CN105294534B - Industrialized method for preparing aplidine and intermediate thereof - Google Patents
Industrialized method for preparing aplidine and intermediate thereof Download PDFInfo
- Publication number
- CN105294534B CN105294534B CN201410335852.6A CN201410335852A CN105294534B CN 105294534 B CN105294534 B CN 105294534B CN 201410335852 A CN201410335852 A CN 201410335852A CN 105294534 B CN105294534 B CN 105294534B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- anhydride
- acid
- drying
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 17
- UUSZLLQJYRSZIS-LXNNNBEUSA-N plitidepsin Chemical compound CN([C@H](CC(C)C)C(=O)N[C@@H]1C(=O)N[C@@H]([C@H](CC(=O)O[C@H](C(=O)[C@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(OC)=CC=2)C(=O)O[C@@H]1C)C(C)C)O)[C@@H](C)CC)C(=O)[C@@H]1CCCN1C(=O)C(C)=O UUSZLLQJYRSZIS-LXNNNBEUSA-N 0.000 title claims abstract description 13
- 229950008499 plitidepsin Drugs 0.000 title claims abstract description 13
- 108010049948 plitidepsin Proteins 0.000 title claims abstract description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229960000583 acetic acid Drugs 0.000 claims abstract description 24
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 18
- PAUAJOABXCGLCN-UHFFFAOYSA-N n-(1,3-dioxo-2-benzofuran-4-yl)acetamide Chemical compound CC(=O)NC1=CC=CC2=C1C(=O)OC2=O PAUAJOABXCGLCN-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010992 reflux Methods 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 3-ethoxy-4-methoxyphenyl Chemical group 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 4
- KFIRODWJCYBBHY-UHFFFAOYSA-N 3-nitrophthalic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O KFIRODWJCYBBHY-UHFFFAOYSA-N 0.000 claims abstract 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 238000001914 filtration Methods 0.000 claims description 18
- 238000005984 hydrogenation reaction Methods 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- MSKNUZSVGYXUBM-UHFFFAOYSA-N 1-aminocyclohexa-3,5-diene-1,2-dicarboxylic acid Chemical compound OC(=O)C1(N)C=CC=CC1C(O)=O MSKNUZSVGYXUBM-UHFFFAOYSA-N 0.000 claims description 3
- WGLQHUKCXBXUDV-UHFFFAOYSA-N 3-aminophthalic acid Chemical compound NC1=CC=CC(C(O)=O)=C1C(O)=O WGLQHUKCXBXUDV-UHFFFAOYSA-N 0.000 claims description 3
- 238000006640 acetylation reaction Methods 0.000 claims description 3
- 238000005580 one pot reaction Methods 0.000 claims description 3
- 230000021736 acetylation Effects 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 7
- DQNFPCOVVBRXOY-UHFFFAOYSA-N 4-amino-2-benzofuran-1,3-dione Chemical compound NC1=CC=CC2=C1C(=O)OC2=O DQNFPCOVVBRXOY-UHFFFAOYSA-N 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 11
- 150000007524 organic acids Chemical class 0.000 abstract description 4
- 150000008065 acid anhydrides Chemical class 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- KKTRZAZFCRHFFW-UHFFFAOYSA-N 1-nitrocyclohexa-3,5-diene-1,2-dicarboxylic acid Chemical compound OC(=O)C1C=CC=CC1(C(O)=O)[N+]([O-])=O KKTRZAZFCRHFFW-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000005406 washing Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000006482 condensation reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- OSYXIXHFZAFQTC-UHFFFAOYSA-N 7a-amino-3ah-2-benzofuran-1,3-dione Chemical compound C1=CC=CC2C(=O)OC(=O)C21N OSYXIXHFZAFQTC-UHFFFAOYSA-N 0.000 description 3
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 description 3
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 description 3
- 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 description 3
- 229960001164 apremilast Drugs 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- TWWJPFGKFSTWRU-UHFFFAOYSA-N 7a-nitro-3ah-2-benzofuran-1,3-dione Chemical compound C1=CC=CC2C(=O)OC(=O)C21[N+](=O)[O-] TWWJPFGKFSTWRU-UHFFFAOYSA-N 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- IMOZEMNVLZVGJZ-UHFFFAOYSA-N n-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindol-4-yl]acetamide Chemical compound C1=C(OC)C(OCC)=CC(C(CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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
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 (7)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410335852.6A CN105294534B (en) | 2014-07-15 | 2014-07-15 | Industrialized method for preparing aplidine and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410335852.6A CN105294534B (en) | 2014-07-15 | 2014-07-15 | Industrialized method for preparing aplidine and intermediate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105294534A CN105294534A (en) | 2016-02-03 |
| CN105294534B true CN105294534B (en) | 2020-04-10 |
Family
