253168-94-4

Basic information

• Product Name: 3-Ethoxy-4-Methoxy-alpha-[(Methylsulfonyl)Methyl]-benzeneMethanaMine
• Synonyms: 3-Ethoxy-4-Methoxy-alpha-[(Methylsulfonyl)Methyl]-benzeneMethanaMine;1-(3-Ethoxy-4-Methoxyphenyl)-2-MethylsulfonylethylaMine;BenzeneMethanaMine, 3-ethoxy-4-Methoxy-a-[(Methylsulfonyl)Methyl]-;ApreMilast interMediate;1-(3-ethoxy-4-Methoxyphenyl)-2-(Methylsulfonyl)ethanaMine;Apremilast Intermediate I;3-Ethoxy-4-methoxy-alpha-[(methylsulfonyl)methyl]-benzenemethanamine 1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine;Benzenemethanamine, 3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]-
• CAS NO: 253168-94-4
• Molecular Formula: C₁₂H₁₉NO₄S
• Molecular Weight: 273.34856
• EINECS: -0
• Product Categories: apremilast intermediates
• Mol File: 253168-94-4.mol
• Article Data: 22

Chemical Properties

• Melting Point: 120 °C
• Boiling Point: 469.6±45.0 °C(Predicted)
• Appearance: /
• Density: 1.195±0.06 g/cm3(Predicted)
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: Chloroform (Slightly, Heated, Sonicated), DMSO (Slightly, Heated), Methanol (Sli
• PKA: 6.84±0.10(Predicted)
• CAS DataBase Reference: 3-Ethoxy-4-Methoxy-alpha-[(Methylsulfonyl)Methyl]-benzeneMethanaMine(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Ethoxy-4-Methoxy-alpha-[(Methylsulfonyl)Methyl]-benzeneMethanaMine(253168-94-4)
• EPA Substance Registry System: 3-Ethoxy-4-Methoxy-alpha-[(Methylsulfonyl)Methyl]-benzeneMethanaMine(253168-94-4)

Safety Data

• Hazardous Substances Data: 253168-94-4(Hazardous Substances Data)

Usage

Uses

1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonylethylamine is used in the enantioselective synthesis of Apremilast (A729700) aminosulfone using catalytic asymetric hydrogenation. Apremilast EP Impurity H

Synthetic route

tert-butyl N-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]carbamate → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With isopropanol hydrochloride In acetonitrile at 25 - 30℃; for 12h;	95%
With hydrogenchloride In water; toluene at 65 - 70℃; for 1h;	145 g

dimethylsulfone (67-71-0) + 3-ethoxy-4-methoxybenzaldehyde (1131-52-8) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Stage #1: dimethylsulfone With n-butyllithium In tetrahydrofuran; hexane at -20 - 0℃; for 1h; Stage #2: 3-ethoxy-4-methoxybenzaldehyde With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -40 - -30℃; for 1h; Stage #3: With boron trifluoride diethyl etherate In tetrahydrofuran; hexane at -30 - 0℃; Temperature;	91.5%
Stage #1: 3-ethoxy-4-methoxybenzaldehyde With lithium hexamethyldisilazane at -78℃; Stage #2: dimethylsulfone With n-butyllithium; boron trifluoride diethyl etherate at -78℃;	41%

C12H19NO5S → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With acetic acid; zinc	91%

1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethen-1-amine (1450657-31-4) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With sodium cyanoborohydride; citric acid In methanol at 5℃; for 1h; Reagent/catalyst; Temperature; Concentration; Solvent;	88%

1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one (1450657-28-9) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With palladium on activated charcoal; ammonium formate In methanol; water for 15h; Reflux;	87.8%
Stage #1: 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one With ammonium acetate In methanol; water for 1h; Reflux; Stage #2: With sodium tris(acetoxy)borohydride In methanol; water at 0 - 10℃; for 7h;	75.3%
With ammonium formate In methanol; water for 20h; Reflux;	42.4%

4-(1-azido-2-(methylsulfonyl)ethyl)-2-ethoxy-1-methoxybenzene → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With triphenylphosphine In tetrahydrofuran; water at 60℃; for 6h; Sealed tube; Inert atmosphere;	87%

1-Bromo-3-ethoxy-4-methoxybenzene (52849-52-2) + methanesulfonyl-acetonitrile (2274-42-2) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Stage #1: 1-Bromo-3-ethoxy-4-methoxybenzene With iodine; magnesium In tetrahydrofuran at 45 - 60℃; for 3.83333h; Stage #2: methanesulfonyl-acetonitrile With hydroxylamine hydrochloride In tetrahydrofuran at -5 - 0℃; for 3.66667h; Stage #3: With hydrogen In tetrahydrofuran at 20 - 25℃; under 760.051 - 1520.1 Torr; for 3h; Reagent/catalyst; Solvent; Autoclave;	86.5%

