Preparation method of Apremilastat

Abstract

The present invention discloses a method for preparing apremilast. The method comprises using 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone as a raw material, subjecting the raw material to amination and reduction in the presence of a catalyst to obtain (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine. The obtained (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine is then reacted with 3-acetamidophthalic anhydride to obtain apremilast. The method has a short synthesis cycle, fewer reaction steps, a shortened reaction process, improved synthesis efficiency, and a high yield.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical and chemical intermediate synthesis, and in particular to a method for preparing apremilast. Background Art

[0002] Apremilast (also known as Apremilast) is used to treat adult patients with moderate to severe plaque psoriasis who are eligible for phototherapy or systemic therapy. The chemical name of Apremilast is N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, and its structural formula is as follows:

[0003] .

[0004] The chiral intermediate (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethylamine is the key to the synthesis of apremilast. (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethylamine reacts with 3-acetamidophthalic anhydride to obtain apremilast:

[0005] .

[0006] The chiral intermediate (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine can be prepared by either resolution or chiral synthesis. Compared to resolution, chiral synthesis offers advantages such as reduced cost, increased yield, and environmental friendliness. However, chiral synthesis has a longer process cycle.

[0007] For example, U.S. Patent US2013217918 discloses the following synthesis route:

[0008] .

[0009] Chinese patent document CN 104744323 B (application number 201510106728.7) uses 1-(3-ethoxy-4-methoxyphenyl)ethanone as a starting material to first prepare 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone; 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone obtained in step (1) is added to a dry reactor under a nitrogen atmosphere, dissolved with solvent D, (S)-(-)-1-phenylethylamine and catalyst C are added, stirred at 0-60°C for 20-30h, reducing agent E is added, reacted at 20-30°C for 1-10h, diluted hydrochloric acid is added to quench the reaction, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, washed with water, dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation to obtain (S)-1-( (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-N-((S)-1-phenylethyl)ethanamine; (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-N-((S)-1-phenylethyl)ethanamine was dissolved in solvent F, palladium carbon was added, and the mixture was stirred and hydrogenated at 10-30°C for 15-40h. The mixture was filtered, and the solvent was removed by rotary evaporation. The crude product was recrystallized to obtain (S)-2-[1-(3-ethoxy-4-methoxyphenyl)]-1-methylsulfonyl-2-ethanamine.

[0010] Chinese patent document CN 104761474 B (application number 201510107040.0) uses 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone as the raw material, and undergoes asymmetric hydrogenation reduction to methylsulfonylethanol, methylsulfonyl ester, azidation, and hydrogenation reduction to obtain a chiral amine intermediate with high chiral purity. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a preparation method of apremilast with a short synthesis cycle and high yield.

[0012] The technical solution for achieving the purpose of the present invention is a method for preparing Apremilast, comprising the following steps:

[0013] ① Add 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone, catalyst Ru(OAc)2[(S)-DTBM-SEGPHOS], ammonium acetate, and solvent to a reaction flask, and place the reaction flask in a high-pressure reactor. First, introduce argon to replace the air in the reactor, then introduce hydrogen to replace the argon. Raise the hydrogen pressure in the reactor to and maintain it at 2-4 MPa. React at 50°C-70°C for 8-16 hours. After the reaction, remove the solvent by rotary evaporation. Dissolve the residue in water and extract with dichloromethane. Combine the organic phases and concentrate to dryness to obtain (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine for later use.

[0014] ② Add (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethylamine, 3-acetamidophthalic anhydride, and glacial acetic acid prepared in step ① to the reaction flask, stir evenly, and reflux for 20-24 hours. Then, remove the glacial acetic acid under reduced pressure. Dissolve the remaining material in ethyl acetate, wash with water and saturated brine in sequence, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting solid is recrystallized from isopropanol to obtain apremilast.

[0015] Optionally, in the above step ①, the molar ratio of the catalyst Ru(OAc)2[(S)-DTBM-SEGPHOS] to 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone is 1:125-150.

[0016] In the above step ①, the solvent is cyclohexane and / or isopropanol.

[0017] Optionally, in the above step ①, the molar ratio of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone to ammonium acetate is 1:1.5-2.

[0018] Preferably, in step ①, the hydrogen pressure in the autoclave is increased to and maintained at 3-4 MPa, and the reaction is carried out at 50° C.-60° C. for 12-16 hours.