ID=55192456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410335852.6A Expired - Fee Related CN105294534B (en) | 2014-07-15 | 2014-07-15 | Industrialized method for preparing aplidine and intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105294534B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892486B (en) * | 2015-06-25 | 2017-12-08 | 济南纽华医药科技有限公司 | The crystal formation B of Apremilast+And preparation method thereof |
| CN107188842A (en) * | 2017-04-12 | 2017-09-22 | 广州艾格生物科技有限公司 | A kind of method for preparing high-purity Apremilast |
| CN109384704A (en) * | 2017-08-03 | 2019-02-26 | 重庆医药工业研究院有限责任公司 | A kind of preparation method of Apremilast |
| CN107602514A (en) * | 2017-08-21 | 2018-01-19 | 赵剑锋 | A kind of 3 acetylamino phthalic anhydride preparation methods |
| CN110467557B (en) * | 2018-05-11 | 2021-02-26 | 北京大学 | Apst's three-component one-pot synthesis method |
| CN110818583A (en) * | 2018-08-13 | 2020-02-21 | 江苏正大清江制药有限公司 | Preparation and refining method of apremilast key intermediate |
| CN113121404B (en) * | 2019-12-30 | 2024-07-09 | 江苏先声药业有限公司 | Synthesis method of apremilast |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652772A (en) * | 2002-03-20 | 2005-08-10 | 细胞基因公司 | (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof |
| CN102046167A (en) * | 2008-03-27 | 2011-05-04 | 细胞基因公司 | Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof |
| CN102558022A (en) * | 2010-12-22 | 2012-07-11 | 康塞特医药品有限公司 | Substituted isoindoline-1,3-dione derivative |
| CN102702070A (en) * | 2008-03-27 | 2012-10-03 | 细胞基因公司 | Solid form containing (+)-2-[1-(3-oxethyl-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, composition and application thereof |
| CN103635188A (en) * | 2011-04-28 | 2014-03-12 | 细胞基因公司 | Methods and compositions using PDE4 inhibitors for the treatment and management of autoimmune and inflammatory diseases |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070155791A1 (en) * | 2005-12-29 | 2007-07-05 | Zeldis Jerome B | Methods for treating cutaneous lupus using aminoisoindoline compounds |
-
2014
- 2014-07-15 CN CN201410335852.6A patent/CN105294534B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652772A (en) * | 2002-03-20 | 2005-08-10 | 细胞基因公司 | (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof |
| CN102046167A (en) * | 2008-03-27 | 2011-05-04 | 细胞基因公司 | Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof |
| CN102702070A (en) * | 2008-03-27 | 2012-10-03 | 细胞基因公司 | Solid form containing (+)-2-[1-(3-oxethyl-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, composition and application thereof |
| CN102558022A (en) * | 2010-12-22 | 2012-07-11 | 康塞特医药品有限公司 | Substituted isoindoline-1,3-dione derivative |
| CN103635188A (en) * | 2011-04-28 | 2014-03-12 | 细胞基因公司 | Methods and compositions using PDE4 inhibitors for the treatment and management of autoimmune and inflammatory diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105294534A (en) | 2016-02-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105294534B (en) | Industrialized method for preparing aplidine and intermediate thereof | |
| CN109369545B (en) | Synthesis process of 2-methyl-5-pyrazine formate | |
| CN102924386A (en) | Industrial preparation method of 4-bromopyridazine | |
| CN103664923B (en) | The preparation method of Nifuratel | |
| CN116102464B (en) | A method for preparing amino alcohols by asymmetric hydrogenation and its application | |
| CN107721999A (en) | A kind of preparation method of the quinuclidinol of optical activity 3 | |
| CN101298413A (en) | Preparation of 3-methylcy-clopentadecanone | |
| CN103450069B (en) | Preparation method of mitiglinide calcium | |
| CN101555223B (en) | A kind of pyrilimycin intermediate and preparation method thereof | |
| CN113717132B (en) | Key intermediate of antiepileptic drug and preparation method thereof | |
| CN106542958B (en) | A kind of preparation method of o-iodoaniline | |
| CN105439837B (en) | Synthetic method of 6-bromoisovanillin | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| CN105348285B (en) | Low-cost and high-yield adenine preparation method | |
| CN102140056A (en) | Method for preparing coking gallic acid | |
| CN107936045A (en) | A kind of preparation method of high-purity Flurbiprofen known impurities | |
| CN114478658A (en) | Synthesis method of monatibavir | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN107311998A (en) | A kind of preparation method of high-purity 9-hydroxy-risperidone intermediate | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| CN106518687A (en) | Efficient preparation method of high-purity tetraethyl ammonium chloride | |
| CN109456172B (en) | Method for purifying dodecanedioic acid in water phase | |
| CN112266360B (en) | Synthesis method of high-purity histamine dihydrochloride | |
| CN113004281A (en) | Preparation method of entecavir intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200410 Termination date: 20200715 |