2-(methylsulfonyl)acetic acid (2516-97-4) + 3-ethoxy-4-methoxybenzaldehyde (1131-52-8) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With thionyl chloride; ammonium acetate In ethanol for 16h; Reflux;	78%

dimethylsulfone (67-71-0) + 3-ethoxy-4-methoxybenzenecarbonitrile (60758-86-3) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Stage #1: dimethylsulfone With n-butyllithium In tetrahydrofuran; hexane at 0 - 5℃; Stage #2: 3-ethoxy-4-methoxybenzenecarbonitrile In tetrahydrofuran; hexane at 0 - 20℃; Product distribution / selectivity; Inert atmosphere;	76.1%
Stage #1: dimethylsulfone With potassium hexamethylsilazane In tetrahydrofuran at 0 - 10℃; for 1h; Large scale; Stage #2: 3-ethoxy-4-methoxybenzenecarbonitrile In tetrahydrofuran for 0.5h; Large scale; Stage #3: With sodium tetrahydroborate; acetic acid In tetrahydrofuran at 0 - 62℃; Temperature; Large scale;	65%
Stage #1: dimethylsulfone With potassium tert-butylate In dimethyl sulfoxide at 30℃; for 3h; Stage #2: 3-ethoxy-4-methoxybenzenecarbonitrile In tetrahydrofuran; dimethyl sulfoxide for 3.5h; Stage #3: With sodium tetrahydroborate In tetrahydrofuran; dimethyl sulfoxide at 30℃; for 1h;	50%
Stage #1: dimethylsulfone With n-butyllithium In tetrahydrofuran at 0 - 5℃; for 1.5h; Stage #2: 3-ethoxy-4-methoxybenzenecarbonitrile In tetrahydrofuran at 0 - 30℃; for 1.5h; Further stages;

(E)-2-ethoxy-1-methoxy-4-(2-(methylsulfonyl)vinyl)benzene → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Stage #1: (E)-2-ethoxy-1-methoxy-4-(2-(methylsulfonyl)vinyl)benzene With boric acid In water at 50 - 60℃; for 0.166667h; Stage #2: With ammonium hydroxide In water at 80℃; for 72h; Reagent/catalyst; Temperature;	75%
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; triethylamine / ethanol / 24 h / 80 °C 2: zinc; acetic acid View Scheme

dimethylsulfone (67-71-0) + 3-ethoxy-4-methoxybenzaldehyde (1131-52-8) → 1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonylethylamine + 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With hydrogenchloride; n-butyllithium; trifluoroborane diethyl ether In tetrahydrofuran; hexane; lithium hexamethyldisilazane	A 39% B n/a

isovanillin (621-59-0) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / -78 °C / Inert atmosphere 2.2: 20 °C / Cooling with salt-ice; Inert atmosphere 3.1: hydrogenchloride; water / diethyl ether / 0.5 h / 20 °C 3.2: pH 12 / Cooling with ice View Scheme

3-ethoxy-4-methoxybenzaldehyde (1131-52-8) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium hydroxide / N,N-dimethyl-formamide / 0.25 h / 20 °C 1.2: 2 h 2.1: boric acid / water / 0.17 h / 50 - 60 °C 2.2: 72 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: caesium carbonate / 0.25 h / 20 °C 1.2: 48 h / 60 °C 2.1: formic acid; dihydrogen peroxide / water; dichloromethane / 0 - 27 °C 3.1: boric acid / water / 0.17 h / 50 - 60 °C 3.2: 72 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / 0.17 h 1.2: 100 °C 2.1: formic acid; dihydrogen peroxide / water / 0 - 27 °C 3.1: boric acid / water / 0.17 h / 50 - 60 °C 3.2: 72 h / 80 °C View Scheme

1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-N-(trimethylsilyl)ethylamine (1255909-21-7) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Stage #1: 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-N-(trimethylsilyl)ethylamine With hydrogenchloride; water In diethyl ether at 20℃; for 0.5h; Stage #2: With sodium hydroxide In water pH=12; Cooling with ice;

C12H16O2S → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: formic acid; dihydrogen peroxide / water / 0 - 27 °C 2.1: boric acid / water / 0.17 h / 50 - 60 °C 2.2: 72 h / 80 °C View Scheme

