CN105294534B

CN105294534B - Industrialized method for preparing aplidine and intermediate thereof

Info

Publication number: CN105294534B
Application number: CN201410335852.6A
Authority: CN
Inventors: 罗军芝; 曾玉平
Original assignee: Utopharm Shanghai Co ltd
Current assignee: Utopharm Shanghai Co ltd
Priority date: 2014-07-15
Filing date: 2014-07-15
Publication date: 2020-04-10
Anticipated expiration: 2034-07-15
Also published as: CN105294534A

Abstract

The invention discloses an industrialized method for preparing high-purity aplidine (formula I) and an intermediate thereof. The method takes 3-nitrophthalic acid (compound II) as a starting material, takes organic acid or acid anhydride as a solvent, prepares high-purity 3-acetamino phthalic anhydride (compound IV) through different intermediates, and directly reacts the obtained product with (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl) ethylamine (compound V) or salt thereof in glacial acetic acid under reflux without drying to obtain the aplidine. The preparation method has the advantages of simple operation, low energy consumption and high yield, and is suitable for industrial production.

Description

Industrialized method for preparing aplidine and intermediate thereof

Technical Field

The invention relates to an industrialized method for preparing aplidine and an intermediate thereof, in particular to an industrialized method for preparing a small molecule inhibitor of phosphodiesterase 4(PDE4) aplidine and an intermediate thereof. The invention belongs to the field of pharmaceutical chemistry.

Background

Apremilast (Apremilast, Compound I, chemical name: (+) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione) is a small molecule inhibitor of phosphodiesterase 4(PDE4), and specifically acts on cyclic adenosine monophosphate (cAMP), and PDE4 inhibition can cause an increase in intracellular cAMP levels, and can reduce joint swelling and improve physiological functions at joint sites. The structural formula is as follows:

the drug has been approved for marketing in the united states 3 months 2014 for the treatment of psoriatic arthritis. The current synthetic literature reports about the drug are mainly CN1652772A, CN102702070, US20030392195 and the like.

In the preparation method reported in the document, ethanol is used as a solvent in the first hydrogenation reaction, the yield is only 84%, acetic anhydride is used as a solvent in the second hydrogenation reaction, the yield is only 61%, the yield in the first two steps is only 51%, the yield in the third step is only 75%, the total yield is only 38%, the optical purity of the target product is only 98%, and the chemical purity of the target product and the chemical purity of the intermediate are not reported.

Obviously, the existing method has low yield, high cost and difficult industrialization.

Disclosure of Invention

The invention aims to provide a simple method for preparing the aplidine and the intermediate thereof, which has high yield and low cost and is suitable for industrialization.

The technical scheme of the invention is as follows:

i) 2-nitrophthalic acid (compound II) is used as a starting material, organic acid or acid anhydride is used as a solvent, the 2-nitrophthalic acid (compound III) or salt thereof is prepared by catalytic hydrogenation on palladium carbon, and then

ii) refluxing reaction in acetic anhydride to obtain high purity 3-acetamidophthalic anhydride (compound IV), and final reaction

iii) reacting with (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl) ethylamine or a salt thereof (compound V or a salt thereof) in glacial acetic acid under reflux to give aplidine.

Specifically, in the first step of the present invention, the organic acid or acid anhydride is selected from formic acid, acetic acid, propionic acid, formic anhydride, acetic anhydride, etc., preferably glacial acetic acid, acetic anhydride; the palladium carbon is selected from 5% or 10% anhydrous palladium carbon.

According to the process of the present invention, the hydrogenation reaction temperature is 0 to 100 ℃, preferably room temperature; the hydrogen pressure is from 0.1 to 4MPa, preferably from 0.1 to 0.8 MPa. After the hydrogenation reaction is finished, the reaction liquid is filtered to obtain 2-aminophthalic acid (compound III) or salt thereof, then the obtained product is refluxed in acetic anhydride without being dried, and after the reaction is finished, the product is filtered thermally, cooled and crystallized, and then the high-purity 3-acetamidophthalic anhydride is obtained by filtering.

