Apremilast supplier | CasNO.608141-41-9

Name
ApreMilast
EINECS 807-237-6
CAS No. 608141-41-9
Article Data55
CAS DataBase
Density 1.382 g/cm³
Solubility
Melting Point
Formula C₂₂H₂₄N₂O₇S
Boiling Point 741.342 °C at 760 mmHg
Molecular Weight 460.508
Flash Point 402.149 °C
Transport Information
Appearance
Safety
Risk Codes
Molecular Structure
Hazard Symbols
Synonyms CC 10004;(S)-N-(2-(1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide;(S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione;
PSA 127.46000
LogP 3.52590

Synthetic route

: 635705-72-5
4-amino-2-[(1S)-1-(3-ethoxy 4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione

: 108-24-7
acetic anhydride

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
at 135 - 139℃; Large scale;	98.2%
at 70℃; for 3h; Inert atmosphere; enantioselective reaction;	94%

: 6296-53-3
3-acetylaminophthalic anhydride

: 608141-42-0
(S)-2-[1 (3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine

: 608141-41-9
Apremilast

Conditions

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%

: 6296-53-3
3-acetylaminophthalic anhydride

: 608141-43-1
(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine-(S)-2-acetamido-4-methylpentanoate

: 608141-41-9
Apremilast

Conditions

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%

: 6296-53-3
3-acetylaminophthalic anhydride

: (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylthio)ethan-1-amine

: 608141-41-9
Apremilast

Conditions

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

: N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)(methylthio)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Stage #1: N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)(methylthio)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide With acetic acid In acetonitrile at 20℃; Stage #2: With sodium tungstate (VI) dihydrate; dihydrogen peroxide In acetonitrile at 20℃; for 7h;	91%

: 608141-43-1
(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine-(S)-2-acetamido-4-methylpentanoate

: 15371-06-9
3-acetylaminophthalic acid

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
With acetic acid at 100 - 120℃; for 2h; Reagent/catalyst;	86.7%
With acetic acid at 110 - 115℃; for 1h;	3.4 g

: 6296-53-3
3-acetylaminophthalic anhydride

: C12H19NO4S*C10H10ClNO5

: 608141-41-9
Apremilast

Conditions

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

: 6296-53-3
3-acetylaminophthalic anhydride

: (R,R)-O,O’-di-p-toluoyl-tartrate

: 608141-41-9
Apremilast

Conditions

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

: 635705-72-5
4-amino-2-[(1S)-1-(3-ethoxy 4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione

: 75-36-5
acetyl chloride

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
With iodine In dichloromethane at 25 - 30℃;	81%
With potassium carbonate In ethyl acetate at 25 - 30℃; for 3h; Solvent; Temperature; Concentration; Reflux;	9 g

: 635705-72-5
4-amino-2-[(1S)-1-(3-ethoxy 4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione

: 108-24-7
acetic anhydride

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
at 135 - 139℃; Large scale;	98.2%
at 70℃; for 3h; Inert atmosphere; enantioselective reaction;	94%
at 70℃; for 3h;	97 %Chromat.

: 915201-13-7
(3-ethoxy-4-methoxyphenyl)boronic acid

: C13H12N2O5S

A: 608141-41-9
Apremilast

B: C22H30O6S

Conditions

Conditions	Yield
With chlorobis(ethylene)rhodium(I) dimer; triethylamine In methanol at 60℃;	A 7% B 81%
With chlorobis(ethylene)rhodium(I) dimer; triethylamine In methanol at 0℃;	A 10% B 7%

...Expand

: 6296-53-3
3-acetylaminophthalic anhydride

: 1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (-)-dibenzoyl-L-tartaric acid salt

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
In N,N-dimethyl-formamide at 20 - 95℃; for 8h; Concentration; Reagent/catalyst; Temperature; Solvent;	77%

: 6296-53-3
3-acetylaminophthalic anhydride

: (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine N-acetyl-L-leucine salt

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
With acetic acid Reflux;	75%

: 253168-94-4
2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine

: 6296-53-3
3-acetylaminophthalic anhydride

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
With acetic acid at 50℃; Reflux;	73.4%
In acetic acid for 15h; Reflux;	59%
Stage #1: 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine With N-Ac-Leu In methanol Stage #2: 3-acetylaminophthalic anhydride With sodium hydroxide In N,N-dimethyl acetamide

