Triethylamine → HCID 59238198, compound

HRID 2068571Notes

Reaction equation

HRID 2068571 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([OH:26])=O)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(OC(N1CCCN(C2C=CC([N+]([O-])=O)=C(C(NCC(O)=O)=O)C=2)CC1)=O)(C)(C)C>C(Cl)Cl.Cl.COC(=O)CN>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([NH:32][CH2:31][C:30]([O:29][CH3:28])=[O:33])=[O:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 5

HCID 8471Triethylamine2×HCID 757711-Hydroxybenzotriazole2×HCID 122755Glycine methyl ester hydrochlorideHCID 59238174HCID 59238174, compoundHCID 67211503HCID 67211503, compound

Product 1

HCID 59238198HCID 59238198, compoundYield 94.5%

Reagents, catalysts & solvents 2

HCID 122755Glycine methyl ester hydrochlorideCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

4-(3-Carboxy-4-nitro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (37.27 g, 102 mmol) and 107.1 mmol of glycine methyl ester hydrochloride salt were suspended in methylene chloride. To this suspension was added 102 mmol of N-hydroxybenzotriazole and the mixture was cooled with an ice-water bath. Triethylamine (214 mmol) was added, effecting a solution. At this time 1.1 equivalents of 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride was added. This mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 days. At this time, thin layer chromatography indicated the presence of 4-[3-(carboxymethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester. An additional 5.1 mmol each of glycine methyl ester hydrochloride salt and N-hydroxybenzotriazole as well as 10.3 mmol of triethylamine were added. The reaction mixture was stirred at room temperature for another 24 hour. At this time, the reaction mixture was diluted with methylene chloride, washed with water, with 10% (wt/vol) KHSO4 solution, with water again, with saturated sodium bicarbonate aqueous solution, with water again, and finally with brine. The methylene chloride solution was concentrated to dryness in vacuo, resulting in a dark brown oil. The oil was purified by flash column chromatography: the column was loaded with a methylene chloride solution, followed by elution with ethyl acetate:hexane (7:3), and then finally with ethyl acetate. In this manner, fractions were collected and concentrated in vacuo to provide 42.05 g (94.4%) of 4-[3-(methoxycarbonylmethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester.

Workup

  1. temperaturethe mixture was cooled with an ice-water bath
  2. waitat room temperature for 3 days
  3. stirringThe reaction mixture was stirred at room temperature for another 24 hour
  4. washwashed with water, with 10% (wt/vol) KHSO4 solution, with water again
  5. concentrationThe methylene chloride solution was concentrated to dryness in vacuo
  6. customresulting in a dark brown oil
  7. customThe oil was purified by flash column chromatography
  8. washfollowed by elution with ethyl acetate:hexane (7:3)
  9. customIn this manner, fractions were collected
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-cebaa0119c4549448bf3fe77d38c962d
Source dataset
uspto-grants-2012_10
Patent number
US08299023B2

Reaction notes

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