CN107628983B - Apremilast of high chiral purity - Google Patents
Apremilast of high chiral purity Download PDFInfo
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Abstract
The invention discloses apremilast with high chiral purity. Prepared from key intermediates with low chiral purity. Specifically, 1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt as an apremilast key intermediate with an ee value of 65% -89% is recrystallized by water to obtain an intermediate refined product with an ee value of more than 99.9%, and the intermediate refined product is further reacted to obtain apremilast with an ee value of more than 99.9%, so that the safety and the effectiveness of a pharmaceutical preparation are ensured. The method is simple to operate, environment-friendly and suitable for industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a refining method of an apremilast key intermediate and prepared apremilast with high chiral purity.
Background
Apremilast (Apremilast), the first PDE4 inhibitor developed by Celgene corporation, usa, was approved by the FDA in us in 2014 for the treatment of psoriatic arthritis and plaque psoriasis. The Apremilast chemical name is (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, and the structural formula is as follows:
according to the literature (J.Med.chem.2009,52, 1522-.
At present, there are a plurality of preparation methods for apremilast and its intermediate, and one common method is:
resolving A1 into A2 by using a chiral reagent N-acetyl-L-leucine, and reacting A2 with A3 to obtain apremilast. Since the intermediate A2 prepared preliminarily contains a certain amount of isomers, and racemization phenomenon does not exist in the reaction of synthesizing Apremilast from A2 and A3, the obtained Apremilast has low chiral purity and contains enantiomers which are difficult to remove by recrystallization. The diastereoisomer of intermediate A2 can be easily purified and removed, so that Apremilast with high chiral purity can be obtained by purifying intermediate A2. The methods disclosed so far for obtaining apremilast of high chiral purity by purifying intermediate a2 include:
CN100427085 (pharmaceutical application of (+) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetamido isoindoline-1, 3-dione) discloses a preparation method of apremilast, wherein A1 reacts with N-acetyl-L-leucine to generate a crude product A2, and the crude product is heated, refluxed and pulped by methanol to obtain a refined product with ee value of 98.4%; recrystallizing Apremilast prepared from the refined product with ethanol water solution to obtain the final product with ee value of 98%.
CN105218428 (a preparation method of Apremilast with high chiral purity) discloses a method for preparing Apremilast by heating, refluxing, pulping and refining crude product A2 with methanol, adding refined product A3 into toluene solution, and adding acetic acid as catalyst. The maximum chiral purity of the finally prepared apremilast can reach 99.8%.
CN104529869 (preparation method of (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione isomer) discloses heating, refluxing and pulping A2 crude product in methanol water solution, ethanol water solution, acetone water solution or acetonitrile water solution and other organic solvent water solution to obtain intermediate A2 with chiral purity of more than 99%, wherein, the reaction effect is best by using methanol aqueous solution, especially 50 percent methanol aqueous solution, the crude product with ee value of 89.4 percent, can be refined to obtain A2 with ee value of 99.9%, thereby further obtaining Apremilast with ee value of 99.9%, for the crude product with ee value of 85.8-88.5%, the ee value of the purified refined product is less than 99.9%, and the ee value of the obtained Apremilast is less than 99.9%.
In addition, WO2016161996(A method of the chiral resolution of the key interaction of the synthesis of the ingredient and the use for the preparation of the pure ingredient) reacts A1 with a chiral tartaric acid derivative (3) to form a chiral salt intermediate (S) -4a, preferably (S) -4 aa. When the (S) -4aa crude product with the ee value of more than 92 percent is selected for water recrystallization, the (S) -4aa refined product with the ee value of more than 99 percent can be obtained, and finally the apremilast with the ee value of more than 99 percent can be obtained. The purification method for obtaining the intermediate with high chiral purity in the patent is suitable for crude products with high chiral purity (ee value is more than 92%). The recrystallization effect is not disclosed for crude products with ee value less than 92% before refining.
In summary, a new purification process is still required to be developed to refine the crude intermediate a2, especially to refine the crude product with a low ee value, so as to obtain apremilast with an ee value of 99.9%, which can simultaneously meet the requirements of pharmaceutical production and industrial production.
