- A new enantioselective synthesis of antiobesity drug lorcaserin
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A simple and efficient enantioselective synthesis of anti-obesity drug lorcaerin starting from easily accessible 3-chlorostyrene oxide has been described for the first time employing hydrolytic kinetic resolution as a source of chirality. The protocol might also be useful in the synthesis of structural variants of lorcaserin.
- Ghotekar, Ganesh S.,More, Devidas A.,Nalla, Viswanadh,Muthukrishnan
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- Liquid chromatographic separation and thermodynamic investigation of lorcaserin hydrochloride enantiomers on immobilized amylose–based chiral stationary phase
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A novel liquid chromatographic method was developed for enantiomeric separation of lorcaserin hydrochloride on Chiralpak IA column containing chiral stationary phase immobilized with amylose tris (3.5-dimethylphenylcarbamate) as chiral selector. Baseline separation with resolution greater than 4 was achieved using mobile phase containing mixture of n-hexane/ethanol/methanol/diethylamine (95:2.5:2.5:0.1, v/v/v/v) at a flow rate of 1.2?mL/min. The limit of detection and limit of quantification of the S-enantiomer were found to be 0.45 and 1.5?μg/mL, respectively; the developed method was validated as per ICH guideline. The influence of column oven temperatures studied in the range of 20°C to 50°C on separation was studied; from this, retention, separation, and resolution were investigated. The thermodynamic parameters ΔH°, ΔS°, and ΔG° were evaluated from van't Hoff plots,(Ink′ versus 1/T) and used to explain the strength of interaction between enantiomers and immobilized amylose–based chiral stationary phase.
- Wani, Dattatraya V.,Rane, Vipul P.,Mokale, Santosh N.
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- Synthesis of enantiopure antiobesity drug lorcaserin
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Acylation of enantiomerically pure (R)-2-(3-chlorophenyl)propan-1-amine using chloroacetyl chloride, followed by borane reduction and aluminum chloride catalyzed cyclization yielded enantiopure lorcaserin.
- Smilovic, Ivana Gazic,Cluzeau, Jerome,Richter, Frank,Nerdinger, Sven,Schreiner, Erwin,Laus, Gerhard,Schottenberger, Herwig
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- A Concise Synthesis of Racemic Lorcaserin
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We report herein the concise synthesis of racemic lorcaserin (±)-1, which is an anti-obesity drug. The synthetic route involved the key synthesis of an asymmetrical imide intermediate 11 and its efficient reduction. Imide 11 was synthesized directly by the reaction of nitrile 9 with acid 10. The reducing system of NaBH4, AlCl3, and trimethylsilyl chloride efficiently fulfilled the reduction of imide 11 to amine 8a, which could be converted to (±)-1 via Friedel-Crafts reaction as reported. This route afforded 69% two-step yield of 8a from 9 via 11, and the concise synthesis of (±)-1 was completed in three steps. This route offers an alternative pathway to the synthesis of (±)-1 and its analogues.
- Xu, Bin,Su, Jincai,Wang, Jing,Zhou, Guo-Chun
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- Novel Synthesis of Antiobesity Drug Lorcaserin Hydrochloride
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A novel synthesis of antiobesity drug lorcaserin hydrochloride was accomplished in six steps. N-protection of 2-(4-chlorophenyl)ethanamine with di-tert-butyl dicarbonate, N-alkylation with allyl bromide, deprotection, intramolecular Friedel-Crafts alkylation, chiral resolution with l-(+)-tartaric acid, and the final salification led to the target molecule lorcaserin hydrochloride in 23.1% overall yield with 99.9% purity and excellent enantioselectivity (>99.8% ee). This convenient and economical procedure is remarkably applicable for scale-up production.
- Zhu, Qihua,Wang, Junwei,Bian, Xueguo,Zhang, Lingzhi,Wei, Ping,Xu, Yungen
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- Method for preparing lorcaserin
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The invention discloses a method for preparing lorcaserin. Specifically, the method comprises the steps: taking p-chlorophenylacetonitrile as an initial raw material, preparing p-chlorophenylethylamine through reduction; carrying out a reaction with p-toluenesulfonyl chloride to form an amino occupying intermediate; enabling the intermediate to carry out a reaction with monochloroacetone under analkaline condition to form N-(2-(4-chlorphenyl)ethyl)-4-methyl-N-(2-propionyl)benzenesulfonamide, and then carrying out reduction, chlorination, p-toluenesulfonyl removal and intramolecular Friedel-Crafts alkylation to synthesize 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzoazepine, carrying out L-(+)-tartaric acid resolution and alkalization on azepine to remove tartaric acid, and acting with hydrogen chloride diethyl ether to salify to prepare lorcaserin. The method has the characteristics of simple synthesis method, good reaction selectivity, high product purity, environmental protectionand low preparation cost.
