4-Nitrobenzoic Acid → Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-{[(4-nitrophenyl)carbonyl]oxy}bicyclo[3.1.0]hexane-2,6-dicarboxylate

HRID 2173009Notes

Reaction equation

HRID 2173009 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:59]([C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OC)(C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([O:25][C:66]([C:65]2[CH:64]=[CH:63][C:62]([N+:59]([O-:61])=[O:60])=[CH:70][CH:69]=2)=[O:67])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 61084-Nitrobenzoic AcidHCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 86695972Di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate

Product 1

HCID 86695973Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-{[(4-nitrophenyl)carbonyl]oxy}bicyclo[3.1.0]hexane-2,6-dicarboxylateYield 49.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
23 °C

Procedure

To a solution of di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (539.00 g, 751.00 mmol) in tetrahydrofuran (6.76 L) is added triphenylphosphine (393.96 g, 1.50 mol) and 4-nitrobenzoic acid (251.02 g, 1.50 mol). The mixture is cooled to 10° C. whereupon diisopropyl azodicarboxylate (40% v/v in toluene, 744.41 mL, 759.30 g, 1.50 mol) is added dropwise over 15 minutes and allowed to warm to 23° C. After 18 hours, the mixture is diluted with methyl tert-butyl ether (2 L), washed sequentially with aq. sat. NaHCO3 (2×2 L) and brine (1 L), and concentrated in vacuo. The residue is slurried in heptane (5 L) at 40° C. for 30 minutes then cooled to 23° C. The resulting solid is filtered and washed sequentially with heptane (2×500 mL), heptane/methyl tert-butyl ether (3×1 L). The combined filtrates are concentrated in vacuo and residue is purified by chromatography (2.5 kg of SiO2; eluent:hexane/ethyl acetate 95:5 to 75:25) followed by recrystallization in heptane (10 L/kg) to yield the title compound as a white solid (273 g, 49% yield).

Workup

  1. additionis added dropwise over 15 minutes
  2. washwashed sequentially with aq. sat. NaHCO3 (2×2 L) and brine (1 L)
  3. concentrationconcentrated in vacuo
  4. waitThe residue is slurried in heptane (5 L) at 40° C. for 30 minutes
  5. temperaturethen cooled to 23° C
  6. filtrationThe resulting solid is filtered
  7. washwashed sequentially with heptane (2×500 mL), heptane/methyl tert-butyl ether (3×1 L)
  8. concentrationThe combined filtrates are concentrated in vacuo and residue
  9. customis purified by chromatography (2.5 kg of SiO2; eluent:hexane/ethyl acetate 95:5 to 75:25)
  10. customfollowed by recrystallization in heptane (10 L/kg)

Sources & evidence

ORD record
ord-aa5b7eb524644085b48a3e72e7656258
Source dataset
uspto-grants-2015_06
Patent number
US09056844B2

Reaction notes

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