Disclosure of Invention
The invention aims to provide an Apremilast key intermediate 1- (3-ethoxy-4-methoxybenzene
A process for the purification of the salt of 2-methanesulfonyl-ethylamine-N-acetyl-L-leucine and the highly chiral pure apremilast prepared therefrom. According to the method, a key intermediate 1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethylamine-N-acetyl-L-leucine is recrystallized in a pure solvent, and the recrystallized intermediate with high chiral purity is further reacted to obtain the apremilast with high chiral purity. The purpose of the invention can be realized by the following technical scheme:
the invention provides a method for purifying a compound shown in a formula (I), wherein the ee value of a crude product of the compound shown in the formula (I) is 65-89%,
the method is characterized in that: the crude compound of formula (I) is recrystallized in pure water.
In a preferred embodiment, the recrystallization step is: dissolving the crude product of the compound with the formula (I) with the ee value of 65-89% in water, heating until the solid is completely dissolved under stirring, cooling for crystallization, filtering and drying.
In a preferred embodiment, the weight ratio of crude compound of formula (I) to water is from 1:18 to 1:30, preferably from 1:20 to 1:25, with an ee value of from 65% to 89%.
In a preferred embodiment, the temperature is raised with stirring in the recrystallization step to a temperature of 90 to 100 ℃, preferably 95 to 100 ℃ at which all the solids are dissolved.
In a preferred embodiment, the recrystallization step comprises a crystallization temperature of 0 to 30 ℃, preferably 0 to 10 ℃, more preferably 0 to 5 ℃.
In a preferred embodiment, the recrystallization step comprises a crystallization time of 0.5 to 5 hours.
The invention also provides a method for preparing high chiral purity apremilast, which is characterized by comprising the following steps:
a. recrystallizing the compound of formula (I) with the ee value of 65-89% with water to obtain a refined product of the compound of formula (II) with the ee value of more than 99.9%;
b. reacting the refined product of the compound shown in the formula (I) with 3-acetamidophthalic anhydride to generate apremilast with ee value of more than 99.9%;
the refining process disclosed by the invention aims at the apremilast intermediate with a low ee value, and the method disclosed by WO2016161996 has a good refining effect on the apremilast intermediate with a high ee value, but is not suitable for refining the intermediate with a low ee value.
The method uses water as a solvent to recrystallize the key intermediate of apremilast, greatly reduces the use of organic solvents in the whole process, is safe and environment-friendly, has low cost, and is very suitable for industrial production.
The method is simple to operate, effectively reduces the impurity content of the apremilast idiosome, and finally obtains the apremilast with the ee value of more than 99.9 percent, thereby ensuring the safety and the effectiveness of the final medicinal preparation and meeting the requirements of medicament production.
Drawings
FIG. 1 is an HPLC chromatogram of the crude product used in example 1, with an ee of 67.27%;
FIG. 2 is an HPLC chromatogram of the crude product used in example 2, with an ee of 77.71%;
FIG. 3 is an HPLC chromatogram of the crude product used in example 3, with an ee of 82.96%;
FIG. 4 is an HPLC chromatogram of the crude products used in examples 4 to 8, with an ee value of 88.36%;
FIG. 5 is an HPLC chromatogram of the product of example 1 of the present invention, with an ee of 99.93%;
FIG. 6 shows an HPLC chromatogram of Apremilast obtained in example 9 of the present invention, with an ee value of 99.95%.
Detailed Description
For better understanding of the contents of the present invention, the technical solutions of the present invention are further described below with reference to specific examples, but the specific embodiments are not meant to limit the present invention in any way.
The preparation of the crude product of the compound shown in the formula (I) refers to a patent CN104529869, and the ee value of the prepared crude product is 65-89%;
example 1
To a reaction flask was added crude (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (10g, ee: 67.27%), water (200mL) was added, the temperature was raised to 95 ℃ with stirring, the solid was completely dissolved, and the temperature was naturally lowered to room temperature and kept for 1 hour, and then filtered, and the filter cake was washed with water. The filter cake was dried to obtain a refined product of (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (6.15g, yield based on the content of S-type isomer: 73.6%, ee value: 99.93%), and HPLC chromatogram was as shown in FIG. 5.
