827026-45-9

Basic information

• Product Name: 3-(4-Nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione
• Synonyms: 3-(4-Nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione;3-(4-Nitro-1-oxoisoindolin-2-yl)piperidin-2,6-dione;3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-Nitro LenalidoMide;3-dihydro-4-nitro-1-oxo-2H-isoindol-2-yl)-;6-Piperidinedione;(3S)-3-(4-Nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione;3-(4-nitro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione
• CAS NO: 827026-45-9
• Molecular Formula: C₁₃H₁₁N₃O₅
• Molecular Weight: 289.24354
• EINECS: 1592732-453-0
• Product Categories: Amines;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 827026-45-9.mol
• Article Data: 39

Chemical Properties

• Boiling Point: 616.562 °C at 760 mmHg
• Flash Point: 326.685 °C
• Appearance: /
• Density: 1.546 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.657
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: DMSO (Slightly, Heated), Methanol (Slightly)
• PKA: 10.55±0.40(Predicted)
• CAS DataBase Reference: 3-(4-Nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 3-(4-Nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione(827026-45-9)
• EPA Substance Registry System: 3-(4-Nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione(827026-45-9)

Safety Data

• HazardClass: IRRITANT
• Hazardous Substances Data: 827026-45-9(Hazardous Substances Data)

Usage

Chemical Properties

White crystalline

Uses

Different sources of media describe the Uses of 827026-45-9 differently. You can refer to the following data:
1. Lenalidomide (L328000) analog. Lenalidomide impurity; Lenalidomide intermediate.
2. Lenalidomide (L328000) analog. Lenalidomide impurity.

InChI:InChI=1/C13H11N3O5/c17-11-5-4-10(12(18)14-11)15-6-8-7(13(15)19)2-1-3-9(8)16(20)21/h1-3,10H,4-6H2,(H,14,17,18)

Synthetic route

rac-α-aminoglutarimide hydrochloride (24666-56-6) + 2-bromomethyl-3-nitro-benzoic acid methyl ester (98475-07-1) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Stage #1: rac-α-aminoglutarimide hydrochloride With triethylamine In dimethyl sulfoxide for 0.166667h; Inert atmosphere; Stage #2: 2-bromomethyl-3-nitro-benzoic acid methyl ester In dimethyl sulfoxide at 50 - 55℃; for 12.3333h; Inert atmosphere;	99.73%
With sodium carbonate at 100℃; for 0.75h; Reagent/catalyst; Temperature; Inert atmosphere;	98.5%
With sodium carbonate In acetonitrile at 70℃; for 8h; Solvent; Reagent/catalyst; Temperature;	98.8%

2-bromomethyl-3-nitro-benzoic acid methyl ester (98475-07-1) + (+/-)-α-aminoglutarimide (2353-44-8) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
In N,N-dimethyl-formamide for 3h; Reflux;	96%
Stage #1: 2-bromomethyl-3-nitro-benzoic acid methyl ester; (+/-)-α-aminoglutarimide With sodium carbonate In acetonitrile at 5℃; Inert atmosphere; Reflux; Large scale; Stage #2: With hydrogenchloride In water at 20 - 62℃; for 4h; pH=< 6; Large scale;	79.5%
With triethylamine In N,N-dimethyl-formamide at 25 - 100℃; for 7h; Inert atmosphere;
With potassium hydrogencarbonate In acetonitrile Reflux;
With triethylamine In N,N-dimethyl-formamide at 75℃; for 20h;

3-(4-nitro-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With 5-trimethylammonio-1,3-dioxo-1,3-dihydro-1λ5-benzo[d][1,2]-iodoxol-1-ol anion In water at 50 - 70℃;	94.1%
With tert.-butylhydroperoxide; copper(ll) sulfate pentahydrate; oxygen In 1,4-dioxane at 70℃; for 3h; Temperature; Reagent/catalyst; Solvent;	78%

methyl 2-(chloromethyl)-3-nitrobenzoate + rac-α-aminoglutarimide hydrochloride (24666-56-6) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With triethylamine In acetonitrile at 80℃; for 10h;	93.2%

2-methyl-3-nitro-benzoic acid methyl ester (59382-59-1) + (+/-)-α-aminoglutarimide (2353-44-8) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With N,N,N,N,-tetramethylethylenediamine; zinc dibromide In 1,4-dioxane at 95℃; Temperature;	90.7%

