Hydrochloric Acid → (R)-[2-(7-diethylcarbamoyl-1H-indol-3-yl)-1-methyl-2-oxoethyl]carbamic acid 9H-fluoren-9-ylmethyl ester

HRID 1351934Notes

Reaction equation

HRID 1351934 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:21]([OH:23])=O)[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C1C2C(COC(N[C@@H](C(Cl)=O)C)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:53]([N:55]([CH2:67][CH3:68])[C:56]([C:58]1[CH:59]=[CH:60][CH:61]=[C:62]2[C:66]=1[NH:65][CH:64]=[CH:63]2)=[O:57])[CH3:54].C[Mg]Br.C(OCC)C.Cl>C(Cl)Cl.CN(C)C=O>[CH:6]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([CH3:20])[C:21]([C:63]3[C:62]4[C:66](=[C:58]([C:56](=[O:57])[N:55]([CH2:67][CH3:68])[CH2:53][CH3:54])[CH:59]=[CH:60][CH:61]=4)[NH:65][CH:64]=3)=[O:23])[C:13]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 65578Oxalyl chlorideHCID 2724627(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acidHCID 11131317Fmoc-D-alanyl chlorideHCID 545468101H-indole-7-carboxylic acid diethylamideHCID 178467822HCID 178467822, compound

Product 1

HCID 69458837(R)-[2-(7-diethylcarbamoyl-1H-indol-3-yl)-1-methyl-2-oxoethyl]carbamic acid 9H-fluoren-9-ylmethyl esterYield 43.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
-20 °C

Procedure

To a suspension of N-(9-fluorenylmethoxycarbonyl)-D-alanine (21.61 g, 69.4 mmol), methylene chloride (230 ml) and N,N-dimethylformamide (0.37 ml) is added dropwise oxalyl chloride (6.46 ml, 74.0 mmol) at room temperature with stirring, and the mixture is further stirred for 2 hours. The reaction solution is concentrated to dryness under reduced pressure to give an oil containing N-(9-fluorenylmethoxy-carbonyl)-D-alanyl chloride. A solution of 1H-indole-7-carboxylic acid diethylamide (10.0 g, 46.3 mmol) in methylene chloride (120 ml) is cooled to −20° C., and thereto is added dropwise a 3M solution of methyl magnesium bromide/diethyl ether (54 ml, 162 mmol). After the addition, the mixture is further stirred at −20° C. for 2 hours. This reaction solution is cooled to −25-−15° C., and thereto is added dropwise a solution of the above obtained N-(9-fluorenylmethoxycarbonyl)-D-alanyl in methylene chloride (140 ml), and the mixture is further stirred at −20° C. for 2 hours. The mixture is warmed to about −5° C., and poured into 2N hydrochloric acid. The organic layer is separated, washed with water (25 ml) and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate/hexane=1/2→5/1) to give the desired (R)-[2-(7-diethylcarbamoyl-1H-indol-3-yl)-1-methyl-2-oxoethyl]carbamic acid 9H-fluoren-9-ylmethyl ester (10.24 g, yield: 43%).

Workup

  1. stirringthe mixture is further stirred for 2 hours
  2. concentrationThe reaction solution is concentrated to dryness under reduced pressure
  3. customto give an oil
  4. additionAfter the addition
  5. stirringthe mixture is further stirred at −20° C. for 2 hours
  6. additionis added dropwise a solution of the
  7. stirringthe mixture is further stirred at −20° C. for 2 hours
  8. temperatureThe mixture is warmed to about −5° C.
  9. customThe organic layer is separated
  10. washwashed with water (25 ml)
  11. dry with materialdried over anhydrous magnesium sulfate
  12. customThe solvent is evaporated under reduced pressure
  13. customthe residue is purified by silica gel column chromatography (ethyl acetate/hexane=1/2→5/1)

Sources & evidence

ORD record
ord-79b3268545fa48eb8923d991b7d177c4
Source dataset
uspto-grants-2007_05
Patent number
US07217724B2

Reaction notes

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