Diisopropylethylamine → [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester

HRID 1926981Notes

Reaction equation

HRID 1926981 reaction equation
[C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH2:51]([O:58][P:59]([CH2:68][C@H:69]([OH:72])[CH2:70][NH2:71])([CH2:61][CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][P:59]([CH2:68][C@H:69]([OH:72])[CH2:70][NH:71][C:16](=[O:18])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:13]([CH3:14])[CH3:15])([CH2:61][CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:60])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 726987N-Carbobenzoxy-L-valineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 68622110((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride

Product 1

HCID 68620942[(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl esterYield 48.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A flask was charged with N-Cbz-L-valine (1.02 g, 4.04 mmol) and DMF (60 mL) and stirred under nitrogen. To this was added diisopropylethylamine (2.11 mL, 12.1 mmol) followed by TBTU (1.30 g, 4.04 mmol). After stirring for 5 minutes, a solution of ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (8.08 mmol) dissolved in DMF (10 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (300 mL) and the organic layer washed with 1N HCl (2×100 mL), water (100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as an amber oil. The crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a 120 g RediSep disposable column to give (1.10 g, 1.97 mmol) of [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester as a white foam. 1H NMR (CDCl3, 300 MHz): δ 7.40-7.25 (m, 10H), 6.70-6.51 (m, 1H), 5.48-5.35 (m, 1H), 5.18-5.01 (m, 4H), 4.20-3.98 (m, 2H), 3.62-3.42 (m, 1H), 3.38-3.18 (m, 1H), 2.30-2.05 (m, 1H), 2.03-1.60 (m, 10H, 1.38-1.02 (m, 5H), 0.98 (dd, 6H). LCMS m/z: [M+H]+=559.

Workup

  1. stirringAfter stirring for 5 minutes
  2. additionwas added
  3. stirringThe reaction mixture was stirred overnight at room temperature
  4. washthe organic layer washed with 1N HCl (2×100 mL), water (100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL)
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give the crude product as an amber oil
  9. customThe crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a 120 g RediSep disposable column

Sources & evidence

ORD record
ord-c4a7cba4548840129f474ca8c052adee
Source dataset
uspto-grants-2012_05
Patent number
US08183231B2

Reaction notes

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