: 6118-65-6
3-acetamidophthalimide

: (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methanesulfonyl)ethanol

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 4h;	70%

: 6118-65-6
3-acetamidophthalimide

: 1450657-24-5
(R)-3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]benzyl alcohol

A: 608141-41-9
Apremilast

B: 608141-44-2
R-Apremilast

Conditions

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at -5 - 20℃; for 7h; Mitsunobu Displacement; Inert atmosphere;	A 65% B n/a
With triphenylphosphine; diethylazodicarboxylate In dichloromethane; toluene at 20℃; Cooling with ice;	A 22% B n/a

...Expand

: 6118-65-6
3-acetamidophthalimide

: 1450657-24-5
(R)-3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]benzyl alcohol

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; for 15h; Solvent; Inert atmosphere;	62%
Stage #1: 3-acetamidophthalimide With triphenylphosphine In dichloromethane at 20℃; for 0.25h; Stage #2: (R)-3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]benzyl alcohol With diethylazodicarboxylate In dichloromethane; toluene at 20℃; Cooling with ice;	22%

: 1450657-31-4
1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethen-1-amine

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1: bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; hydrogen; (R)-(-)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine / 2,2,2-trifluoroethanol / 18 h / 50 °C / 4654.46 Torr / Inert atmosphere 2: acetic acid / Reflux View Scheme
Multi-step reaction with 3 steps 1: sodium cyanoborohydride; citric acid / methanol / 1 h / 5 °C 2: acetic acid / water / 3 h / 20 - 97 °C 3: N,N-dimethyl-formamide / 8 h / 20 - 95 °C View Scheme
Multi-step reaction with 4 steps 1: sodium cyanoborohydride; citric acid / methanol / 1 h / 5 °C 2: acetic acid / water / 3 h / 20 - 97 °C 3: sodium hydroxide / water; toluene / 3 h / 20 °C 4: acetic acid / toluene / 100 - 105 °C View Scheme

: 60758-86-3
3-ethoxy-4-methoxybenzenecarbonitrile

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 1 h / 0 - 5 °C 1.2: 2 h / 0 - 30 °C 2.1: bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; hydrogen; (R)-(-)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine / 2,2,2-trifluoroethanol / 18 h / 50 °C / 4654.46 Torr / Inert atmosphere 3.1: acetic acid / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 3 h / 0 - 10 °C / Inert atmosphere 1.2: 6 h / 0 - 20 °C 2.1: (S)-diphenylprolinol; Trimethyl borate; borane dimethyl sulphide complex / tetrahydrofuran / 8 h / 0 - 25 °C / Inert atmosphere 3.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 4 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1.5 h / 0 - 5 °C 1.2: 1.5 h / 0 - 30 °C 2.1: methanol / 5.5 h / 45 °C / Reflux 3.1: acetic acid / 15 h / Reflux View Scheme

: 5434-20-8
3-aminophthalic acid

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1: 3 h / Reflux 2: acetic acid / Reflux View Scheme
Multi-step reaction with 2 steps 1: 3 h / Reflux 2: acetic acid / 15 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: 3 h / Reflux 2: acetic acid / Reflux View Scheme

: 603-11-2
3-nitrophthalic acid

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 13 h / 2585.81 - 2844.39 Torr / Inert atmosphere 2: 3 h / Reflux 3: acetic acid / Reflux View Scheme
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 13 h / 2585.81 - 2844.39 Torr 2: 3 h / Reflux 3: acetic acid / 15 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 13 h / 2585.81 - 2844.39 Torr 2: 3 h / Reflux 3: acetic acid / Reflux View Scheme

: 253168-94-4
2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / 1 h / Reflux 2: acetic acid / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: methanol / 1 h / Inert atmosphere; Reflux 2.1: sodium hydroxide / dichloromethane / 2 h / 0 - 5 °C 2.2: 3.33 h / 45 °C / Reflux View Scheme
Multi-step reaction with 3 steps 1: methanol / 1 h / Inert atmosphere; Reflux 2: sodium hydroxide / dichloromethane / 2 h / 0 - 5 °C 3: acetic acid; perchloric acid / 2.5 h / 85 °C / Reflux View Scheme

