WO2017175087A1 - Process for preparation of amorphous apremilast - Google Patents
Process for preparation of amorphous apremilast Download PDFInfo
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- WO2017175087A1 WO2017175087A1 PCT/IB2017/051704 IB2017051704W WO2017175087A1 WO 2017175087 A1 WO2017175087 A1 WO 2017175087A1 IB 2017051704 W IB2017051704 W IB 2017051704W WO 2017175087 A1 WO2017175087 A1 WO 2017175087A1
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- Prior art keywords
- apremilast
- amorphous
- solvent
- preparation
- mixture
- Prior art date
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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 70
- 229960001164 apremilast Drugs 0.000 title claims abstract description 68
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 19
- 239000012296 anti-solvent Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 150000002576 ketones Chemical class 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 3
- 238000002441 X-ray diffraction Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- -1 alkyl formamide Chemical compound 0.000 description 6
- 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 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 4
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- KFIRODWJCYBBHY-UHFFFAOYSA-N 3-nitrophthalic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O KFIRODWJCYBBHY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- AINBZKYUNWUTRE-UHFFFAOYSA-N ethanol;propan-2-ol Chemical compound CCO.CC(C)O AINBZKYUNWUTRE-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 229940011530 otezla Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- BXUJVINGXQGNFD-UHFFFAOYSA-N 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine Chemical compound CCOC1=CC(C(N)CS(C)(=O)=O)=CC=C1OC BXUJVINGXQGNFD-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 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
Definitions
- the present invention relates to process for preparation of amorphous form of apremilast (I).
- “Apremilast” is a phosphodiesterase-4 (PDE4) inhibitor. Apremilast is chemically known as N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide. Its empirical formula is C 22 H 24 N 2 O 7 S and the molecular weight is 460.5.
- Apremilast is approved in the United States for treatment of adult with active psoriatic arthritis. It is also being tested for treating other chronic inflammatory diseases such as psoriasis, Ankylosing Spondylitis, Behcet's disease, and rheumatoid arthritis. It is available under the trade name of OTEZLA " as an inhibitor of phosphodieasterase 4 (PDE4) and OTEZLA tablets are supplied in 10, 20 and 30 mg strengths for oral administration.
- PDE4 phosphodieasterase 4
- 6,020,358 discloses racemic 2-[l-(3-Ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-acetamidoisoindoline-l ,3-dione and process for its preparation, which is incorporated herein by reference.
- WO 2003/080048 and WO 2003/080049 discloses the use of the (-) and (+) enantiomers of apremilast respectively in the treatment or prevention of diseases or disorders by the inhibiting TNF-a production or PDE4.
- US Patent No. 7,427,638 discloses stereomerically pure (+)-2-[l-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline- 1 ,3 -dione, substantially free of its (-) isomer, or a pharmaceutically acceptable metabolite, salt, solvate or hydrate, thereof and its pharmaceutical composition.
- (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-acetylaminoisoindoline-l ,3-dione is the (+)-isomer of racemic 2-[l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro- 1 ,3-dioxo-lH-isoindol-4-yl]acetamide.
- WO 2009/120167 and US Patent No. 7,893,101 disclose various solid forms of apremilast including crystal forms and amorphous forms and their mixture.
- WO 2014/072259 discloses pharmaceutical composition of amorphous apremilast with at least one excipients prepared by melt extrusion technique.
- WO 2015/173792 and US 9,351 ,957 disclose the process for preparation of an amorphous form of apremilast.
- the different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g. differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g. tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g. tablets of one polymorph are more susceptible to breakdown at high humidity).
- chemical reactivity e.g. differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
- mechanical changes e. g. tablets crumble on storage as a kinetically favored crystalline
- An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc. which are important for formulation and product manufacturing.
- the main object of the present invention is to provide a process for preparation of amorphous apremilast (I)
- Another object of the present invention is to provide a process for preparation of amorphous apremilast (I), wherein the process includes dissolving apremilast in a suitable solvent or mixture thereof followed by addition of anti-solvent to obtain amorphous apremilast.
