4-Methylmorpholine → (2R)-3-({2-[(4-[1-(tert-Butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetyl}amino)-2-[(2-naphthylsulphonyl)amino]propanoic Acid

HRID 2271224Notes

Reaction equation

HRID 2271224 reaction equation
ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH:24]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[NH2:54][CH2:55][C@@H:56]([NH:60][S:61]([C:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=1)(=[O:63])=[O:62])[C:57]([OH:59])=[O:58]>C1COCC1.O>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32][CH:24]([CH2:23][CH2:22][CH:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)[C:25]([NH:27][CH2:28][C:29]([NH:54][CH2:55][C@@H:56]([NH:60][S:61]([C:64]2[CH:73]=[CH:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[CH:65]=2)(=[O:63])=[O:62])[C:57]([OH:59])=[O:58])=[O:30])=[O:26])[CH2:39][CH2:38]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 15433187HCID 15433187, compound2×HCID 70238132(2R)-3-amino-2-[(2-naphthylsulphonyl)amino]propanoic acid

Product 1

HCID 70236594(2R)-3-({2-[(4-[1-(tert-Butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetyl}amino)-2-[(2-naphthylsulphonyl)amino]propanoic AcidYield 51%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Isobutyl chloroformate (3.3 g, 24.2 mmol) is added, at room temperature, to a solution of 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetic acid (compound 4) (10.8 g, 20 mmol) in 200 ml of THF and N-methylmorpholine (5 g, 49.5 mmol). A suspension is obtained. After stirring for 20 minutes, a mixture of (2R)-3-amino-2-[(2-naphthylsulphonyl)amino]propanoic acid (8 g, 25 mmol) and water (80 ml) is added, at 0° C. Stirring is continued at 0˜5° C. for 30 minutes and then at room temperature for 18 hours. The THF is evaporated off and the aqueous solution is acidified to pH 2 with 1N hydrochloric acid. The mixture is extracted with ether. The extracts are washed with water, dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (10/0.5/0.5 dichloromethane/methanol/acetic acid) to give 8.3 g of a beige-coloured solid.

Workup

  1. customA suspension is obtained
  2. additionis added, at 0° C
  3. stirringStirring
  4. waitis continued at 0˜5° C. for 30 minutes
  5. waitat room temperature for 18 hours
  6. customThe THF is evaporated off
  7. extractionThe mixture is extracted with ether
  8. washThe extracts are washed with water
  9. dry with materialdried over sodium sulphate
  10. customevaporated
  11. customto give the crude product, which
  12. customis purified by flash chromatography (10/0.5/0.5 dichloromethane/methanol/acetic acid)

Sources & evidence

ORD record
ord-6a0e2e9ffc2b42999656507f792e23ad
Source dataset
uspto-grants-2001_12
Patent number
US06333338B1

Reaction notes

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