Triethylamine hydrochloride → [4-(3-Hydroxypyrrolidinyl)-2-phenylbenzoyl]methionine methyl ester

HRID 325239Notes

Reaction equation

HRID 325239 reaction equation
CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7](CCl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.C([O-])([O-])=O.[K+].[K+].O[Li].O.Cl.[CH3:35][O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH2:41][S:42][CH3:43])[NH2:39].ON1C(=O)C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.C(N(CC)CC)C>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CC#N.CO.C(OCC)(=O)C>[CH3:35][O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH2:41][S:42][CH3:43])[NH:39][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)=[CH:6][C:5]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1

Participants

12

Reactant 8

HCID 11130Triethylamine hydrochlorideHCID 11430Potassium CarbonateHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 730263-hydroxy-1,2,3-benzotriazin-4(3H)-oneHCID 982104-HydroxypyrrolidineHCID 168937Lithium hydroxide, monohydrateHCID 11435579L-Methionine, methyl ester, hydrochlorideHCID 544945664-Chloromethyl-2-phenylbenzoic acid methyl ester

Product 1

HCID 70226038[4-(3-Hydroxypyrrolidinyl)-2-phenylbenzoyl]methionine methyl esterYield 57.6%

Reagents, catalysts & solvents 3

HCID 67553Tetrabutylammonium IodideCatalystHCID 6342AcetonitrileSolvent2×HCID 21584119Ethylacetate methanolSolvent

Procedure

A solution of 4-chloromethyl-2-phenylbenzoic acid methyl ester (0.521 g, 2.00 mmol), prepared as in Example 286A, 3-pyrrolidinol (0.178 g, 2.00 mmol), K2CO3 (0.553 g, 4.00 mmol), and Bu4NI (0.0754 g, 0.20 mmol) in CH3CN (5 mL) was stirred for 15 hours, treated with LiOH.H2O (0.506 g, 12.0 mmol), and then heated at reflux for 5 hours. The solution was cooled to ambient temperature and added to a mixture of L-methionine methyl ester hydrochloride (0.807 g, 4.00 mmol), 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.66 g, 10.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.96 g, 10.00 mmol), and triethylamine hydrochloride (2.81 g, 20 mmol) in CH3CN (15 mL). After 12 days the mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was extracted with a 1:1 mixture of H2O and saturated aqueous NaHCO3 (4×) and brine. The organic phase was dried (MgSO4) and concentrated to provide a gold oil. Radial chromatography (12% methanol-ethyl acetate) afforded the desired compound (0.494 g, 56%).

Workup

  1. temperatureheated
  2. temperatureat reflux for 5 hours
  3. concentrationAfter 12 days the mixture was concentrated under reduced pressure
  4. dissolutionthe residue was dissolved in ethyl acetate
  5. extractionThe solution was extracted with a 1:1 mixture of H2O and saturated aqueous NaHCO3 (4×) and brine
  6. dry with materialThe organic phase was dried (MgSO4)
  7. concentrationconcentrated
  8. customto provide a gold oil

Sources & evidence

ORD record
ord-12062b0b96474b3db5312d55de694777
Source dataset
uspto-grants-2001_04
Patent number
US06221865B1

Reaction notes

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