Or more advantageously, after the hydrogenation reaction in the step one, directly adding acetic anhydride to carry out reflux reaction without filtering reaction liquid, carrying out hot filtration after the reaction is finished, cooling and crystallizing, and filtering to obtain the high-purity 3-acetamidophthalic anhydride, wherein the yield reaches 70-80%, and the HPLC is more than 99%.

According to another preferred scheme of the invention, 2-nitrophthalic acid (compound II) is used as a starting material, acetic anhydride is directly used as a solvent, palladium-carbon catalytic hydrogenation is carried out in a hydrogenation kettle to obtain 2-aminophthalic acid, namely phthalic acid condensation is carried out to obtain 2-aminophthalic anhydride, then the 2-aminophthalic anhydride is heated in an autoclave or transferred to equipment with a recovery device to complete acetylation reaction, namely the one-pot method is used for preparing high-purity 3-acetaminophthalic anhydride from 2-nitrophthalic acid (compound II), the yield of the obtained product reaches 80-85%, and the purity of the product is more than 99%.

In another preferred embodiment of the invention, acetic anhydride is used as a solvent, 2-nitrophthalic acid (compound II) is subjected to condensation reaction at normal temperature or under heating condition to obtain 2-nitrophthalic anhydride (compound VII), then catalytic hydrogenation reaction is carried out to reduce nitro group to obtain 2-aminophthalic anhydride (compound VIII), and finally heating reflux acetylation is carried out to prepare high-purity 3-acetamidophthalic anhydride.

And finally, washing the glacial acetic acid of the high-purity 3-acetamino phthalic anhydride (compound III) obtained by filtering, and directly reacting the washed glacial acetic acid with (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl) ethylamine or a salt thereof in the glacial acetic acid without drying to obtain the aplidine, wherein the yield is about 95%, the chemical purity of a crude product reaches more than 99.5%, and the optical purity reaches 99%. The total yield of the aplidine prepared by the method reaches 66-76%. Obviously, the method of the invention has the advantages of simple operation, high yield, low cost and easy industrialization.

According to the method reported in the document CN102702070, the research shows that after the first step of reaction is finished, vacuum concentration of ethanol generates more byproducts at a slightly higher temperature (more than 40 ℃) and is particularly easy to generate a yellow substance, while concentration at a low temperature (less than 40 ℃) causes a long time and is also easy to generate a yellow substance, so that the product in the first step is impure, and the yield of the next step of condensation reaction is influenced, and the yield of the two steps of reaction is only 51%, and the purity of the obtained product is not high and is only 85-90%. Particularly, the method is disadvantageous in that the removal of ethanol or methanol serving as a reaction solvent by low-temperature high-vacuum concentration is extremely impractical for future industrialization. Similar side reactions also occur when methanol is used as the solvent. And the obtained product needs diethyl ether for crystallization and drying, otherwise, the residual alcohol solvent is greatly unfavorable for the next reaction.

The inventor of the invention has surprisingly found that the reaction solvent in the first step is changed into organic acid, such as formic acid, acetic acid, propionic acid, etc., so that the hydrogenation reaction temperature is increased, side reactions such as ethanol, methanol, etc. are not generated, and the condensation reaction in the second step is carried out by directly adding acetic anhydride without concentrating and removing the reaction solvent after the reaction is finished, so that the whole post-reaction treatment is very simple, the industrialization is easy, and more importantly, the yield of the two-step reaction reaches 70-80%, which is far higher than the 51% yield reported by the literature. The acetic acid generated in the hydrogenation reaction is easy to recycle. In addition, the one-pot reaction is easier to realize by using anhydride as a solvent, particularly acetic anhydride as a solvent.