Example 2
To a reaction flask was added crude (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine (10g, ee: 77.71%), water (200mL) was added, the temperature was raised to 95 ℃ with stirring, the solid was completely dissolved, the temperature was naturally lowered to 10 ℃ and kept for 1 hour, and the filter cake was washed with water. The filter cake was dried to give a refined product of (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (6.62g, yield based on the content of S-type isomer: 75.6%, ee value: 99.92%), and HPLC chromatogram was similar to that of FIG. 5.
Example 3
To a reaction flask was added crude (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (10g, ee: 82.96%), water (200mL) was added, the temperature was raised to 95 ℃ with stirring, the solid was completely dissolved, the temperature was naturally lowered to 10 ℃ and kept for 1.5 hours, and the filter cake was washed with water. The filter cake was dried to obtain a refined product of (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (7.15g, yield based on the content of S-type isomer: 78.2%, ee value: 99.94%), and HPLC chromatogram was similar to that of FIG. 5.
Example 4
Adding (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethylamine-N-acetyl-L-leucine crude salt (10g, ee value: 88.36%) into a reaction bottle, adding water (180mL), heating to reflux under stirring, dissolving clearly, naturally cooling to 5 ℃, maintaining the temperature for 1 hour, filtering, leaching a filter cake with water, and drying the filter cake to obtain (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethylamine-N-acetyl-L-leucine refined salt (7.60g, yield based on the content of S-type isomer: 80.7%, ee value: 99.96%), wherein an HPLC chromatogram is similar to that in FIG. 5.
Example 5
The crude (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (10g, ee value: 88.36%) was added to the reaction flask, water (200mL) was added, the temperature was raised to 90 ℃ with stirring, the solution was dissolved, the temperature was naturally lowered to 5 ℃ and maintained at this temperature for 1 hour, filtration was carried out, the filter cake was rinsed with water, and the filter cake was dried to obtain a refined (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (7.74g, yield based on the content of S-type isomer: 82.2%, ee value: 99.95%) whose HPLC chromatogram was similar to that of FIG. 5.
Example 6
A30L reaction kettle is added with (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethylamine-N-acetyl-L-leucine crude product (1kg, ee value: 88.36%), water (20L) is added, the temperature is raised to reflux under stirring, the solid is completely dissolved, the temperature is naturally reduced to 0 ℃ and maintained for 3 hours, the filtration is carried out, the filter cake is rinsed with water, the filter cake is dried to obtain (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethylamine-N-acetyl-L-leucine refined product (0.786kg, yield based on the content of S-type isomer: 83.5%, ee value: 99.95%), and an HPLC chromatogram is similar to that of FIG. 5.
Example 7
A reaction flask was charged with a crude (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (10g, ee: 88.36%), water (250mL) was added, the temperature was raised to 90 ℃ with stirring, the solution was dissolved, cooled naturally to 0 ℃ and kept at 0 ℃ for 3 hours, filtration was carried out, the filter cake was washed with water, and the filter cake was dried to obtain a refined (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (7.52g, yield based on the content of S-type isomer: 79.8%, ee: 99.93%), and an HPLC chromatogram was similar to that of FIG. 5.
Example 8
A reaction flask was charged with a crude (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (10g, ee: 88.36%), water (300mL) was added, the temperature was raised to 90 ℃ with stirring, the solution was dissolved, cooled naturally to 0 ℃ and kept at 0 ℃ for 5 hours, filtration was carried out, the filter cake was washed with water, and the filter cake was dried to obtain a refined (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt (7.36g, yield based on the content of S-type isomer: 78.1%, ee: 99.94%), and an HPLC chromatogram was similar to that of FIG. 5.
