Dimethylacetamide → HCID 66771849, compound

HRID 1645729Notes

Reaction equation

HRID 1645729 reaction equation
[CH3:1]C(N(C)C)=O.[CH3:7][C:8]1[N:9]=[C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[CH:12][N:11]2[C:22]=1[C:23](=O)[CH3:24].Cl.[NH:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)[C:28]([NH2:30])=[NH:29].N12CCCN=C1CCCCC2>CN(C=O)C.O.C(#N)C>[CH3:7][C:8]1[N:9]=[C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[CH:12][N:11]2[C:22]=1[C:23]1[CH:24]=[CH:1][N:30]=[C:28]([NH:27][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)[N:29]=1

Participants

8

Reactant 4

HCID 31374DimethylacetamideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 66772764HCID 66772764, compoundHCID 178479383HCID 178479383, compound

Product 1

HCID 66771849HCID 66771849, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolvent

Procedure

A solution of 4-chloro-pyridin-2-ylamine (800 mg, 6.22 mmol) and morpholine (8.1 mL, 93.34 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) was heated in a microwave (Emry's Optimizer) at 200° C. for 10 minutes. The resulting solution was directly purified by flash chromatography (SiO2, 95:5:0.5/DCM:MeOH:NH4OH) to give 4-morpholin-4-yl-pyridin-2-ylamine (Int-1). MS found for C9H13N3O as (M+H)+ 180.39. A solution of Int-1 (418 mg, 2.34 mmol) and 3-chloro-pentane-2,4-dione (0.3 mL, 2.45 mmol) in NMP (2.5 mL) was added and heated in a microwave (Emry's Optimizer) at 150° C. for 30 minutes. The resulting solution was directly purified by flash chromatography (SiO2, 96:4:/DCM:MeOH) to give 1-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-ethanone (Int-2). MS found for C14H17N3O2 as (M+H)+ 260.39. A mixture of Int-2 (293 mg, 1.13 mmol) and DMF.DMA (2.3 mL) was heated at 150° C. for 10 hours. The mixture was concentrated and used further without purification. MS found for C17H22N4O2 as (M+H)+ 315.23. A solution of 1-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-ethanone (263 mg, 0.84 mmol), 4-guanidinobenzoic acid hydrochloride (180 mg, 0.841) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.25 mL, 1.67 mmol) in DMF (3 mL) was heated in a microwave (Emry's Optimizer) at 150° C. for 30 minutes. The reaction mixture was then diluted with water and acetonitrile and purified by preparative HPLC affording 4-[4-(2-methyl-7-morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-ylamino]-benzoic acid after lyophilization. MS found for C23H22N6O3 as (M+H)+ 431.46. To the above carboxylic acid (10 mg, 0.023 mmol) in DMF (1 mL), was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (13 mg, 0.034 mmol), 1,2-phenylenediamine (5 mg, 0.046 mmol), DIPEA (0.01 mL, 0.068 mmol), and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound after lyophilization. MS found for C29H28N8O2 as (M+H)+ 521.28. 1H NMR (400 MHz, dmso-d6): δ 9.54 (d, J=8.0 Hz, 1H); 8.41 (d, J=5.6 Hz, 1H); 7.90 (d, J=8.4 Hz, 2H); 7.79 (d, J=8.4 Hz, 2H); 7.11 (d, J=7.6 Hz, 1H); 7.02-6.97 (m, 2H); 6.83 (d, J=7.6 Hz, 2H); 6.71-6.67 (m, 2H); 3.76 (m, 4H); 3.29 (m, 4H); 2.58 (s, 3H).

Workup

  1. concentrationThe mixture was concentrated
  2. customused further without purification
  3. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-a712ae268b2746a0b28e764475d50d00
Source dataset
uspto-grants-2012_02
Patent number
US08124764B2

Reaction notes

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