Oxalyl chloride → 4-Cyano-1H-pyrrole-2-carboxylic acid [4-methyl-6'-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-yl]-amide

HRID 646923Notes

Reaction equation

HRID 646923 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH3:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[C:38]([NH2:39])=[CH:37][CH:36]=[C:35]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[N:34]=2)[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC=CC=1.CN(C=O)C>[CH3:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33]2[C:38]([NH:39][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[CH:37][CH:36]=[C:35]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[N:34]=2)[CH2:31][CH2:32]1

Participants

9

Reactant 5

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 118048114-cyano-1H-pyrrole-2-carboxylic acidHCID 586385234-methyl-6'-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-ylamine

Product 1

HCID 116900064-Cyano-1H-pyrrole-2-carboxylic acid [4-methyl-6'-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-yl]-amideYield 7%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

A flask was charged with 4-cyano-pyrrole-2-carboxylic acid (as prepared in Example 2, 200 mg, 1.43 mmol), dichloromethane (30 ml), DMF (150 μL), and oxalyl chloride (275 μL, 1.60 mmol) and the mixture was stirred for 20 min at RT. Toluene (10 mL) was then added and the solvents were removed in vacuo. To the resulting acid chloride, dichloromethane (30 mL), DIEA (750 μL, 4.30 mmol), and 4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine (as prepared in Example 55, step (c), 385 mg, 1.33 mmol) were added and the mixture was stirred at RT for 4 days. The mixture was poured into saturated aq sodium bicarbonate (100 mL), and extracted with dichloromethane (2×25 mL) and the solvents were removed in vacuo. Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane, then repurification by alumina preparative TLC eluting with dichloromethane-acetonitrile-methanol (7:2.5:0.5) yielded 38 mg (7%) of the title compound as a green solid. 1H-NMR (400 MHz, CDCl3): δ 11.32 (br s, 1H), 8.33 (d, 1H, J=8.8 Hz), 7.44 (s, 1H), 6.87 (s, 1H), 6.39 (d, 1H, J=8.8 Hz), 3.54 (m, 4H), 3.18-3.15 (m, 2H), 2.84 (m, 2H), 2.56 (m, 4H), 2.38 (s, 3H), 1.82-1.79 (m, 2H), 1.56 (m, 1H), 1.40-1.33 (m, 2H) 1.06 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C22H30N7O, 408.2 (M+H); found: 408.2.

Workup

  1. customthe solvents were removed in vacuo
  2. stirringthe mixture was stirred at RT for 4 days
  3. extractionextracted with dichloromethane (2×25 mL)
  4. customthe solvents were removed in vacuo
  5. customPurification of the resulting residue by silica gel preparative TLC
  6. washeluting with 10% methanol in dichloromethane
  7. customrepurification by alumina preparative TLC
  8. washeluting with dichloromethane-acetonitrile-methanol (7:2.5:0.5)

Sources & evidence

ORD record
ord-542d625681d84fad9b28ed105d4f1448
Source dataset
uspto-grants-2010_04
Patent number
US07705042B2

Reaction notes

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