Example 9
Adding refined product of (S) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethylamine-N-acetyl-L-leucine salt (1.0kg, ee value: 99.95%), 3-acetaminophthalic anhydride (0.47kg) and glacial acetic acid (10L) into a reaction bottle, heating the system to reflux, stirring for 5 hours, naturally cooling to room temperature, concentrating under reduced pressure, adding water (5L) and dichloromethane (5L) into the residue, standing for liquid separation, washing organic phase with water (5L), saturated sodium bicarbonate solution (5L x 2) and water (5L), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, adding acetone (3L) into the residue, heating to clear, adding anhydrous ethanol (6L), naturally cooling to room temperature, stirring for 10 hr, filtering, and oven drying to obtain Apremilast (0.81kg, yield: 78.6%, ee value: 99.95%), and HPLC chromatogram shown in FIG. 6.
Example 10
Crude (S) -4aa crude was prepared as described in WO2016161996, and its ee value was found to be 88.0%. A purified product of (S) -4aa was obtained by recrystallization from water as in example 8 of WO2016161996, and its ee value was found to be 98.8%.
Claims (9)
1. A method for purifying a compound shown as a formula (I), wherein the ee value of a crude product of the compound shown as the formula (I) is 65-77.71%,
the method is characterized in that: recrystallizing the crude compound of the formula (I) in pure water; the recrystallization step is as follows: dissolving a crude product of the compound of the formula (I) with an ee value of 65-77.71% in water, heating while stirring until all solids are dissolved, cooling for crystallization, filtering and drying; wherein the weight-volume ratio of the crude compound of the formula (I) with the ee value of 65-77.71% to the water is 1: 18-30.
2. A process for the purification of a compound of formula (I) according to claim 1, characterized in that: the weight-volume ratio of the crude compound of the formula (I) with the ee value of 65-77.71% to the water is 1: 20-25.
3. A process for the purification of a compound of formula (I) according to claim 1, characterized in that: and heating the mixture under stirring until the temperature of the solid is completely dissolved is 90-100 ℃.
4. A process for the purification of a compound of formula (I) according to claim 3, characterized in that: and heating the mixture under stirring until the temperature of the solid is completely dissolved is 95-100 ℃.
5. A process for the purification of a compound of formula (I) according to claim 1, characterized in that: the temperature of the crystallization process is 0-30 ℃.
6. The method of purifying a compound of formula (I) according to claim 5, characterized in that: the temperature of the crystallization process is 0-10 ℃.
7. The method of purifying a compound of formula (I) according to claim 5, characterized in that: the temperature of the crystallization process is 0-5 ℃.
8. A process for the purification of a compound of formula (I) according to claim 1, characterized in that: the time of the crystallization process is 0.5-5 hours.
9. A method for preparing high chiral purity apremilast is characterized by comprising the following steps:
a. recrystallizing the compound shown in the formula (I) with the ee value of 65-77.71% by using water to obtain a refined product of the compound shown in the formula (I) with the ee value of more than 99.9%, wherein the weight-volume ratio of the crude product of the compound shown in the formula (I) with the ee value of 65-77.71% to the water in recrystallization is 1: 18-30;
b. reacting the refined product of the compound shown in the formula (I) with 3-acetamidophthalic anhydride to generate apremilast with ee value of more than 99.9%;
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CN104529869A (en) * | 2014-12-19 | 2015-04-22 | 苏州亚宝药物研发有限公司 | Preparation method of (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetyl amino isoindoline-1, 3-diketone isomer |
WO2017033116A1 (en) * | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
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WO2016161996A1 (en) * | 2015-04-09 | 2016-10-13 | Zentiva, K.S. | A method of chiral resolution of the key intermediate of the synthesis of apremilast and its use for the preparation of pure apremilast |
CN105218428A (en) * | 2015-10-20 | 2016-01-06 | 南京美嘉宁逸医药研究开发有限公司 | A kind of preparation method of Apremilast of high chiral purity |
CN105348172B (en) * | 2015-12-04 | 2017-11-14 | 新发药业有限公司 | (S) preparation method of the preparation of the mesyl ethamine of 1 (ethyoxyl of 4 methoxyl group 3) phenyl 2 and Apremilast |
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CN104529869A (en) * | 2014-12-19 | 2015-04-22 | 苏州亚宝药物研发有限公司 | Preparation method of (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetyl amino isoindoline-1, 3-diketone isomer |
WO2017033116A1 (en) * | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
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