Dimethylformamide → 4-[Bis(2-chloroethyl)amino]phenyl-3-[6-methoxy-2-(4-methoxyphenyl)quinolin-4-yl]urea

HRID 716836

Reaction equation

HRID 716836 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)[O:28][C:29](Cl)(Cl)Cl)Cl.[NH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[N:39]=[C:38]([C:48]2[CH:53]=[CH:52]C=[C:50](OC)[CH:49]=2)[CH:37]=1.CN([CH:59]=[O:60])C>C(Cl)(Cl)Cl>[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:59]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[C:38]([C:48]3[CH:49]=[CH:50][C:27]([O:28][CH3:29])=[CH:52][CH:53]=3)[CH:37]=2)=[O:60])=[CH:8][CH:7]=1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 94429TriphosgeneHCID 2157271,4-Benzenediamine, N1,N1-bis(2-chloroethyl)-, hydrochloride (1:?)HCID 692397584-Amino-6-methoxy-2-(3-methoxyphenyl)quinoline

Product 1

HCID 250183104-[Bis(2-chloroethyl)amino]phenyl-3-[6-methoxy-2-(4-methoxyphenyl)quinolin-4-yl]urea

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

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). This intermediate was dissolved in anhydrous DMF (1 mL) and then added dropwise to a solution of 4-amino-6-methoxy-2-(3-methoxyphenyl)quinoline (280 mg, 1.0 mmol) in dry DMF (1 mL). The reaction mixture was stirred at 50° C. for 9 h and the solvent was removed by vacuum distillation. The residue was chromatographed on a silica gel column (2×24 cm) using CHCl3/MeOH/(100:1 v/v) as eluent. The fractions containing the desired product were combined, evaporated and the solid residue was recrystallized from EtOH to give 1-{4-[bis(2-chloroethyl)amino]phenyl-3-[6-methoxy-2-(4-methoxyphenyl)quinolin-4-yl]urea (BO-1049); 400 mg (74.2%); mp 112-113° C.; 1H NMR (DMSO-d6) δ 3.72 (8H, m, 4×CH2), 3.87 (3H, s, OMe), 4.01 (3H, s, OMe), 6.72 (2H, d, J=8.8 Hz, ArH), 7.07 (1H, dd, J=2.2 and 8.1 Hz, ArH), 7.41 (2H, d, J=8.8 Hz, 2×ArH), 7.47 (2H, m, 2×ArH), 7.65 (3H, m, ArH), 7.99 (2H, d, J=10.3 Hz, 2×ArH), 8.80 (1H, d, J=8.8 Hz, ArH), 9.25 (2H, brs, exchangeable, 2×NH). Anal. Calcd. for (C28H28Cl2N4O3): C, 62.61; H, 5.23; N, 10.39. Found: C, 62.34; H, 4.99; N, 10.59.

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. dissolutionThis intermediate was dissolved in anhydrous DMF (1 mL)
  6. stirringThe reaction mixture was stirred at 50° C. for 9 h
  7. customthe solvent was removed by vacuum distillation
  8. customThe residue was chromatographed on a silica gel column (2×24 cm)
  9. additionThe fractions containing the desired product
  10. customevaporated
  11. customthe solid residue was recrystallized from EtOH

Sources & evidence

ORD record
ord-8079b067715748ac82997979cebaf59d
Source dataset
uspto-grants-2015_11
Patent number
US09193687B2

Linked notes

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