- Methods for preparation of apremilast
-
The present invention discloses a method for preparation of Apremilast. β-phthalimino vinylsulfones are reacted through the asymmetric addition reaction to form an addition product, and the drug of Apremilast can be obtained from the addition product through simple reactions. The method is a process for synthesizing Apremilast in a more efficient way.
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Page/Page column 26
(2021/05/19)
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- Directed evolution of an amine transaminase for the synthesis of an Apremilast intermediate via kinetic resolution
-
Apremilast is an important active pharmaceutical ingredient that relies on a resolution to produce the key chiral amine intermediate. To provide a new catalytic and enzymatic process for Apremilast, we performed the directed evolution of the amine transaminase from Vibrio fluvialis. Six rounds of evolution resulted in the VF-8M-E variant with > 400-fold increase specific activity over the wildtype enzyme. A homology model of VF-8M-E was built and a molecular docking study was performed to explain the increase in activity. The purified VF-8M-E was successfully applied to produce the key chiral amine intermediate in enantiopure form and 49% conversion via a kinetic resolution, representing a new enzymatic access towards Apremilast.
- Xiang, Chao,Wu, Shuke,Bornscheuer, Uwe T.
-
-
- Chemoenzymatic synthesis of apremilast: A study using ketoreductases and lipases
-
The key step in the chemoenzymatic synthesis of apremilast was to produce the chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated to obtain (R)-3, one using ketoreductases and the other lipases. Bioreduction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), using ketoreductase KRED.P2-D12, led to (R)-3 with 48% conversion and 93% enantiomeric excess (ee). Kinetic resolution of rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, with 20% of n-butanol, catalyzed by lipase from Aspergillus niger yielded (R)-3 with > 99% ee, 50% conversion and E-value (enantiomeric ratio) > 200. The reaction between enantiomerically pure (R)-3 and 4-acetylamino-isoindol-1,3-dione (8) afforded apremilast in 65% yield and 67% ee.
- Vega, Kimberly B.,Cruz, Daniel M. V.,Oliveira, Artur R. T.,Da Silva, Marcos R.,De Lemos, Telma L. G.,Oliveira, Maria C. F.,Bernardo, Ricardo D. S.,De Sousa, Jackson R.,Zanatta, Geancarlo,Nasário, Fábio D.,Marsaioli, Anita J.,De Mattos, Marcos C.
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p. 1100 - 1110
(2021/05/19)
-
- Apremilast preparation method
-
The present invention relates to a preparation method of apremilast represented by a formula I, wherein the method comprises: carrying out a reaction on a compound represented by a formula II and a compound represented by a formula III in a reaction solvent to obtain an apremilast crude product, and crystallizing with acetone and ethanol to obtain the finished apremilast. According to the presentinvention, the apremilast obtained by the method has the purity of more than 99.3% and the yield of more than 80%, the process is simple, and the cost is low. The formulas I, II and III are defined inthe specification.
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Paragraph 0033; 0034; 0035; 0036
(2019/03/10)
-
- Asymmetric Synthesis of β-Aryl β-Imido Sulfones Using Rhodium Catalysts with Chiral Diene Ligands: Synthesis of Apremilast
-
A chiral rhodium(I)-diene catalyst enabled the one-step synthesis of β-aryl β-imido sulfones under mild reaction conditions. By selection of the chiral diene ligand L1a or L2, each enantiomer of the chiral β-aryl β-imido sulfone target can be accessed with high stereoselectivity. Demonstration of the scope of the reaction, which includes the synthesis of an N-protected chiral β-amino β-phenyl sulfone, culminated with the efficient synthesis of the heteroatom-rich active pharmaceutical ingredient apremilast.
- Syu, Jin-Fong,Gopula, Balraj,Jian, Jia-Hong,Li, Wei-Sian,Kuo, Ting-Shen,Wu, Ping-Yu,Henschke, Julian P.,Hsieh, Meng-Chi,Tsai, Ming-Kang,Wu, Hsyueh-Liang
-
supporting information
p. 4614 - 4618
(2019/06/27)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF APREMILAST AND ITS INTERMEDIATE
-
The present invention provides an improved process for preparation of pure N-(2-(l-(3- ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-l,3-dioxoisoindolin-4-yl)acetamide (1) (commonly known as Apremilast); wherein the content of des-acetyl apremilast (la) is less than 1% w/w and having total amount of genotoxic substances less than 25 ppm; comprising the steps of reacting the compound l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan- 1-amine (A) or its chiral acid salt with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) in presence of ether or amide solvent and optionally, in presence of an acid; followed by the treatment with an acetylating agent.
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Page/Page column 17; 20
(2019/05/02)
-
- Synthesis of Substituted β-Functionalised Styrenes by Microwave-Assisted Olefin Cross-Metathesis and Scalable Synthesis of Apremilast
-
Preparation of diversely substituted β-functionalised styrenes by microwave-assisted olefin cross-metathesis (CM) is described. This method can be also employed in the synthesis of β-deuterated α,β-unsaturated sulfones from inexpensive allylbenzenes, though unprecedented one-pot isomerisation/deuteration/cross-metathesis sequence. One of such obtained CM products has been utilised in a new scalable synthesis of Apremilast (6), a potent and orally active phosphodiesterase 4 and tumour necrosis factor-α inhibitor. The same strategy was used in synthesis of an optical antipode of 6, ent-Apremilast.
- Jana, Anupam,Zieliński, Grzegorz Krzysztof,Czarnocka-?niada?a, Sylwia,Grudzień, Krzysztof,Podwysocka, Dominika,Szulc, Marcin,Kajetanowicz, Anna,Grela, Karol
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p. 5808 - 5813
(2019/11/03)
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- APREMILAST FOR THE TREATMENT OF A LIVER DISEASE OR A LIVER FUNCTION ABNORMALITY
-
Methods of treating, managing or preventing liver disease are disclosed. Specific methods encompass the administration of apremilast, alone or in combination with additional active agents or treatment regimens.
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-
Paragraph 0097
(2019/09/15)
-
- METHODS FOR THE TREATMENT OF OBESITY USING APREMILAST
-
Methods of treating, managing or preventing obesity and overweight are disclosed. Specific methods encompass the administration of apremilast, alone or in combination with additional active agents or treatment regimens.
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Paragraph 0082
(2019/05/22)
-
- A NOVEL PROCESS FOR THE PREPARATION OF APREMILAST IN AMORPHOUS FORM
-
The present invention is directed to a novel process for the preparation of Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3- acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-1- (methylsulfonyl)-eth-2-ylamine, isolated in amorphous form using a solvent-antisolvent mixture comprising acetonitrile-water, dimethylformamide-water, dimethylsulfoxide-water, acetonitrile- dimethylformamide-water or mixtures thereof.
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Page/Page column 26; 28-34
(2019/02/13)
-
- Apremilast three-component one-pot-boiling synthesis method
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The invention provides an apremilast three-component one-pot-boiling synthesis method. According to the apremilast three-component one-pot-boiling synthesis method, 3-aminophthalic acid, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine salt, and acetic anhydride are taken as raw materials to prepare apremilast through one-pot-boiling method. The apremilast three-component one-pot-boiling synthesis method is simple and convenient in operation, high in yield, low in pollution, and is suitable for large scale preparation.
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-
Paragraph 0031-0039; 0044
(2019/11/29)
-
- NOVEL PROCESS FOR THE PREPARATION OF 1-(3-ETHOXY-4-METHOXY-PHENYL)-2-METHYLSULFONYL-ETHANAMINE
-
The present invention relates to a process for the preparation of 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine, an intermediate for the preparation of apremilast via a compound of Formula (V) wherein R is (C1-C4)alkyl, (C1-C4)haloalkyl, -O(C1-C4)alkyl, or –O-benzyl, and L is a leaving group.
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-
-
- For treating psoriasis sexual arthritis disease apps is special synthetic method (by machine translation)
-
The invention discloses a method for treating psoriasis sexual arthritis disease apps is special synthetic method, the method to 3 - ethoxy - 4 - methoxybenzaldehyde as the starting material, by with the dimethyl sulfone, n-butyl reaction, to obtain 3 - ethoxy - 4 - methoxy - α - [(methylsulfonyl) methyl] - benzene methanol, through the oxidation reaction to obtain 1 - (3 - ethoxy - 4 - methoxyphenyl) - 2 - methyl-sulfonyl - ethanone, through the reduction reaction to obtain the R - 3 - ethoxy - 4 - methoxy - α - [(methylsulfonyl) methyl] - benzene methanol, finally with 3 - acetamide group ortho-phthalic acid imide by Mitsunobu reaction, to obtain the target product apps is special. The invention has mild reaction condition, the process is simple, the yield is good, easy industrialization and the like. (by machine translation)
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- NOVEL PROCESS TO PREPARE N-[2-[(1S)-1-(3-ETHOXY-4-METHOXYPHENYL)-2-(METHYLSULPHONYL) ETHYL]-1, 3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YL]ACETAMIDE
-
An alternative and improved process for the preparation of Apremilast (Formula I) and Apremilast form B or a pharmaceutically acceptable salt thereof is provided. The novel process includes hydrogenation in acetone, Cyclization and acetylation followed by condensation in methyl isobutyl ketone (MIBK) and acetic acid mixture in specific volume ratios.
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- A method for purification of the product apps is special method
-
The invention discloses a purification method for Apremilast in the preparation process. The purification method comprises steps as follows: (1), acid anhydride and chiral amine serving as reaction raw materials have a reaction in glacial acetic acid serving as a solvent, TLC (thin-layer chromatography) is used for detecting the reaction, after the chiral amine has a complete reaction, acetic anhydride is added, a reaction is performed for 1-1.5 h, glacial acetic acid is evaporated, residues are poured into water and stirred, suspended substances are formed, and coarse Apremilast products are obtained after suction filtration, filter cake washing and drying; (2), the coarse Apremilast prodcuts are added to EtOH, heating reflux is performed for 1-3 h, the mixture is cooled to the room temperature while being stirred, and the pure Apremilast products are obtained after vacuum suction filtration, filter cake washing and drying. Acid anhydride is added after the principal reaction is finished, and the pure Apremilast products with the purity higher than 99.9% can be obtained just through one-time crystallization, and the total yield is increased by more than 20%.
- -
-
Paragraph 0030; 0033; 0034
(2018/03/26)
-
- Refining preparation process of high-purity apremilast
-
The invention discloses a refining preparation process of high-purity apremilast. The refining preparation process comprises the following steps: (1) carrying out heating and reflux for 2-5 hours on anhydride and chiral amine as the raw materials in a solvent A, so as to obtain an apremilast crude product; and (2) adding the apremilast crude product into a solvent B, heating for dissolving, and refining the mixture, so as to obtain an apremilast pure product. According to the refining preparation process, water and 2-butanone are compounded into a purifying solvent for purification, so that arelatively good technical effect is achieved, and the contents of main impurity raw material intermediates a and b and process impurities in the apremilast crude product can be remarkably decreased; and an HPLC detection result shows that the purity of apremilast reaches above 99.7%, and the impurity limits are all less than 0.1%.
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Paragraph 0027; 0028; 0029; 0030; 0031
(2018/04/02)
-
- NOVEL PROCESS FOR PREPARATION OF APREMILAST
-
The present invention related to a novel compound of Formula II, its enantiomers or acid addition salts thereof and process for its preparation. The compound of Formula II can be used for preparation of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide also known as apremilast.
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-
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- Synthesis and refining method of apremilast
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The invention relates to the field of chemical synthesis, in particular to a novel method for synthesizing and refining apremilast. A new starting raw material is introduced; in a preparation process, by selection of the type and the proportion of a specific solvent and control over reaction conditions, the product yield is high, and particle size of a refined product is qualified; no secondary smashing treatment is needed, and the optical purity is improved; therefore, the requirement on experimental equipment and the cost are reduced, the toxicity is reduced, and occurrence of adverse events is avoided.
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-
- AN IMPROVED PROCESS AND NOVEL POLYMORPHIC FORM OF APREMILAST
-
The present invention provides an improved process for the preparation of Apremilast using novel intermediates. The present invention also relates to the novel crystalline polymorphic form of Apremilast.
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- PROCESS FOR PREPARATION OF APREMILAST
-
The present invention relates to a process for preparation of apremilast. The present invention relates to p-xylene solvate of apremilast and process for its preparation.
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-
-
- A SYNTHETIC PATHWAY TOWARDS APREMILAST
-
The present invention relates to an asymmetric process for providing N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide (apremilast) or a pharmaceutically acceptable salt or solvate thereof.
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-
-
- Preparation method of apremilast
-
The invention discloses a preparation method of apremilast; an intermediate (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfinyl)ethamine undergoes an oxidation reaction to obtain (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethamine, then (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethamine undergoes a reaction with 3-acetyl amino phthalic anhydride to prepare the apremilast. According to the method, through a chiral induction method, a chiral center is introduced during preparation of the intermediate (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfinyl)ethamine by using steric hindrance. Compared with the prior art, the step of using N-acetyl-L-leucine for splitting is avoided, a synthetic route is simplified, and the method is high in yield, low in cost and suitable for industrialized mass production.
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- PROCESSES FOR THE PREPARATION OF APREMILAST AND INTERMEDIATES THEREOF
-
Disclosed are processes for the preparation of Apremilast and intermediates for its preparation.
- -
-
Paragraph 00120
(2017/07/29)
-
- Method for preparing apremilast with high optical purity
-
The invention discloses a method for preparing apremilast with high optical purity. The method comprises the following steps: carrying out amination reaction between (S)-2-(3-ethoxyl-4-methoxyphenyl)-1-(methanesulfonyl)-ethyl-2-base amine or salt thereof and 3-acetamide phthalic anhydride in an aromatic solvent to prepare the apremilast. The optical purity of the apremilast prepared by using the method can reach 99.0 percent or above.
- -
-
Paragraph 0016; 0063; 0064; 0066-89
(2017/08/31)
-
- Method for preparing high-purity Apremilast
-
The invention is named 'a method for preparing high-purity Apremilast', and relates to the technical field of pharmaceutical chemistry, in particular to the preparation method of high-purity Apremilast. The invention provides the preparation method of high-purity Apremilast with a prepared formula (I) (S)-2-[1-(3-oxethyl-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetamido Isoindoline-1,3-diketone. The preparation method comprises the following steps that chiral amine: (S)-1-(3-oxethyl-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine and anhydride: 3-acetylamino-phthalic-anhydride react in an acetic acid solvent to generate Apremilast with the formula (I), wherein alkali metal acetic acid salt is a catalyst, after crystallization and refining are conducted with an acetone and ethanol mixed solvent, high-purity finished products of which the purity reaches 99.9% and the single impurity is no greater than 0.05% are obtained, and the reaction yield reaches 90% or above. The process is mild in reaction condition, low in production cost and suitable for industrialized production, and has a very good economic effect.
- -
-
Paragraph 0037-0044
(2017/10/09)
-
- CRYSTALLINE FORMS OF APREMILAST
-
The invention particularly relates to crystailine (solid) forms of N-[2-[(1S)-1-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]acetamide), i.e. Form N, Form M, Form O and Form P. It also refers to a pharmaceutical composition or dosage form comprising said crystalline forms. The invention also concerns said pharmaceuticai composition or dosage form for use in a method of treating a disease or disorder defined in the claims. Finally, the invention pertains to the use of said novel crystalline forms for the preparation of a pharmaceutical composition or dosage form.
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Page/Page column 31-32
(2017/12/01)
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- IMPROVED PROCESS FOR THE PREPARATION OF APREMILAST
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The present invention relates to an improved process for the preparation of Apremilast of formula (I).
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Page/Page column 16; 17
(2017/11/16)
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- PROCESS FOR PREPARATION OF APREMILAST AND ITS INTERMEDIATES
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Present application relates to the process for the preparation of 1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of the formula (II), its resolution and its use in preparation of Apremilast of formula (I), process for the preparation of crystalline form B of apremilast, process for preparation of amorphous form of apremilast and the crystalline form of (S)-1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine of the formula (Va).
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- PROCESS FOR THE ENANTIOMERIC RESOLUTION OF APREMILAST INTERMEDIATES
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A process for the resolution of racemic 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine using novel chiral salts is disclosed. An L-phenylalanine p-toluene-sulfonamide salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine and a di-p-toluoyl-L-tartaric acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine are also provided.
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- A NOVEL SYNTHETIC PATHWAY TOWARDS APREMILAST
-
The present invention relates to a process for providing a chiral β-hydroxysulfone compound, an intermediate useful in the synthesis of the isoindoline-based compound apremilast.
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- IMPROVED PROCESS FOR THE PREPARATION OF APREMILAST
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The present invention relates to novel processes for the preparation of apremilast of formula I, or a pharmaceutically acceptable salt thereof.
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Page/Page column 18; 19
(2016/10/04)
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- Preparation method of Apremilast and intermediate
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The invention provides a preparation method of Apremilast and its intermediate. The invention provides an Apremilast intermediate as shown in the formula III. According to the preparation method, the compound as shown in the formula III reacts with methanesulfinate to obtain a compound as shown in the formula IV; the compound as shown in the formula IV undergoes reductive amination to obtain a compound as shown in the formula V; the compound as shown in the formula V and asymmetry acid undergo salifying to obtain a compound as shown in the formula VI; and the compound as shown in the formula VI reacts with 3-acetamido-phthalic anhydride to obtain Apremilast. By the method for synthesizing Apremilast, usage of an n-butyllithium hexane solution can be avoided. Production cost is reduced, and operation process is convenient. In addition, safety in the industrial production is raised to a great extent, and the preparation method is more suitable for industrial continuous production. According to the preparation method of 3-acetamido-phthalic anhydride, yield is raised to 81%. As the yield is high, the method provided by the invention is extremely suitable for industrial production of Apremilast.
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- DOSAGE TITRATION OF APREMILAST FOR THE TREATMENT OF DISEASES AMELIORATED BY PDE4 INHIBITION
-
Administration of apremilast in a specific dosage titration schedule, alone or in combination with a second active agent for use in methods of treating, managing or preventing diseases ameliorated by inhibiting PDE4 such as psoriasis, ankylosing spondylitis, Behcet's disease, rheumatoid arthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis.
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Paragraph 0097
(2016/02/29)
-
- Methods and compositions using PDE4 inhibitors for the treatment and management of autoimmune and inflammatory diseases
-
Methods of treating, preventing, or managing autoimmune inflammatory diseases and disorders including but not limited to spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis by the administration of phosphodiesterase 4 (PDE4) inhibitors in combination with other therapeutics are disclosed. Pharmaceutical compositions, dosage forms, and kits suitable for use in methods of the invention are also disclosed.
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- CONTROLLED RELEASE ORAL DOSAGE FORMS OF POORLY SOLUBLE DRUGS AND USES THEREOF
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Provided herein are controlled release oral dosage forms of poorly soluble drugs, methods of making the dosage forms, and methods of their use for the treatment of various diseases and/or disorders.
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- Methods for treating diseases using isoindoline compounds
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Methods of treating a disease selected from dermatomyositis, prurigo nodularis, pyoderma gangrenosum, alopecia areata, hidradenitis suppurtiva, rosacea, lichen planus, giant cell arteritis, Sjogren's syndrome, gout, chronic prostatitis, posterior uveitis, vulvodynia and interstitial cystitis in a human are disclosed. Specific methods encompass the administration of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, cyclopropyl {2-[(15)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide or a combination thereof, or a pharmaceutically acceptable prodrug, metabolite, polymorph, salt, solvate or clathrate thereof.
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- Industrial method for preparing apremilast and intermediate thereof
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The invention discloses an industrial method for preparing high-purity apremilast (described in formula I) and an intermediate thereof. With 3-nitrophthalic acid (compound II) adopted as the starting raw material, and organic acid or acid anhydride adopted as the solvent, the method comprises the following steps: preparing high-purity 3-acetamido phthalic anhydride (compound IV) through different intermediates; directly enabling the obtained undried product to react with (S)-1-(3-oxethyl-4-methoxy phenyl)-2-mesyl) ethylamine (compound V) or the salt during reflux in glacial acetic acid, so as to obtain the apremilast. The preparation method is easy to operate, low in energy consumption, high in yield, and applicable to industrial production.
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-
- Preparation method of Apremilast
-
The invention relates to a preparation method of Apremilast, comprising the following steps: by taking 3-hydroxy-4-methoxybenzaldehyde as a staring material, reacting with hydroxylamine hydrochloride to obtain 3-hydroxy-4-methoxy cyanobenzene, reacting with bromoethane to obtain 3-ethyoxyl-4-methoxy cyanobenzene, and then reacting with dimethyl sulfone under the action of n-butyllithium, and hydrolyzing in aqueous hydrochloric acid solution to obtain 1-(3-ethyoxyl-4-methoxyphenyl)-2-(mesyl)ketol); finally by taking S-(-)-alpha, alpha-diphenyl-2-pyrrolidine methanol as a chiral catalyst and taking borane dimethyl sulfide complex solution as a reductant, obtaining chirality S-3-ethyoxyl-4-methoxy group-alpha[(mesyl)benzyl alcohol], and then reacting with 3-acetamido-phthalimide under the action of triphenylphosphine and diethyl azodicarboxylate, thus obtaining the Apremilast. According to the preparation method, the process is effectively simplified, the reaction conditions are mild, the product yield and purity are relatively high, and large-scale industrial production is benefited.
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- AN IMPROVED PROCESS FOR PREPARATION OF APREMILAST AND NOVEL POLYMORPHS THEREOF
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The present invention provides an improved process for preparation of an intermediate of apremilast. The present invention also provides an improved process for preparation of apremilast. This invention also provides novel polymorphs of apremilast. The present invention also provides pharmaceutical compositions of novel polymorphs of apremilast. This invention also provides a process for preparation of novel polymorphs of apremilast, which are cost-effective, robust, and viable at plant scale.
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- A PROCESS FOR PREPARING THE KEY INTERMEDIATE OF APREMILAST, USING ENZYMATIC RESOLUTION OF THE RACEMIC AMINES
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The invention relates to a preparation method of (S)-l-(3-ethoxy-4-methoxyphenyl)- 2-(methylsulfonyl)-ethyl-amine (S)-l, or its N-acyl derivatives of general formula (S)-2. The amine (S)-l is the key intermediate in the synthesis of (S)-{2-[l-(3-ethoxy-4- methoxyphenyi)-2-methyisulfonylethyl]-4-acetylaminoisoindolin-l ?3-dione, known as Apremilast. In this synthesis, the amine (S)-l, or its respective salts, are subjected to condensation with 3-acetamidophthalic anhydride 4, providing the desired product 3 (Scheme 1).
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Page/Page column 22
(2016/12/22)
-
- Preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and preparation method of apremilast
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The invention relates to preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and a preparation method of apremilast. 4-methoxy-3-ethoxy phenylmagnesium bromide is prepared from 4-methoxy-3-ethoxy bromobenzene through Grignard reaction; 4-methoxy-3-ethoxy phenylmagnesium bromide is in addition reaction with methylsulfonyl acetonitrile, and then hydrolysis and reduction are carried out, so that (R,S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine (III) is obtained; separation and filtering are carried out, so that (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine N-acetyl-L-leucine salt (IV) is obtained; through neutralization, (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine (II) is obtained; the compound (II) is subjected to imidization, so that apremilast (1) is obtained. The mother liquor obtained after separation is recycled and converted into a compound IV, so that discharge of waste liquid is reduced, environment friendliness is realized and the cost is reduced.
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Paragraph 0068; 0069
(2016/10/07)
-
- A METHOD OF CHIRAL RESOLUTION OF THE KEY INTERMEDIATE OF THE SYNTHESIS OF APREMILAST AND ITS USE FOR THE PREPARATION OF PURE APREMILAST
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The present invention provides a method of chiral resolution of racemic amines of the benzyl type by means of salts formed with tartaric acid of formula (3) and intermediate of formula (2), and their use in the synthesis of Apremilast of formula 1.
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Page/Page column 24
(2016/10/31)
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- Methods for preparing apremilast
-
The invention relates to methods for preparing apremilast as shown in a formula I. The first method comprises the following step of enabling (S)-1-(3-ethyoxyl-4-methoxy phenyl)-2-(methanesulfonyl) ethylamine N-acetyl-L-leucine salt in a formula II and 3-acetyl amino phthalic anhydride in a formula III to be subjected to a reaction in an aprotic solvent so as to obtain a compound as shown in the formula I. The second method comprises the following step of enabling the enabling (S)-1-(3-ethyoxyl-4-methoxy phenyl)-2-(methanesulfonyl) ethylamine N-acetyl-L-leucine salt in the formula II and 3-acetyl amino phthalic anhydride in the formula III to be subjected to a reaction in the presence of organic alkali or alkali metal hydride so as to obtain the compound as shown in the formula I. According to the preparation methods of the apremilast provided by the invention, required raw materials and required reagents are cheap, the preparation method is suitable for industrial production, and good economic effects are achieved.
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Paragraph 0014; 0026; 0027; 0028; 0029; 0030-0033
(2017/04/29)
-
- Preparation method of apremilast with high optical purity, obtained product and application thereof
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The invention discloses a preparation method of apremilast which has the high optical purity and is shown in a formula I, an obtained product and application thereof. The preparation method of the apremilast comprises the steps that in a condensation reaction which takes a compound IV and a compound V as reaction raw materials and takes glacial acetic acid as a reaction menstruum, a catalyst selected from anhydrous magnesium sulfate or anhydrous sodium sulfate or anhydrous calcium chloride or anhydrous cupric sulfate or anhydrous molecular sieve or the like is used, so that the preparation method of the apremilast has the advantages of being efficient, high in yield and high in optical purity and is more suitable for industrial production; the apremilast product is high in optical purity and has a better curative effect by serving as a bulk pharmaceutical chemical to be prepared into drugs, and therefore treatment compliance of patients is improved. Please see the formula in the description.
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Paragraph 0039; 0040; 0041
(2017/01/02)
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- A SOLID FORM OF APREMILAST AND A PROCESS FOR PREPARING THE SAME
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The invention relates to a solvate of apremilast with tetrahydrofuran - THF of formula 1, wherein the molar ratio of apremilast and THF is 2:1. The THF solvate of apremilast exhibits the characteristic melting point of 79.4°C. Another aspect provides a process for preparing the THF solvate of apremilast. An alternative process for preparing a solvate of apremilast with tetrahydrofuran comprises a reaction of (S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine of formula (S)-3 with 3-acetamidophtalic anhydride of formula 5 in a mixture of tetrahydrofuran and an acid, or a reaction of a diastereoisomeric salt of (S)-1- (3-ethoxy-4-memoxyphenyl)-2-(methylsulfonyl)-ethylamine with tartaric acid or their derivatives of formula (S-6) with a base, producing (S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine of formula (S)-3, and its reaction with 3-acetamidophtalic anhydride of formula 5 in a mixture of tetrahydrofuran and an acid. Another aspect provides a pharmaceutical composition comprising the THF solvate of apremilast and at least one pharmaceutically acceptable excipient selected from the group of lactose, microcrystalline cellulose, sodium crosscarmellose, and magnesium stearate.
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Page/Page column 11; 12
(2016/11/14)
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- The purity of effecting apps is special a process for the preparation of (by machine translation)
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The invention discloses a apps is special of effecting the purity of the preparation method, 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-b-2-amine and N-acetyl-L-leucine salt forming reaction to obtain (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-b-2-ylamine-N-acetyl-L-leucine salt, the purified (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-b-2-ylamine-? N-acetyl-L-leucine salt with 3-acetyl amino phthalic anhydride in the presence of toluene and acetic acid react to generate the receive? (S)-2-[ 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetyl amino indoline -1, 3-diketone, through the acetone and ethanol mixed solvent recrystallization to obtain stereomeride relatively pure apps is special. The advantage of this invention lies in: the invention by replacing the solvent, adding catalyst, reaction time is greatly shortened, the chiral purity as high as 99.8% apps is special of. (by machine translation)
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Paragraph 0012; 0021; 0222
(2016/10/08)
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- An improved economical process for preparation of apremilast and identified their impurities
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The object of the present study is to provide an improved and commercially viable process for the preparation of apremilast, which is simple, cost effective and non-hazardous. In this process avoided the usage of acetic anhydride and high temperature. In this method, an alternative process using protected 3-aminophthalic acid (2) with acetyl chloride in the presence of triethanolamine as catalyst in dichloromethane solvent at 0 to 5 °C for 1 h. then followed by condensed with compound 3 to get the final compound 4. Besides, there were two unknown impurities like 3-(amino-1,3-dioxoisoindolin-2-yl)phthalic acid (5) and 4-aminoisobenzofuran-1,3-dione (6) identified by HPLC. A thorough study has been under taken to synthesize and characterize these unknown impurities. This improved process has a number of industrial advantages, such as economical material cost and relatively high yield. The structure of the synthesized compounds was elucidated by IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analyses.
- Jagannadham,Ramadevi,Prasanna
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p. 2749 - 2751
(2016/10/18)
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- Apremilast crystal form, and preparation method, pharmaceutical composition and application thereof
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The invention relates to an apremilast novel crystal form. Compared to a known apremilast solid form, the novel crystal form provided by the invention has good stability and beneficial processing and handling characteristics. The crystal form is suitable for solid preparation application. The invention also relates to a preparation method and a pharmaceutical composition of the novel crystal form, as well as an application of the novel crystal form in preparing medicines used for treating psoriatic arthritis.
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Paragraph 0059
(2017/03/08)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES WITH PDE4 MODULATORS
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Provided herein are methods of treating, preventing or managing atherosclerosis by administering a PDE4 modulator. Pharmaceutical compositions, dosage forms, and kits suitable for use in methods are also provided.
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- AMORPHOUS FORM OF APREMILAST
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The present invention provides an amorphous form of apremilast and process for preparation thereof. The present invention also provides a pharmaceutical composition comprising an amorphous apremilast and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of active psoriatic arthritis.
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