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Paragraph 0035; 0037-0039; 0041-0043
(2020/08/22)
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- Niclosin hydrochloride pellet, and preparation method and preparation thereof
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A lorcaserin hydrochloride mini-pill is provided. The mini-pill comprises a blank pill core, a medicine loading layer, a slow-release layer and a quick-release layer in order from inside to outside. The medicine loading layer comprises lorcaserin hydrochloride, lactose monohydrate, highly substituted hydroxypropylcellulose and talcum powder. The slow-release layer comprises ethyl cellulose, highly substituted hydroxypropylcellulose, talcum powder and triethyl citrate. The quick-release layer comprises lorcaserin hydrochloride, lactose monohydrate, highly substituted hydroxypropylcellulose and talcum powder. The mass ratio of the sum of the weight of the blank pill core and the weight of the medicine loading layer to the mass of the slow-release layer is 1:(0.25-0.35). The mini-pill comprises the slow-release layer and the quick-release layer, and therefore a medicine can rapidly work and functions of the medicine in a body are prolonged. A preparing method of the lorcaserin hydrochloride mini-pill and a preparation of the lorcaserin hydrochloride mini-pill are also provided.
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Paragraph 0049; 0084; 0089
(2020/05/14)
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- Synthesis process of weight-reducing drug lorcaserin hydrochloride intermediate
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The invention discloses a synthesis process of a weight-reducing drug lorcaserin hydrochloride intermediate (compound V), which is characterized in that p-chlorophenylethylamine is used as a raw material, acetic anhydride is subjected to acylation to prot
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- MODIFIED-RELEASE DOSAGE FORMS OF 5-HT2C AGONISTS USEFUL FOR WEIGHT MANAGEMENT
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The present invention relates to methods for weight management that utilize modified-release dosage forms comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts and crystalline forms thereof. The present invention further relates to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts, crystalline forms thereof and modified-release dosage forms comprising them.
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Paragraph 1182-1186; 1189-1192; 1197
(2019/05/30)
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- Light-Enabled Enantiodivergence: Stereospecific Reduction of Activated Alkenes Using a Single Organocatalyst Enantiomer
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Light-enabled enantiodivergence is demonstrated in which the alkene substrate configuration is manipulated (E → Z) prior to organocatalytic reduction with a chiral thiourea and Hantzsch ester. This allows stereodivergent reduction to be regulated at the substrate level with high fidelity and mitigates the need for a second, enantiomeric catalyst (up to 93:07 and 95:5 er). The synthetic utility of this strategy has been demonstrated in the synthesis of the weight-loss drug (R)-Lorcaserin (Belviq) and a potent AMPA modulator.
- Hostmann, Theresa,Molloy, John J.,Bussmann, Kathrin,Gilmour, Ryan
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p. 10164 - 10168
(2019/12/24)
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- Preparation method of key intermediate I of lorcaserin
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The invention discloses a preparation method of a key intermediate I of lorcaserin. The preparation method comprises the steps as follows: (1) in an organic solvent A, 2,4'-dichloroacetophenone is subjected to a condensation reaction with isopropanolamine under catalysis of alkali, and 1-(4-chlorophenyl)-2-((2-hydroxypropyl)amino)ethane-1-one is obtained; (2) the 1-(4-chlorophenyl)-2-((2-hydroxypropyl)amino)ethane-1-one obtained in the step (1) is subjected to catalytic reduction with sodium borohydride and acid in a solvent B, and the key intermediate I of lorcaserin is obtained. The preparation method can synthesize the key intermediate I of lorcaserin from cheap and easily available raw materials under mild reaction conditions, has the advantages of being simple to operate, low in costand high in yield, and is energy-saving, environmentally friendly and suitable for mass production.
