cas 616201-80-0, LorcaserinA | Articles data

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Niclosin hydrochloride pellet, and preparation method and preparation thereof
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; 0088

(2020/05/14)

Method for preparing lorcaserin
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 0029-0034

(2020/08/22)

Preparation method of key intermediate I of lorcaserin
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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(2018/09/26)

Preparation method of lorcaserin intermediate
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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(2017/08/29)

Preparation method and use of lorcaserin hydrochloride
The invention provides a preparation method of lorcaserin hydrochloride, wherein the preparation method comprises the synthetic route described in the specification. The preparation method of lorcaserin hydrochloride has the advantages of simpliness, cheap and easily available raw materials, convenient and safe post-processing, and more green and environmental-protection preparation process, and is an economic synthetic method which can be industrialized.
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Paragraph 0032; 0033

(2017/08/28)

Preparation method for hemihydrate lorcaserin hydrochloride
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 0053; 0054; 0055

(2017/08/28)

A preparing method of (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a lorcaserin intermediate
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 0023; 0080; 0081; 0082

(2016/10/17)

Lorcaserin hydrochloride hemihydrate preparation method
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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(2016/11/17)

A kind of products and intermediates green card color forest hydrochloride method for the preparation of (by machine translation)
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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Paragraph 0068; 0069

(2016/10/07)

A Concise Synthesis of Racemic Lorcaserin
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
p. 770 - 774
(2016/08/09)

Preparation method of lorcaserin hydrochloride
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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Paragraph 0046; 0047; 0048; 0049

(2017/01/09)

PROCESSES FOR THE PREPARATION OF LORCASERIN
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 0091; 0092

(2016/10/20)

1 - (phenethyl-amino) propane-2-ol compound or its salt for the preparation of
The invention relates to a preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof, shown in a formula II. The preparation method comprises the following step: reacting a compound shown in a formula I with epoxy propane to generate a compound shown in the formula II. According to the preparation method provided by the invention, cheap and accessible raw materials are adopted to prepare a target compound through a one-step reaction, so that the preparation method is low in cost, simple and convenient to operate, high in yield, environmental-friendly and suitable for industrial production. The invention also relates to a preparation method of lorcaserin or salts thereof. The lorcaserin is prepared from the high-purity 1-((4-chlorophenethyl) amino) propane-2-alcohol or the salts thereof, thereby being beneficial to improvement of the quality and stability of the product.
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Paragraph 0076; 0081-0082; 0092-0093

(2016/11/24)

8-chloro-1-methyl -2, 3, 4, 5-tetrahydro -1H-3-Benzazepine preparation method
The invention discloses a preparation method of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzoazatropylidene. The preparation method comprises the following steps: firstly, enabling a compound with a formula (III) to react with aluminium chloride to obtain a compound with a formula (II); and carrying out reduction reaction on the compound with the formula (II) under the combined action of sodium borohydride and aluminium chloride used in the step i) to obtain a compound in a formula (I). The invention also discloses a method for preparing a compound with a formula (V) or a salt thereof. The method comprises the following steps: with chlorobenzyl cyanide and 2-chloropropionic acid as raw materials, reacting under the existence of a carboxylic acid activation reagent to generate a compound in a formula (IV); and carrying out reduction reaction on the compound with the formula (IV) under the action of a reducing agent to obtain the compound with the formula (V). Compared with the prior art, the method disclosed by the invention has the advantages of low cost, convenience for operation, safety of production, high yield and the like.
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(2017/02/02)

Synthesis of 3-Benzazepines by Metal-Free Oxidative C–H Bond Functionalization–Ring Expansion Tandem Reaction
A metal-free synthesis of biologically important benzazepines is achieved through a single synthetic operation involving an oxidative C–H bond functionalization and ring expansion with diazomethanes as key reagent. This represents a new, strong methodology for the straightforward construction of the seven-ring N-heterocyclic structures under mild conditions using a 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) oxoammonium salt as oxidant. Moderate to good yields are achieved from simple, readily available tetrahydroisoquinolines, and this methodology has been further successfully applied for the synthesis of the 3-benzazepine drug Lorcaserin. A possible mechanistic pathway for the ring expansion step, comprising the extrusion of nitrogen in a concerted asynchronic process, is proposed based on both mechanistic proof and density function theory (DFT) calculations. (Figure presented.).
Gini, Andrea,Bamberger, Julia,Luis-Barrera, Javier,Zurro, Mercedes,Mas-Ballesté, Rubén,Alemán, José,Manche?o, Olga García
supporting information
p. 4049 - 4056
(2016/12/30)

Novel Synthesis of Antiobesity Drug Lorcaserin Hydrochloride
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
p. 1263 - 1267
(2015/09/28)

METHOD OF RACEMISATION OF UNDESIRED ENANTIOMERS
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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Page/Page column 34

(2015/02/02)

ADMINISTRATION OF LORCASERIN TO INDVIDUALS WITH RENAL IMPAIRMENT
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 0762; 0763

