2,6-Lutidine → (S)-3-[4-(2,6-Dichloro-benzoylamino)-phenyl]-2-{[1-(4-methoxy-benzyl)-cyclopentanecarbonyl]-amino}-propionic acid

HRID 393429Notes

Reaction equation

HRID 393429 reaction equation
C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35].N1C(C)=CC=CC=1C>ClCCl.CCOCC>[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@@H:4]([C:3]([OH:2])=[O:30])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:24][CH:25]=1)=[O:35]

Participants

6

Reactant 3

HCID 79372,6-LutidineHCID 783922,6-Dichlorobenzoyl chlorideHCID 544852054-Amino-N-[[1[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester

Product 1

HCID 10153070(S)-3-[4-(2,6-Dichloro-benzoylamino)-phenyl]-2-{[1-(4-methoxy-benzyl)-cyclopentanecarbonyl]-amino}-propionic acidYield 29.1%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent2×

Procedure

4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (66 mg, 0.17 mmol) and 2,6-dichlorobenzoyl chloride (50 mg, 0.23 mmol) were dissolved in 5 mL of dichloromethane and 2,6-lutidine (50 μL, 0.43 mmol) were added. After 4 hours, the mixture was diluted with ether and dichloromethane and washed with 1 N HCl, water, and saturated NaHCO3 and was dried (MgSO4). The crude product was dissolved in methanol (4 mL) and treated with 4 N NaOH (0.1 mL). After 2 hours, the excess base was quenched with acetic acid (0.1 mL), the solution was filtered through a 0.2μ nylon filter and the filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 35 min. The peak eluting at 79% acetonitrile was concentrated and lyophilized to give 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (28.2 mg), HR—FABMS: obs. mass 591.1445. Calcd. mass 591.1430 (M+Na).

Workup

  1. washwashed with 1 N HCl, water, and saturated NaHCO3
  2. dry with materialwas dried (MgSO4)
  3. dissolutionThe crude product was dissolved in methanol (4 mL)
  4. additiontreated with 4 N NaOH (0.1 mL)
  5. waitAfter 2 hours
  6. customthe excess base was quenched with acetic acid (0.1 mL)
  7. filtrationthe solution was filtered through a 0.2μ nylon
  8. filtrationfilter
  9. customthe filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column
  10. waitwater containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 35 min
  11. washThe peak eluting at 79% acetonitrile
  12. concentrationwas concentrated

Sources & evidence

ORD record
ord-4672bc7d18d148ae845a2558e1a7d85a
Source dataset
uspto-grants-2004_10
Patent number
US06806365B2

Reaction notes

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