CN105218428A - A kind of preparation method of Apremilast of high chiral purity - Google Patents
A kind of preparation method of Apremilast of high chiral purity Download PDFInfo
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- CN105218428A CN105218428A CN201510677834.0A CN201510677834A CN105218428A CN 105218428 A CN105218428 A CN 105218428A CN 201510677834 A CN201510677834 A CN 201510677834A CN 105218428 A CN105218428 A CN 105218428A
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- methoxyphenyl
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- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 title claims abstract description 45
- 229960001164 apremilast Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000002904 solvent Substances 0.000 claims abstract description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000001953 recrystallisation Methods 0.000 claims abstract description 13
- 150000001412 amines Chemical class 0.000 claims abstract description 12
- KMOUUZVZFBCRAM-OLQVQODUSA-N (3as,7ar)-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione Chemical compound C1C=CC[C@@H]2C(=O)OC(=O)[C@@H]21 KMOUUZVZFBCRAM-OLQVQODUSA-N 0.000 claims abstract description 11
- 239000012046 mixed solvent Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000010992 reflux Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 abstract description 4
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GVFODJRDMQTOEU-UHFFFAOYSA-N C(C)(=O)NC1C2C(C(=O)OC2=O)C=CC1 Chemical compound C(C)(=O)NC1C2C(C(=O)OC2=O)C=CC1 GVFODJRDMQTOEU-UHFFFAOYSA-N 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940011530 otezla Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of Apremilast of high chiral purity, 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine and N-ethanoyl-L-Leu salt-forming reaction obtain (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl-2-base amine-N-ethanoyl-L-Leu salt, (S)-2-(3-ethoxy-4-methoxyphenyl after purifying)-1-(methylsulfonyl)-ethyl-2-base amine-? does N-ethanoyl-L-Leu salt react generation with 3-kharophen Tetra hydro Phthalic anhydride again and obtains under toluene and acetic acid existent condition? (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, 3-diketone, the purer Apremilast of steric isomer is obtained by acetone and alcohol mixed solvent recrystallization.The invention has the advantages that: the present invention, by changing solvent, adding catalyzer, substantially reduces the reaction times, and obtained chiral purity is up to the Apremilast of 99.8%.
Description
Technical 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:
Apremilast obtains U.S. FDA approval listing on March 25th, 2014, and commodity are called Otezla, are used for the treatment of psoriatic arthritis.Apremilast is phosphodiesterase (PDE4) the inhibitor class new small molecule oral medicine of first granted listing, manufactured by the Celgene company of New Jersey Summit, there is good curative effect and high security, change the current treatment status of global psoriatic arthritis.
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.
Claims (5)
1. the preparation method of the Apremilast of a high chiral purity, it is characterized in that: 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.
2. the preparation method of the Apremilast of a kind of high chiral purity according to claim 1, it is characterized in that: 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.
3. the preparation method of the Apremilast of a kind of high chiral purity according to claim 1, it is characterized in that: 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.
4. the preparation method of the Apremilast of a kind of high chiral purity according to claim 1, it is characterized in that: 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.
5. a kind of preparation method preparing the Apremilast of high chiral purity according to claim 1; it is characterized in that: 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.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187857A (en) * | 2016-06-30 | 2016-12-07 | 浙江华海药业股份有限公司 | A kind of method preparing Apremilast |
| CN106995401A (en) * | 2016-01-29 | 2017-08-01 | 浙江京新药业股份有限公司 | A kind of method for preparing high-optical-purity Apremilast |
| CN107628983A (en) * | 2017-05-19 | 2018-01-26 | 杭州华东医药集团新药研究院有限公司 | The Apremilast of high chiral purity |
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| WO2018001353A1 (en) * | 2016-06-30 | 2018-01-04 | 浙江华海药业股份有限公司 | Method for preparing apremilast |
| US10781173B2 (en) | 2016-06-30 | 2020-09-22 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for preparing apremilast |
| CN107628983A (en) * | 2017-05-19 | 2018-01-26 | 杭州华东医药集团新药研究院有限公司 | The Apremilast of high chiral purity |
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