CN105085373A - Purification method of apremilast product - Google Patents
Purification method of apremilast product Download PDFInfo
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- CN105085373A CN105085373A CN201510556248.0A CN201510556248A CN105085373A CN 105085373 A CN105085373 A CN 105085373A CN 201510556248 A CN201510556248 A CN 201510556248A CN 105085373 A CN105085373 A CN 105085373A
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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 41
- 229960001164 apremilast Drugs 0.000 title claims abstract description 40
- 238000000746 purification Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title abstract description 4
- 239000000047 product Substances 0.000 claims abstract description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229960000583 acetic acid Drugs 0.000 claims abstract description 15
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 15
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 239000012065 filter cake Substances 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 7
- 238000000967 suction filtration Methods 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000004809 thin layer chromatography Methods 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 235000021463 dry cake Nutrition 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 3
- 229940059260 amidate Drugs 0.000 claims description 3
- 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 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 235000012970 cakes Nutrition 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 abstract description 7
- 230000008025 crystallization Effects 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract 2
- 150000008064 anhydrides Chemical class 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 238000001704 evaporation Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000003828 vacuum filtration Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 230000006196 deacetylation Effects 0.000 description 6
- 238000003381 deacetylation reaction Methods 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 2
- 230000001185 psoriatic effect Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- -1 decompress filter Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229940011530 otezla Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a purification method of apremilast in a preparation process, which comprises the following steps: (1) using acid anhydride and chiral amine as reaction raw materials, using glacial acetic acid as a solvent, carrying out reaction, detecting by TLC, adding acetic anhydride after the chiral amine raw materials completely react, continuing to react for 1-1.5h, evaporating the glacial acetic acid, pouring residues into water, stirring to form suspended matters, carrying out suction filtration, washing a filter cake, and drying to obtain an apremilast crude product; (2) and adding the apremilast crude product into EtOH, heating and refluxing for 1-3h, cooling to room temperature under the condition of stirring, carrying out vacuum filtration, washing a filter cake, and drying to obtain the apremilast pure product. According to the invention, the anhydride is added after the main reaction is finished, so that the pure Apremilast product with the purity of more than 99.9% can be obtained by one-time crystallization, and the total yield is improved by more than 20%.
Description
Technical field
The present invention relates to the purification process of the product in chemicals synthesis technical field, be related specifically to the purification process to Apremilast product.
Background technology
In medical medicine field, for the psoriatic of psoriatic (being commonly called as psoriasis) especially patch type, that be almost of no curative effect, cheap and good-quality medicine.So that many patient's acute diseases are disorderly seeked medical advice, find informal, use earthwork to cure the disease, rarely have the case of recovery from illness, instead grow many side effects, cause other disease.
Apremilast (Apremilast) product of U.S. Sai Er gene (Celgene) company research and development is oral pharmaceutical for the treatment of reactivity psoriatic arthritis.Ratify this product in March, 2014 U.S. food Drug Administration (FoodandDrugAdministration is called for short FDA) to go on the market with trade(brand)name Otezla.Since listing, it is also the oral pharmaceutical, the oral small molecules phosphodiesterase inhibitor (PDE4) that are uniquely used for the treatment of psoriasis in plaques treatment that this medicine has become first; Become the first-selected oral pharmaceutical for the treatment of psoriasis arthropathica.Be applicable to the adult patients for the treatment of reactivity psoriasis arthropathica.
Apremilast, chemistry (+)-2-[1-(3-oxyethyl group-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetamido isoindoline-1,3-diketone by name, structural formula is as follows:
The synthetic method of Apremilast, especially intermediate have multiple preparation method.But final synthesis Apremilast method is often as shown in following reaction equation:
With acid anhydrides (1) and Chiral Amine (2) for reaction raw materials, Glacial acetic acid is solvent, carries out sub-amidate action.By thin-layer chromatography (TLC) detection reaction.
The major impurity of above-mentioned reaction is deacetylation product (3), and content is about 2-3%, and this impurity needs repeatedly crystallization to remove, and Comparatively speaking, other impurity all remove easily via primary crystallization.This how subcrystalline operation makes product have more loss, and total recovery is not high yet
Summary of the invention
The present invention seeks to: overcome deficiency of the prior art, a kind of purification process to Apremilast product is provided.As long as carry out the purity that primary crystallization just can improve Apremilast product, and then improve total recovery, reduce total production cost.
Technical scheme of the present invention is: a kind of purification process to Apremilast product, and described purification step is:
(A) with acid anhydrides and Chiral Amine for reaction raw materials, Glacial acetic acid is solvent, carries out sub-amidate action.By thin-layer chromatography (TLC) detection reaction;
(B) show until thin-layer chromatography (TLC) detection: after Chiral Amine (2) reacts completely, add acetic anhydride, continue reaction 1-1.5 hour;
(C) boil off Glacial acetic acid, resistates is poured into water, stir, form suspended substance, suction filtration, washing leaching cake, dry cake, obtain Apremilast crude product;
(D) add in ethanol by Apremilast crude product, reflux 1-3h, agitation condition drops to room temperature;
(E) above-mentioned material is carried out reduce pressure, suction filtration, and use washing with alcohol filter cake, dry cake, obtain Apremilast sterling;
At this, represent the precedence of these purification steps with (A) ~ (E).
