6296-53-3

Usage

Uses

Used in Pharmaceutical Industry:
Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)is used as a key intermediate in the synthesis of Apremilast, a potent phosphodiesterase 4 (PDE4) and tumor necrosis factor-α (TNF-α) inhibitor. Apremilast is utilized in the treatment of psoriatic arthritis, a chronic inflammatory disease that affects the skin and joints. Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)-'s unique structure allows it to modulate the activity of PDE4 and TNF-α, providing relief from inflammation and pain associated with the condition.
Additionally, Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)serves as a reagent in the preparation of Tillivalline, another bioactive compound with potential therapeutic applications.
Used in Chemical Synthesis:
Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)is also used as a reagent in various chemical synthesis processes. Its versatile chemical structure allows it to be employed in the production of a wide range of compounds, including pharmaceuticals, agrochemicals, and other specialty chemicals. Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)-'s reactivity and functional groups make it a valuable building block for the development of new molecules with diverse applications.

InChI:InChI=1/C10H7NO4/c1-5(12)11-7-4-2-3-6-8(7)10(14)15-9(6)13/h2-4H,1H3,(H,11,12)

Synthetic route

3-aminophthalic acid + acetic anhydride (108-24-7) → 3-acetylaminophthalic anhydride (6296-53-3)

Conditions	Yield
In Isopropyl acetate at 75 - 95℃; Temperature; Large scale;	88.6%

3-nitrophthalic acid (603-11-2) + acetic anhydride (108-24-7) → 3-acetylaminophthalic anhydride (6296-53-3)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen at 80 - 115℃; under 7500.75 Torr; Temperature; Autoclave;	83%

3-aminophthalic acid (5434-20-8) + acetic anhydride (108-24-7) → 3-acetylaminophthalic anhydride (6296-53-3)

Conditions	Yield
for 4h; Concentration; Temperature; Reflux;	78.5%
at 0 - 5℃; for 4h; Heating / reflux;	61%
for 3h; Reflux;	61%

3-nitrophthalic acid anhydride (641-70-3) → 3-acetylaminophthalic anhydride (6296-53-3)

Conditions	Yield
With acetic anhydride; palladium Hydrogenation;

3-amino-phthalic acid-hydrochloride → 3-acetylaminophthalic anhydride (6296-53-3)

Conditions	Yield
With acetic anhydride

acetic anhydride (108-24-7) + <3-amino-phthalic acid >-anhydride → 3-acetylaminophthalic anhydride (6296-53-3)

acetic anhydride (108-24-7) + zinc-acetat-<3-amino phthalate> → 3-acetylaminophthalic anhydride (6296-53-3)

3-nitrophthalic acid (603-11-2) → 3-acetylaminophthalic anhydride (6296-53-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: tin dichloride; hydrochloric acid View Scheme
Multi-step reaction with 2 steps 1: hydrogen / palladium-carbon / ethanol 2: acetic anhydride View Scheme
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 13 h / 2585.81 - 2844.39 Torr / Inert atmosphere 2: 3 h / Reflux View Scheme

3-aminophthalic acid (5434-20-8) → 3-acetylaminophthalic anhydride (6296-53-3)

Conditions	Yield
With acetic anhydride
With acetic anhydride
With acetic anhydride
With acetic anhydride
Multi-step reaction with 2 steps 1: hydrogenchloride / water / 15 h / 25 °C 2: water / 15 h / 100 °C View Scheme

acetic anhydride (108-24-7) + 3-aminophthalic acid hydrochloride (6946-22-1) → 3-acetylaminophthalic anhydride (6296-53-3)

Conditions	Yield
In water at 100℃; for 15h;	94 g
at 110℃; for 2h;	45 g
at 80 - 140℃; for 3h;

3-acetylaminophthalic anhydride (6296-53-3) + 3,4,5-tris(dodec-1-yloxy)aniline (151237-05-7) → 3-acetylamino-N-(3,4,5-tridodecyloxyphenyl)phthalimide

Conditions	Yield
With acetic acid at 100℃; for 12h;	98%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-2-[1 (3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine (608141-42-0) → Apremilast (608141-41-9)

Conditions	Yield
With acetic acid for 1h; Reflux; Large scale;	97%
With acetic acid In acetonitrile at 40℃; for 6h; Reflux;	94%
With acetic acid for 3h; Time; Reflux;	92%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine-(S)-2-acetamido-4-methylpentanoate (608141-43-1) → Apremilast (608141-41-9)

