1-(2-Hydroxyethyl)piperazine → (Z)-2-(4-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}piperazin-1-yl)ethanol monohydrochloride

HRID 1251077Notes

Reaction equation

HRID 1251077 reaction equation
[F:1][C:2]1([F:31])[CH2:3][CH2:4][N:5]([C:17]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:30])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([OH:12])=O.ON1C2C=CC=CC=2N=N1.[ClH:42].C(N=C=NCCCN(C)C)C.[N:54]1([CH2:60][CH2:61][OH:62])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:42].[F:31][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:17]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:30])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:57]1[CH2:58][CH2:59][N:54]([CH2:60][CH2:61][OH:62])[CH2:55][CH2:56]1)=[O:12]

Participants

7

Reactant 5

HCID 76771-(2-Hydroxyethyl)piperazineHCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 70160918(Z)-2-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetic acid

Product 1

HCID 70160897(Z)-2-(4-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}piperazin-1-yl)ethanol monohydrochlorideYield 22.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 8.26 g of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetic acid in 150 ml of tetrahydrofuran were added 2.79 g of 1-hydroxybenzotriazole, 5.40 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 3.18 g of 2-(piperazin-1-yl)ethanol, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, the mixture was extracted with chloroform, and the solvent was evaporated from the extract. The residue was dissolved in 300 ml of 0.1N hydrochloric acid, washed with ethyl acetate, made alkaline with a 1N aqueous solution of sodium hydroxide, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate, and the solvent was evaporated off. The residue was crystallized from ethyl acetate, collected by filtration, and washed with ethyl acetate. The resulting crystals (9.0 g) were dissolved in 100 ml of chloroform, and 6 ml of a 4N HCl/ethyl acetate solution was added, followed by stirring at room temperature. The resulting crystals were collected by filtration and washed with chloroform. Those crude crystals (3.0 g of the above-obtained ones in 10.0 g) were recrystallized from a 90% aqueous ethanol solution to give 2.48 g of (Z)-2-(4-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}piperazin-1-yl)ethanol monohydrochloride as a colorless powder.

Workup

  1. extractionthe mixture was extracted with chloroform
  2. customthe solvent was evaporated from the extract
  3. dissolutionThe residue was dissolved in 300 ml of 0.1N hydrochloric acid
  4. washwashed with ethyl acetate
  5. extractionextracted with chloroform
  6. washThe organic layer was washed with a saturated aqueous solution of NaCl
  7. dry with materialdried over magnesium sulfate
  8. customthe solvent was evaporated off
  9. customThe residue was crystallized from ethyl acetate
  10. filtrationcollected by filtration
  11. washwashed with ethyl acetate
  12. dissolutionThe resulting crystals (9.0 g) were dissolved in 100 ml of chloroform
  13. addition6 ml of a 4N HCl/ethyl acetate solution was added
  14. stirringby stirring at room temperature
  15. filtrationThe resulting crystals were collected by filtration
  16. washwashed with chloroform
  17. customThose crude crystals (3.0 g of the above-obtained ones in 10.0 g) were recrystallized from a 90% aqueous ethanol solution

Sources & evidence

ORD record
ord-afbc8316ae554694bc1e0350fe4901a5
Source dataset
uspto-grants-2002_01
Patent number
US06340678B1

Reaction notes

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