Methane → 9-[5-(3-{4-[Bis(2-chloroethyl)amino]phenyl}ureido)-2-methyl-phenylamino]-5-methyl-acridine-4-carboxylic acid (2-dimethylaminoethyl)amide

HRID 1514807Notes

Reaction equation

HRID 1514807 reaction equation
Cl.Cl.[Cl:3][CH2:4][CH2:5][N:6]([CH2:14][CH2:15][Cl:16])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.C.O=C(Cl)[O:20][C:21](Cl)(Cl)Cl.[CH3:26][N:27]([CH3:57])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:46]2[C:37](=[C:38]([NH:48][C:49]3[CH:54]=[C:53]([NH2:55])[CH:52]=[CH:51][C:50]=3[CH3:56])[C:39]3[C:44]([N:45]=2)=[C:43]([CH3:47])[CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1)=[O:32]>O1CCOCC1.CN(C=O)C.N1C=CC=CC=1>[CH3:57][N:27]([CH3:26])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:46]2[C:37](=[C:38]([NH:48][C:49]3[CH:54]=[C:53]([NH:55][C:21]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([N:6]([CH2:14][CH2:15][Cl:16])[CH2:5][CH2:4][Cl:3])=[CH:8][CH:9]=4)=[O:20])[CH:52]=[CH:51][C:50]=3[CH3:56])[C:39]3[C:44]([N:45]=2)=[C:43]([CH3:47])[CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1)=[O:32]

Participants

8

Reactant 4

HCID 297MethaneHCID 10426DiphosgeneHCID 111778369-(5-Amino-2-methyl-phenylamino)-5-methylacridine-4-carboxylic acid (2-dimethylaminoethyl)amideHCID 21276262N1,N1-bis(2-chloroethyl)benzene-1,4-diamine dihydrochloride

Product 1

HCID 250198579-[5-(3-{4-[Bis(2-chloroethyl)amino]phenyl}ureido)-2-methyl-phenylamino]-5-methyl-acridine-4-carboxylic acid (2-dimethylaminoethyl)amide

Reagents, catalysts & solvents 3

HCID 1049PyridineSolventHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
92.5 °C

Procedure

To a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (37) (0.918 g, 3 mmol) and charcoal (20 mg) in dry dioxane (30 mL) was added diphosgene (0.494 g, 2.5 mmol). The reaction mixture was heated at 90-95° C. for 5 h. After cooling, the reaction mixture was filtered through a pad of Celite and the filtrate containing crude mustard isocyanate 39 was added dropwise into the solution of 9-(5-amino-2-methyl-phenylamino)-5-methylacridine-4-carboxylic acid (2-dimethylaminoethyl)amide (0.732 g, 1.7 mmol)33 in dry DMF (25 mL) containing pyridine (2 mL) at −10° C. and then stirred at room temperature for 24 h. The solvent removed under reduced pressure to dryness and the residue was dissolved in a mixture of CHCl3/MeOH containing silica gel (10 gm) and evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (4×30 cm) and chromatographed using CHCl3/MeOH (100:5 v/v) as eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness. The residue was recrystallized from EtOH/hexane to give 9-[5-(3-{4-[bis(2-chloroethyl)amino]phenyl}ureido)-2-methyl-phenylamino]-5-methyl-acridine-4-carboxylic acid (2-dimethylaminoethyl)amide (19, BO-1053); 0.385 g (32%); mp 286-289° C.; 1H NMR (DMSO-d6) δ 2.19 (3H, s, Me), 2.67 (6H, m, NMe2), 2.85 (3H, s, Me), 3.14 (2H, brs, CH2), 3.63-3.69 (8H, m, 4×CH2), 3.85 (2H, brs, CH2), 6.41 (1H, m, ArH,), 6.65 (2H, d, J=9.0 Hz, ArH), 6.97 (1H, m, ArH), 7.24 (2H, d, J=9.0 Hz, ArH), 7.36-7.44 (1H, m, ArH), 7.51 (1H, m, ArH), 7.74 (2H, m, ArH), 7.93 (1H, m, ArH), 8.09 (1H, m, ArH), 8.41 (1H, m, ArH), 8.67 (1H, m, ArH), 9.04 (1H, brs, exchangeable, NH), 9.45 (1H, brs, exchangeable, NH), 12.18 (1H, brs, exchangeable, NH). Anal. Calcld. for (C37H41Cl2N7O2.6H2O): C, 54.91; H, 5.20; N, 12.34. Found: C, 55.08; H, 5.32; N, 12.44.

Workup

  1. temperatureAfter cooling
  2. filtrationthe reaction mixture was filtered through a pad of Celite
  3. additionthe filtrate containing crude mustard isocyanate 39
  4. customThe solvent removed under reduced pressure to dryness
  5. dissolutionthe residue was dissolved in a mixture of CHCl3/MeOH
  6. additioncontaining silica gel (10 gm)
  7. customevaporated in vacuo to dryness
  8. customchromatographed
  9. additionThe fractions containing the main product
  10. customevaporated in vacuo to dryness
  11. customThe residue was recrystallized from EtOH/hexane

Sources & evidence

ORD record
ord-a5d6772116a544a994c92601610fb765
Source dataset
uspto-grants-2012_07
Patent number
US08222297B2

Reaction notes

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