Described acid anhydrides is 3-kharophen Tetra hydro Phthalic anhydride.
Described Chiral Amine is (+)-1-(4-methoxyl group-3-oxyethyl group) phenyl-2-(methylsulfonyl) ethamine (II).
In step (A) and (B), the ratio of the add-on of acid anhydrides, Chiral Amine, Glacial acetic acid and acetic anhydride is (20-21) mmol:(19-20) mmol:(60-70) ml:60mmol.
In step (A), it is methyl alcohol and methylene dichloride that thin-layer chromatography (TLC) detects developping agent used, and their volume parts ratio is: methyl alcohol: methylene dichloride=1:10.
In step (C), the volume of the water that resistates is poured into and the volume parts of Glacial acetic acid are than being 10:6.5.
In step (C), the temperature of dry cake is 50 DEG C, and time of drying is 4-5h.
In step (D), the ratio of Apremilast crude product and amount of alcohol added is 8g:(65-75) ml.
In step (D), the temperature 60 C of dry cake, time of drying is 2-3h.
Adopt purification process of the present invention, only through primary crystallization, the by product of deacetylation can be reduced to 0.05% by original 2-3%, can obtain the Apremilast sterling of purity more than 99.9%, total recovery improves more than 20%.The improvement of technique substantially reduces the operation steps of crystallization and the usage quantity of solvent, improves product yield, makes production cost reduce by more than 20%.
Accompanying drawing explanation
Fig. 1 is that the high performance liquid chromatography (HPLC) of embodiment 1 product detects figure;
Fig. 2 is the hydrogen spectrogram of embodiment 1 product;
Fig. 3 is the carbon spectrogram of embodiment 1 product.
Embodiment
Embodiment 1: by acid anhydrides (4.16g, 20.26mmol), Chiral Amine (19.3mmol) adds in the reaction flask of 250mL, add Glacial acetic acid (65mL) again, reflux at 120 DEG C, thin-layer chromatography (TLC) detection reaction (methyl alcohol: methylene chloride volume portion rate=1:10), treat that Chiral Amine raw material reaction completely (about 5-6h), add acetic anhydride (60mmol), continue reaction 1h, boil off Glacial acetic acid, resistates is poured in the water of 100mL vigorous stirring, forms suspended substance.Suction filtration; filter cake 4 × 50mL water washing, is placed in the dry approximately 4-5h of 50 DEG C of loft drier, obtains yellow Apremilast crude product 8.0g by filter cake; it is 98.8% that high performance liquid chromatography (HPLC) detects its purity, and the by-products content of deacetylation is about 0.05%.Above-mentioned crude product is added in ethanol (70mL), reflux 2h, then be slowly down to room temperature under stirring, separate out solid, decompress filter, filter cake ethanol (2 × 10mL) washs, dry (60 DEG C, dry 3h), obtaining Apremilast product is 7.5g, total recovery 84%, high performance liquid chromatography (HPLC) detects its purity >99.9%.What high performance liquid chromatography (HPLC) detected the results are shown in Figure 1, and the hydrogen spectrum measurement result of product is shown in Fig. 2, and carbon spectrum measurement result is shown in Fig. 3, and result shows, the product obtained is highly purified Apremilast product.
1HNMR(400MHz,CDCl3)δ9.46(s,1H),8.75(d,J＝8.5Hz,1H),7.65(t,J＝7.9Hz,1H),7.48(d,J＝7.3Hz,1H),7.10(d,J＝6.8Hz,2H),6.84(d,J＝8.9Hz,1H),5.87(dd,J＝10.5,4.3Hz,1H),4.55(dd,J＝14.3,10.6Hz,1H),4.11(q,J＝7.0Hz,2H),3.85(s,3H),3.74(dd,J＝14.4,4.4Hz,1H),2.88(s,3H),2.26(s,3H),1.47(t,J＝7.0Hz,3H).
