Dimethylformamide → 4-[(4-Methylpiperazin-1-yl)methyl]benzoyl chloride--hydrogen chloride (1/2)

HRID 1404422Notes

Reaction equation

HRID 1404422 reaction equation
[ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.S(Cl)([Cl:22])=O.CN(C)C=O>ClCCl>[ClH:22].[ClH:1].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 24386Thionyl ChlorideHCID 103353464-[(4-methylpiperazin-1-yl)methyl]benzoic Acid Dihydrochloride

Product 1

HCID 202270424-[(4-Methylpiperazin-1-yl)methyl]benzoyl chloride--hydrogen chloride (1/2)

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-(4-methylpiperzin-1-ylmethyl)benzoic acid dihydrochloride (2.5 kg), thionyl chloride (16.2 kg) and N,N-dimethylformamide (0.62 L) was refluxed for 20 hours. After completion of reaction, the reaction mass was distilled out completely under vacuum to give residue which was diluted with dichloromethane (5.0 L). Solid thus precipitated was filtered and washed to give 4-(4-methylpiperzin-1-ylmethyl)benzoyl chloride dihydrochloride. Dichloromethane (25.0 L), potassium carbonate (4 kg) was added to the above product and stirred for 30 minutes. The reaction mass was cooled to 0-5° C. and 4-methyl-N-(4-pyridin-3-yl-pyridin-2-yl)benzene-1,3-diamine (1.0 kg) was added to the reaction mixture. The reaction mass was refluxed for 10 hours. After completion of reaction, the reaction mass was quenched with dilute hydrochloric acid (21.0 L) up to pH 2.5-3.0 and layers were separated. Aqueous layer was washed with dichloromethane, diluted with tetrahydrofuran (6.0 L) and basified up to pH 8.0-8.5 with aqueous sodium hydroxide solution (20%, 10.0 L). Solid thus precipitated was filtered, washed with sodium hydroxide solution and demineralised water to give title compound having amine intermediate 29 ppm. Resulting solid was dissolved in a mixture of dichloromethane and methanol (8.0 L+2.0 L), washed with water and concentrated to give residue: Methanol (20.0 L) was added to the resulting residue, refluxed and charcoalized. Methanol was partially distilled out and resulting reaction mass was cooled down to 25-30° C. Reaction mixture was stirred for 1.0 hour. Reaction mixture was filtered, washed and dried to give 1.3 kg (yield: 73%) of title compound having purity 99.8% by HPLC and amine intermediate: 9.0 ppm.

Workup

  1. temperaturewas refluxed for 20 hours
  2. customAfter completion of reaction
  3. distillationthe reaction mass was distilled out completely under vacuum
  4. customto give residue which
  5. customSolid thus precipitated
  6. filtrationwas filtered
  7. washwashed

Sources & evidence

ORD record
ord-428e097e2a0644d1a7f4753855c60083
Source dataset
uspto-grants-2014_12
Patent number
US08912325B2

Reaction notes

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