Conditions	Yield
With triethylamine In ethyl acetate at 75 - 80℃; for 18h; Reagent/catalyst; Solvent;	95.1%
With sodium acetate; acetic acid at 80℃; for 5h; Reagent/catalyst; Temperature;	91.3%
Stage #1: (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine-(S)-2-acetamido-4-methylpentanoate With sodium hydroxide In dichloromethane at 0 - 5℃; for 2h; Stage #2: 3-acetylaminophthalic anhydride With perchloric acid; acetic acid In dichloromethane at 45℃; for 3.33333h; Reflux;	89.2%

3-acetylaminophthalic anhydride (6296-53-3) + rac-α-aminoglutarimide hydrochloride (24666-56-6) → N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (444289-17-2)

Conditions	Yield
With sodium acetate; acetic acid at 105℃; for 24h; Reagent/catalyst; Temperature;	95%

3-acetylaminophthalic anhydride (6296-53-3) + (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylthio)ethan-1-amine → Apremilast (608141-41-9)

Conditions	Yield
Stage #1: 3-acetylaminophthalic anhydride; (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylthio)ethan-1-amine With acetic acid In acetonitrile for 12h; Reflux; Stage #2: With sodium tungstate (VI) dihydrate; dihydrogen peroxide In acetonitrile at 20℃; for 7h; Cooling;	94%
Multi-step reaction with 2 steps 1.1: acetic acid / acetonitrile / 12 h / Reflux 2.1: acetic acid / acetonitrile / 20 °C 2.2: 7 h / 20 °C View Scheme

3-acetylaminophthalic anhydride (6296-53-3) + (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine-(S)-2-acetamido-4-methylpentanoate (608141-43-1) + toluene (108-88-3) → apremilast hemitoluene

Conditions	Yield
With acetic acid; sodium hydroxide In dichloromethane; water at 90℃; for 3h; Reagent/catalyst; Solvent;	91%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt (1258598-01-4) → (S)-N-(2-(1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (1258597-45-3)

Conditions	Yield
With acetic acid for 24h; Reflux;	89%
With acetic acid for 24h; Reflux;	89%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine → (S)-N-(2-(1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (1258597-45-3)

Conditions	Yield
With acetic acid for 24h; Reflux;	89%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-1-d-2-(methylsulfonyl)ethanamine N-acetyl-leucine salt (1258597-97-5) → (S)-N-(2-(1-d-1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (1258597-44-2)

Conditions	Yield
Stage #1: 3-acetylaminophthalic anhydride; (S)-1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-1-d-2-(methylsulfonyl)ethanamine N-acetyl-leucine salt With acetic acid for 24h; Reflux; Stage #2: With sodium hydrogencarbonate In water	87%
With acetic acid for 24h; Reflux;	87%
With acetic acid for 24h; Reflux;	87%

tetrahydrofuran (109-99-9) + 3-acetylaminophthalic anhydride (6296-53-3) + (S)-2-[1 (3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine (608141-42-0) → 2C22H24N2O7S*C4H8O

Conditions	Yield
With acetic acid for 4h; Reagent/catalyst; Reflux;	87%

3-acetylaminophthalic anhydride (6296-53-3) → 3-acetamidophthalimide (6118-65-6)

Conditions	Yield
With urea In N,N-dimethyl-formamide at 100℃; for 6h; Concentration; Temperature; Solvent;	85%

3-acetylaminophthalic anhydride (6296-53-3) + C12H19NO4S*C10H10ClNO5 → Apremilast (608141-41-9)

Conditions	Yield
With acetic acid for 24h; Time; Reflux;	85%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-2-((methyl-d3)sulfonyl)-2,2-d2-ethanamine N-acetyl-L-leucine salt (1258598-13-8) → (S)-N-(2-(1-(3-(ethoxy-d5)-4-(methoxy-d3)phenyl)-2-((methyl-d3)sulfonyl)-2,2-d2-ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (1258597-49-7)

Conditions	Yield
With deuteroacetic acid for 24h; Reflux;	84%
With acetic acid for 24h; Reflux;	84%
With acetic acid for 24h; Reflux;	84%

3-acetylaminophthalic anhydride (6296-53-3) + C13H21NO3S → C23H26N2O6S

Conditions	Yield
With formic acid In methanol at 30℃; for 12h; Reagent/catalyst;	84%

3-acetylaminophthalic anhydride (6296-53-3) + C17H19F2NO4S → C27H24F2N2O7S

Conditions	Yield
With acetic acid at 100 - 110℃; for 2h;	83.7%

C2H4O2*C12H16N2O2 + 3-acetylaminophthalic anhydride (6296-53-3) → C22H21N3O5 (882052-94-0)

Conditions	Yield
With acetic acid for 17h;	83%

3-acetylaminophthalic anhydride (6296-53-3) + (R,R)-O,O’-di-p-toluoyl-tartrate → Apremilast (608141-41-9)

