CN105085373B - A kind of purification process to Apremilast product - Google Patents
A kind of purification process to Apremilast product Download PDFInfo
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- CN105085373B CN105085373B CN201510556248.0A CN201510556248A CN105085373B CN 105085373 B CN105085373 B CN 105085373B CN 201510556248 A CN201510556248 A CN 201510556248A CN 105085373 B CN105085373 B CN 105085373B
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- apremilast
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- glacial acetic
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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 38
- 229960001164 apremilast Drugs 0.000 title claims abstract description 37
- 238000000746 purification Methods 0.000 title claims abstract description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229960000583 acetic acid Drugs 0.000 claims abstract description 15
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 13
- 239000012065 filter cake Substances 0.000 claims abstract description 13
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 238000001514 detection method Methods 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 239000000725 suspension Substances 0.000 claims abstract description 5
- 238000010992 reflux Methods 0.000 claims abstract description 4
- -1 stirring Substances 0.000 claims abstract 2
- 239000000047 product Substances 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000004809 thin layer chromatography Methods 0.000 claims description 14
- 235000021463 dry cake Nutrition 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000011938 amidation process Methods 0.000 claims description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 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 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 abstract description 7
- 230000008025 crystallization Effects 0.000 abstract description 7
- 238000011084 recovery Methods 0.000 abstract description 7
- 238000005406 washing Methods 0.000 abstract description 4
- 230000006837 decompression Effects 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 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
- 239000003814 drug Substances 0.000 description 5
- 201000004681 Psoriasis Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229940126701 oral medication Drugs 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
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 2
- 235000013305 food Nutrition 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
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 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
- 125000003368 amide group Chemical group 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 238000011017 operating method Methods 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
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 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
Abstract
The invention discloses a kind of purification process of Apremilast in preparation process, step are as follows：(1) using acid anhydrides and Chiral Amine as reaction raw materials, glacial acetic acid is solvent, is reacted, TLC detection reactions, after the reaction completely of Chiral Amine raw material, add acetic anhydride, continue to react 1 1.5h, boil off glacial acetic acid, residue is poured into water, stirring, suspension is formed, is filtered, Washing of Filter Cake, dry, obtain Apremilast crude product；(2) Apremilast crude product is added in EtOH, is heated to reflux 1 3h, stirring condition drops to room temperature, and decompression filters, and Washing of Filter Cake, dries, produces Apremilast sterling.The present invention only needs primary crystallization to can obtain Apremilast sterling of the purity more than 99.9%, total recovery improves more than 20% by adding acid anhydrides after the completion of being reacted in main body.
Description
Technical field
The present invention relates to the purification process of the product in chemicals synthesis technical field, it is related specifically to A Pusi
The purification process of special product product.
Background technology
In medical medicine field, for the psoriasis of psoriasis (being commonly called as psoriasis) especially patch type, almost do not have
Eutherapeutic, cheap and good-quality medicine.So that many patient's acute diseases are disorderly seeked medical advice, and are found informal, are cured the disease, rarely had using earthwork
The case of recovery from illness, instead growing many side effects, cause other diseases.
Apremilast (Apremilast) product of the U.S. Sai Er genes (Celgene) company research and development is treatment activity silver
The arthritic oral drugs of bits disease.In March, 2014 U.S.'s food and medicine Surveillance Authority (Food and Drug
Administration, abbreviation FDA) ratify the product with trade name Otezla listings.Since listing, the medicine has become head
Individual is also to be uniquely used for treating the oral drugs of psoriasis in plaques treatment, oral small molecule phosphodiesterase inhibitors
(PDE4)；As the preferred oral drugs for the treatment of psoriasis arthropathica.There is activity psoriasis arthropathica suitable for treatment
Adult patients.
Apremilast, entitled (+) -2- [1- (3- ethyoxyl -4- anisyls) -2- the methylsulfonylethyls] -4- second of chemistry
Amide groups isoindoline -1,3- diketone, structural formula are as follows：
The synthetic method of Apremilast, especially intermediate have a variety of preparation methods.But finally synthesize Apremilast side
Method is often as shown in following reaction equations：
With acid anhydrides (1) and Chiral Amine (2) for reaction raw materials, glacial acetic acid is solvent, carries out sub- amidation process.With thin layer color
Compose (TLC) detection reaction.
The major impurity of above-mentioned reaction is deacetylation product (3), and content is about 2-3%, and this impurity needs are more
Secondary crystallization could remove, and Comparatively speaking, other impurities are all easy to remove by primary crystallization.This more subcrystalline operation makes
Product has a more loss, and total recovery is not also high
The content of the invention
The present invention seeks to：Overcome deficiency of the prior art, there is provided a kind of purification process to Apremilast product.Only
The purity that primary crystallization can improves Apremilast product is carried out, and then improves total recovery, reduces total production cost.
