Triethylamine → (S)-2-((S)-2-(3'-chloro-biphenyl-4-yl)-1-{[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-carbamoyl}ethylamino)-propionic acid ethyl ester

HRID 331664Notes

Reaction equation

HRID 331664 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21])[C:16]([OH:18])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:46][O:47][C:48]1[CH:61]=[CH:60][C:51]([CH2:52][N:53]2[C:57]([NH:58][CH3:59])=[N:56][N:55]=[N:54]2)=[CH:50][CH:49]=1>ClCCl.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[C@@H:20]([NH:19][C@H:15]([C:16](=[O:18])[N:58]([C:57]1[N:53]([CH2:52][C:51]2[CH:60]=[CH:61][C:48]([O:47][CH3:46])=[CH:49][CH:50]=2)[N:54]=[N:55][N:56]=1)[CH3:59])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:21])[CH3:26]

Participants

8

Reactant 4

HCID 8471Triethylamine2×HCID 94429TriphosgeneHCID 58280516(S)-3-(3'-Chloro-[1,1'-biphenyl]-4-yl)-2-(((S)-1-ethoxy-1-oxopropan-2-yl)amino)propanoic acidHCID 671541201-(4-Methoxybenzyl)-N-methyl-1H-tetrazol-5-amine2×

Product 1

HCID 58280554(S)-2-((S)-2-(3'-chloro-biphenyl-4-yl)-1-{[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-carbamoyl}ethylamino)-propionic acid ethyl esterYield 75.5%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a suspension of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (225 mg, 0.599 mmol) in dichloromethane (4 mL) and saturated aqueous NaHCO3 (1 mL) was added triphosgene (178 mg, 0.599 mmol). After vigorously stirred for 10 min, the reaction mixture was diluted with EtOAc and partially concentrated under reduced pressure. Excess of triphosgene was quenched by adding saturated aqueous NaHCO3 and stirred for 0.5 hour. The mixture was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5 mL). To the mixture were added triethylamine (0.167 mL, 1.197 mmol) and [1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-amine (197 mg, 0.898 mmol) and stirred at 45° C. overnight. Additional triethylamine (0.167 mL, 1.197 mmol) and [1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-amine (197 mg, 0.898 mmol) were added and stirred at 45° C. for 30 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give (S)-2-((S)-2-(3′-chloro-biphenyl-4-yl)-1-{[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-carbamoyl}ethylamino)-propionic acid ethyl ester (261 mg). MS: m/z (MW) 577; HPLC retention time 1.36 min (HPLC condition C).

Workup

  1. concentrationpartially concentrated under reduced pressure
  2. customExcess of triphosgene was quenched
  3. additionby adding saturated aqueous NaHCO3
  4. stirringstirred for 0.5 hour
  5. extractionThe mixture was extracted with EtOAc
  6. washwashed with brine
  7. dry with materialThe organic layer was dried over Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. dissolutionThe obtained residue was dissolved in dichloromethane (5 mL)
  10. stirringstirred at 45° C. overnight
  11. stirringstirred at 45° C. for 30 hours
  12. concentrationThe reaction mixture was concentrated under reduced pressure
  13. custompurified by silica gel column chromatography (eluent: 10% MeOH in DCM)

Sources & evidence

ORD record
ord-995b7409556c4f7b8a4d2eb1cbb1a45b
Source dataset
uspto-grants-2014_11
Patent number
US08877786B2

Reaction notes

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