3-Aminopropionitrile → (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2-methyl pentanoic acid ethyl ester

HRID 2384081

Reaction equation

HRID 2384081 reaction equation
[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH2:6][C@H:7]([NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25](O)=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.[NH2:53][CH2:54][CH2:55][C:56]#[N:57].C(N(CC)CC)C.NC(C)C#N>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH2:6][C@H:7]([NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25](=[O:26])[NH:57][CH2:56][CH2:55][C:54]#[N:53])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]

Participants

9

Reactant 6

HCID 16473-AminopropionitrileHCID 8471Triethylamine2×HCID 181649HOAt2×HCID 411840Propanenitrile, 2-amino-HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 9811834Sacubitril

Product 1

HCID 59608195(2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2-methyl pentanoic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester (prepared by using the procedure described in US005217996) (200 mg, 0.486 mmol) in DMF (3 mL) are added EDC-HCl (112 mg, 0.583 mmol) and HOAt (79 mg, 0.583 mmol) at room temperature. After stirring for 10 minutes, 3-aminopropionitrile (41 mg, 0.583 mmol) and triethylamine (0.081 mL, 0.583 mmol) is added and stirred overnight. Additional EDC-HCl (66 mg, 0.292 mmol), HOAt (40 mg, 0.292 mmol), aminopropionitrile (21 mg, 0.292 mmol), and triethylamine (0.081 mL, 0.583 mmol) are added. After stirring for 1 hour, the reaction mixture is heated to 50° C. and stirred for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with H2O and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by silica gel column chromatography to give (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2-methyl pentanoic acid ethyl ester. HPLC Retention time 1.37 minutes (condition B); MS 464 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (d, J=7.33 Hz, 3H), 1.25 (t, J=7.07 Hz, 3H), 1.51 (ddd, J=4.29, 0.85, 14.14 Hz, 1H), 1.95 (ddd, J=4.29, 9.60, 13.89 Hz, 1H), 2.41-2.59 (m, 5H), 2.58 (t, J=6.57 Hz, 2H), 2.83 (d, J=6.57 Hz, 2H), 3.45 (ddd, J=2.53, 8.00, 12.0 Hz, 2H), 4.14 (ddd, J=2.53, 8.00, 14.01 Hz, 2H), 4.21-4.31 (m, 1H), 5.64 (d, J=9.09 Hz, 1H), 6.60-6.67 (m, 1H), 7.24 (d, J=8.34 Hz, 2H), 7.34 (t, J=7.33 Hz, 1H), 7.43 (t, J=7.83 Hz, 2H), 7.53 (d, J=8.34 Hz, 2H), 7.58 (d, J=7.07 Hz, 2H).

Workup

  1. stirringstirred overnight
  2. stirringAfter stirring for 1 hour
  3. stirringstirred for 5 hours
  4. washwashed with H2O and brine
  5. dry with materialThe organic layer is dried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue is purified by silica gel column chromatography

Sources & evidence

ORD record
ord-c9654ab838fe4524b2278ab3d5ce778f
Source dataset
uspto-grants-2012_09
Patent number
US08263629B2

Linked notes

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