The technical scheme is that：A kind of purification process to Apremilast product, described purification step are：
(A) using acid anhydrides and Chiral Amine as reaction raw materials, glacial acetic acid is solvent, carries out sub- amidation process.Use thin-layer chromatography
(TLC) detection reaction；
(B) treat that thin-layer chromatography (TLC) detection shows：After Chiral Amine (2) reaction completely, acetic anhydride is added, continues to react 1-
1.5 hour；
(C) glacial acetic acid is boiled off, residue is poured into water, is stirred, forms suspension, is filtered, washs filter cake, dries filter
Cake, obtain Apremilast crude product；
(D) Apremilast crude product is added in ethanol, is heated to reflux 1-3h, stirring condition drops to room temperature；
(E) above-mentioned material is depressurized, filtered, and filter cake is washed with ethanol, dry cake, it is pure to produce Apremilast
Product；
Here, the precedence of these purification steps is represented with (A)~(E).
Described acid anhydrides is 3-acetamidophthalic anhydride.
Described Chiral Amine is (+) -1- (4- methoxyl group -3- ethyoxyls) phenyl -2- (mesyl) ethamine (II).
In step (A) and (B), acid anhydrides, Chiral Amine, the ratio of the addition of glacial acetic acid and acetic anhydride are (20-21) mmol：
(19-20)mmol：(60-70)ml：60mmol.
In step (A), thin-layer chromatography (TLC) detection solvent used is methanol and dichloromethane, their volume
Portion rate is：Methanol：Dichloromethane=1:10.
In step (C), the volume for the water that residue is poured into and the volume parts ratio of glacial acetic acid are 10:6.5.
In step (C), the temperature of dry cake is 50 DEG C, drying time 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, drying time 2-3h.
Using the purification process of the present invention, only pass through primary crystallization, can be by the accessory substance of deacetylation by original 2-
3% is reduced to 0.05%, can obtain Apremilast sterling of the purity more than 99.9%, and total recovery improves more than 20%.
The improvement of technique substantially reduces the operating procedure of crystallization and the usage amount of solvent, improves product yield, drops production cost
Low more than 20%.
Brief description of the drawings
Fig. 1 is high performance liquid chromatography (HPLC) the detection figure of the product of embodiment 1；
Fig. 2 is the hydrogen spectrogram of the product of embodiment 1；
Fig. 3 is the carbon spectrogram of the product of embodiment 1.
Embodiment
Embodiment 1：By acid anhydrides (4.16g, 20.26mmol), Chiral Amine (19.3mmol) is added in 250mL reaction bulb,
Glacial acetic acid (65mL) is added, is flowed back at 120 DEG C, thin-layer chromatography (TLC) detection reaction (methanol：Methylene chloride volume portion rate
=1:10), treat the reaction of Chiral Amine raw material completely (about 5-6h), add acetic anhydride (60mmol), continue to react 1h, boil off ice vinegar
Acid, residue are poured into the water that 100mL is stirred vigorously, and form suspension.Filter, filter cake 4 × 50mL water washings, filter cake is put
About 4-5h is dried in 50 DEG C of drying boxes, obtains yellow Apremilast crude product 8.0g, high performance liquid chromatography (HPLC) detects it
Purity is 98.8%, and the by-products content of deacetylation is about 0.05%.Above-mentioned crude product is added in ethanol (70mL), heated back
2h is flowed, room temperature is slowly dropped under then stirring, separates out solid, decompression is filtered, and filter cake is washed with ethanol (2 × 10mL), dries (60
DEG C, dry 3h), it is 7.5g to obtain Apremilast product, total recovery 84%, and high performance liquid chromatography (HPLC) detects its purity>
99.9%.The result of high performance liquid chromatography (HPLC) detection is shown in Fig. 1, and the hydrogen spectrum measurement result of product is shown in Fig. 2, carbon spectrum measurement result
See Fig. 3, the results showed that, obtained product is the Apremilast product of high-purity.
1H NMR (400MHz, CDCl3) δ 9.46 (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)
13C NMR(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) is added in 250mL reaction bulb, adds ice
Acetic acid (65mL), flow back at 120 DEG C, thin-layer chromatography (TLC) detection reaction (methanol：Methylene chloride volume portion rate=1:10),
Treat the reaction of Chiral Amine raw material completely (about 5-6h), boil off glacial acetic acid, residue is poured into the water that 100mL is stirred vigorously, and is formed
Suspension.Filter, filter cake 4x50mL water washings, filter cake is placed in 50 DEG C of drying boxes and dries about 4-5h, obtain yellow Huang
Color Apremilast crude product 8.0g, high performance liquid chromatography (HPLC) detect its purity 96.0%, and the by-products content of deacetylation is about
For 2-3%.Crude product is added in ethanol (70mL), is heated to reflux 2h, room temperature is slowly dropped under then stirring, solid is separated out, subtracts
Pressure filters, and filter cake wash with ethanol (2 × 10mL), drying, and it is 7.5g to obtain Apremilast product, high performance liquid chromatography (HPLC)
The by-products content for analyzing deacetylation is about 1.5%.Repeat this crystallization operation three times, obtain Apremilast product 5.5g,
Total recovery 62%, HPLC purity>99.9%, the by-products content of deacetylation is 0.08%.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto,
It is any to be familiar with those skilled in the art in the technical scope that the present invention discloses, technique according to the invention scheme and its invention
Design is subject to equivalent substitution or change, should all be included within the scope of the present invention.