- Yet another object of the invention is to provide a process for preparation of amorphous apremilast wherein the process includes dissolving apremilast in a solvent selected from alkyl formamide such as dimethyl formamide, ketone such as acetone, alkanol such as ethanol or a mixture thereof followed by addition of anti-solvent such as water to obtain amorphous apremilast.
- a solvent selected from alkyl formamide such as dimethyl formamide, ketone such as acetone, alkanol such as ethanol or a mixture thereof followed by addition of anti-solvent such as water to obtain amorphous apremilast.
- Yet another object of the invention is to provide a process for preparation of amorphous apremilast wherein the process includes dissolving apremilast in a solvent selected from dimethyl formamide, or mixture of acetone and ethanol followed by addition of anti-solvent such as water to obtain amorphous apremilast.
- the main aspect of the present invention is to provide a process for preparation of amorphous apremilast (I).
- the present invention provides a process to prepare amorphous apremilast wherein apremilast is dissolved in a suitable solvent or mixture of solvent followed by addition of anti-solvent to obtain amorphous apremilast.
- Another aspect of the present invention is to provide a process for preparation of amorphous apremilast wherein, the process comprises steps of:
- step (b) adding anti-solvent to the solution obtained in step (a);
- Yet another aspect of the present invention is to provide a process for preparation of amorphous apremilast comprising steps of:
- step (b) adding the solution obtained in step (a) to water;
- Yet another aspect of the invention is to provide a process for preparation of amorphous apremilast comprising steps of:
- step (b) adding the solution obtained in step (a) to water;
- Fig.l Discloses XRPD pattern of amorphous form of apremilast as prepared by Example 1.
- Fig.2 Discloses XRPD pattern of amorphous form of apremilast as prepared by Example 2. DETAILED DESCRIPTION OF THE INVENTION
- the main embodiment of the present invention is to provide a process for preparation of amorphous apremilast (I).
- the present invention provides a process wherein apremilast is dissolved in a suitable solvent or mixture thereof to form a solution, followed by combining said solution with a suitable anti-solvent to obtain amorphous apremilast.
- step (b) adding solution obtained in step (a) to anti-solvent or
- step (c) adding anti-solvent to solution obtained in step (a);
- the solvent used in step (a) can be selected from dialkyl formamide such as dimethyl formamide, ketone such as acetone, alkanol such as ethanol, methanol or a mixture of solvent can be used for the purpose of present invention.
- the anti-solvent used in step (b) can be water or any solvent in which apremilast is less soluble.
- the apremilast solution obtained in step (a) is added to anti- solvent such as water or as an alternate; anti-solvent can be added to the apremilast solution.
- anti- solvent such as water or as an alternate
- anti-solvent can be added to the apremilast solution.
- the process can be carried out at a suitable temperature ranging from room temperature to the temperature suitable for dissolving apremilast in the selected solvent or mixture of solvents.
- Amorphous apremilast precipitated after addition of anti- solvent can be isolated by filtration or any other similar technique.
- the product may be further dried under vacuum at a temperature of about 25 °C.
- amorphous apremilast is prepared by solvent-anti-solvent precipitation technique.
- the starting material i.e. apremilast used in present invention may be prepared in accordance with any method known in the art, including for example, the methods described in WO 2009/120167, WO 2003/080049, WO 2003/080049 and US 6,020,538. The contents of each of which are hereby incorporated by reference in their entirety.
- Step 1 of the above scheme relates to reaction of 3-nitrophthalic acid (II) with 1- (3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-l -amine (III) to obtain compound of formula IV i.e. (S)-2-(l-(3-ethoxy-4-methoxyphenyl)2- (methylsulfonyl)ethyl-4-nitro isoindoline-l ,3-dione. Nitro compound of formula IV is subjected to reduction to obtain amino compound of formula V.
- Reduction can be carried out in presence of Pd/C and solvents selected from alkanol such as methanol, ethanol, propanol, isopropanol, butanol alkyl acetate such as ethyl acetate, isopropyl acetate or any other suitable solvent.