[0019] The present invention has positive effects: 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone is used as a raw material, and (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine is directly aminized and reduced in the presence of a catalyst. The obtained (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine is then reacted with 3-acetamidophthalic anhydride to obtain apremilast. The present invention has a short synthesis cycle and fewer reaction steps, shortening the reaction process, improving synthesis efficiency, and achieving a high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the HPLC spectrum of Apremilast prepared in Example. DETAILED DESCRIPTION

[0021] Introduced below are some of the multiple possible embodiments of the present invention, which are intended to provide a basic understanding of the present invention, and are not intended to identify the key or decisive elements of the present invention or to limit the scope of protection. It is easy to understand that according to the technical solution of the present invention, without changing the essential spirit of the present invention, those skilled in the art can propose other mutually interchangeable implementations. Therefore, the following specific embodiments are only exemplary descriptions of the technical solution of the present invention, and should not be regarded as the entirety of the present invention or as a limitation or restriction of the technical solution of the present invention.

[0022] (Example 1)

[0023] The preparation method of Apremilast in this embodiment comprises the following steps:

[0024] ① Preparation of (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine from 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone.

[0025]

[0026] To a reaction flask, add 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (0.1 mmol, 27.23 mg, CAS NO. 1450657-28-9), catalyst Ru(OAc)2[(S)-DTBM-SEGPHOS] (1 mg, CAS NO. 1025476-84-9), ammonium acetate (0.15 mmol, 11.5 mg), and 1 mL of cyclohexane. The reaction flask was placed in a high-pressure autoclave. Argon was first introduced to displace the air in the autoclave, followed by hydrogen. The hydrogen pressure in the autoclave was increased to and maintained at 3 MPa. The reaction was then carried out at 55°C for 12 h.

[0027] After the reaction, the solvent was removed by rotary evaporation, the residue was dissolved in water and extracted with dichloromethane (3×5 mL), and the organic phases were combined and concentrated to dryness to obtain 22.4 mg of (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine (yield 82%).

[0028] ② Apremilast was prepared by the reaction of (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethylamine with 3-acetamidophthalic anhydride.

[0029] To a reaction flask, add 20 mg of (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethylamine prepared in step ①, 15 mg of 3-acetamidophthalic anhydride, and 100 mg of glacial acetic acid. After stirring, reflux for 20-24 hours. Then, remove the glacial acetic acid under reduced pressure. The remaining material is dissolved in ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid is recrystallized from isopropanol to yield 26.9 mg of solid (yield 80%) with a purity of 99.5%. The HPLC spectrum of the obtained product is shown in [Chapter 1]. Figure 1 .

[0030] (Example 2)

[0031] The preparation method of this embodiment is the same as that of Example 1 except that:

[0032] In step ①, the solvent is isopropanol, and the reaction materials are reacted at 2 MPa and 65° C. for 16 h.

[0033] (Example 3)

[0034] The preparation method of this embodiment is the same as that of Example 1 except that:

[0035] In step ①, the reaction material was reacted at 4 MPa and 70° C. for 8 h.

[0036] (Example 4)

[0037] The preparation method of this embodiment is the same as that of Example 1 except that:

[0038] In step ①, the molar ratio of the catalyst to 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone is 1:150.

Claims

1. A method for preparing Apremilast, characterized in that The following steps are involved: ① Add 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone, catalyst Ru(OAc)2[(S)-DTBM-SEGPHOS], ammonium acetate, and solvent cyclohexane to a reaction flask, and place the reaction flask in a high-pressure reactor. First, introduce argon to replace the air in the reactor, then introduce hydrogen to replace the argon. Raise the hydrogen pressure in the reactor to and maintain it at 3-4 MPa. React at 50-60°C for 12-16 hours. After the reaction, remove the solvent by rotary evaporation. Dissolve the residue in water and extract with dichloromethane. Combine the organic phases and concentrate to dryness to obtain (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methylsulfonylethylamine for later use. The molar ratio of the catalyst Ru(OAc)2[(S)-DTBM-SEGPHOS] to 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone is 1:125-150; the molar ratio of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone to ammonium acetate is 1:1.5-2; ② Add (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethylamine, 3-acetamidophthalic anhydride, and glacial acetic acid prepared in step ① to the reaction flask, stir evenly, and reflux for 20-24 hours. Then, remove the glacial acetic acid under reduced pressure. Dissolve the remaining material in ethyl acetate, wash with water and saturated brine in sequence, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting solid is recrystallized from isopropanol to obtain apremilast.

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