1,2-Dichloroethane → 1-[2-(4-Amino-3-chloro-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester

HRID 2363380Notes

Reaction equation

HRID 2363380 reaction equation
[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH:14]([NH:16][C:17]([O:19]CC1C=CC=CC=1)=O)[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:37]=[CH:36][C:32](C(O)=O)=[CH:31][C:30]=1[Cl:38].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CO.CCOC(C)=O.C(Cl)Cl.[Pd].CN(C=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH:14]([NH:16][C:17](=[O:19])[C:32]1[CH:36]=[CH:37][C:29]([NH2:28])=[C:30]([Cl:38])[CH:31]=1)[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

11

Reactant 5

HCID 111,2-DichloroethaneHCID 172114-Amino-3-chlorobenzoic acidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 221684141-(2-Benzyloxycarbonylamino-propionyl)-pyrrolidine-2-carboxylic acid tert-butyl ester

Product 1

HCID 536934251-[2-(4-Amino-3-chloro-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl esterYield 72%

Reagents, catalysts & solvents 5

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a solution of 95 (10.50 g, 27.9 mmol) in MeOH (100 ml) was added a suspension of 10% Pd/C (5.00 g) in EtOAc (50 ml). The mixture was stirred under H2 for 48 hours, filtered through celite and the solvent evaporated to yield a waxy solid. This was dissolved in CH2Cl2 (100 ml) and DMF (50 ml) and the solution cooled to 0° C. 4-Amino-3-chlorobenzoic acid (5.82 g, 27.2 mmol), DIEA (14.58 mL, 83.7 mmol), HOBT (3.77 g, 27.9 mmol) and EDC (6.68 g, 34.8 mmol) were added and the solution stirred at 0° C. for 15 mins then at room temperature for 24 hours. The reaction mixture was diluted with EtOAc, washed with NaHSO4 (2×), 10% NaHCO3 (2×) and brine then dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography, using CH2Cl2/MeOH (99/1 to 97/3%) to yield the title compound as a white solid (7.75 g, 70% yield). 1H-NMR (500 MHz, CD3OD) δ 1.27-1.67 (m, 12H), 1.82-2.14 (m, 4H), 3.48-3.85 (m, 2H), 4.26-4.53 (m, 3H), 4.81-4.98 (m, 1H), 6.71 (d, 1H), 7.15 (m, 1H), 7.50 (dd, 1H), 7.75 (d, 1H). Analytical HPLC 10.83 min. LC-MS (ES+) m/e=396.3 (MH+).

Workup

  1. filtrationfiltered through celite
  2. customthe solvent evaporated
  3. customto yield a waxy solid
  4. stirringthe solution stirred at 0° C. for 15 mins
  5. waitat room temperature for 24 hours
  6. washwashed with NaHSO4 (2×), 10% NaHCO3 (2×) and brine
  7. dry with materialthen dried over MgSO4
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude product was purified by flash column chromatography

Sources & evidence

ORD record
ord-55ace0b5e3ca44cb8d1f3a937c80906d
Source dataset
uspto-grants-2014_04
Patent number
US08691848B2

Reaction notes

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