(E)-2-ethoxy-1-methoxy-4-(2-(methylsulfinyl)vinyl)benzene → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: formic acid; dihydrogen peroxide / water; dichloromethane / 0 - 27 °C 2.1: boric acid / water / 0.17 h / 50 - 60 °C 2.2: 72 h / 80 °C View Scheme

2-chloro-1-(3-ethoxy-4-methoxyphenyl)ethanone → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 15 h / Reflux 2: ammonium formate; palladium on activated charcoal / methanol; water / 15 h / Reflux View Scheme

3-hydroxy-4-methoxyacetophenone (6100-74-9) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 25 °C 2: 1,3-dichloro-5,5-dimethylhydantoin; toluene-4-sulfonic acid / methanol / 15 h / 5 - 25 °C 3: ethanol / 15 h / Reflux 4: ammonium formate; palladium on activated charcoal / methanol; water / 15 h / Reflux View Scheme

3-ethoxy-4-methoxy-acetophenone (31526-71-3) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1,3-dichloro-5,5-dimethylhydantoin; toluene-4-sulfonic acid / methanol / 15 h / 5 - 25 °C 2: ethanol / 15 h / Reflux 3: ammonium formate; palladium on activated charcoal / methanol; water / 15 h / Reflux View Scheme

3-ethoxy-4-methoxybenzenecarbonitrile (60758-86-3) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium amide / tetrahydrofuran; dimethyl sulfoxide / 40 °C 1.2: 3.5 h / 20 °C 2.1: sodium cyanoborohydride; citric acid / methanol / 1 h / 5 °C View Scheme

2-ethoxy-1-methoxy-4-vinylbenzene → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: tris(triphenylphosphine)ruthenium(II) chloride / benzene / 20 h / 110 °C / Inert atmosphere 2: ammonia; triethylamine; sodium iodide / methanol / 16 h / 50 °C / Sealed tube View Scheme
Multi-step reaction with 3 steps 1: 1,3-bis-(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)dichloro(5-nitro-2-isopropoxyphenylmethylene)ruthenium / 0.83 h / 120 °C / Microwave irradiation 2: hydroxylamine hydrochloride; triethylamine / ethanol / 24 h / 80 °C 3: zinc; acetic acid View Scheme

4-[(1-chloro-2-methanesulfonyl)ethyl]-2-ethoxy-1-methoxybenzene → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With ammonia; triethylamine; sodium iodide In methanol at 50℃; for 16h; Temperature; Sealed tube;

N-[3-ethoxy-4-methoxymethylbenzene]-1-(3-ethoxy-4-methoxy phenyl)-2-methylsulfonylethenamine → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; toluene-4-sulfonic acid In water; ethyl acetate at 27℃;

1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl-N-[1-phenylmethyl]ethanamine → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
With hydrogenchloride; palladium 10% on activated carbon; hydrogen In water at 60 - 65℃; under 75.0075 - 150.015 Torr; for 6h; Temperature; Pressure;	102 g

tert-butyl N-[(3-ethoxy-4-methoxyphenyl)-p-tolylsulfonylmethyl]carbamate → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / water; tetrahydrofuran / 1 h / -5 - 0 °C 1.2: 1 h / -5 - 0 °C 2.1: isopropanol hydrochloride / acetonitrile / 12 h / 25 - 30 °C View Scheme

3-hydroxy-4-methoxybenzoate (6702-50-7) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 6.5 h / 60 °C 2: potassium tert-butylate / dimethyl sulfoxide / 1.5 h / 55 °C / Inert atmosphere 3: ammonium formate / methanol; water / 20 h / Reflux View Scheme

Isovanillic acid (645-08-9) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / 65 °C 2: potassium carbonate / acetone / 6.5 h / 60 °C 3: potassium tert-butylate / dimethyl sulfoxide / 1.5 h / 55 °C / Inert atmosphere 4: ammonium formate / methanol; water / 20 h / Reflux View Scheme

2-methoxyphenyl acetate (613-70-7) → 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / dichloromethane / 2 h / -5 - 5 °C / Inert atmosphere; Heating 2.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 50 - 55 °C 3.1: ammonium acetate / methanol; water / 1 h / Reflux 3.2: 7 h / 0 - 10 °C View Scheme

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + N-Ac-Leu (1188-21-2) → 1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-leucine salt

Conditions	Yield
In methanol at 20℃; for 4h; Reflux;	98%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + (R,R)-(+)-4-chlorotartranilic acid (17447-35-7) → C12H19NO4S*C10H10ClNO5