13CNMR(100MHz,CDCl3)δ169.05,168.75,167.04,149.27,148.17,137.15,135.67,130.58,128.77,124.51,119.84,117.78,114.66,111.93,110.97,64.06,55.48,53.99,48.07,41.18,24.50,14.23。
Comparative example 1:
By acid anhydrides (4.16g, 20.26mmol), Chiral Amine (19.3mmol) adds in the reaction flask of 250mL, add Glacial acetic acid (65mL) again, reflux at 120 DEG C, thin-layer chromatography (TLC) detection reaction (methyl alcohol: methylene chloride volume portion rate=1:10), treat that Chiral Amine raw material reaction completely (about 5-6h), boil off Glacial acetic acid, resistates is poured in the water of 100mL vigorous stirring, forms suspended substance.Suction filtration; filter cake 4x50mL water washing, is placed in the dry approximately 4-5h of 50 DEG C of loft drier, obtains yellow Apremilast crude product 8.0g by filter cake; high performance liquid chromatography (HPLC) detects its purity 96.0%, and the by-products content of deacetylation is about 2-3%.Crude product is added in ethanol (70mL); reflux 2h; then slowly room temperature is down under stirring; separate out solid; decompress filter, filter cake ethanol (2 × 10mL) washing, dry; obtaining Apremilast product is 7.5g, and the by-products content that deacetylation analyzed by high performance liquid chromatography (HPLC) is about 1.5%.Repeat this crystallization operation three times again, obtain Apremilast product 5.5g, total recovery 62%, HPLC purity >99.9%, the by-products content of deacetylation is 0.08%.
The above; be only the present invention's preferably embodiment; but protection scope of the present invention is not limited thereto; any those skilled in the art of being familiar with are in the technical scope that the present invention discloses; be equal to according to technical scheme of the present invention and inventive concept thereof and replace or change, all should be encompassed within protection scope of the present invention.
Claims (9)
1. to a purification process for Apremilast product, its feature is: described purification step is:
(A) with acid anhydrides and Chiral Amine for reaction raw materials, Glacial acetic acid is solvent, carries out sub-amidate action.By thin-layer chromatography (TLC) detection reaction;
(B) show until thin-layer chromatography (TLC) detection: after Chiral Amine reacts completely, add acetic anhydride, continue reaction 1-1.5 hour;
(C) boil off Glacial acetic acid, resistates is poured into water, stir, form suspended substance, suction filtration, washing leaching cake, dry cake, obtain Apremilast crude product;
(D) add in ethanol by Apremilast crude product, reflux 1-3h, agitation condition drops to room temperature;
(E) above-mentioned material is carried out reduce pressure, suction filtration, and use washing with alcohol filter cake, dry cake, obtain Apremilast sterling;
At this, represent the precedence of these purification steps with (A) ~ (E).
2. a kind of purification process to Apremilast product according to claim 1, its feature is: described acid anhydrides is 3-kharophen Tetra hydro Phthalic anhydride.
3. a kind of purification process to Apremilast product according to claim 1, its feature is: described Chiral Amine is (+)-1-(4-methoxyl group-3-oxyethyl group) phenyl-2-(methylsulfonyl) ethamine (II).
4. a kind of purification process to Apremilast product according to claim 1, its feature is: in step (A) and (B), and the ratio of the add-on of acid anhydrides, Chiral Amine, Glacial acetic acid and acetic anhydride is (20-21) mmol:(19-20) mmol:(60-70) ml:60mmol.
5. a kind of purification process to Apremilast product according to claim 1, its feature is: in step (A), it is methyl alcohol and methylene dichloride that thin-layer chromatography (TLC) detects developping agent used, and their volume parts ratio is: methyl alcohol: methylene dichloride=1:10.
6. a kind of purification process to Apremilast product according to claim 1, its feature is: in step (C), and the volume of the water that resistates is poured into and the volume parts of Glacial acetic acid are than being 10:6.5.
7. a kind of purification process to Apremilast product according to claim 1, its feature is: in step (C), and the temperature of dry cake is 50 DEG C, and time of drying is 4-5h.
8. a kind of purification process to Apremilast product according to claim 1, its feature is: in step (D), and the ratio of Apremilast crude product and amount of alcohol added is 8g:(65-75) ml.
9. a kind of purification process to Apremilast product according to claim 1, its feature is: in step (D), the temperature 60 C of dry cake, and time of drying is 2-3h.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105388237A (en) * | 2015-12-28 | 2016-03-09 | 成都百裕金阁莱药业有限公司 | Detection method for 3-acetamido phthalic acid in Apremilast |
| CN106008315A (en) * | 2016-06-16 | 2016-10-12 | 珠海联邦制药股份有限公司 | Apremilast crystal form S and preparing method thereof |
| CN107151227A (en) * | 2016-03-04 | 2017-09-12 | 广东东阳光药业有限公司 | The unbodied preparation method of Apremilast |
| 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 |
| WO2019073431A1 (en) * | 2017-10-12 | 2019-04-18 | Piramal Enterprises Limited | An improved process for the preparation of apremilast and its intermediate |
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Cited By (6)
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| CN105388237A (en) * | 2015-12-28 | 2016-03-09 | 成都百裕金阁莱药业有限公司 | Detection method for 3-acetamido phthalic acid in Apremilast |
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| CN106008315A (en) * | 2016-06-16 | 2016-10-12 | 珠海联邦制药股份有限公司 | Apremilast crystal form S and preparing 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 |
| WO2019073431A1 (en) * | 2017-10-12 | 2019-04-18 | Piramal Enterprises Limited | An improved process for the preparation of apremilast and its intermediate |
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