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

HRID 72148

Reaction equation

HRID 72148 reaction equation
Cl.[CH2:2]([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.OC1C2N=NNC=2C=CC=1.[C:34]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH2:2]([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH:22][C:49](=[O:50])[C@@H:45]([NH:44][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH:46]([CH3:48])[CH3:47])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 726987N-Carbobenzoxy-L-valineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68622110((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochlorideHCID 178418300HCID 178418300, compound

Product 1

HCID 68620942[(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl esterYield 61.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

((R)-3-Amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (2.10 mmol) was dissolved in DMF (30 mL) under nitrogen and stirred at 0° C. To this was added sequentially hydroxybenzotriazole (0.91 g, 6.72 mmol), N-Cbz-L-valine (0.63 g, 2.52 mmol), triethylamine (0.58 mL, 4.2 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.48 g, 2.52 mmol). The stirred reaction mixture was allowed to warm to room temperature and continued to stir overnight. The reaction was diluted with ethyl acetate (300 mL) and was washed with brine (100 mL). The brine layer was back extracted with ethyl acetate (2×100 mL) and the organic fractions were combined and were washed with 10% citric acid (2×100 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 which was purified by flash chromatography (as in Method A) to give (0.72 g, 1.29 mmol) of [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester as a white foam. NMR and MS spectra were substantially similar to the product obtained via Method A set forth above.

Workup

  1. customThe stirred reaction mixture
  2. temperatureto warm to room temperature
  3. stirringto stir overnight
  4. washwas washed with brine (100 mL)
  5. extractionThe brine layer was back extracted with ethyl acetate (2×100 mL)
  6. washwere washed with 10% citric acid (2×100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL)
  7. dry with materialThe organic layer was dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto give the crude product which
  11. customwas purified by flash chromatography (as in Method A)

Sources & evidence

ORD record
ord-d4195a092585484f9ff74857721ff750
Source dataset
uspto-grants-2014_09
Patent number
US08828974B2

Linked notes

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