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- Synthesis method of lorcaserin
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Belonging to the field of pharmaceutical chemistry, the invention discloses a synthesis method of lorcaserin. The method includes: taking 4-chlorophenethylamine as the raw material, carrying out reductive amination reaction with acrolein to prepare N-allyl-4-chloro-phenethylamine (compound 2), protecting the amino of compound2 by with t-butyloxycarboryl (Boc) to obtain N-Boc-N-allyl-4-chloro-phenethylamine (compound 3), subjecting the compound 3 to palladium acetate catalyzed cyclization to obtain a compound 4, conducting catalytic hydrogenation on the compound 4 to obtain N-Boc-lorcaserin, removing the Boc group under an acidic condition to obtain a lorcaserin crude product, and performing further purification to obtain lorcaserin. The synthesis method provided by the invention has the advantages of cheap and easily available reagent, safe and reliable reaction, recyclable reaction solvent, simple post-treatment operation, and environment-friendliness, and is conducive to large-scale industrial production.
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- A green card color lin hydrochloride semi-hydrate crystal preparation method (by machine translation)
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The invention belongs to the field of the preparation of the crystalline form of the compound in a green card color lin hydrochloride semi-hydrate crystal preparation method, the method comprises the following steps: (1) the green card color lin hydrochloric acid salt can be dissolved in the organic solvent after 1st, adding water, stirring, concentrated to remove the solvent, to obtain the oily matter; (2) the oil-like to 2nd is added in the organic solvent, stirring, to obtain a green card color lin hydrochloride semi-hydrate crystalline form. The method without the control of the hydrogen chloride gas into the amount and does not need to realize the process by heating the crystal, with easy control of reaction conditions, moderate, high yield and good quality of the products and the like. (by machine translation)
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Paragraph 0022; 0023; 0032; 0033; 0038; 0039; 0044; 0045
(2017/07/06)
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- COCRYSTAL OF LORCASERIN, PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS AND USE THEREOF (AS AMENDED)
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The present invention relates to a new type of eutectic crystal of lorcaserin hydrochloride and benzoic acid. Compared with the prior art, the eutectic crystal has the improved properties of good stability, low solubility, and being suitable for the application of controlled-release preparation. The present invention also relates to a method for preparing the eutectic crystal, a pharmaceutical composition thereof and the use thereof in the manufacture of drugs for treating and/or preventing diseases associated with 5HT2C.
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Paragraph 0089-0093
(2017/12/08)
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- Preparation method for hemihydrate lorcaserin hydrochloride
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The invention discloses a preparation method for hemihydrate lorcaserin hydrochloride. The preparation method comprises the following steps: (1) making a compound shown as a formula III react with ammonia to obtain a compound shown as a formula II; (2) under the protection of nitrogen gas, dissolving the compound shown as the formula II in an organic solvent, adding a hydrogen chloride solution of which the solvent is the organic solvent to salify, and adding water and cyclohexane to form a hemihydrate in order to obtain the compound shown as a formula I, wherein the organic solvent is isopropanol or 1,4-dioxane. In the preparation method disclosed by the invention, ammonium hydroxide substitutes for potassium carbonate in the prior art, so that unqualified ignition residues of a finial product caused by potassium chloride generated after salt removal can be avoided; an isopropoxide hydrochloride solution substitutes for the conventional hydrogen chloride gas, so that other impurities can be prevented from being introduced in a preparation process under the improper control of dosage and rate of the gas.
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Paragraph 0097; 0099; 0100; 0101
(2017/08/28)
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- Preparation method of lorcaserin intermediate
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The invention discloses a preparation method of a lorcaserin intermediate (I). According to the preparation method, p-chlorobenzyl cyanide is taken as the primary raw material, and the lorcaserin intermediate (I) is obtained after reduction reactions and condensation reactions. The primary raw materials (p-chlorobenzyl cyanide and 1-chloro-2-propanol) are cheap and easily available; raw materials, which can easily get polluted and are explosive, such as sulfoxide chloride, hydrobromic acid, borane, and the like are not used; the preparation method will not produce a large amount of wastewater and is beneficial for the environment protection; moreover, the requirements on the protection of workers are lowered, and safe production is guaranteed. The route design is novel, the raw materials are easily available, the operation is simple and feasible, and the preparation method is environment-friendly and can be applied to massive industrial production.