2-amino-3-tert-butoxypropionic acid (17083-25-9) + 2-bromomethyl-3-nitro-benzoic acid methyl ester (98475-07-1) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Stage #1: 2-amino-3-tert-butoxypropionic acid; 2-bromomethyl-3-nitro-benzoic acid methyl ester With sodium hydrogencarbonate In acetonitrile at 5 - 20℃; Reflux; Stage #2: With hydrogenchloride In water at 58 - 62℃; for 4.16667h; pH=< 6; Temperature; Time;	79.5%

4-carbamoyl-4-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)butyric acid (1198299-72-7) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide at 0℃;	78%

methyl 2-(chloromethyl)-3-nitrobenzoate + (+/-)-α-aminoglutarimide (2353-44-8) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With ammonium hydroxide In N,N-dimethyl-formamide for 2h; Reflux;	75%

2-bromomethyl-3-nitro-benzoic acid methyl ester (98475-07-1) + (RS)-2,6-dioxopiperidin-3-yl-ammonium trifluoroacetate → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With potassium carbonate In N,N-dimethyl acetamide at 20 - 50℃; for 40.5h; Inert atmosphere;	73%

3-aminopiperidine-2,6-dione hydrobromide (90802-45-2) + 2-bromomethyl-3-nitro-benzoic acid methyl ester (98475-07-1) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With triethylamine In acetonitrile at 20 - 80℃; for 10h;	65.2%

3-aminopiperidine-2,6-dione hydrochloric acid salt + 2-bromomethyl-3-nitro-benzoic acid methyl ester (98475-07-1) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With triethylamine In N,N-dimethyl acetamide at 85℃; for 4h;	56%

2-methyl-3-nitro-benzoic acid methyl ester (59382-59-1) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: NBS / CCl4 / Heating; Irradiation 2: Et3N / dimethylformamide / 80 °C View Scheme
Multi-step reaction with 2 steps 1.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 93 h / Reflux 2.1: acetonitrile / 0.25 h / 20 °C 2.2: 7 h / 20 °C / Reflux View Scheme
Multi-step reaction with 2 steps 1: N-Bromosuccinimide / 2,2'-azobis(isobutyronitrile) / chlorobenzene / 6 h / 90 - 95 °C / Inert atmosphere 2: triethylamine / N,N-dimethyl-formamide / 7 h / 25 - 100 °C / Inert atmosphere View Scheme

Cbz-L-Gln (2650-64-8) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: CDI / tetrahydrofuran / Heating 2: H2, aq. HCl / 10 percent Pd/C / ethyl acetate / 2585.74 - 3102.89 Torr 3: Et3N / dimethylformamide / 80 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 2.5 h / 25 - 70 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 25 - 35 °C 2.2: 6 h / 25 - 35 °C View Scheme
Multi-step reaction with 3 steps 1: dmap; 1,1'-carbonyldiimidazole / 1,4-dioxane / 15 h / 100 °C 2: hydrogen bromide; acetic acid / 1 h / 60 °C 3: triethylamine / acetonitrile / 10 h / 20 - 80 °C View Scheme

3-(benzyloxycarbonyl)-amino-2,6-dioxopiperidine (24666-55-5) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2, aq. HCl / 10 percent Pd/C / ethyl acetate / 2585.74 - 3102.89 Torr 2: Et3N / dimethylformamide / 80 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogen bromide; acetic acid / 1 h / 60 °C 2: triethylamine / acetonitrile / 10 h / 20 - 80 °C View Scheme

2-(4-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-pentanedioic acid diamide → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With formamide at 160 - 170℃; Product distribution / selectivity;

2-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)glutaric acid dimethyl ester (827026-43-7) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
With formamide at 160 - 170℃; Product distribution / selectivity;
With sodium amide In tetrahydrofuran; water at 20℃; Product distribution / selectivity;

N-benzyloxycarbonyl-L-isoglutamine (6398-06-7) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dmap; 1,1'-carbonyldiimidazole / tetrahydrofuran / 20 h / Reflux 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / methanol / 23 h / 760.05 Torr 3.1: acetonitrile / 0.25 h / 20 °C 3.2: 7 h / 20 °C / Reflux View Scheme

N-(2,6-dioxopiperidin-3-yl)-2-phenylacetamide → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / methanol / 23 h / 760.05 Torr 2.1: acetonitrile / 0.25 h / 20 °C 2.2: 7 h / 20 °C / Reflux View Scheme

2-bromomethyl-3-nitro-benzoic acid methyl ester (98475-07-1) + 3-(benzyloxycarbonyl)-amino-2,6-dioxopiperidine (24666-55-5) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Stage #1: 3-(benzyloxycarbonyl)-amino-2,6-dioxopiperidine With palladium 10% on activated carbon; hydrogen In methanol at 25 - 35℃; for 2h; Stage #2: 2-bromomethyl-3-nitro-benzoic acid methyl ester With triethylamine In N,N-dimethyl-formamide at 25 - 35℃; for 6h;	77 g