Claims (7)
1. a kind of purification process to Apremilast product, its feature is：Described purification step is：
(A) using acid anhydrides and Chiral Amine as reaction raw materials, glacial acetic acid is solvent, carries out sub- amidation process, is detected with thin-layer chromatography
Reaction, described acid anhydrides is 3-acetamidophthalic anhydride, and described Chiral Amine is (+) -1- (4- methoxyl group -3- ethoxies
Base) phenyl -2- (mesyl) ethamine；
Treat that thin-layer chromatography detection shows：After Chiral Amine reaction completely, acetic anhydride is added, continues to react 1-1.5 hours；
(B) glacial acetic acid is boiled off, residue is poured into water, is stirred, forms suspension, is filtered, filter cake is washed, dry cake, obtains
Obtain Apremilast crude product；
(C) Apremilast crude product is added in ethanol, is heated to reflux 1-3h, stirring condition drops to room temperature；
(D) above-mentioned material is depressurized, filtered, and filter cake is washed with ethanol, dry cake, produce Apremilast sterling；
Here, the precedence of these purification steps is represented with (A)~(D).
2. a kind of purification process to Apremilast product according to claim 1, its feature is：In step (A) and
(B) in, acid anhydrides, Chiral Amine, the ratio of the addition of glacial acetic acid and acetic anhydride are (20-21) mmol：(19-20)mmol：(60-70)
ml：60mmol.
3. a kind of purification process to Apremilast product according to claim 1, its feature is：In step (A),
Thin-layer chromatography detection solvent used is methanol and dichloromethane, and their volume parts ratio is：Methanol：Dichloromethane=1:
10。
4. a kind of purification process to Apremilast product according to claim 1, its feature is：In step (B),
The volume for the water that residue is poured into and the volume parts ratio of glacial acetic acid are 10:6.5.
5. a kind of purification process to Apremilast product according to claim 1, its feature is：In step (B),
The temperature of dry cake is 50 DEG C, drying time 4-5h.
6. a kind of purification process to Apremilast product according to claim 1, its feature is：In step (C),
Apremilast crude product and the ratio of amount of alcohol added are 8g：(65-75)ml.
7. 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, drying time 2-3h.
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| CN105388237B (en) * | 2015-12-28 | 2017-02-01 | 成都百裕金阁莱药业有限公司 | Detection method for 3-acetamido phthalic acid in Apremilast |
| 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 |
| 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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| WO2003080048A1 (en) * | 2002-03-20 | 2003-10-02 | Celgene Corporation | (-)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof |
| CN1965823B (en) * | 2002-03-20 | 2010-05-12 | 细胞基因公司 | (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4 acetylaminoisoindoline 1,3-dione, its preparation method and its compound |
| WO2012083153A1 (en) * | 2010-12-16 | 2012-06-21 | Nektar Therapeutics | Oligomer-containing apremilast moiety compounds |
| CN103635188B (en) * | 2011-04-28 | 2017-03-22 | 细胞基因公司 | Methods and compositions using PDE4 inhibitors for the treatment and management of autoimmune and inflammatory diseases |
| US8981117B2 (en) * | 2012-09-14 | 2015-03-17 | Celgene Corporation | Processes for the preparation of isoindole compounds and isotopologues thereof |
| CN103864670B (en) * | 2014-03-17 | 2015-08-26 | 苏州明锐医药科技有限公司 | The preparation method of A Pusite |
| CN104447445B (en) * | 2014-12-05 | 2016-07-06 | 新发药业有限公司 | A kind of preparation method synthesizing Apremilast intermediate |
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Effective date of registration: 20200528 Address after: 215500 No.13, Caotang Road, Changshu, Suzhou, Jiangsu Province Patentee after: Changshu intellectual property operation center Co., Ltd Address before: 710018 unit 1, building 1, Wangjing international building, Fengcheng 6th Road, Xi'an Economic and Technological Development Zone, Shaanxi Province Patentee before: SHAANXI ZHUANYI INTELLECTUAL PROPERTY OPERATION Co.,Ltd. |
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Address after: 215500 5th floor, building 4, 68 Lianfeng Road, Changfu street, Changshu City, Suzhou City, Jiangsu Province Patentee after: Changshu intellectual property operation center Co.,Ltd. Address before: No.13 caodang Road, Changshu City, Suzhou City, Jiangsu Province Patentee before: Changshu intellectual property operation center Co.,Ltd. |