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- Lorcaserin hydrochloride hemihydrate preparation method
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The invention provides a lorcaserin hydrochloride hemihydrate preparation method. The method comprises the following steps: taking ethylamine as an initial raw material, performing an aminolysis ring-opening reaction with epoxypropane, chloridizing the material, performing friedel-Crafts alkylation cyclization on the material, splitting the material with tartaric acid, dissociating tartrate and forming hydrochloride to obtain the lorcaserin hydrochloride hemihydrate. The preparation method has the characteristics of less reaction steps, mild reaction condition, low cost of a comprehensive reagent, less three wastes, simple post-treatment and simple operation, so that the preparation method has the advantage of brand new, economy and environmental protection, high efficiency, and realization of industrial production.
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- A kind of products and intermediates green card color forest hydrochloride method for the preparation of (by machine translation)
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The invention relates to the field of pharmaceutical chemistry, in particular relates to a diet green card color forest hydrochloride method for the preparation of intermediates thereof. The utility model is characterized in that the preparation method comprises: to the chlorobenzene ethylamine as raw materials, after sequentially acidylated protecting amino group, allyl substituted, deprotected, gram alkylate tougheness, split, a green card color forest of the hydrochloric acid salt. green card color forest hydrochloric acid of the present invention and wherein the intermediate preparation method is low in cost, simple in operation, after treatment is convenient, is an economical, can be industrial synthetic method. (by machine translation)
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- Preparation method of lorcaserin hydrochloride
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The invention relates to the field of medicinal chemistry, and specifically discloses a preparation method of lorcaserin hydrochloride namely (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. The preparation method is characterized in that 4-chlorophenethylamine as a raw material is successively subjected to acylation and amino protection, allyl substitution, Friedel-Crafts alkylation, resolution and salifying to obtain lorcaserin hydrochloride. The preparation method of lorcaserin hydrochloride has the advantages of high yield, low cost, simple operation and the like, and is an economic and industrializable synthesis method.
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- PROCESSES FOR THE PREPARATION OF LORCASERIN
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The present invention relates to stable crystalline Form A of lorcaserin hydrochloride of Formula (IA) and processes for its preparation. The invention also relates to processes for the preparation of lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof.
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Paragraph 0094
(2016/10/20)
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- A preparing method of (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a lorcaserin intermediate
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A preparing method of (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine that is a lorcaserin intermediate is disclosed. The method includes (1) dehydrating a compound 1 and a compound 2 under catalysis by boric acid to generate an amide 3, (2) reducing the intermediate 3 with a borane dimethylsulfide complex to obtain a compound 4, and (3) subjecting the compound 4 to direct ring closing with the existence of aluminum chloride to generate the lorcaserin intermediate that is the (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine that is the compound 6. The method avoids use of 3,4,5-trimethoxyphenylboronic acid that is an expensive reagent, thus reducing the cost. The method avoids use of thionyl chloride so that the method is environmental friendly. A step of hydroxy chlorination is reduced so that the method is simple in process. The conversion ratio of raw materials and the total yield of reactions are increased. The yield of the compound 6 is increased from 60% in a patent to 82%. The method is suitable for industrial production. A reaction equation is shown in the description.
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Paragraph 0107; 0108; 0109; 0110
(2016/10/17)
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- METHOD OF RACEMISATION OF UNDESIRED ENANTIOMERS
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The present invention provides a very simple, efficient and economic technology for racemisation of amines, alcohols or thioalcohols where the chiral carbon (benzylic position) is located at the β-position of the heteroatom (amino, hydroxyl or mercapto group) or even more distant therefrom. Special focus is oriented in efficient and simple racemisation of an undesired enantiomer of a chiral pharmaceutically active ingredient, preferably lorcaserin or a salt thereof, preferably the hydrochloride salt thereof. The approach according to the invention enables a use of cheaper and shorter racemic synthetic schemes not requiring expensive and toxic reagents and catalysts. Present methodology enables industrialy convenient process.