(S)-methyl 5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoate (4976-88-9) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 48 h / Reflux 2: water; sodium chloride / 4 h / Reflux 3: N,N-dimethyl-formamide / 3 h / Reflux View Scheme

(RS)-(2,6-dioxopiperidin-3-yl)carbamic acid tert-butyl ester (31140-42-8) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: water; sodium chloride / 4 h / Reflux 2: N,N-dimethyl-formamide / 3 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 20 °C 2: potassium hydrogencarbonate / acetonitrile / Reflux View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / water; tert-butyl methyl ether / 0.33 h / 0 °C 2: ammonium hydroxide / N,N-dimethyl-formamide / 2 h / Reflux View Scheme

Boc-Gln-OH (13726-85-7) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide; dmap / acetonitrile / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C 3: potassium hydrogencarbonate / acetonitrile / Reflux View Scheme

2-methyl-3-nitrobenzic acid (1975-50-4) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / dichloromethane / Reflux 1.2: Reflux 2.1: bromine / tetrachloromethane / 20 °C 3.1: potassium hydrogencarbonate / acetonitrile / Reflux View Scheme
Multi-step reaction with 3 steps 1: bis(trichloromethyl) carbonate / N,N-dimethyl-formamide / 6 h / Reflux 2: N-Bromosuccinimide; dibenzoyl peroxide / 8 h / Reflux 3: triethylamine / acetonitrile / 3 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: acetone / 0.17 h / 25 - 30 °C 1.2: 1.5 h / 25 - 30 °C 2.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / acetonitrile / 12 h / 55 - 60 °C 3.1: triethylamine / dimethyl sulfoxide / 0.17 h / Inert atmosphere 3.2: 12.33 h / 50 - 55 °C / Inert atmosphere View Scheme

L-glutamic acid (56-86-0) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: water / 2 h / 0 °C 2: urea / dimethyl sulfoxide / 2 h / 150 °C 3: hydrogenchloride / dimethyl sulfoxide 4: triethylamine / acetonitrile / 3 h / Reflux View Scheme

N-benzyloxycarbonyl-L-glutamic acid (1155-62-0) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: urea / dimethyl sulfoxide / 2 h / 150 °C 2: hydrogenchloride / dimethyl sulfoxide 3: triethylamine / acetonitrile / 3 h / Reflux View Scheme

4-nitroisoindoline → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: copper(l) iodide; potassium carbonate / tetrahydrofuran / 6 h / 60 °C 2: 5-trimethylammonio-1,3-dioxo-1,3-dihydro-1λ5-benzo[d][1,2]-iodoxol-1-ol anion / water / 50 - 70 °C View Scheme

3-(4-nitro-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione → 4-NT (19171-18-7) + 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) + 3-(4-nitro-3-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (1063995-54-9)

Conditions	Yield
With potassium permanganate In water at 50 - 70℃;

isoindoline (496-12-8) → 4-NT (19171-18-7) + 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) + 3-(4-nitro-3-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (1063995-54-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid / 8.5 h / 20 °C / Cooling with ice 2: copper(l) iodide; potassium carbonate / tetrahydrofuran / 6 h / 60 °C 3: potassium permanganate / water / 50 - 70 °C View Scheme

isoindoline (496-12-8) → 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid / 8.5 h / 20 °C / Cooling with ice 2: copper(l) iodide; potassium carbonate / tetrahydrofuran / 6 h / 60 °C 3: 5-trimethylammonio-1,3-dioxo-1,3-dihydro-1λ5-benzo[d][1,2]-iodoxol-1-ol anion / water / 50 - 70 °C View Scheme

3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → Lenalidomide (879126-98-4, 879126-99-5, 191732-72-6)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In ethanol at 40℃; under 3000.3 Torr; Pressure; Temperature;	98.2%
With sodium sulfide; ethanol at 20℃; for 1h;	98%
With sodium tetrahydroborate; ammonium chloride In ethanol; water at 90℃; for 1h; Reagent/catalyst;	98%

3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → 4-nitro-1-thioxo-2-(2-oxo-6-thioxopiperidine-3-yl)phthalimidine (1195729-61-3)

Conditions	Yield
With Lawessons reagent In toluene for 26h; Inert atmosphere; Reflux;	85.8%
With Lawessons reagent In 1,4-dioxane for 5h; Reflux;	64%

3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → (RS)-3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione hydrochloride (1243329-97-6)

