A kind of preparation method of Apremilast of high chiral purityTechnical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of Apremilast of high chiral purity
Preparation method.
Background technology
Apremilast chemistry (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-diketone by name, its chemical structural formula is:
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Existing but (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1; 3-diketone is by 3-acetamido Tetra hydro Phthalic anhydride and (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine flows reaction overnight next time in the situation that acetic acid is solvent and generates; long reaction time, and the chiral purity of Apremilast reduces.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, a kind of high chiral purity is now provided
The preparation method of Apremilast.
For achieving the above object, technical scheme of the present invention is: a kind of preparation method of Apremilast of high chiral purity, its innovative point is: described preparation method is as follows: by compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and compound N-acetyl-L-Leu salt-forming reaction obtain compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, compound (S)-2-(3-ethoxy-4-methoxyphenyl after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt reacts generation again and obtains compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1 under toluene and acetic acid existent condition with compound 3-kharophen Tetra hydro Phthalic anhydride, 3-diketone, the purer Apremilast of steric isomer is obtained by the mixed solvent recrystallization of acetone and ethanol.
Further, described compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl) the concrete preparation method of-ethyl-2-base amine-N-ethanoyl-L-Leu salt is: be 65 ~ 70 DEG C in temperature of reaction, select the methyl alcohol of 280 ~ 420ml as under the condition of solvent, by 40 ~ 60g compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and 16 ~ 22g compound N-acetyl-L-Leu salt-forming reaction obtain 40 ~ 60g compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt.
Further; described compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl) the concrete purification process of-ethyl-2-base amine-N-ethanoyl-L-Leu salt is: be 65 ~ 70 DEG C in temperature of reaction; select 220 ~ 420ml methyl alcohol as solvent; refining (the S)-2-(3-ethoxy-4-methoxyphenyl obtaining purifying under reflux temperature)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, described reflux temperature is 65 ~ 70 DEG C.
Further, described compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, the concrete preparation method of 3-diketone is: select 320 ~ 480ml toluene to be solvent, 32 ~ 48ml acetic acid is catalyzer, 16 ~ 24g compound (S)-2-(3-ethoxy-4-methoxyphenyl by after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt and 8 ~ 12g compound 3-kharophen Tetra hydro Phthalic anhydride react 2 ~ 3h at a reflux temperature, obtain 16 ~ 24g compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, 3-diketone, described reflux temperature is 110 ~ 120 DEG C.
Further; the preparation method of the Apremilast of described high chiral purity is specially: by 16 ~ 24g compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1; 3-diketone puts into solvent; under 50 ~ 60 DEG C of conditions, recrystallization obtains high purity Apremilast, and described solvent is the mixture of 64 ~ 96ml acetone and 126 ~ 192ml ethanol.
Beneficial effect of the present invention is as follows: the present invention is by changing solvent, adding catalyzer, substantially reduce the reaction times, obtained Apremilast crude product, again through acetone and alcohol mixed solvent recrystallization, effectively can suppress the upset of chiral centre in Apremilast building-up process, thus obtained chiral purity is up to the Apremilast of 99.6%.
Embodiment
By particular specific embodiment, embodiments of the present invention are described below, person skilled in the art scholar the content disclosed by this specification sheets can understand other advantages of the present invention and effect easily.
Reactional equation of the present invention is as follows:
Embodiment 1
A kind of preparation method of Apremilast of high chiral purity, by compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and compound N-acetyl-L-Leu salt-forming reaction obtain compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, compound (S)-2-(3-ethoxy-4-methoxyphenyl after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt reacts generation again and obtains compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1 under toluene and acetic acid existent condition with compound 3-kharophen Tetra hydro Phthalic anhydride, 3-diketone, the purer Apremilast of steric isomer is obtained by the mixed solvent recrystallization of acetone and ethanol.
Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl) the concrete preparation method of-ethyl-2-base amine-N-ethanoyl-L-Leu salt is: be 65 ~ 70 DEG C in temperature of reaction; select the methyl alcohol of 280ml as under the condition of solvent, by 40g compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and 16g compound N-acetyl-L-Leu salt-forming reaction obtain 40g compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt.
Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl) the concrete purification process of-ethyl-2-base amine-N-ethanoyl-L-Leu salt is: be 65 ~ 70 DEG C in temperature of reaction; select 220ml methyl alcohol as solvent; refining (the S)-2-(3-ethoxy-4-methoxyphenyl obtaining purifying under reflux temperature)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, reflux temperature is 65 DEG C.
Compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, the concrete preparation method of 3-diketone is: select 320ml toluene to be solvent, 32ml acetic acid is catalyzer, 16g compound (S)-2-(3-ethoxy-4-methoxyphenyl by after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt and 8g compound 3-kharophen Tetra hydro Phthalic anhydride react 2 ~ 3h at a reflux temperature, obtain 16g compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, 3-diketone, reflux temperature is 110 DEG C.
