Diethyl Ether → HCID 22741843, compound

HRID 49825Notes

Reaction equation

HRID 49825 reaction equation
F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:18][CH2:17]1.C(N(CC)CC)C.C(OCC)C>CN1C(=O)CCC1>[N+:12]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[CH:23]=1)([O-:14])=[O:13]

Participants

6

Reactant 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 111272614-Fluoro-3-nitrophenylacetic acidHCID 115646133-(4-Methylpiperazin-1-yl)aniline

Product 1

HCID 22741843HCID 22741843, compoundYield 29.1%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of 1i (3.0 g, 15.1 mmol) in anhydrous NMP (2 ml) was added 2c (2.88 g, 15.1 mmol) and triethylamine (2.1 ml, 30.2 mmol). The mixture was stirred at 80° C. under a stream of nitrogen overnight. The cooled mixture was poured into a mixture of diethyl ether and petroleum ether (100 ml, 1:1 v/v) resulting in separation of an oily lower phase. The mixture was decanted and the oil was dissolved in dichloromethane and eluted through silica gel with a mixture of dichloromethane and methanol (4:1 v/v) to yield 3-nitro-4-(3-(4-methylpiperazin-1-yl)phenylamino)-phenylacetic acid (1.63 g, 29%). This acid (0.64 g, 1.73 mmol) was dissolved in methanol and concentrated hydrochloric acid (0.2 ml) was added. The mixture was heated to reflux for 4 days. The solvent was removed under reduced pressure and the residue was purified by column-chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) as the eluent to leave the ester (0.47 g, 71%) as a red oil. This oil was hydrogenated in methanol at ambient pressure using Pd (5% on activated carbon) as the catalyst to yield the corresponding diamine (0.38 g). This diamine was treated with triethyl orthoformate (0.35 ml, 2.14 mmol) and a catalytic amount of pTSA in THF (5 ml) at 80° C. for 30 min. The solvent was evaporated and the residue was partitioned between aqueous sodium hydroxide (1 M) and ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and eluted through a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v). The product precipitated as the hydrochloride by addition of a solution of anhydrous hydrogen chloride in diethyl ether to the eluate. Yield of 4l1: 0.2 g (41%). M.p. 140-142° C.

Workup

  1. customresulting in separation of an oily lower phase
  2. customThe mixture was decanted
  3. dissolutionthe oil was dissolved in dichloromethane
  4. washeluted through silica gel with a mixture of dichloromethane and methanol (4:1 v/v)

Sources & evidence

ORD record
ord-74f7ac61e67c40ef88468071d06e3376
Source dataset
uspto-grants-2004_03
Patent number
US06710044B2

Reaction notes

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