4-Methoxyphenylacetic Acid → (3R*,4R*)-3-({cyclopropyl-[2-(4-methoxy-phenyl)-acetyl]-amino}-methyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1158360Notes

Reaction equation

HRID 1158360 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:43]([O:47][C:48]([N:50]1[CH2:54][C@@H:53]([CH2:55][N:56]([CH:73]([CH3:75])[CH3:74])[C:57](=[O:72])[C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[C:60]([O:66][CH2:67][CH2:68][CH2:69][O:70][CH3:71])[CH:59]=2)[C@H:52]([CH2:76][NH:77][CH:78]2[CH2:80][CH2:79]2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:43]([O:47][C:48]([N:50]1[CH2:54][C@@H:53]([CH2:55][N:56]([CH:73]([CH3:74])[CH3:75])[C:57](=[O:72])[C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[C:60]([O:66][CH2:67][CH2:68][CH2:69][O:70][CH3:71])[CH:59]=2)[C@H:52]([CH2:76][N:77]([CH:78]2[CH2:79][CH2:80]2)[C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:51]1)=[O:49])([CH3:45])([CH3:46])[CH3:44]

Participants

8

Reactant 6

HCID 76904-Methoxyphenylacetic AcidHCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 68616408(3R*,4R*)-3-Cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 68618061(3R*,4R*)-3-({cyclopropyl-[2-(4-methoxy-phenyl)-acetyl]-amino}-methyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 4-methoxyphenylacetic acid (0.075 g, 0.45 mmol) in CH2Cl2 (3 mL), are added triethylamine (0.063 mL, 0.45 mmol), 1-hydroxy-benzotriazol hydrate (0.061 g, 0.45 mmol) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC) (0.086 g, 0.45 mmol) followed by (3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.375 mmol). The resulting mixture is stirred for 2 days at RT, then diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 50:50 to 0:100) to give the title compound. TLC, Rf (CH2Cl2/MeOH 95:5)=0.35. MS (LC-MS): 682.4 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.77 min.

Workup

  1. customThe organic layer is separated
  2. extractionthe aqueous one is extracted twice with CH2Cl2
  3. dry with materialThe combined organic extracts are dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 50:50 to 0:100)

Sources & evidence

ORD record
ord-1308e7d191a3457d97e5d8343f967e27
Source dataset
uspto-grants-2010_10
Patent number
US07807709B2

Reaction notes

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