(2015/11/24)

PREPARATION OF CHIRAL 1-METHYL-2,3,4,5-1H-BENZODIAZEPINES VIA ASYMMETRIC REDUCTION OF ALPHA-SUBSTITUTED STYRENES
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)

NOVEL SYNTHETIC PROCESS TO 8-CHLORO-1-METHYL-BENZO[D]AZEPINE, NOVEL INTERMEDIATES AND THE PRODUCTION THEREOF
The present invention is directed to a simple and economical process for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine via novel intermediates and a highly selective asymmetric synthesis leading to enantiopure (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d] azepine or its (S)-enantiomer, in order to avoid or overcome chemical optical resolution.
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Page/Page column 64

(2014/11/13)

NOVEL SYNTHETIC PROCESSES TO 8-CHLORO-3-BENZO[D]AZEPINE VIA FRIEDEL-CRAFTS ALKYLATION OF OLEFIN
The present invention is directed to a short, facile, effective and industrially applicable process for obtaining 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine, or its salt, preferably lorcaserin hydrochloride. The present invention is further directed to a simple and effective ring closing methodology for obtaining 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine, or its salt, preferably lorcaserin hydrochloride. The present invention is also directed to a novel intermediate which can be suitably used in the process for producing 8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[d]azepine, or its salt, preferably lorcaserin hydrochloride and to a process for producing the novel intermediate.
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(2014/12/12)

FAST-DISSOLVE DOSAGE FORMS OF 5-HT2C AGONISTS
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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Page/Page column 86-87

(2012/03/26)

SALTS OF LORCASERIN WITH OPTICALLY ACTIVE ACIDS
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 83-84

(2012/03/26)

Processes for the Preparation of 8-Chloro-1-Methyl-2,3,4,5-Tetrahydro-1H-3-Benzazepine and Intermediates Related Thereto
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 6; 11-13

(2009/06/27)

5ht2c receptor modulator compositions and methods of use
The present invention relates to a composition comprising phentermine and a selective 5HT-2C receptor agonist. In addition, the invention relates to a composition comprising phentermine and a selective 5HT-2C receptor agonist having Formula (I): or a pharmaceutically acceptable salt, solvate or hydrate thereof. These compositions are useful in pharmaceutical compositions whose use includes the treatment of obesity.
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(2009/08/16)

PROCESSES FOR PREPARING (R)-8-CHLORO-1-METHYL-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINE AND INTERMEDIATES THEREOF
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 23-25

(2008/12/06)

Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5- tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity
The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [3H]phosphoinositol turnover: 5-HT 2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
Smith, Brian M.,Smith, Jeffrey M.,Tsai, James H.,Schultz, Jeffrey A.,Gilson, Charles A.,Estrada, Scott A.,Chen, Rita R.,Park, Douglas M.,Prieto, Emily B.,Gallardo, Charlemagne S.,Sengupta, Dipanjan,Dosa, Peter I.,Covel, Jon A.,Ren, Albert,Webb, Robert R.,Beeley, Nigel R. A.,Martin, Michael,Morgan, Michael,Espitia, Stephen,Saldana, Hazel R.,Bjenning, Christina,Whelan, Kevin T.,Grottick, Andrew J.,Menzaghi, Frederique,Thomsen, William J.
p. 305 - 313
(2008/09/19)

Discovery and SAR of new benzazepines as potent and selective 5-HT 2C receptor agonists for the treatment of obesity
We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT2C receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT2C, h5-HT2A or h5-HT2B receptors. Several compounds are shown to be potent and selective 5-HT 2C receptor agonists, which decrease food intake in a rat feeding model.
Smith, Brian M.,Smith, Jeffrey M.,Tsai, James H.,Schultz, Jeffrey A.,Gilson, Charles A.,Estrada, Scott A.,Chen, Rita R.,Park, Douglas M.,Prieto, Emily B.,Gallardo, Charlemagne S.,Sengupta, Dipanjan,Thomsen, William J.,Saldana, Hazel R.,Whelan, Kevin T.,Menzaghi, Frederique,Webb, Robert R.,Beeley, Nigel R.A.
p. 1467 - 1470
(2007/10/03)

BENZAZEPINE DERIVATIVES USEFUL FOR THE TREATMENT OF 5HT2C RECEPTOR ASSOCIATED DISEASES
The present invention relates to certain 1-substituted-2,3,4,5-tetrahydro-3-benzazepine derivatives of Formula (I), that are modulators of the 5HT2C receptor. Accordingly, compounds of the present invention are useful for the prophylaxis or treatment of 5HT2C receptor associated diseases, conditions or disorders, such as, obesity and related disorders.
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Page 52-53

(2008/06/13)

5HT2c receptor modulators
The present invention relates to novel compounds of Formula (I): which act as 5HT2C receptor modulators. These compounds are useful in pharmaceutical compositions whose use includes the treatment of obesity.
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Page 21

(2010/02/05)