3-Aminopropionitrile → (R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric acid ethyl ester

HRID 1945043Notes

Reaction equation

HRID 1945043 reaction equation
[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](O)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:51][CH2:52][CH2:53][C:54]#[N:55]>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](=[O:25])[NH:55][CH2:54][CH2:53][C:52]#[N:51])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2]

Participants

6

Reactant 4

HCID 16473-Aminopropionitrile2×HCID 757711-Hydroxybenzotriazole2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 49822223(R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester

Product 1

HCID 67208765(R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric acid ethyl esterYield 96%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Next, to a solution of (R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester (200 mg, 0.522 mmol) in THF (10 mL) at room temperature is added EDC HCl (120 mg, 0.626 mmol) and HOBT (96 mg, 0.626 mmol). The reaction is stirred at room temperature for 10 minutes then added 3-aminopropionitrile (0.046 ml, 0.626 mmol) and TEA (0.087 ml, 0.626 mmol). After 1 hour, 0.5 equivalent of EDC HCl, HOBT, and 3-aminopropionitrile are added and stirred for 16 hours. The reaction mixture is quenched by brine and is extracted with ethylacetate. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 2% to 5% EtOH/DCM) to give (R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric acid ethyl ester (218 mg, 96% yield). HPLC retention time=0.77 minutes (condition E); MS=436 (m+1).

Workup

  1. waitAfter 1 hour
  2. stirringstirred for 16 hours
  3. customThe reaction mixture is quenched by brine
  4. extractionis extracted with ethylacetate
  5. washThe combined organic layer is washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe obtained residue is purified by flash chromatography (silica gel, 2% to 5% EtOH/DCM)

Sources & evidence

ORD record
ord-21f254a63d6245b2a033c054a3a11f0a
Source dataset
uspto-grants-2013_03
Patent number
US08394853B2

Reaction notes

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