6296-53-3

Basic information

• Product Name: Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)-
• Synonyms: Phthalicanhydride, 3-acetamido- (6CI,8CI);3-Acetamidophthalic anhydride;3-Acetylaminophthalic anhydride;NSC 16261;NSC 17048;AC1L5EJ7;AC1Q6H8C;n-(1,3-Dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide;AKOS002687661;N-(1,3-dioxo-2-benzofuran-4-yl)acetamide
• CAS NO: 6296-53-3
• Molecular Formula: C₁₀H₇NO₄
• Molecular Weight: 205.1669
• EINECS: 808-040-8
• Mol File: 6296-53-3.mol
• Article Data: 23

Chemical Properties

• Melting Point: 185-186℃
• Boiling Point: 489.1 °C at 760 mmHg
• Flash Point: 249.6 °C
• Appearance: /
• Density: 1.512 g/cm³
• Vapor Pressure: 1.03E-09mmHg at 25°C
• Refractive Index: 1.657
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: Chloroform (Slightly, Sonicated), Ethyl Acetate (Slightly, Sonicated), Methanol
• PKA: 13.81±0.20(Predicted)
• Stability: Moisture Sensitive
• CAS DataBase Reference: Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)-(CAS DataBase Reference)
• NIST Chemistry Reference: Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)-(6296-53-3)
• EPA Substance Registry System: Acetamide,N-(1,3-dihydro-1,3-dioxo-4-isobenzofuranyl)-(6296-53-3)

Safety Data

• Hazardous Substances Data: 6296-53-3(Hazardous Substances Data)

Usage

Uses

3-Acetylaminophthalic Anhydride is used in the synthesis of Apremilast, a potent phosphodiesterase 4 and tumor necrosis Factor-α inhibitor used in the treatment of psoriatic arthritis. Also a reagent in the preparation of Tillivalline. Apremilast Impurity 2

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

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

Downstream Products

• 19171-19-8 pomalidomide 
• 608141-41-9 Apremilast 
• 635705-72-5 4-amino-2-[(1S)-1-(3-ethoxy 4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione 
• 6118-65-6 3-acetamidophthalimide 

Relevant articles and documents

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.

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.