: 52849-52-2
1-Bromo-3-ethoxy-4-methoxybenzene

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1.1: magnesium; iodine / tetrahydrofuran / 3.83 h / 45 - 60 °C 1.2: 3.67 h / -5 - 0 °C 1.3: Raney nickel / 3 h / 20 - 25 °C / 760.05 - 1520.1 Torr / Autoclave 2.1: methanol / 1 h / Inert atmosphere; Reflux 3.1: sodium hydroxide / dichloromethane / 2 h / 0 - 5 °C 3.2: 3.33 h / 45 °C / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: magnesium; iodine / tetrahydrofuran / 3.83 h / 45 - 60 °C 1.2: 3.67 h / -5 - 0 °C 1.3: Raney nickel / 3 h / 20 - 25 °C / 760.05 - 1520.1 Torr / Autoclave 2.1: methanol / 1 h / Inert atmosphere; Reflux 3.1: sodium hydroxide / dichloromethane / 2 h / 0 - 5 °C 4.1: acetic acid; perchloric acid / 2.5 h / 85 °C / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 1.2: 16 h / -78 - 20 °C / Inert atmosphere 2.1: triethylamine; chlorobis(ethylene)rhodium(I) dimer; (1S,4S)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene / methanol / 2 h / 60 °C / Inert atmosphere 3.1: 3 h / 70 °C / Inert atmosphere View Scheme

: 2-chloro-1-(3-ethoxy-4-methoxyphenyl)ethanone

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1.1: ethanol / 15 h / Reflux 2.1: ammonium formate; palladium on activated charcoal / methanol; water / 15 h / Reflux 3.1: methanol / 4 h / 25 °C / Reflux 4.1: acetic acid / 15 h / Reflux 4.2: 3.25 h / 25 °C / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: ethanol / 3 h / Reflux 2.1: D-glucose / water / 48 h / 30 °C / Enzymatic reaction 3.1: tributylphosphine; diethylazodicarboxylate; hydrogen azide / toluene; tetrahydrofuran / 22 h / -70 - 20 °C / Inert atmosphere 4.1: triphenylphosphine / water; tetrahydrofuran / Inert atmosphere; Reflux; Sealed tube 4.2: Reflux 4.3: 1 h / 80 °C / Sealed tube 5.1: acetic acid / Reflux View Scheme

Yield

Multi-step reaction with 4 steps
1.1: ethanol / 15 h / Reflux
2.1: ammonium formate; palladium on activated charcoal / methanol; water / 15 h / Reflux
3.1: methanol / 4 h / 25 °C / Reflux
4.1: acetic acid / 15 h / Reflux
4.2: 3.25 h / 25 °C / Reflux
View Scheme

Multi-step reaction with 5 steps
1.1: ethanol / 3 h / Reflux
2.1: D-glucose / water / 48 h / 30 °C / Enzymatic reaction
3.1: tributylphosphine; diethylazodicarboxylate; hydrogen azide / toluene; tetrahydrofuran / 22 h / -70 - 20 °C / Inert atmosphere
4.1: triphenylphosphine / water; tetrahydrofuran / Inert atmosphere; Reflux; Sealed tube
4.2: Reflux
4.3: 1 h / 80 °C / Sealed tube
5.1: acetic acid / Reflux
View Scheme

: 1450657-28-9
1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ammonium formate; palladium on activated charcoal / methanol; water / 15 h / Reflux 2.1: methanol / 4 h / 25 °C / Reflux 3.1: acetic acid / 15 h / Reflux 3.2: 3.25 h / 25 °C / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: D-glucose / water / 48 h / 30 °C / Enzymatic reaction 2.1: tributylphosphine; diethylazodicarboxylate; hydrogen azide / toluene; tetrahydrofuran / 22 h / -70 - 20 °C / Inert atmosphere 3.1: triphenylphosphine / water; tetrahydrofuran / Inert atmosphere; Reflux; Sealed tube 3.2: Reflux 3.3: 1 h / 80 °C / Sealed tube 4.1: acetic acid / Reflux View Scheme