Conditions	Yield
Stage #1: 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione With hydrogen; palladium 10% on activated carbon In methanol at 21 - 35℃; under 2400.24 Torr; for 18h; Stage #2: With hydrogenchloride In water	83.5%

methanesulfonic acid (75-75-2) + 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → methanesulfonate salt of 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione

Conditions	Yield
With hydrogen; palladium 10% on activated carbon In methanol under 4654.46 Torr;
With hydrogen; palladium 10% on activated carbon In methanol at 30℃; under 4654.46 Torr; for 3 - 4h;

3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → Reaxys ID: 20308519

methanesulfonic acid (75-75-2) + 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)piperidine-2,6-dione methylsufonate (1187443-54-4)

Conditions	Yield
With hydrogen; palladium 10% on activated carbon In methanol at 30℃; under 4654.46 Torr;
With palladium 10% on activated carbon; hydrogen In water at 25 - 30℃; under 4654.46 Torr;

3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → (RS)-3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione hydrogen sulfate (1243330-05-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 42 h / 2362.74 Torr 2: sulfuric acid / water / 50 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 18 h / 21 - 35 °C / 2400.24 Torr 2: sodium hydrogencarbonate / water / 65 - 70 °C / pH 8 3: sulfuric acid / water / 50 °C View Scheme

3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → (RS)-3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione sulfate

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 42 h / 2362.74 Torr 2: sulfuric acid / acetic acid / 0.75 h / 70 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 18 h / 21 - 35 °C / 2400.24 Torr 2: sodium hydrogencarbonate / water / 65 - 70 °C / pH 8 3: sulfuric acid / acetic acid / 0.75 h / 70 °C View Scheme

3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → (RS)-3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione sulfate/hydrogen sulfate

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 42 h / 2362.74 Torr 2: sulfuric acid / water / 50 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 18 h / 21 - 35 °C / 2400.24 Torr 2: sodium hydrogencarbonate / water / 65 - 70 °C / pH 8 3: sulfuric acid / water / 50 °C View Scheme

3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (827026-45-9) → 1,6′-dithiolenalidomide (1195729-60-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: Lawessons reagent / toluene / 26 h / Inert atmosphere; Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 69 h / 20 °C View Scheme

Upstream product

• 24666-56-6 rac-α-aminoglutarimide hydrochloride 
• 98475-07-1 2-bromomethyl-3-nitro-benzoic acid methyl ester 
• 59382-59-1 2-methyl-3-nitro-benzoic acid methyl ester 
• 603-62-3 4-nitro-1H-isoindole-1,3(2H)-dione 
• 56-85-9 GLUTAMINE 
• 1218991-05-9 glutamine methyl ester 
• 2353-44-8 (+/-)-α-aminoglutarimide 
• 2686-86-4 3-aminopiperidine-2,6-dione hydrochloric acid salt 
• 90802-45-2 DL-3-amino-2,6-piperidinone hydrobromide 
• 65399-18-0 4-nitrophthalide 
• 21606-04-2 methyl 2-carboxy-3-nitrobenzoate 
• 603-11-2 3-nitrophthalic acid 
• 638-07-3 ethyl (2-chloroaceto)acetate 
• 496-12-8 isoindoline 

Downstream Products

• 1243329-97-6 (RS)-3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione hydrochloride 
• 444289-22-9 N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)benzamide 
• 1421593-80-7 N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide 

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Herein a practical and efficient system for concise synthesis of isoindolinones is described by using substituted methyl 2-(halomethyl)benzoates and substituted amines. Structurally various methyl 2-(halomethyl)benzoates and amines were transformed into isoindolinones 80–99% yield and purity in catalyst-free and solvent-free conditions. The method has a wide substrate scope. The synthetic utility of the one-pot reaction was demonstrated by the concise syntheses of Lenalidomide intermediate and DWP205190.

Method for synthesizing lenalidomide

The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing lenalidomide. The method adopts three-step polymerization, and specifically comprises: (1) carrying out a bromination reaction on 2-methyl-3-nitromethyl benzoate as a starting raw material and a bromination reagent to generate a compound 1 2-bromomethyl-3-nitromethyl benzoate; (2) performing cyclization on the compound 1 and 3-aminopiperidine-2,6-dione hydrochloride under a solvent-free condition to generate a compound 2 3-(4-nitro-1-oxo-1,3-dihydroisoindole-2-yl)piperidine-2,6-dione; and (3) reducing the compound 2 with a reducing agent to obtain lenalidomide. According to the invention, the method is a novel preparation process method of lenalidomide, and has advantages of easily available process raw materials, short steps, simple and convenient operation, environmental friendliness, implementation value of industrial production, and social and economic benefits.