Hydrochloric Acid → 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid

HRID 881834Notes

Reaction equation

HRID 881834 reaction equation
[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][C:4]([C:11]([OH:13])=[O:12])=[CH:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.C([O:44][C:45](=[O:64])[C@H:46]([CH3:63])[CH2:47][C@H:48]([NH2:62])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)C1C=CC=CC=1.C(N(CC)CC)C.C(OC([C@H](C)C[C@H](NC(C1OC(C(O)=O)=CC(=O)C=1)=O)CC1C=CC(C2C=CC=CC=2)=CC=1)=O)C1C=CC=CC=1.B(Cl)(Cl)Cl.Cl>CN(C=O)C.C(Cl)Cl.O>[C:53]1([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:52]=[CH:51][C:50]([CH2:49][C@@H:48]([NH:62][C:8]([C:6]2[O:5][C:4]([C:11]([OH:13])=[O:12])=[CH:3][C:2](=[O:1])[CH:7]=2)=[O:10])[CH2:47][C@H:46]([C:45]([OH:64])=[O:44])[CH3:63])=[CH:55][CH:54]=1

Participants

12

Reactant 8

HCID 313Hydrochloric AcidHCID 7431Chelidonic acidHCID 8471TriethylamineHCID 25135Boron TrichlorideHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 67505899HCID 67505899, compound2×HCID 866482066-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid

Product 1

HCID 596081716-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 4-oxo-4H-pyran-2,6-dicarboxylic acid (99 mg. 0.535 mmol) in DMF (10 mL) is added HOBt (98 mg. 0.643 mmol) and EDCl (123 mg, 0.643 mmol) and the mixture is stirred at room temperature for 10 minutes. To this is then added (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (Intermediate 30: 200 mg, 0.535 mmol) and triethylamine (0.224 mL, 1.61 mmol) and the mixture is stirred at room temperature for 48 hours. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1% TFA) to elute the product, 6-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid. MS 540.2 (M+1). Next, to a solution of 6-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid (100 mg, 0.185 mmol) in methylene chloride (5 mL) is added BCl3 (65.1 mg, 0.556 mmol) and the mixture is stirred at room temperature for 10 minutes. The mixture is acidified to pH 2-3 with aqueous 1M HCl and is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1% TFA) to elute the product. The proper fractions are lyophilized to furnish 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid. MS 450.1 (M+1); 1H-NMR (400 Hz, DMSO-d6); δ ppm 1.07 (d, J=7.07 Hz, 3H), 1.59 (m, 1H), 1.88 (m, 1H), 2.45 (m, 1H), 2.84 (d, J=6.69 Hz, 2H), 4.19 (m, 1H), 6.84 (s, 1H), 6.93 (s, 1H), 7.32 (dd, J=8.08 Hz, 6.57 Hz, 3H), 7.45 (t, J=7.83 Hz, 2H), 7.58 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.33 Hz, 2H), 8.61 (d, J=8.72 Hz, 1H).

Workup

  1. extractionthe mixture is extracted with ethyl acetate
  2. washThe organic phase is washed with water and brine
  3. dry with materialis dried over magnesium sulfate
  4. customThe solvent is removed under reduced pressure
  5. customthe residue is purified by preparative HPLC
  6. washto elute the product, 6-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid
  7. stirringthe mixture is stirred at room temperature for 10 minutes
  8. extractionis extracted with ethyl acetate
  9. washThe organic phase is washed with water and brine
  10. dry with materialis dried over magnesium sulfate
  11. customThe solvent is removed under reduced pressure
  12. customthe residue is purified by preparative HPLC
  13. washto elute the product

Sources & evidence

ORD record
ord-86bfdb39f03741929eaee88ba2b3fff3
Source dataset
uspto-grants-2015_03
Patent number
US08993631B2

Reaction notes

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