: 6946-22-1
3-aminophthalic acid hydrochloride

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water / 15 h / 100 °C 2.1: acetic acid / 15 h / Reflux 2.2: 3.25 h / 25 °C / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: 2 h / 110 °C 2.1: acetonitrile / 80 - 85 °C 2.2: 60 - 65 °C View Scheme
Multi-step reaction with 2 steps 1: 2 h / 110 °C 2: acetonitrile / 3 h / Reflux View Scheme

: 6100-74-9
3-hydroxy-4-methoxyacetophenone

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 25 °C 2.1: 1,3-dichloro-5,5-dimethylhydantoin; toluene-4-sulfonic acid / methanol / 15 h / 5 - 25 °C 3.1: ethanol / 15 h / Reflux 4.1: ammonium formate; palladium on activated charcoal / methanol; water / 15 h / Reflux 5.1: methanol / 4 h / 25 °C / Reflux 6.1: acetic acid / 15 h / Reflux 6.2: 3.25 h / 25 °C / Reflux View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 30 - 35 °C 2.1: toluene-4-sulfonic acid; N-Bromosuccinimide / ethyl acetate / 16 h / 25 - 30 °C 3.1: methanol; water / 0.01 h / 35 - 40 °C 4.1: titanium(IV) isopropylate; (R)-2-methylpropane-2-sulfinamide / ethyl acetate / 65 h / 45 °C 4.2: 0.75 h / 0 - 20 °C 4.3: 1 h / 20 °C 5.1: sodium hydroxide / water 6.1: acetic acid / acetonitrile / 12 h / Reflux 6.2: 7 h / 20 °C / Cooling View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 30 - 35 °C 2.1: toluene-4-sulfonic acid; N-Bromosuccinimide / ethyl acetate / 16 h / 25 - 30 °C 3.1: methanol; water / 0.01 h / 35 - 40 °C 4.1: titanium(IV) isopropylate; (R)-2-methylpropane-2-sulfinamide / ethyl acetate / 65 h / 45 °C 4.2: 0.75 h / 0 - 20 °C 4.3: 1 h / 20 °C 5.1: sodium hydroxide / water 6.1: acetic acid / acetonitrile / 12 h / Reflux 6.2: 7 h / 20 °C / Cooling View Scheme
Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 30 - 35 °C 2.1: toluene-4-sulfonic acid; N-Bromosuccinimide / ethyl acetate / 16 h / 25 - 30 °C 3.1: methanol; water / 0.01 h / 35 - 40 °C 4.1: titanium(IV) isopropylate; (R)-2-methylpropane-2-sulfinamide / ethyl acetate / 65 h / 45 °C 4.2: 0.75 h / 0 - 20 °C 4.3: 1 h / 20 °C 5.1: sodium hydroxide / water 6.1: acetic acid / acetonitrile / 12 h / Reflux 7.1: acetic acid / acetonitrile / 20 °C 7.2: 7 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 30 - 35 °C 2.1: toluene-4-sulfonic acid; N-Bromosuccinimide / ethyl acetate / 16 h / 25 - 30 °C 3.1: methanol; water / 0.01 h / 35 - 40 °C 4.1: titanium(IV) isopropylate; (R)-2-methylpropane-2-sulfinamide / ethyl acetate / 65 h / 45 °C 4.2: 0.75 h / 0 - 20 °C 4.3: 1 h / 20 °C 5.1: sodium hydroxide / water 6.1: acetic acid / acetonitrile / 12 h / Reflux 7.1: acetic acid / acetonitrile / 20 °C 7.2: 7 h / 20 °C View Scheme