Conditions	Yield
With acetic acid for 24h; Reflux;	83%

tetrahydrofuran (109-99-9) + 3-acetylaminophthalic anhydride (6296-53-3) + C12H19NO4S*C10H10ClNO5 → 2C22H24N2O7S*C4H8O

Conditions	Yield
Stage #1: tetrahydrofuran; C12H19NO4S*C10H10ClNO5 With potassium carbonate In dichloromethane; water at 30 - 33℃; for 0.5h; Stage #2: 3-acetylaminophthalic anhydride With acetic acid Reflux;	83%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-2-[1 (3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine (608141-42-0) → C21H22N2O7S

Conditions	Yield
In acetic acid butyl ester at 110 - 125℃; Temperature; Large scale;	80.4%

R-4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol (340020-00-0) + 3-acetylaminophthalic anhydride (6296-53-3) → N-{2-[1-(R)-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide

Conditions	Yield
With triethylamine at 80 - 90℃; for 7h;	80%

3-acetylaminophthalic anhydride (6296-53-3) + ((S)-1-(ethoxy-d5)-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-acetyl-L-leucine salt (1258598-09-2) → (S)-N-(2-(1-(3-(ethoxy-d5)-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (1258597-47-5)

Conditions	Yield
With acetic acid for 24h; Reflux;	80%
With acetic acid for 24h; Reflux;	80%
With acetic acid for 24h; Reflux;	80%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-2-[1 (3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine (608141-42-0) → 4-amino-2-[(1S)-1-(3-ethoxy 4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione (635705-72-5)

Conditions	Yield
With perchloric acid; acetic acid at 65 - 85℃; for 2.5h; Inert atmosphere; Reflux;	80%

3-acetylaminophthalic anhydride (6296-53-3) + aniline (62-53-3) → 3-acetylamino-N-phenylphthalimide (20871-13-0)

Conditions	Yield
With acetic acid at 100℃; for 17h;	79%

3-acetylaminophthalic anhydride (6296-53-3) + (S)-1-(3-(ethoxy)-4-(methoxy-d3)phenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine → C22H21(2)H3N2O7S

Conditions	Yield
Stage #1: (S)-1-(3-(ethoxy)-4-(methoxy-d3)phenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine With sodium hydroxide In dichloromethane for 0.0833333h; Stage #2: 3-acetylaminophthalic anhydride With acetic acid In tetrahydrofuran at 70℃; for 24h;	79%

tetrahydrofuran (109-99-9) + 3-acetylaminophthalic anhydride (6296-53-3) + (R,R)-O,O’-di-p-toluoyl-tartrate → 2C22H24N2O7S*C4H8O

Conditions	Yield
Stage #1: (R,R)-O,O’-di-p-toluoyl-tartrate With potassium carbonate In dichloromethane; water at 30 - 33℃; for 0.5h; Stage #2: tetrahydrofuran; 3-acetylaminophthalic anhydride With acetic acid	79%

S-4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol (340020-01-1) + 3-acetylaminophthalic anhydride (6296-53-3) → N-{2-[1S-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide

Conditions	Yield
With triethylamine In DMF (N,N-dimethyl-formamide) at 80 - 90℃; for 7h;	78%

3-acetylaminophthalic anhydride (6296-53-3) + (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine (608142-27-4) → R-Apremilast (608141-44-2)

Conditions	Yield
With acetic acid Microwave irradiation;	78%
With acetic acid Reflux;

Upstream product

• 641-70-3 3-nitrophthalic acid anhydride 
• 5434-20-8 3-aminophthalic acid 
• 108-24-7 acetic anhydride 
• 1852533-96-0 3-amino-o-benzenedicarboxylic acid hydrochloride dihydrate 
• 603-11-2 3-nitrophthalic acid 
• 6946-22-1 3-aminophthalic acid hydrochloride 

Downstream Products

• 68854-23-9 2-amino-6-benzoyl-benzoic acid 
• 13711-56-3 3-amino-2-benzoyl-benzoic acid 
• 943430-53-3 3-amino-N-(4-octyloxyphenyl)phthalimide 
• 943430-54-4 3-amino-N-(3,4,5-tridodecyloxyphenyl)phthalimide 
• 20579-79-7 3-amino-N-phenylphthalimide 
• 253168-86-4 rac-Apremilast 
• 608141-41-9 Apremilast 
• 1258597-47-5 (S)-N-(2-(1-(3-(ethoxy-d5)-4-methoxyphenyl)-2-(methanesulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide 
• 608141-44-2 R-Apremilast 

Relevant academic research and scientific papers

ISOINDOLE DERIVATIVE

Disclosed is a compound of formula (I) and a stereoisomer thereof: wherein R1, R2, R3 and R4 are as defined in the present disclosure.