Conditions	Yield
With hydrogenchloride In water at 60 - 70℃; Solvent; Resolution of racemate; Heating;	92%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + N-Ac-Leu (1188-21-2) → (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine-(S)-2-acetamido-4-methylpentanoate (608141-43-1)

Conditions	Yield
In methanol at 20℃; for 8h; Reflux; Resolution of racemate;	90%
Stage #1: 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine; N-Ac-Leu In methanol for 1h; Reflux; Stage #2: In methanol at 20℃; for 4h; Reflux;	90%
In methanol at 20℃; for 4h; Reflux;	90%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + methyl methoxyacetate (6290-49-9) → (S)-N-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-2-methoxyacetamide

Conditions	Yield
With Novozym 435; Shvo's catalyst at 105℃; for 37h; Reagent/catalyst; Enzymatic reaction;	90%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + 4-nitrophthalic anhydride (5466-84-2) → 2-[1-(3-Ethoxy-4methoxyphenyl)-2-methylsutfonyletllyl]-5-nitro-iso-indoline-1,3-dione + 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-5-nitro-isoindoline-1,3-dione (253168-80-8)

Conditions	Yield
	A 87% B n/a

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + N-(1,3-dioxo-1,3-dihydroisobenzofuran-5-yl)-acetamide (22235-04-7) → N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)acetamide

Conditions	Yield
With triethylamine In ethyl acetate at 80℃; for 12h; Sealed tube;	86%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + 3-nitrophthalic acid anhydride (641-70-3) → 2-[1-(3-Ethoxy-4methoxyphenyl)-2-methylsunylethyl]-4nitroisoindoline-1,3-dione + 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-4-nitroisoindoline-1,3-dione

Conditions	Yield
In acetic acid	A 81% B n/a

3-dimethylaminophthalic anhydride (27086-53-9) + 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) → 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonylethyl]-4-dimetilylamino isoindoline-1,3-dione + 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione (253168-88-6)

Conditions	Yield
In acetic acid	A 80% B n/a

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + 3-acetylaminophthalic anhydride (6296-53-3) → Apremilast (608141-41-9)

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

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + quinoline-7,8-dicarboxylic acid-anhydride (143092-07-3) → 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-3-pyrrolino[3,4-h]quinoline-1,3-dione (340019-20-7)

Conditions	Yield
With sodium acetate In acetic acid for 18h; Heating / reflux;	70%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + water(2 mL each) + N-ethoxycarbonylphthalimide (22509-74-6) → 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsutfonyleethyl]isoindoline-1,3-dione + 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]isoindoline-1,3-dione

Conditions	Yield
With hydrogenchloride; sodium bicarbonate In water; acetonitrile	A 70% B n/a

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + 1,2-phthalic dicarboxaldehyde → 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-metlylsuffonylethyl]isoindolin-1-one + 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindolin-1-one

Conditions	Yield
In acetic acid	A 70% B n/a

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + N-acetyl-L-tyrosine (537-55-3) → (S)-(2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine)-N-acetyl-L-tyrosine salt

Conditions	Yield
In methanol at 60℃; for 2h; Solvent; Temperature;	69%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + carbonic acid dimethyl ester (616-38-6) → methyl (S)-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate

Conditions	Yield
With 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II) at 90℃; for 5h; Catalytic behavior; Reagent/catalyst; Temperature;	68%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + 3-methoxyphthalic anhydride (14963-96-3) → 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindoline-1,3-dione (253168-91-1) + 2-[1-(3-Etloxy-4methoxyphenyl)-2-methylsutfonylethyl]-4-methoxy-isoindoline-1,3-dione

Conditions	Yield
In acetic acid	A n/a B 67%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + 3-acetylaminophthalic anhydride (6296-53-3) → rac-Apremilast (253168-86-4)

Conditions	Yield
In acetic acid	59%
In acetic acid	59%
With acetic acid for 15h; Reflux;	59%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + 3-acetylaminophthalic anhydride (6296-53-3) → rac-Apremilast (253168-86-4) + 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acedtamidoisoindoline-1,3-dione

Conditions	Yield
In acetic acid	A 59% B n/a

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + Di-p-toluoyl-L-tartaric acid (32634-66-5) → (R,R)-O,O’-di-p-toluoyl-tartrate

Conditions	Yield
With hydrogenchloride In methanol at 50 - 65℃;	59%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + 2-aminopyridine-3,4-dicarboxylic acid + acetic anhydride (108-24-7) + acetic acid (64-19-7) → N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide

Conditions	Yield
Stage #1: 2-aminopyridine-3,4-dicarboxylic acid; acetic anhydride under 760.051 Torr; for 3h; Reflux; Stage #2: 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine; acetic acid at 25 - 85℃; under 760.051 Torr; Reflux;	58%

2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (253168-94-4) + N-(7-fluoro-1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide → (N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-7-fluoro-1,3-dioxoisoindolin-4-yl)acetamide)

Conditions	Yield
With acetic acid at 100℃;	51%

Upstream product

• 67-71-0 dimethylsulfone 
• 1131-52-8 3-ethoxy-4-methoxybenzaldehyde 
• 613-70-7 2-methoxyphenyl acetate 
• 2516-97-4 2-(methylsulfonyl)acetic acid 
• 60758-86-3 3-ethoxy-4-methoxybenzenecarbonitrile 
• 1450657-31-4 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethen-1-amine 
• 31526-71-3 3-ethoxy-4-methoxy-acetophenone 
• 6100-74-9 3-hydroxy-4-methoxyacetophenone 
• 1450657-28-9 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one 
• 52849-52-2 1-Bromo-3-ethoxy-4-methoxybenzene 
• 2274-42-2 methanesulfonyl-acetonitrile 
• 1255909-21-7 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-N-(trimethylsilyl)ethylamine 

Downstream Products

• 340019-20-7 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-3-pyrrolino[3,4-h]quinoline-1,3-dione 
• 253168-86-4 rac-Apremilast 
• 253168-80-8 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-5-nitro-isoindoline-1,3-dione 
• 253168-88-6 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione 
• 253168-91-1 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindoline-1,3-dione 
• 253168-87-5 N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)acetamide 
• 608142-27-4 (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine 
• 608141-42-0 (S)-2-[1 (3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine 
• 253168-84-2 C₂₁H₂₃NO₆S 
• 1140885-73-9 C₂₀H₂₁NO₇S 
• 1255908-81-6 5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1-amino-5H-thiopheno[3,4-c]pyrrole-4,6-dione 

Relevant articles and documents

Synthetic method of apremilast intermediate

The invention discloses a synthetic method of an apremilast intermediate. The method comprises the following steps of by taking 2-methoxyphenyl acetate and 2-(methylsulfonyl) acetyl chloride as starting materials, carrying out acylation reaction and hydrolysis under the catalysis of aluminum trichloride to obtain 1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl ketone, carrying out alkylation reaction with bromoethane, and then forming imine with ammonium acetate, and reducing to form the 1-(3-ethoxy-4-methoxy phenyl)-2-(methylsulfonyl) ethylamine. The method is simple to operate, avoids the use of n-butyllithium, palladium on carbon and mesylate, avoids the problems of high risk, high cost and the like, and is suitable for industrial production.

RACEMIC BETA-AMINOSULFONE COMPOUNDS

It is described an industrially viable and advantageous process for the preparation of racemic beta-aminosulfone (1), an useful intermediate for the preparation of N-(2-((1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl)acetamide, also known as Apremilast, the latter being suitable for use in methods of treating, preventing and/or managing psoriasis or psoriatic arthritis.

Method for preparing intermediate of Apremilast

The invention provides a method for preparing an intermediate 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (I), shown in a following figure, of Apremilast. The method comprises the following steps: (1) adding dimethyl sulfone in a suitable solvent, and performing a reaction with an organolithium compound at -40-10 DEG C for 0.5-2 hours so as to obtain a reaction liquid R1; (2) adding 3-ethoxy-4-methoxybenzaldehyde in a suitable solvent, and performing a reaction with a weak-nucleophilicity strong base at -40-10 DEG C for 0.5-2 hours so as to obtain a reaction liquid R2; (3) adding the R2 into R1 dropwise, and performing a reaction at -60-0 DEG C for 0.5-2 hours so as to obtain a reaction liquid R3; (4) adding boron trifluoride diethyl etherate to the R3, and performing a reaction at -80-0 DEG C; (5) quenching the reaction, performing filtration, performing pulping and washing on the obtained filter cake by using dichloromethane, performing extraction on the aqueous layer with the dichloromethane, combining the organic layer, and performing concentration; (6) adding dichloromethane to the residues obtained after concentration, performing washing with acid water, and performing liquid separation; and (7) adjusting the pH value of the water layer to 10-14, performing extraction with dichloromethane, and concentrating the organic layer so as to obtain the 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine crude product. The method is based on a synthetic method firstly reported by an original research company, the feeding mode and feeding ratio are changed, control on reaction conditions is achieved, and the method has high operability, and is conducive to large-scale industrial production.