: 31526-71-3
3-ethoxy-4-methoxy-acetophenone

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 1,3-dichloro-5,5-dimethylhydantoin; toluene-4-sulfonic acid / methanol / 15 h / 5 - 25 °C 2.1: ethanol / 15 h / Reflux 3.1: ammonium formate; palladium on activated charcoal / methanol; water / 15 h / Reflux 4.1: methanol / 4 h / 25 °C / Reflux 5.1: acetic acid / 15 h / Reflux 5.2: 3.25 h / 25 °C / Reflux View Scheme
Multi-step reaction with 6 steps 1.1: N-chloro-succinimide; toluene-4-sulfonic acid / acetonitrile / 40 °C 2.1: ethanol / 3 h / Reflux 3.1: D-glucose / water / 48 h / 30 °C / Enzymatic reaction 4.1: tributylphosphine; diethylazodicarboxylate; hydrogen azide / toluene; tetrahydrofuran / 22 h / -70 - 20 °C / Inert atmosphere 5.1: triphenylphosphine / water; tetrahydrofuran / Inert atmosphere; Reflux; Sealed tube 5.2: Reflux 5.3: 1 h / 80 °C / Sealed tube 6.1: acetic acid / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: toluene-4-sulfonic acid; N-Bromosuccinimide / ethyl acetate / 16 h / 25 - 30 °C 2.1: methanol; water / 0.01 h / 35 - 40 °C 3.1: titanium(IV) isopropylate; (R)-2-methylpropane-2-sulfinamide / ethyl acetate / 65 h / 45 °C 3.2: 0.75 h / 0 - 20 °C 3.3: 1 h / 20 °C 4.1: sodium hydroxide / water 5.1: acetic acid / acetonitrile / 12 h / Reflux 5.2: 7 h / 20 °C / Cooling View Scheme
Multi-step reaction with 6 steps 1.1: toluene-4-sulfonic acid; N-Bromosuccinimide / ethyl acetate / 16 h / 25 - 30 °C 2.1: methanol; water / 0.01 h / 35 - 40 °C 3.1: titanium(IV) isopropylate; (R)-2-methylpropane-2-sulfinamide / ethyl acetate / 65 h / 45 °C 3.2: 0.75 h / 0 - 20 °C 3.3: 1 h / 20 °C 4.1: sodium hydroxide / water 5.1: acetic acid / acetonitrile / 12 h / Reflux 6.1: acetic acid / acetonitrile / 20 °C 6.2: 7 h / 20 °C View Scheme

: 608141-42-0
(S)-2-[1 (3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine

: 15371-06-9
3-acetylaminophthalic acid

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
With triethanolamine; benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h;	4.2 g

: 621-59-0
isovanillin

: 608141-41-9
Apremilast

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium formate; hydroxylamine hydrochloride / formic acid / 5 h / 85 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 8 h / 100 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 3 h / 0 - 10 °C / Inert atmosphere 3.2: 6 h / 0 - 20 °C 4.1: (S)-diphenylprolinol; Trimethyl borate; borane dimethyl sulphide complex / tetrahydrofuran / 8 h / 0 - 25 °C / Inert atmosphere 5.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 4 h / 0 - 20 °C View Scheme

Yield

Multi-step reaction with 5 steps
1.1: sodium formate; hydroxylamine hydrochloride / formic acid / 5 h / 85 °C
2.1: potassium carbonate / N,N-dimethyl-formamide / 8 h / 100 °C
3.1: n-butyllithium / tetrahydrofuran; hexane / 3 h / 0 - 10 °C / Inert atmosphere
3.2: 6 h / 0 - 20 °C
4.1: (S)-diphenylprolinol; Trimethyl borate; borane dimethyl sulphide complex / tetrahydrofuran / 8 h / 0 - 25 °C / Inert atmosphere
5.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 4 h / 0 - 20 °C
View Scheme

: 608141-41-9
Apremilast

: 823-96-1
Trimethylboroxine

: C23H26N2O7S

Conditions

Conditions	Yield
With pentamethylcyclopentadienyl(benzene)cobalt(III) hexafluorophosphate; potassium carbonate; silver carbonate In 2-methyltetrahydrofuran at 100℃; for 16h; Inert atmosphere; Sealed tube;	23%

: 608141-41-9
Apremilast

: octa-acetyl lactulose

: C48H58N2O24S

Conditions

Conditions	Yield
Stage #1: Apremilast With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile for 3h; Reflux; Stage #2: octa-acetyl lactulose With trimethylsilyl trifluoromethanesulfonate at 20℃; for 14h;	16.7%
Stage #1: Apremilast With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile for 3h; Reflux; Stage #2: octa-acetyl lactulose With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 20℃; for 14.0833h;	16.7%

: 608141-41-9
Apremilast

: 1384967-20-7
(S)-N-{2-[1-(3-hydroxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide

Conditions

Conditions	Yield
With aluminum (III) chloride In dichloromethane at 20℃; for 1h;

: 608141-41-9
Apremilast

: 1384441-38-6
(S)-N-(2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide

Conditions

Conditions	Yield
With trimethylsilyl iodide In dichloromethane at 20℃; for 24h;

