Triethylamine → HCID 118276993, compound

HRID 1053693Notes

Reaction equation

HRID 1053693 reaction equation
[C:1]([O:5][C:6](=[O:28])[CH2:7][CH:8]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21](O)=[O:22])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[Cl:53][CH2:54][CH2:55][NH:56][CH2:57][CH2:58][Cl:59].C(N(CC)CC)C>C(#N)C>[Cl:53][CH2:54][CH2:55][N:56]([CH2:57][CH2:58][Cl:59])[C:21]([C:20]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:18]([CH:8]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH:19]=1)=[O:22]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 10868DicyclohexylcarbodiimideHCID 80170N-HydroxysuccinimideHCID 522769Bis(2-chloroethyl)amine hydrochlorideHCID 118276936HCID 118276936, compound

Product 1

HCID 118276993HCID 118276993, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Adapting a literature known protocol (U.S. Pat. No. 3,235,594), to a reaction mixture of 3-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-3-oxo-propyl]-4-methyl-benzoic acid (8e) (787 mg, 2.0 mmol), N-hydroxysuccinimide (NHS, HOSu) (235 mg, 2.2 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added solid dicyclohexylcarbodiimide (DCC) (433 mg, 2.1 mmol) in small portions at about room temperature. The reaction mixture is stirred for about 12 hours and the precipitated dicyclohexylurea side product is filtered off using a Biichner funnel. The filtrate is treated with commercial di-(2-chloroethyl)amine hydrochloride (2-chloro-N-(2-chloroethyl)ethanamine hydrochloride; HN(CH2—CH2—Cl)2.HCl) (393 mg, 2.2 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 hours at room temperature. The reaction is followed by TLC and/or LC/MS to completion. The volatile solvents are removed under reduced pressure using a rotary evaporator. The residue is diluted with 1.0M hydrochloric acid (HCl). The aqueous phase is extracted with ethyl acetate (EtOAc) and the combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and evaporated to dryness. Purification by silica gel column chromatography using EtOAc and hexane mixtures furnishes the target compound (8f).

Workup

  1. filtrationthe precipitated dicyclohexylurea side product is filtered off
  2. stirringThe reaction mixture is stirred for about 12 hours at room temperature
  3. customThe volatile solvents are removed under reduced pressure
  4. customa rotary evaporator
  5. additionThe residue is diluted with 1.0M hydrochloric acid (HCl)
  6. extractionThe aqueous phase is extracted with ethyl acetate (EtOAc)
  7. washthe combined organic extracts are washed with brine
  8. dry with materialdried over anhydrous magnesium sulfate (MgSO4)
  9. filtrationfiltered
  10. customevaporated to dryness
  11. customPurification by silica gel column chromatography

Sources & evidence

ORD record
ord-921d99935bba404894aeb3fa95f5f0f9
Source dataset
uspto-grants-2016_07
Patent number
US09394236B2

Reaction notes

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