4-Nitrobenzoic Acid → (3R,5S)-1-((1R,2S)-1-(ethoxycarbonyl)-2-vinyl-cyclopropylcarbamoyl)-5-(hex-5-enyl(methyl)carbamoyl)pyrrolidin-3-yl 4-nitrobenzoate

HRID 1960193Notes

Reaction equation

HRID 1960193 reaction equation
[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:19]([O:21][C:22]([C@@:24]1([NH:29][C:30]([N:32]2[CH2:36][C@H:35](O)[CH2:34][C@H:33]2[C:38](=[O:47])[N:39]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[CH3:40])=[O:31])[CH2:26][C@@H:25]1[CH:27]=[CH2:28])=[O:23])[CH3:20].C(N(CC)CC)C>C(Cl)Cl.C(Cl)Cl.CO.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@@H:35]2[CH2:34][C@@H:33]([C:38](=[O:47])[N:39]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[CH3:40])[N:32]([C:30](=[O:31])[NH:29][C@:24]3([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:26][C@H:25]3[CH:27]=[CH2:28])[CH2:36]2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]

Participants

8

Reactant 4

HCID 61084-Nitrobenzoic AcidHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 66650543(1R)-1-{[2(S)-(hex-5-enyl-methyl-carbamoyl)-4(R)-hydroxy-pyrrolidine-N-carbonyl]amino}-2(R)-vinyl-cyclopropanecarboxylic acid ethyl ester

Product 1

HCID 57816658(3R,5S)-1-((1R,2S)-1-(ethoxycarbonyl)-2-vinyl-cyclopropylcarbamoyl)-5-(hex-5-enyl(methyl)carbamoyl)pyrrolidin-3-yl 4-nitrobenzoateYield 94%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent3×HCID 21226129Dichloromethane methanolSolvent

Procedure

To a solution of 4-nitrobenzoic acid (3.1 g, 1.5 eq) in CH2Cl2 (61 mL) were added dropwise 3.1 mL oxalyl chloride (3 eq), followed by 60 μL DMF. The reaction mixture was stirred at room temperature for 2 hrs and concentrated in vacuo. A solution of the resulting solid in CH2Cl2 (30 mL) was added dropwise to a solution of compound 50 (5.0 g, 1 eq) and triethylamine (3.4 mL, 2 eq) in CH2Cl2 (30 mL). The reaction mixture was stirred at room temperature for 2 hrs, and then washed with water and a saturated aqueous solution of sodium carbonate. The aqueous layer was extracted with CH2Cl2. The combined organic phases were dried on sodium sulphate, filtered, and concentrated to dryness. Recrystallisation with TBME gave compound BI as a yellow powder, and the filtrate was submitted to flash chromatography using CH2Cl2/MeOH as an eluant, affording a total of 6.42 g of compound BI in 93% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.23 (m, 3H), 1.36-1.61 (m, 5H), 1.69 (m, 1H), 1.86 (td, J=5.1 and 7.8 Hz, 1H), 2.05-2.19 (m, 3H), 2.35-2.50 (m, 2H), 2.95 and 3.15 (2s, rotamers, 3H), 3.21 and 3.80 (2m, rotamers, 1H), 3.38 (m, 1H), 3.61 (m, 1H), 4.09 (m, 2H), 4.21 (m, 1H), 4.94-5.00 (m, 1H), 5.05 (br d, J=10.3 Hz, 2H), 5.10 (dd, J=1.30 and 10.2 Hz, 1H), 5.27 (d, J=17.0 Hz, 1H), 5.68-5.84 (m, 3H), 8.20 (d, J=8.8 Hz, 2H), 8.31 (d, J=8.8 Hz, 2H).

Workup

  1. concentrationconcentrated in vacuo
  2. stirringThe reaction mixture was stirred at room temperature for 2 hrs
  3. washwashed with water
  4. extractionThe aqueous layer was extracted with CH2Cl2
  5. customThe combined organic phases were dried on sodium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customRecrystallisation with TBME
  9. customgave compound BI as a yellow powder

Sources & evidence

ORD record
ord-c623855fcf644f38baa6f0f06bb405a2
Source dataset
uspto-grants-2013_04
Patent number
US08410313B2

Reaction notes

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