: 608141-41-9
Apremilast

: 1384439-79-5
(S)-N-{2-[1-(3,4-dihydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1: trimethylsilyl iodide / dichloromethane / 24 h / 20 °C 2: aluminum (III) chloride / dichloromethane / 1 h / 20 °C View Scheme

: 608141-41-9
Apremilast

: 1384967-21-8
(2S,3R,4S,5S,6S)-2-(4-((S)-1-(4-acetamido-1,3-dioxoisoindolin-2-yl)-2-(methylsulfonyl)ethyl)-2-ethoxyphenoxy)-6-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1: trimethylsilyl iodide / dichloromethane / 24 h / 20 °C 2: boron trifluoride diethyl etherate / dichloromethane / 6 h / -18 - 25 °C / Molecular sieve View Scheme

: 608141-41-9
Apremilast

: 1384967-22-9
C33H36N2O16S

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1: trimethylsilyl iodide / dichloromethane / 24 h / 20 °C 2: boron trifluoride diethyl etherate / dichloromethane / 6 h / -18 - 25 °C / Molecular sieve 3: hydrogen / palladium 10% on activated carbon / ethyl acetate / 12 h / 1551.49 - 2068.65 Torr View Scheme

: 608141-41-9
Apremilast

: 1384814-89-4
(S)-N-{2-[1-(3-ethoxy-4-glucopyranuroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1: trimethylsilyl iodide / dichloromethane / 24 h / 20 °C 2: boron trifluoride diethyl etherate / dichloromethane / 6 h / -18 - 25 °C / Molecular sieve 3: hydrogen / palladium 10% on activated carbon / ethyl acetate / 12 h / 1551.49 - 2068.65 Torr 4: sodium carbonate / methanol / 2 h / 60 °C View Scheme

Apremilast Specification

The Apremilast, with the CAS registry number 608141-41-9, is also known as (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione. This chemical's molecular formula is C₂₂H₂₄N₂O₇S and molecular weight is 460.50. What's more, its systematic name is N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide. Its classification code is Treatment of chronic inflammatory conditions including psoriasis, arthritis, asthma and cutaneous lupus erythematosus (CLE). This chemical is an orally available small molecule inhibitor of PDE4 being developed by Celgene for ankylosing spondylitis, psoriasis, and psoriatic arthritis

Physical properties of Apremilast are: (1)ACD/LogP: 1.754; (2)# of Rule of 5 Violations: 0; (3)ACD/LogD (pH 5.5): 1.75; (4)ACD/LogD (pH 7.4): 1.75; (5)ACD/BCF (pH 5.5): 12.68; (6)ACD/BCF (pH 7.4): 12.68; (7)ACD/KOC (pH 5.5): 214.35; (8)ACD/KOC (pH 7.4): 214.35; (9)#H bond acceptors: 9; (10)#H bond donors: 1; (11)#Freely Rotating Bonds: 8; (12)Polar Surface Area: 127.46 Å²; (13)Index of Refraction: 1.612; (14)Molar Refractivity: 115.86 cm³; (15)Molar Volume: 333.272 cm³; (16)Polarizability: 45.931×10^-24cm³; (17)Surface Tension: 60.6 dyne/cm; (18)Density: 1.382 g/cm³; (19)Flash Point: 402.149 °C; (20)Enthalpy of Vaporization: 108.117 kJ/mol; (21)Boiling Point: 741.342 °C at 760 mmHg; (22)Vapour Pressure: 0 mmHg at 25°C.

You can still convert the following datas into molecular structure:
(1)SMILES: O=S(=O)(C)C[C@H](c1ccc(OC)c(OCC)c1)N3C(=O)c2cccc(c2C3=O)NC(=O)C
(2)Std. InChI: InChI=1S/C22H24N2O7S/c1-5-31-19-11-14(9-10-18(19)30-3)17(12-32(4,28)29)24-21(26)15-7-6-8-16(23-13(2)25)20(15)22(24)27/h6-11,17H,5,12H2,1-4H3,(H,23,25)/t17-/m1/s1
(3)Std. InChIKey: IMOZEMNVLZVGJZ-QGZVFWFLSA-N

Product Name

ApreMilast

Synthetic route

Apremilast Specification

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