Synthetic method of apremilast

The invention relates to a synthesis method of apremilast, which comprises the following steps: (1): reacting 3-aminophthalic acid or salt thereof with acetic anhydride to obtain 3-acetamido phthalic anhydride; and (2) suspending 3-acetamido phthalic anhydride in a first solvent, adding into a suspension consisting of free amine (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethylamine and a second solvent at a certain temperature, reacting, and adding a C1-C6 alcohol solvent for crystallization after the reaction is finished, thereby obtaining the apremilast. According to the synthesis method of apremilast, the production cost is reduced, the operation process is facilitated, the safety in industrial production is improved to a great extent, the yield is high, and the effect is good.

Synthesis method of methyl 2-acetyl-6-aminobenzoate

The invention provides a synthesis method of methyl 2-acetyl-6-aminobenzoate. The target product methyl 2-acetyl-6-aminobenzoate is prepared from cheap and easily available 3-nitrophthalic acid through a six-step reaction. The synthesis method has the characteristics of easily available raw materials, short route, high yield, easiness in operation, small environmental pollution and the like, and is suitable for large-scale industrial production.

Apremilast three-component one-pot-boiling synthesis method

The invention provides an apremilast three-component one-pot-boiling synthesis method. According to the apremilast three-component one-pot-boiling synthesis method, 3-aminophthalic acid, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine salt, and acetic anhydride are taken as raw materials to prepare apremilast through one-pot-boiling method. The apremilast three-component one-pot-boiling synthesis method is simple and convenient in operation, high in yield, low in pollution, and is suitable for large scale preparation.

NOVEL PROCESS TO PREPARE N-[2-[(1S)-1-(3-ETHOXY-4-METHOXYPHENYL)-2-(METHYLSULPHONYL) ETHYL]-1, 3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YL]ACETAMIDE

An alternative and improved process for the preparation of Apremilast (Formula I) and Apremilast form B or a pharmaceutically acceptable salt thereof is provided. The novel process includes hydrogenation in acetone, Cyclization and acetylation followed by condensation in methyl isobutyl ketone (MIBK) and acetic acid mixture in specific volume ratios.

PROCESS FOR PREPARATION OF APREMILAST

The present invention relates to a process for preparation of apremilast. The present invention relates to p-xylene solvate of apremilast and process for its preparation.

Industrial method for preparing apremilast and intermediate thereof

The invention discloses an industrial method for preparing high-purity apremilast (described in formula I) and an intermediate thereof. With 3-nitrophthalic acid (compound II) adopted as the starting raw material, and organic acid or acid anhydride adopted as the solvent, the method comprises the following steps: preparing high-purity 3-acetamido phthalic anhydride (compound IV) through different intermediates; directly enabling the obtained undried product to react with (S)-1-(3-oxethyl-4-methoxy phenyl)-2-mesyl) ethylamine (compound V) or the salt during reflux in glacial acetic acid, so as to obtain the apremilast. The preparation method is easy to operate, low in energy consumption, high in yield, and applicable to industrial production.

DOSAGE TITRATION OF APREMILAST FOR THE TREATMENT OF DISEASES AMELIORATED BY PDE4 INHIBITION

Administration of apremilast in a specific dosage titration schedule, alone or in combination with a second active agent for use in methods of treating, managing or preventing diseases ameliorated by inhibiting PDE4 such as psoriasis, ankylosing spondylitis, Behcet's disease, rheumatoid arthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis.

Methods and compositions using PDE4 inhibitors for the treatment and management of autoimmune and inflammatory diseases

Methods of treating, preventing, or managing autoimmune inflammatory diseases and disorders including but not limited to spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis by the administration of phosphodiesterase 4 (PDE4) inhibitors in combination with other therapeutics are disclosed. Pharmaceutical compositions, dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Preparation method of 3-acetyl aminophthalimide

The invention relates to a preparation method of 3-acetyl aminophthalimide, comprising the following steps: dissolving 3-nitro phthalic acid in sodium hydroxide aqueous solution, then adding a reducer and a catalyst, heating to 70 to 80 DEG C, stirring and reacting for 1 to 20 hours, and recrystallizing to obtain 3-amino phthalic acid; stirring with acetic anhydride and performing reflux reaction for 1 to 10 hours to obtain N-(1,3-Dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide; dissolving the N-(1,3-Dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide in an organic solvent, adding an amino donor, and stirring and refluxing for 1 to 10 hours, thus obtaining the 3-acetyl aminophthalimide. The method is simple in operation, high in yield, short in reaction route, less in the three wastes (waste gas industrial residue), and easy for industrial production.