In addition, the acetic anhydride is used for condensation reaction in the second step, then the thermal filtration is carried out, the cooling crystallization is carried out, the reaction in the third step can be carried out without drying the filtered product, the complex steps of washing with ether, drying and the like reported in the document CN102702070 are avoided, the safety and the energy consumption are reduced, and the industrialization is facilitated. The used solvent is easy to recycle.

It is clear that when preparing 3-acetamidophthalic anhydride in acetic acid or acetic anhydride as solvent according to the process of the present invention, the target product can be prepared successively via different intermediates by adjusting the reaction conditions. And in the actual reaction, one or more different intermediates may be present in the reaction solution, but none of them affect the final high yield preparation of high purity 3-acetamidophthalic anhydride.

The method is safer, energy-saving and environment-friendly, is simple to operate, has high yield and low cost, is easy to industrialize, and has extremely high industrial application value.

Detailed Description

The present invention is further illustrated by the following examples, which are not intended to limit the scope of the present invention in any way.

Example 1: preparation of 3-aminophthalic acid

2-Nitrophthalic acid (1.0kg), glacial acetic acid (8.5L), 10% Pd/C (30g) were added successively to the autoclave, replaced twice with nitrogen, hydrogen was introduced to 1MPa, the pressure was maintained at room temperature until no more hydrogen was taken up, vented, purged with nitrogen, cooled, filtered to give 920g of a product containing palladium on carbon, containing about 15% of solvent.

Example 2: preparation of 3-acetamidophthalic anhydride

Transferring the undried product obtained in example 1 into a 5L three-neck flask, adding acetic anhydride (4.5L), heating and refluxing for 1-2 hours, filtering while hot, washing with glacial acetic acid, then cooling the filtrate to 0-5 ℃, stirring until the product is fully separated out, filtering, washing with glacial acetic acid to obtain 827g of yellow needle-shaped crystals, about 12% of solvent, 728g after drying, 75% of yield in two steps and 99.8% of HPLC.

Example 3: preparation of apremilast

Adding the undried product (728 g after drying), glacial acetic acid (4.2L), (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl) ethylamine N-acetyl-L-leucine salt (1570g, ee 99.3%) into a reaction bottle in sequence, heating until reflux reaction lasts for 1 hour, stopping the reaction after TLC detection raw materials disappear, recovering glacial acetic acid under reduced pressure, adding dichloromethane 10L for dissolving, washing with water 5L, saturated sodium bicarbonate aqueous solution 5L 3 and saturated sodium chloride 5L in sequence, drying with anhydrous magnesium sulfate, concentrating to dryness under reduced pressure, adding anhydrous ethanol 10L, refluxing for 30 minutes, filtering, washing with ethanol, and drying at 60 ℃ to obtain 1584g of product, the yield is 97%, the HPLC content is more than 99.8%, and ee 99.2%.

Example 4: preparation of 3-acetamidophthalic anhydride

2-nitrophthalic acid (1.0kg), glacial acetic acid (8.5L) and 10% Pd/C (30g) are sequentially added into an autoclave, replaced by nitrogen twice, hydrogen is introduced to 1Mpa, the pressure reaction is maintained at room temperature until no hydrogen is absorbed, the reaction is vented, nitrogen is used for blowing, then the reaction solution is transferred into a reaction kettle with a return device, acetic anhydride (4.5L) is added, the reaction is heated and refluxed for 2 hours, the reaction solution is filtered while hot, washed by glacial acetic acid, then the filtrate is cooled to 0-5 ℃, the reaction solution is stirred until products are fully separated out, the filtration is carried out, the glacial acetic acid is washed, 840g of yellow needle-shaped crystals are obtained, the content of the solvent is about 11%, 747g is obtained after drying, the yield of the two steps is 77%, and.

