Oxalyl chloride → 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester

HRID 2427249Notes

Reaction equation

HRID 2427249 reaction equation
[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:37][CH2:38][O:39][C:40]([N:42]1[C:46]([NH2:47])=[C:45]2[CH2:48][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C:50]([CH3:52])([CH3:51])[C:44]2=[N:43]1)=[O:41]>ClCCl.O1CCCC1.CN(C)C=O>[CH3:37][CH2:38][O:39][C:40]([N:42]1[C:46]([NH:47][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[C:45]2[CH2:48][N:49]([C:53]([O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[O:54])[C:50]([CH3:51])([CH3:52])[C:44]2=[N:43]1)=[O:41]

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 33132882-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzoic acidHCID 575232455-tert-Butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate

Product 1

HCID 670099703-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl esterYield 63.8%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a suspension of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid (1.35 g, 4.8 mmol) in dry dichloromethane (30 mL), at 0° C., under stirring, was added oxalyl chloride (2.1 mL, 24 mmol) and dry N,N-dimethylformamide (35 microL). The mixture was allowed to warm to room temperature, stirred for 1.5 hours then evaporated to dryness. The residue was diluted with dry toluene and evaporated again. The crude acyl chloride thus obtained (yellow solid) was dissolved in dry tetrahydrofuran (20 mL) and treated with N,N-diisopropylethylamine (2.5 mL, 15 mmol) and with a solution of 3-amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (1.3 g, 4 mmol) in 15 mL of dry tetrahydrofuran. The mixture was stirred at room temperature for 2 days then evaporated to dryness. The residue was dissolved in dichloromethane, washed with 1N HCl, water, saturated solution of NaHCO3, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol 98.5:1.5 as the eluant affording the title compound as white solid (1.5 g).

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 1.5 hours
  3. customthen evaporated to dryness
  4. additionThe residue was diluted with dry toluene
  5. customevaporated again
  6. customThe crude acyl chloride thus obtained (yellow solid)
  7. stirringThe mixture was stirred at room temperature for 2 days
  8. customthen evaporated to dryness
  9. dissolutionThe residue was dissolved in dichloromethane
  10. washwashed with 1N HCl, water, saturated solution of NaHCO3, brine
  11. dry with materialdried over sodium sulfate
  12. customevaporated to dryness
  13. customThe crude was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-9bcb6ec1d89c49bd8daafffcd96be1b7
Source dataset
uspto-grants-2011_06
Patent number
US07968583B2

Reaction notes

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