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

HRID 716845Notes

Reaction equation

HRID 716845 reaction equation
Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.CCN(CC)CC.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]([CH3:66])[CH2:37][CH2:38][NH:39][C:40]([C:42]1[C:55]2[C:46](=[C:47]([NH:57][C:58]3[CH:63]=[C:62]([NH2:64])[CH:61]=[CH:60][C:59]=3[CH3:65])[C:48]3[C:53]([N:54]=2)=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=3)[CH:45]=[CH:44][CH:43]=1)=[O:41]>C(Cl)(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[CH3:66][N:36]([CH3:35])[CH2:37][CH2:38][NH:39][C:40]([C:42]1[C:55]2[C:46](=[C:47]([NH:57][C:58]3[CH:63]=[C:62]([NH:64][C:27]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([N:5]([CH2:13][CH2:14][Cl:15])[CH2:4][CH2:3][Cl:2])=[CH:7][CH:8]=4)=[O:33])[CH:61]=[CH:60][C:59]=3[CH3:65])[C:48]3[C:53]([N:54]=2)=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=3)[CH:45]=[CH:44][CH:43]=1)=[O:41]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 2157271,4-Benzenediamine, N1,N1-bis(2-chloroethyl)-, hydrochloride (1:?)HCID 111778369-(5-Amino-2-methyl-phenylamino)-5-methylacridine-4-carboxylic acid (2-dimethylaminoethyl)amide

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 6212ChloroformSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (18, 0.918 g, 3.0 mmol) in dry CHCl3 (35 mL) containing Et3N (0.6 mL) was added dropwise a solution of triphosgene (356 mg, 1.2 mmol.) in an ice bath with vigorous stirring for 30 min. The reaction mixture was evaporated and the residue diluted with THF (20 mL), filtered through a pad of Celite, washed with THF (5 mL). The filtrate containing crude N-mustard isocyanate 19 was evaporated in vacuo to dryness and the residue was dissolved in dry DMF (5 mL) and then 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 (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. customThe reaction mixture was evaporated
  2. additionthe residue diluted with THF (20 mL)
  3. filtrationfiltered through a pad of Celite
  4. washwashed with THF (5 mL)
  5. additionThe filtrate containing crude N-mustard isocyanate 19
  6. customwas evaporated in vacuo to dryness
  7. dissolutionthe residue was dissolved in dry DMF (5 mL)
  8. stirringstirred at room temperature for 24 h
  9. customThe solvent removed under reduced pressure to dryness
  10. dissolutionthe residue was dissolved in a mixture of CHCl3/MeOH
  11. additioncontaining silica gel (10 gm)
  12. customevaporated in vacuo to dryness
  13. customchromatographed
  14. additionThe fractions containing the main product
  15. customevaporated in vacuo to dryness
  16. customThe residue was recrystallized from EtOH/hexane

Sources & evidence

ORD record
ord-a10a52ac549f4b0786141af416bc908a
Source dataset
uspto-grants-2015_11
Patent number
US09193687B2

Reaction notes

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