Example 5: preparation of 3-acetamidophthalic anhydride

2-nitrophthalic acid (1.0kg), acetic anhydride (8.5L) and 10% Pd/C (30g) are sequentially added into an autoclave, replaced by nitrogen twice, hydrogen is introduced to 1MPa, the pressure is maintained at room temperature until no hydrogen is absorbed, the autoclave is vented, nitrogen is used for blowing, the temperature is increased to 110-115 ℃ for reaction until the raw materials or the intermediate state disappears, heat filtration is carried out, the temperature is cooled to 0-5 ℃, filtration is carried out, glacial acetic acid is washed, pale yellow crystals 914g are obtained, the solvent content is about 15%, drying is carried out for 778g, the yield is 80%, and HPLC is 99.0%.

Example 6: preparation of 3-acetamidophthalic anhydride

Adding 2-nitrophthalic acid (100.0g) and acetic anhydride (1L) into a hydrogenation kettle, heating to 80 ℃, cooling to room temperature after the raw materials disappear, adding 10% Pd/C (3g), replacing twice with nitrogen, introducing hydrogen to 1MPa, maintaining the pressure at room temperature until no hydrogen is absorbed, emptying, blowing with nitrogen, heating to 110-115 ℃ for reaction until the raw materials or the intermediate state disappear, performing heat filtration, cooling to 0-5 ℃, filtering, washing with glacial acetic acid to obtain light yellow crystals, drying 80.6g, obtaining the yield of 83%, and performing HPLC (high performance liquid chromatography) 99.0%.

Claims

1. An industrial process for the preparation of aplotax of formula (I), characterized in that:

i) using 3-nitrophthalic acid (compound II) as initial raw material, using acetic acid or acetic anhydride as solvent, using palladium-carbon to make catalytic hydrogenation to obtain 3-aminophthalic acid (compound III) or 3-aminophthalic anhydride (compound VI) or their mixture or their salt, then making said mixture undergo the processes of reaction, drying, mixing, drying and drying

ii) reflux reaction in acetic anhydride, cooling, crystallization to obtain high purity 3-acetamido phthalic anhydride (compound IV), and final

iii) reacting compound IV without drying with (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl) ethylamine (compound V) or a salt thereof directly under reflux in glacial acetic acid to give aplidine.

2. An industrial process for the preparation of aplite according to claim 1, characterized in that the 3-aminophthalic acid (compound III) or a salt thereof is prepared by catalytic hydrogenation of palladium on carbon using 3-nitrophthalic acid (compound II) as a starting material, acetic acid or acetic anhydride as a reaction solvent.

3. The industrial process for the preparation of aplidine according to claim 1, wherein the hydrogenation reaction temperature is 0-100 ℃.

4. The industrial process for the preparation of aplidine according to claim 1, wherein the hydrogenation reaction temperature is 0-25 ℃.

5. The industrial process for producing aplite according to claim 1, wherein after the hydrogenation reaction is completed, the reaction solution is filtered to obtain 2-aminophthalic acid (compound III) or a salt thereof, and then the reaction solution is refluxed in acetic anhydride, and after the reaction is completed, the reaction solution is filtered thermally, cooled and crystallized, and filtered to obtain high-purity 3-acetamidophthalic anhydride; or directly adding acetic anhydride into the reaction solution for reflux reaction without filtering after the hydrogenation reaction is finished, and carrying out hot filtration, cooling and crystallization after the reaction is finished, and filtering to obtain the high-purity 3-acetamidophthalic anhydride.

6. The industrial method for preparing aplite according to claim 1, wherein the 3-acetamidophthalic anhydride is prepared by using 3-nitrophthalic acid (compound II) as a starting material and acetic anhydride as a reaction solvent, and sequentially carrying out palladium-carbon catalytic hydrogenation, condensation and acetylation one-pot reaction.

7. The industrial process for preparing aplite according to claim 1, wherein the high purity 3-acetamidophthalic anhydride obtained by filtration is reacted directly with (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl) ethylamine or a salt thereof in glacial acetic acid without drying to obtain aplite.