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Apremilast preparation method

A solvent and reaction technology, which is applied in the field of preparing apremilast for treating psoriatic arthritis, can solve the problems of harsh reaction conditions and high production cost, and achieve the effect of high reaction selectivity

Pending Publication Date: 2019-02-26
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In order to solve the technical problems of harsh reaction conditions and high production costs in the prior art, the purpose of the present invention is to provide a preparation method of Apremilast that is easy to industrialize, and its technical scheme is as follows

Method used

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Effect test

Embodiment 1

[0035] Embodiment 1 Preparation of Apremilast

[0036] Add (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine.N-acetyl-L-leucine salt ( Formula II compound) 4.5g, 2.4g of 3-acetamidophthalic acid, 31.5g of glacial acetic acid. After the addition, the temperature was raised to 100-120°C, and the reaction was maintained for 2 hours, then 1.0 g of acetic anhydride was added, and the reaction was continued for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, the residue was dissolved with ethyl acetate, washed with alkaline water, dried and concentrated, and recrystallized from acetone and ethanol to obtain 3.7 g of Apremilast with a yield of 80.3% and a purity of 99.4%.

Embodiment 2

[0037] Embodiment 2 Preparation of Apremilast

[0038] Add (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine.N-acetyl-L-leucine salt ( Formula II compound) 4.5g, 3-acetamidophthalic acid 3.3g, glacial acetic acid 13.5g. After the addition, the temperature was raised to 100-120°C, and the reaction was maintained for 2 hours, then 1.0 g of acetic anhydride was added, and the reaction was continued for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, the residue was dissolved with ethyl acetate, washed with alkaline water, dried and concentrated, and recrystallized from acetone and ethanol to obtain 3.9 g of Apremilast with a yield of 84.5% and a purity of 99.6%.

Embodiment 3

[0039] Embodiment 3 Preparation of Apremilast

[0040] Add (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine.N-acetyl-L-leucine salt ( Compound of formula II) 45g, 26.4g of 3-acetamidophthalic acid, 135g of glacial acetic acid. After the addition, the temperature was raised to 100-120°C, and the reaction was maintained for 2 hours, then 10.2 g of acetic anhydride was added, and the reaction was continued for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, the residue was dissolved with ethyl acetate, washed with alkaline water, dried and concentrated, and recrystallized from acetone and ethanol to obtain 40 g of Apremilast with a yield of 86.7% and a purity of 99.7%.

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Abstract

The present invention relates to a preparation method of apremilast represented by a formula I, wherein the method comprises: carrying out a reaction on a compound represented by a formula II and a compound represented by a formula III in a reaction solvent to obtain an apremilast crude product, and crystallizing with acetone and ethanol to obtain the finished apremilast. According to the presentinvention, the apremilast obtained by the method has the purity of more than 99.3% and the yield of more than 80%, the process is simple, and the cost is low. The formulas I, II and III are defined inthe specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing apremilast for treating psoriatic arthritis. Background technique [0002] The chemical structural formula of Apremilast (trade name: Otezla) is shown in the following formula I, and the chemical name is N -[2-[(1 S )-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1 H -Isoindol-4-yl]acetamide [0003] [0004] Apremilast, developed by Celgene, is the first and only PDE-4 inhibitor approved by the FDA for the treatment of plaque psoriasis. [0005] Apremilast is a small molecule phosphodiesterase 4 (PDE-4) inhibitor that regulates the production of pro-inflammatory and anti-inflammatory mediators in cells. PDE-4, a cyclic adenosine monophosphate (cAMP)-specific PDE, is the major PDE in inflammatory cells. PDE-4 inhibitors can increase the level of intracellular cAMP, and correspondingly down-regulate the inf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 郑波张上华罗绪张耀春左小勇雷皇书
Owner CHONGQING PHARMA RES INST
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