Phosphoric Acid → (2R,4S)-2-methyl-4-((2-methylpropan-2-yl)oxycarbonylamino)-5-(4-phenylphenyl)pentanoic acid

HRID 1021042Notes

Reaction equation

HRID 1021042 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].P(=O)(O)(O)[OH:31]>C1COCC1>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][C:14]([CH2:13][C@@H:12]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][C@@H:10]([CH3:26])[C:9]([OH:27])=[O:31])=[CH:19][CH:18]=1

Participants

5

Reactant 3

HCID 1004Phosphoric AcidHCID 3939Lithium Hydroxide2×HCID 66739124(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 46193546(2R,4S)-2-methyl-4-((2-methylpropan-2-yl)oxycarbonylamino)-5-(4-phenylphenyl)pentanoic acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

5 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (2-a, R1=BOC) was dissolved in 50 ml of a mixture of THF and a 2 M lithium hydroxide solution (ratio 1:1). After 1 hour at room temperature, phosphoric acid was added to neutralise the excess of lithium hydroxide. The slurry was concentrated under vacuum to remove most of the solvent and extracted with iso-propyl acetate. The organic phase was then washed with water, partially concentrated under vacuum and brought to crystallisation upon addition of heptane. The crystalline solid obtained was collected and dried under vacuum to yield about 3.6 g of [(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid] (3-a, R1=BOC, R2=R3=H). Mpt 146-147° C.; δH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3)3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H, m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); δC (500 MHz, DMSO) 18.1 (1-CH3), 28.3 [(CH3)3], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar—CH), 137.7 (Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2 (NCO), 177.2 (CO2H); m/z (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19); Found: [MH]+, 384.21691. C23H30NO4 requires MH 384.21693.

Workup

  1. concentrationThe slurry was concentrated under vacuum
  2. customto remove most of the solvent
  3. extractionextracted with iso-propyl acetate
  4. washThe organic phase was then washed with water
  5. concentrationpartially concentrated under vacuum
  6. custombrought to crystallisation upon addition of heptane
  7. customThe crystalline solid obtained
  8. customwas collected
  9. customdried under vacuum

Sources & evidence

ORD record
ord-fbc928903b1c484a9fdaf21cb7419215
Source dataset
uspto-grants-2014_05
Patent number
US08716495B2

Reaction notes

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