- solvents selected from alkanol such as methanol, ethanol, propanol, isopropanol, butanol alkyl acetate such as ethyl acetate, isopropyl acetate or any other suitable solvent.
- Reaction of amino compound of formula V with acetic anhydride provides apremilast (I)
- the reaction can be carried out in presence of solvent selected from halogenated solvents like dichloromethane or alcohols such as methanol, ethanol isopropanol or mixture thereof.
- Apremilast thus prepared can be further purified from any suitable solvent or mixture of solvent.
- Solvent for purification/ recrystallization of apremilast can be affected in presence of alkanol like methanol, ethanol isopropanol, butanol, nitrile such as acetonitrile or any other suitable solvent.
- alkanol like methanol, ethanol isopropanol, butanol, nitrile such as acetonitrile or any other suitable solvent.
- Example-1 Preparation of amorphous apremilast
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to novel process for preparation of amorphous apremilast.
Description
PROCESS FOR PREPARATION OF AMORPHOUS APREMILAST
RELATED APPLICATIONS
This application is related to Indian Provisional Application No. IN 201621012398 filed on 08th April, 2016 and is incorporated herein in its entirety. FIELD OF THE INVENTION
The present invention relates to process for preparation of amorphous form of apremilast (I).
Formula (I) BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however reference to any prior-art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
"Apremilast" is a phosphodiesterase-4 (PDE4) inhibitor. Apremilast is chemically known as N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide. Its empirical formula is C22H24N2O7S and the molecular weight is 460.5.
Apremilast is approved in the United States for treatment of adult with active psoriatic arthritis. It is also being tested for treating other chronic inflammatory diseases such as psoriasis, Ankylosing Spondylitis, Behcet's disease, and
rheumatoid arthritis. It is available under the trade name of OTEZLA " as an inhibitor of phosphodieasterase 4 (PDE4) and OTEZLA tablets are supplied in 10, 20 and 30 mg strengths for oral administration. US Patent No. 6,020,358 discloses racemic 2-[l-(3-Ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-acetamidoisoindoline-l ,3-dione and process for its preparation, which is incorporated herein by reference.
WO 2003/080048 and WO 2003/080049 discloses the use of the (-) and (+) enantiomers of apremilast respectively in the treatment or prevention of diseases or disorders by the inhibiting TNF-a production or PDE4.
US Patent No. 7,427,638 discloses stereomerically pure (+)-2-[l-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline- 1 ,3 -dione, substantially free of its (-) isomer, or a pharmaceutically acceptable metabolite, salt, solvate or hydrate, thereof and its pharmaceutical composition. The stereomerically pure (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-acetylaminoisoindoline-l ,3-dione is the (+)-isomer of racemic 2-[l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro- 1 ,3-dioxo-lH-isoindol-4-yl]acetamide.
WO 2009/120167 and US Patent No. 7,893,101 disclose various solid forms of apremilast including crystal forms and amorphous forms and their mixture. WO 2014/072259 discloses pharmaceutical composition of amorphous apremilast with at least one excipients prepared by melt extrusion technique.
WO 2015/173792 and US 9,351 ,957 disclose the process for preparation of an amorphous form of apremilast.
The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g. differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g. tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g. tablets of one polymorph are more susceptible to breakdown at high humidity).
An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc. which are important for formulation and product manufacturing.
There is no enabling disclosure available in the prior art for the preparation of an amorphous form of apremilast which can suffice to meet the emerging need of the large scale preparation at industrial level. In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of amorphous form of apremilast. The amorphous form provided herein is stable under ordinary stability conditions with respect to purity and storage.
OBJECTS OF THE INVENTION The main object of the present invention is to provide a process for preparation of amorphous apremilast (I)
Formula (I)
Another object of the present invention is to provide a process for preparation of amorphous apremilast (I), wherein the process includes dissolving apremilast in a suitable solvent or mixture thereof followed by addition of anti-solvent to obtain amorphous apremilast.
Yet another object of the invention is to provide a process for preparation of amorphous apremilast wherein the process includes dissolving apremilast in a solvent selected from alkyl formamide such as dimethyl formamide, ketone such as acetone, alkanol such as ethanol or a mixture thereof followed by addition of anti-solvent such as water to obtain amorphous apremilast.
Yet another object of the invention is to provide a process for preparation of amorphous apremilast wherein the process includes dissolving apremilast in a solvent selected from dimethyl formamide, or mixture of acetone and ethanol followed by addition of anti-solvent such as water to obtain amorphous apremilast.
SUMMARY OF THE INVENTION The main aspect of the present invention is to provide a process for preparation of amorphous apremilast (I).
Formula (I)
In an aspect the present invention provides a process to prepare amorphous apremilast wherein apremilast is dissolved in a suitable solvent or mixture of solvent followed by addition of anti-solvent to obtain amorphous apremilast. Another aspect of the present invention is to provide a process for preparation of amorphous apremilast wherein, the process comprises steps of:
(a) dissolving apremilast in a solvent selected from alkyl formamide, ketone, alkanol or mixture thereof.
(b) adding anti-solvent to the solution obtained in step (a);
(c) isolating amorphous apremilast.
Yet another aspect of the present invention is to provide a process for preparation of amorphous apremilast comprising steps of:
(a) dissolving apremilast in dimethyl formamide
(b) adding the solution obtained in step (a) to water;
(c) isolating amorphous apremilast.
Yet another aspect of the invention is to provide a process for preparation of amorphous apremilast comprising steps of:
(a) dissolving apremilast in a mixture of acetone and ethanol
(b) adding the solution obtained in step (a) to water;
(c) isolating amorphous apremilast.
DETAILED DESCRIPTION OF THE DRAWINGS
Fig.l : Discloses XRPD pattern of amorphous form of apremilast as prepared by Example 1.
Fig.2: Discloses XRPD pattern of amorphous form of apremilast as prepared by Example 2.
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide a process for preparation of amorphous apremilast (I).
Formula (I)
In another embodiment, the present invention provides a process wherein apremilast is dissolved in a suitable solvent or mixture thereof to form a solution, followed by combining said solution with a suitable anti-solvent to obtain amorphous apremilast.
In an embodiment the process of present invention provides amorphous apremilast by
(a) dissolving apremilast in a solvent or mixture thereof;
(b) adding solution obtained in step (a) to anti-solvent or
(c) adding anti-solvent to solution obtained in step (a);
(d) isolating amorphous apremilast.
The solvent used in step (a) can be selected from dialkyl formamide such as dimethyl formamide, ketone such as acetone, alkanol such as ethanol, methanol or a mixture of solvent can be used for the purpose of present invention.
The anti-solvent used in step (b) can be water or any solvent in which apremilast is less soluble.
In one embodiment, the apremilast solution obtained in step (a) is added to anti- solvent such as water or as an alternate; anti-solvent can be added to the apremilast solution.
The process can be carried out at a suitable temperature ranging from room temperature to the temperature suitable for dissolving apremilast in the selected solvent or mixture of solvents.
Amorphous apremilast precipitated after addition of anti- solvent can be isolated by filtration or any other similar technique. The product may be further dried under vacuum at a temperature of about 25 °C.
In general, amorphous apremilast is prepared by solvent-anti-solvent precipitation technique.
The starting material i.e. apremilast used in present invention may be prepared in accordance with any method known in the art, including for example, the methods described in WO 2009/120167, WO 2003/080049, WO 2003/080049 and US 6,020,538. The contents of each of which are hereby incorporated by reference in their entirety.
