Acetic Acid → tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate

HRID 649385Notes

Reaction equation

HRID 649385 reaction equation
[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][C:45](=O)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][C@@H:45]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 13454543tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetateHCID 14855086Ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-oxovalerate

Product 1

HCID 54047948tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetateYield 9%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Procedure

In 30 ml of ethanol is dissolved 2.1 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 0.4 g of acetic acid, 2.5 g of ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-oxovalerate and 10 g of Molecular sieve 3A are added to the solution. The mixture is stirred at room temperature for 20 minutes, and a solution of 0.4 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise to the mixture at room temperature with stirring over the period of 3 hours. The reaction solution is allowed to stand at room temperature overnight, and concentrated under reduced pressure, and 300 ml of water and 300 ml of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is removed by filtration, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (20 ml) and 2 g of oxalic acid are added to the residue, and the mixture is shaken thoroughly and admixed with 300 ml of petroleum ether, followed by allowing the mixture to stand. The solution portion is removed by decantation, and 100 ml of water and 200 ml of ethyl acetate are added to the precipitate portion, followed by adding excess sodium hydrogencarbonate to conduct neutralization. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily material. This product is separated and purified by silica-gel column chromatography (hexane:ethyl acetate=2:1) to give from the first fraction 0.4 g of tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material.

Workup

  1. additionare added to the solution
  2. stirringwith stirring over the period of 3 hours
  3. waitto stand at room temperature overnight
  4. concentrationconcentrated under reduced pressure, and 300 ml of water and 300 ml of ethyl acetate
  5. additionare added to the residue
  6. stirringby shaking
  7. customThe insoluble matter is removed by filtration
  8. dry with materialthe ethyl acetate layer is dried over anhydrous magnesium sulfate
  9. concentrationconcentrated under reduced pressure
  10. additionEthyl acetate (20 ml) and 2 g of oxalic acid are added to the residue
  11. stirringthe mixture is shaken thoroughly
  12. customThe solution portion is removed by decantation, and 100 ml of water and 200 ml of ethyl acetate
  13. additionare added to the precipitate portion
  14. additionby adding excess sodium hydrogencarbonate
  15. dry with materialThe ethyl acetate layer is dried over anhydrous magnesium sulfate
  16. concentrationconcentrated under reduced pressure
  17. customto give an oily material
  18. customThis product is separated
  19. custompurified by silica-gel column chromatography (hexane:ethyl acetate=2:1)

Sources & evidence

ORD record
ord-7dcc80a45ddb43629d8c681df2bd24db
Source dataset
uspto-grants-1988_04
Patent number
US04739066

Reaction notes

Loading…