The preparation method of the Apremilast of high chiral purity is specially: by 16g compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1; 3-diketone puts into solvent; under 50 ~ 60 DEG C of conditions, recrystallization obtains high purity Apremilast, and solvent is the mixture of 64ml acetone and 126ml ethanol.
The chiral purity of the Apremilast that the present embodiment obtains is up to 99.6%.
Embodiment 2
A kind of preparation method of Apremilast of high chiral purity, by compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and compound N-acetyl-L-Leu salt-forming reaction obtain compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, compound (S)-2-(3-ethoxy-4-methoxyphenyl after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt reacts generation again and obtains compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1 under toluene and acetic acid existent condition with compound 3-kharophen Tetra hydro Phthalic anhydride, 3-diketone, the purer Apremilast of steric isomer is obtained by the mixed solvent recrystallization of acetone and ethanol.
Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl) the concrete preparation method of-ethyl-2-base amine-N-ethanoyl-L-Leu salt is: be 65 ~ 70 DEG C in temperature of reaction; select the methyl alcohol of 420ml as under the condition of solvent, by 60g compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and 22g compound N-acetyl-L-Leu salt-forming reaction obtain 60g compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt.
Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl) the concrete purification process of-ethyl-2-base amine-N-ethanoyl-L-Leu salt is: be 65 ~ 70 DEG C in temperature of reaction; select 420ml methyl alcohol as solvent; refining (the S)-2-(3-ethoxy-4-methoxyphenyl obtaining purifying under reflux temperature)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, reflux temperature is 70 DEG C.
Compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, the concrete preparation method of 3-diketone is: select 480ml toluene to be solvent, 48ml acetic acid is catalyzer, 24g compound (S)-2-(3-ethoxy-4-methoxyphenyl by after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt and 12g compound 3-kharophen Tetra hydro Phthalic anhydride react 2 ~ 3h at a reflux temperature, obtain 24g compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, 3-diketone, reflux temperature is 120 DEG C.
The preparation method of the Apremilast of high chiral purity is specially: by 24g compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1; 3-diketone puts into solvent; under 50 ~ 60 DEG C of conditions, recrystallization obtains high purity Apremilast, and solvent is the mixture of 96ml acetone and 192ml ethanol.
The chiral purity of the Apremilast that the present embodiment obtains is up to 99.6%.
Embodiment 3
A kind of preparation method of Apremilast of high chiral purity, by compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and compound N-acetyl-L-Leu salt-forming reaction obtain compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, compound (S)-2-(3-ethoxy-4-methoxyphenyl after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt reacts generation again and obtains compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1 under toluene and acetic acid existent condition with compound 3-kharophen Tetra hydro Phthalic anhydride, 3-diketone, the purer Apremilast of steric isomer is obtained by the mixed solvent recrystallization of acetone and ethanol.
Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl) the concrete preparation method of-ethyl-2-base amine-N-ethanoyl-L-Leu salt is: be 65 ~ 70 DEG C in temperature of reaction; select the methyl alcohol of 350ml as under the condition of solvent, by 50g compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and 19g compound N-acetyl-L-Leu salt-forming reaction obtain 50g compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt.
Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl) the concrete purification process of-ethyl-2-base amine-N-ethanoyl-L-Leu salt is: be 65 ~ 70 DEG C in temperature of reaction; select 320ml methyl alcohol as solvent; refining (the S)-2-(3-ethoxy-4-methoxyphenyl obtaining purifying under reflux temperature)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, reflux temperature is 67 DEG C.
Compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, the concrete preparation method of 3-diketone is: select 400ml toluene to be solvent, 40ml acetic acid is catalyzer, 20g compound (S)-2-(3-ethoxy-4-methoxyphenyl by after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt and 10g compound 3-kharophen Tetra hydro Phthalic anhydride react 2 ~ 3h at a reflux temperature, obtain 20g compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, 3-diketone, reflux temperature is 115 DEG C.
The preparation method of the Apremilast of high chiral purity is specially: by 20g compound (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1; 3-diketone puts into solvent; under 50 ~ 60 DEG C of conditions, recrystallization obtains high purity Apremilast, and solvent is the mixture of 80ml acetone and 159ml ethanol.
The chiral purity of the Apremilast that the present embodiment obtains is up to 99.8%.
The present invention is by changing solvent, adding catalyzer, substantially reduce the reaction times, obtained Apremilast crude product, through acetone and alcohol mixed solvent recrystallization, effectively can suppress the upset of chiral centre in Apremilast building-up process, thus obtained chiral purity is up to the Apremilast of 99.8%.
Above-described embodiment is preferred embodiment of the present invention; it is not the restriction to technical solution of the present invention; as long as without the technical scheme that creative work can realize on the basis of above-described embodiment, all should be considered as falling within the scope of the rights protection of patent of the present invention.