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- ADMINISTRATION OF LORCASERIN TO INDVIDUALS WITH RENAL IMPAIRMENT
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The present disclosure relates to methods for weight management in an individual in need thereof by determining the level of renal sufficiency of the individual and prescribing or administering a therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-ben-zazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof to the individual, provided that the individual has a level of renal sufficiency selected from the group consisting of: no renal impairment, mild renal impairment, and moderate renal impairment. In addition, the disclosure relates to a method for selecting an individual for treatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-ben-zazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof from a plurality of individuals in need of weight management by determining the level of renal sufficiency of the individual and selecting the individual for treatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-ben-zazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof if the individual has a level of renal sufficiency selected from the group consisting of: no renal impairment, mild renal impairment, and moderate renal impairment.
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Paragraph 0765-0769
(2015/11/24)
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- Stabilized amorphous lorcaserin hydrochloride
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The present invention provides stabilized amorphous lorcaserin hydrochloride ((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]-azepine hydrochloride), a pharmaceutical composition comprising the same, as well as a process for obtaining the same.
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Paragraph 0082
(2015/05/19)
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- Stabilized amorphous lorcaserin hydrochloride
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The present invention providesstabilized amorphous lorcaserin hydrochloride ((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]- azepinehydrochloride), a pharmaceutical composition comprising the same, as well as a process for obtaining the same.
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Page/Page column 28
(2015/05/26)
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- 15A PROCESS FOR THE PREPARATION OF 8-CHLORO-1-METHYL-2,3,4,5-TETRAHYDRO-1H-BENZO[D]AZEPINE ITS ENANTIOMERS
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The present invention discloses a process for synthesis of Lorcaserin and its analogues using epoxide/chiral epoxide.
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Paragraph 0039
(2015/11/27)
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- SOLID DISPERSION COMPRISING AMORPHOUS LORCASERIN HYDROCHLORIDE
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The present invention is directed to an amorphous solid dispersion comphsing lorcaserin hydrochloride ((R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin hydrochloride) of formula (1), and one or more pharmaceutically acceptable water soluble polymers, a pharmaceutical composition comprising the amorphous solid dispersion as well as a process for obtaining the same.
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Page/Page column 19
(2014/09/29)
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- PREPARATION OF CHIRAL 1-METHYL-2,3,4,5-1H-BENZODIAZEPINES VIA ASYMMETRIC REDUCTION OF ALPHA-SUBSTITUTED STYRENES
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The present invention provides an asymmetric and economic synthesis of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine via novel intermediates applying an asymmetric enzymatic, biomimetic or catalytic reduction. The present invention also provides a novel green asymmetric catalytic reduction adapted for an aqueous medium to be applied in the synthesis of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine or novel intermediates.
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Page/Page column 66
(2015/01/07)
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- PROCESS FOR THE ENANTIOSELECTIVE SYNTHESIS OF A TETRAHYDROBENZAZEPINE COMPOUND
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This invention relates to an improved process for the enantioselective synthesis of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
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- FAST-DISSOLVE DOSAGE FORMS OF 5-HT2C AGONISTS
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Salts of the 5-HT2 c-receptor agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and dosage forms comprising them that are useful for, inter alia, weight management
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- SALTS OF LORCASERIN WITH OPTICALLY ACTIVE ACIDS
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Salts of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with optically active acids, and pharmaceutical compositions comprising them that are useful for, inter alia, weight management.
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Page/Page column 85-86
(2012/03/26)
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- Processes for the Preparation of 8-Chloro-1-Methyl-2,3,4,5-Tetrahydro-1H-3-Benzazepine and Intermediates Related Thereto
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The present invention provides processes, methods and intermediates for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, salts, hydrates and crystal forms thereof which are useful as serotonin (5-HT) receptor agonists for the treatment of, for example, central nervous system disorders such as obesity.
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Page/Page column 9; 13-14
(2009/06/27)
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- CRYSTALLINE FORMS OF (R)-8-CHLORO-1-METHYL- 2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINE HYDROCHLORIDE
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The present invention is a process for preparing crystalline form of ( R )-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate.
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Page/Page column 10-11
(2009/09/26)
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- PROCESSES FOR PREPARING (R)-8-CHLORO-1-METHYL-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINE AND INTERMEDIATES THEREOF
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The present invention provides processes and intermediates for the preparation of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and salts thereof which are useful as serotonin-2C (5-HT2C) receptor agonists for the treatment of, for example, obesity.
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Page/Page column 26-27
(2008/12/06)
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