2-Chloro-N,N-dimethylethylamine → Deacetyldiltiazem

HRID 1085328Notes

Reaction equation

HRID 1085328 reaction equation
[OH:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(OCC)(=O)C.[CH3:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C([O-])([O-])=O.[K+].[K+]>O>[CH3:28][N:29]([CH3:30])[CH2:31][CH2:32][N:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@@H:3]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@@H:2]([OH:1])[C:8]1=[O:9]

Participants

6

Reactant 4

HCID 79012-Chloro-N,N-dimethylethylamineHCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 27336733-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, (2S,3S)-

Product 1

HCID 91638DeacetyldiltiazemYield 70%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent3×

Procedure

A 5-L three-necked flask equipped with a heating mantle, a mechanical stirrer and a condenser was charged with 162 g (0.54 mol) of (+)-(2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and then 1 L of ethyl acetate. After stirring to dissolve the solution, 100 g (0.694 mol) of dimethylaminoethyl chloride.HC1 was added in one portion followed by 300 g (2.16 mol) of finely ground K2CO3 and 5 mL of H2O. (The 5 ml. of water was essential to cause a reaction between the phases, while addition of much more water would have resulted in gummy mixture that was difficult to filter.) This heterogeneous mixture was rapidly stirred at reflux for 5 hours. By thin layer chromatography (8:1, CH2C12 -MeOH, short wave UV), reaction was complete and therefore the mixture was allowed to cool to room temperature, filtered through a sintered glass funnel and washed with 100 mL 1:1 hexanes-ethyl acetate. The solvent was evaporated and on standing the oil crystallized. Recrystallization from ether gave 140 g (70%) of colorless crystalline (+)-(2S,3S)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, m.p. 79-81° C., [α]D20=+ 156.4°(C=1.0; CHC13).

Workup

  1. customA 5-L three-necked flask equipped with a heating mantle, a mechanical stirrer and a condenser
  2. additionHC1 was added in one portion
  3. customa reaction between the phases
  4. customwould have resulted in gummy mixture that
  5. filtrationto filter
  6. stirring) This heterogeneous mixture was rapidly stirred
  7. temperatureat reflux for 5 hours
  8. customBy thin layer chromatography (8:1, CH2C12 -MeOH, short wave UV), reaction
  9. filtrationfiltered through a sintered glass funnel
  10. washwashed with 100 mL 1:1 hexanes-ethyl acetate
  11. customThe solvent was evaporated
  12. customcrystallized
  13. customRecrystallization from ether

Sources & evidence

ORD record
ord-ceed1bc369f54150ad8bb952fcdc6f41
Source dataset
uspto-grants-1991_04
Patent number
US05008411

Reaction notes

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