δ ppm 11.35 (bs, 1H), 10.22 (s, 1H), 8.79 (d, 1H, 0.8 Hz), 7.99 (d, 2H, 8.8 Hz), 7.58-7.64 (m, 3H), 7.37 (t, 1H, 8.0 Hz), 7.12 (d, 2H, 8.8 Hz), 6.95 (s, 2H), 6.84-6.87 (m, 1H), 4.70 (q, 2H, 7.2 Hz), 4.53 (bs, 2H), 3.81-3.98 (m, 4H), 3.49-3.58 (m, 4H), 3.18-3.36 (m, 2H), 1.41 (t, 3H, 7.2 Hz). MS (ES+) m/e 571 [M+H]+.

Workup

  1. temperatureThis mixture was then heated
  2. temperatureto reflux until a clear solution
  3. customresulted
  4. concentrationThe reaction mixture was then concentrated
  5. additionadded CH2Cl2 (20 mL)
  6. additionA suspension of the above product in CH2Cl2 (100 mL)
  7. distillationthe CH2Cl2 was distilled off
  8. additionCH2Cl2 (200 mL) was added to the cooled reaction mixture
  9. stirringstirred for 15 min
  10. filtrationfiltered
  11. customto provide a first crop of product (crop 1)
  12. concentrationThe filtrate was concentrated in vacuo
  13. washwashed with water (4×), brine
  14. dry with materialdried over Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customto provide Crop 2
  18. customrecrystallized from MeOH

Sources & evidence

ORD record
ord-67d991b4b00c4f8783cf83db9f5560f1
Source dataset
uspto-grants-2009_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07547779B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes