- Synthetic method of apremilast
-
The invention relates to a synthesis method of apremilast, which comprises the following steps: (1): reacting 3-aminophthalic acid or salt thereof with acetic anhydride to obtain 3-acetamido phthalic anhydride; and (2) suspending 3-acetamido phthalic anhydride in a first solvent, adding into a suspension consisting of free amine (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethylamine and a second solvent at a certain temperature, reacting, and adding a C1-C6 alcohol solvent for crystallization after the reaction is finished, thereby obtaining the apremilast. According to the synthesis method of apremilast, the production cost is reduced, the operation process is facilitated, the safety in industrial production is improved to a great extent, the yield is high, and the effect is good.
- -
-
Paragraph 0009; 0027-0029; 0034-0036; 00038-0040
(2021/07/17)
-
- ISOINDOLE DERIVATIVE
-
Disclosed is a compound of formula (I) and a stereoisomer thereof: wherein R1, R2, R3 and R4 are as defined in the present disclosure.
- -
-
-
- Synthesis method of methyl 2-acetyl-6-aminobenzoate
-
The invention provides a synthesis method of methyl 2-acetyl-6-aminobenzoate. The target product methyl 2-acetyl-6-aminobenzoate is prepared from cheap and easily available 3-nitrophthalic acid through a six-step reaction. The synthesis method has the characteristics of easily available raw materials, short route, high yield, easiness in operation, small environmental pollution and the like, and is suitable for large-scale industrial production.
- -
-
-
- Apremilast three-component one-pot-boiling synthesis method
-
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.
- -
-
Paragraph 0031-0039; 0044
(2019/11/29)
-
- 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.
- -
-
-
- 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.
- -
-
Paragraph 00114
(2017/03/14)
-
- Industrial method for preparing apremilast and intermediate thereof
-
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.
- -
-
Paragraph 0036; 0037
(2017/03/14)
-
- Preparation method of Apremilast and intermediate
-
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.
- -
-
Paragraph 0064; 0065; 0066; 0067
(2016/10/07)
-
- (+)-2-[1-(3-ETHOXY-4-METHOXYPHENYL)-2-METHYLSULFONYLETHYL]-4-ACETYLAMINOISOINDOLINE-1,3-DIONE: METHODS OF USING AND COMPOSITIONS THEREOF
-
Stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a pharmaceutically acceptable polymorph, salt, solvate or hydrate thereof, as well as a pharmaceutical composition or single unit dosage form comprising such compound and such compound for use as a medicine.
- -
-
-
- 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.
- -
-
-
- 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.
- -
-
-
- Preparation method of 3-acetyl aminophthalimide
-
The invention relates to a preparation method of 3-acetyl aminophthalimide, comprising the following steps: dissolving 3-nitro phthalic acid in sodium hydroxide aqueous solution, then adding a reducer and a catalyst, heating to 70 to 80 DEG C, stirring and reacting for 1 to 20 hours, and recrystallizing to obtain 3-amino phthalic acid; stirring with acetic anhydride and performing reflux reaction for 1 to 10 hours to obtain N-(1,3-Dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide; dissolving the N-(1,3-Dioxo-1,3-dihydro-2-benzofuran-4-yl)acetamide in an organic solvent, adding an amino donor, and stirring and refluxing for 1 to 10 hours, thus obtaining the 3-acetyl aminophthalimide. The method is simple in operation, high in yield, short in reaction route, less in the three wastes (waste gas industrial residue), and easy for industrial production.
- -
-
-
- PROCESS FOR THE ENANTIOMERIC RESOLUTION OF APREMILAST INTERMEDIATES
-
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.
- -
-
-
- CONTROLLED RELEASE ORAL DOSAGE FORMS OF POORLY SOLUBLE DRUGS AND USES THEREOF
-
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.
- -
-
Paragraph 0215
(2016/06/06)
-
- Methods for treating diseases using isoindoline compounds
-
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.
- -
-
Page/Page column 27
(2016/08/17)
-
- COMPOSITIONS AND METHODS FOR THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES WITH PDE4 MODULATORS
-
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.
- -
-
-
- USE OF PDE4 INHIBITORS AND COMBINATIONS THEREOF FOR THE TREATMENT OF CYSTIC FIBROSIS
-
Methods of treating cystic fibrosis by administering a PDE4 inhibitor in combination with one or more cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, including ivacaftor, and/or one or more CFTR correctors, including lumacaftor. Pharmaceutical compositions, dosage forms, and kits suitable for use in methods of the invention are also disclosed.
- -
-
-
- METHODS FOR THE TREATMENT OF BONE LOSS
-
Provided herein are methods of treating, preventing and/or managing bone loss using (+)-2- [ 1 -(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindolin- 1,3-dione, alone or in combination with other therapeutics.
- -
-
-
- TREATMENT OF PSORIATIC ARTHRITIS USING APREMILAST
-
Methods of treating, managing or preventing psoriatic arthritis are disclosed. Specific methods encompass the administration of apremilast, alone or in combination with a second active agent.
- -
-
-
- 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.
- -
-
-
- Methods for treating cutaneous lupus using aminoisoindoline compounds
-
Methods of treating cutaneous lupus in a human are disclosed. Specific methods encompass the administration of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (ACTIMID?), 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (REVLIMID?), or cyclopropyl 2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide, alone or alternatively, in combination with a second active agent.
- -
-
Page/Page column 14
(2010/11/27)
-
- (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
-
Stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (?) isomer, and prodrugs, metabolites, polymorphs, salts, solvates, hydrates, and clathrates thereof are discussed. Also discussed are methods of using and pharmaceutical compositions comprising the (+) enantiomer of 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione are disclosed. The methods include methods of treating and/or preventing disorders ameliorated by the reduction of levels of TNF-α or the inhibition of PDE4.
- -
-
-
- CARBOXY AND SUBSTITUTED CARBOXY AROLY PEPTIDES
-
Peptides of the formula STR1 wherein X is various amino or imino acids or esters are useful as hypotensive agents.
- -
-
-