Apremilas me;
Step 1 of the above scheme relates to reaction of 3-nitrophthalic acid (II) with 1- (3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-l -amine (III) to obtain compound of formula IV i.e. (S)-2-(l-(3-ethoxy-4-methoxyphenyl)2- (methylsulfonyl)ethyl-4-nitro isoindoline-l ,3-dione. Nitro compound of formula
IV is subjected to reduction to obtain amino compound of formula V. Reduction can be carried out in presence of Pd/C and solvents selected from alkanol such as methanol, ethanol, propanol, isopropanol, butanol alkyl acetate such as ethyl acetate, isopropyl acetate or any other suitable solvent. Reaction of amino compound of formula V with acetic anhydride provides apremilast (I), the reaction can be carried out in presence of solvent selected from halogenated solvents like dichloromethane or alcohols such as methanol, ethanol isopropanol or mixture thereof. Apremilast thus prepared can be further purified from any suitable solvent or mixture of solvent. Solvent for purification/ recrystallization of apremilast can be affected in presence of alkanol like methanol, ethanol isopropanol, butanol, nitrile such as acetonitrile or any other suitable solvent. The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
EXAMPLES
Example-1: Preparation of amorphous apremilast
N,N-dimethylformamide (30 ml) was taken in a 2 litre round bottom flask, to this 10 g of apremilast was added, the resultant mixture was stirred at 25-30°C to obtain clear solution. This solution was added to 400 ml of pre -cooled water at 0- 5 °C. The product thus precipitated was isolated by filtration. The solid was dried under vacuum at 55-60°C to obtain 8.5 g of title product. Example-2: Preparation of amorphous apremilast
Acetone (6 ml) and ethanol (6 ml) were taken in a 2 litre round bottom flask, to this 10 g of apremilast was added, the resultant mixture was stirred at 50-55°C to obtain clear solution. This solution was added to 360 ml of pre -cooled water at 0- 5 °C. The product thus precipitated was isolated by filtration. The solid was dried under vacuum at 55-60°C to obtain 8.5 g of title product.
Claims
1. A process for preparation of amorphous form of apremilast comprising steps of:
a) dissolving apremilast in a solvent selected from dimethyl formamide, ketone, alkanol and mixture thereof;
b) combining the solution obtained in step (a) with an antisolvent selected from water and n-heptane.
2. The process according to claim 1 , which comprises adding an antisolvent to the apremilast solution.
3. The process according to claim 1, which comprises adding apremilast solution to antisolvent.
4. The process according to claim 1, which comprises use of dimethylformamide and water as solvent- antisolvent mixture.
5. The process according to claim 1 , which comprises use of acetone, ethanol and water as solvent-antisolvent mixture.
6. A process for preparation of amorphous apremilast comprising the steps of :
a) dissolving apremilast in dimethyl formamide
b) combining the solution obtained in step (a), to water.
7. A process for preparation of amorphous apremilast comprising the steps of :
a) dissolving apremilast in a mixture of acetone and ethanol
b) combining the solution obtained in step (a), with water.
8. Amorphous apremilast prepared by process according to claim 1 , 6 or 7.
9. Amorphous apremilast characterized by X-ray diffraction (XRD) profile substantially as shown in figure 1 or 2.
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| IN201621012398 | 2016-04-08 | ||
| IN201621012398 | 2016-04-08 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106977444A (en) * | 2016-01-18 | 2017-07-25 | 重庆医药工业研究院有限责任公司 | A kind of unformed preparation method of Apremilast |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150283249A1 (en) * | 2014-04-04 | 2015-10-08 | Cadila Healthcare Limited | Amorphous form of apremilast |
| WO2015173792A1 (en) * | 2014-05-11 | 2015-11-19 | Mapi Pharma Ltd. | Amorphous form of apremilast |
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2017
- 2017-03-24 WO PCT/IB2017/051704 patent/WO2017175087A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150283249A1 (en) * | 2014-04-04 | 2015-10-08 | Cadila Healthcare Limited | Amorphous form of apremilast |
| WO2015173792A1 (en) * | 2014-05-11 | 2015-11-19 | Mapi Pharma Ltd. | Amorphous form of apremilast |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106977444A (en) * | 2016-01-18 | 2017-07-25 | 重庆医药工业研究院有限责任公司 | A kind of unformed preparation method of Apremilast |
| CN106977444B (en) * | 2016-01-18 | 2021-10-08 | 重庆医药工业研究院有限责任公司 | Preparation method of apremilast amorphous |
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