Methanol → Methyl N-[(2R)-2-(2,3-dihydro-1H-inden-2-yl)-2-({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-N-[1-(2,6-dimethyl-3-pyridinyl)-2-oxo-2-({2-[(phenylmethyl)oxy]phenyl}amino)ethyl]-D-alloisoleucinate

HRID 402850Notes

Reaction equation

HRID 402850 reaction equation
[CH3:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.Cl.[CH3:12][O:13][C:14](=[O:21])[C@@H:15]([C@H:17]([CH2:19][CH3:20])[CH3:18])[NH2:16].C(N(CC)CC)C.[CH2:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH:30]1[C@@H:38]([NH:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:39]([OH:41])=O.[CH2:53]([O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[N+:67]#[C-:68])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C[OH:70]>FC(F)(F)CO>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH:30]1[C@@H:38]([NH:42][C:43]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:44])[C:39]([N:16]([CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:10])=[CH:5][CH:6]=1)[C:68](=[O:70])[NH:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[O:60][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C@@H:15]([C:14]([O:13][CH3:12])=[O:21])[C@H:17]([CH2:19][CH3:20])[CH3:18])=[O:41]

Participants

8

Reactant 6

HCID 887MethanolHCID 8471TriethylamineHCID 27847532,6-DimethylnicotinaldehydeHCID 51261571-(Benzyloxy)-2-isocyanobenzeneHCID 11631222(R)-Benzyloxycarbonylamino-indan-2-yl-acetic acidHCID 12890355D-Alloisoleucine, methyl ester, hydrochloride (1:1)

Product 1

HCID 57722468Methyl N-[(2R)-2-(2,3-dihydro-1H-inden-2-yl)-2-({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-N-[1-(2,6-dimethyl-3-pyridinyl)-2-oxo-2-({2-[(phenylmethyl)oxy]phenyl}amino)ethyl]-D-alloisoleucinate

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Procedure

2,6-dimethylpyridine-3-carboxaldehyde (Aurora Feinchemie GmbH) (2.00 g, 16.1 mmol) and (D)-alloisoleucine methyl ester hydrochloride (2.93 g, 16.1 mmol) in methanol (50 mL) and 2,2,2-trifluoroethanol (50 mL) were treated with triethylamine (2.24 mL, 16.1 mmol) and the mixture was stirred under nitrogen at room temperature for 20 h. (2R)-2,3-dihydro-1H-inden-2-yl({[(phenylmethyl)oxy]carbonyl}amino)ethanoic acid (5.24 g, 16.1 mmol) and 2-benzyloxyphenylisonitrile (3.37 g, 16.1 mmol) were added and the mixture was stirred at room temperature under nitrogen for 4 days. The mixture was concentrated under reduced pressure then partitioned between ethyl acetate (150 mL) and water (150 mL) plus saturated aqueous sodium hydrogen carbonate (6 mL). The aqueous phase was back-extracted with ethyl acetate (50 mL) and the combined organic extracts were washed successively with semi-saturated aqueous solutions of sodium hydrogen carbonate, ammonium chloride and sodium chloride (100 mL each), dried over anhydrous magnesium sulphate and evaporated under reduced pressure to give the crude product (12.01 g). This was purified on a Redisep silica column (330 g) eluted with 20-50% ethyl acetate in cyclohexane to afford 7.46 g of the title compound as a pair of diastereomers.

Workup

  1. additionwere added
  2. concentrationThe mixture was concentrated under reduced pressure
  3. customthen partitioned between ethyl acetate (150 mL) and water (150 mL) plus saturated aqueous sodium hydrogen carbonate (6 mL)
  4. extractionThe aqueous phase was back-extracted with ethyl acetate (50 mL)
  5. washthe combined organic extracts were washed successively with semi-saturated aqueous solutions of sodium hydrogen carbonate, ammonium chloride and sodium chloride (100 mL each)
  6. dry with materialdried over anhydrous magnesium sulphate
  7. customevaporated under reduced pressure
  8. customto give the crude product (12.01 g)
  9. customThis was purified on a Redisep silica column (330 g)
  10. washeluted with 20-50% ethyl acetate in cyclohexane

Sources & evidence

ORD record
ord-f02a77d86a8e46b1b5454fcd567ae497
Source dataset
uspto-grants-2014_06
Patent number
US08742099B2

Reaction notes

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