953789-37-2

Usage

Uses

Used in Pharmaceutical Industry:
1-[[2-(4-Chlorophenyl)ethyl]amino]-2-chloropropane is used as a reagent for the synthesis of Lorcaserin (L469890, HCl), a selective 5-HT2C-receptor agonist, for the treatment of obesity. It plays a crucial role in the development of this medication, which helps in managing weight by targeting the serotonin receptors in the brain.

InChI:InChI=1/C11H15Cl2N.ClH/c1-9(12)8-14-7-6-10-2-4-11(13)5-3-10;/h2-5,9,14H,6-8H2,1H3;1H

Synthetic route

4-chloro-N-(2-chloro-1-oxopropyl)benzeneacetamide → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
With aluminum (III) chloride; sodium tetrahydroborate; chloro-trimethyl-silane In tetrahydrofuran at 70℃; for 24h; Inert atmosphere;	96%

1-[[2-(4-chlorophenyl)ethyl]amino]-2-hydroxypropane (847063-13-2) → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
With thionyl chloride In N,N-dimethyl acetamide; toluene at 50 - 65℃; for 3h; Inert atmosphere;	88.3%
With thionyl chloride In toluene at 70℃; for 10h;	85%
With thionyl chloride In N,N-dimethyl acetamide; toluene at 45 - 60℃;	81.3%

1-((4-chlorophenethyl)amino)propan-2-ol hydrochloride (1030624-41-9) → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
With thionyl chloride; N,N-dimethyl acetamide In toluene at 50 - 65℃; for 2.5h; Product distribution / selectivity;	85.82%
With thionyl chloride In N,N-dimethyl acetamide; toluene at 50 - 65℃; Inert atmosphere;	85.66%
With thionyl chloride at 50 - 62℃; for 2h; Product distribution / selectivity; Neat (no solvent);	69.52%

N-(2-(4-chlorophenyl)ethyl)-4-methyl-N-(2-chloropropyl)benzenesulfonamide → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
With sulfuric acid In water at 120℃; for 2h; Temperature; Reagent/catalyst;	84.7%

4-chlorophenylethylamine (156-41-2) → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium triflate / methanol / 6.5 h / 30 - 60 °C 2: N,N-dimethyl-formamide; thionyl chloride / toluene / 2 h / 45 - 60 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 20 - 60 °C / Inert atmosphere 2: thionyl chloride / N,N-dimethyl acetamide; toluene / 45 - 60 °C View Scheme

2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide (1030624-36-2) → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
Stage #1: 2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 65℃; Inert atmosphere; Stage #2: With hydrogenchloride In water; toluene at 30 - 40℃; for 0.5h;

p-chlorobenzyl cyanide (140-53-4) → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 0 - 55 °C / Inert atmosphere 2: potassium carbonate / acetonitrile / 20 - 60 °C / Inert atmosphere 3: thionyl chloride / N,N-dimethyl acetamide; toluene / 45 - 60 °C View Scheme

1-(4-chlorophenyl)-2-((2-hydroxypropyl)amino)ethane-1-one → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / 2-methyltetrahydrofuran / 0.25 h / 15 - 20 °C 1.2: 10 h / 60 °C 2.1: thionyl chloride / toluene / 10 h / 70 °C View Scheme

p-chlorophenacyl chloride (937-20-2) → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium carbonate / ethanol / 8 h / 60 °C 2.1: sodium tetrahydroborate / 2-methyltetrahydrofuran / 0.25 h / 15 - 20 °C 2.2: 10 h / 60 °C 3.1: thionyl chloride / toluene / 10 h / 70 °C View Scheme

2-(4-Chlorophenyl)ethanol (1875-88-3) → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen bromide / 91 - 96 °C / 517.55 - 1807.68 Torr 3: thionyl chloride; N,N-dimethyl acetamide / toluene / 50 - 65 °C View Scheme

2-(4-chlorophenyl)-N-(2-chloropropyl)acetamide → 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2)

Conditions	Yield
Stage #1: 2-(4-chlorophenyl)-N-(2-chloropropyl)acetamide With sodium tetrahydroborate; boron trifluoride-tetrahydrofuran complex at 60℃; Stage #2: With hydrogenchloride In water for 0.5h; Reflux;	315.2 g

1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2) → (+/-)-Lorcaserin (616201-80-0)

Conditions	Yield
With aluminum (III) chloride In 1,2-dichloro-benzene at 120 - 125℃; Inert atmosphere;	99%
With aluminum (III) chloride at 120 - 125℃; for 3h; Inert atmosphere; Large scale;	97%
With aluminum (III) chloride In 1,2-dichloro-benzene at 135 - 140℃;	96.1%

1-[[2-(4-chlorophenyl)ethyl]amino]-2-hydroxypropane (847063-13-2) + 1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2) → 1-((4-chlorophenethyl)(1-((4-chlorophenethyl)amino)propan-2-yl)amino)propan-2-ol

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70 - 75℃; for 5h;	22.3%

1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2) + 1,2-dichloro-benzene (95-50-1) → (+/-)-Lorcaserin (616201-80-0)

Conditions	Yield
Stage #1: 1-[[2-(4-chlorophenyl)ethyl]amino]-2-chloropropane hydrochloride; 1,2-dichloro-benzene With aluminum (III) chloride at 126℃; for 16h; Friedel Crafts; Industry scale; Inert atmosphere; Stage #2: With sodium hydroxide In cyclohexane; water pH=12; Product distribution / selectivity; Industry scale;

1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2) → Lorcaserin hydrochloride (846589-98-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / 1,2-dichloro-benzene / 3 h / 125 - 130 °C 2.1: L-Tartaric acid / acetone; water / 0.5 h / 45 - 50 °C 3.1: potassium carbonate / water / 0.33 h / 10 - 25 °C 3.2: 0 - 5 °C View Scheme

1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2) → bis((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) L-(+)-tartarate

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride / 1,2-dichloro-benzene / 3 h / 125 - 130 °C 2: L-Tartaric acid / acetone; water / 0.5 h / 45 - 50 °C View Scheme

1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2) → 2C11H14ClN*C4H6O6

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum oxide / 1,2-dichloro-benzene / 130 - 140 °C / Inert atmosphere 2: acetone; water / 0 - 55 °C View Scheme

1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2) → (S)-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine hydrochloride

Conditions	Yield
Multi-step reaction with 3 steps 1: aluminum oxide / 1,2-dichloro-benzene / 130 - 140 °C / Inert atmosphere 2: acetone; water / 0 - 55 °C 3: potassium carbonate / water; ethyl acetate / 0.5 h / 25 - 30 °C View Scheme

1-((2-(4-chlorophenyl)ethyl)amino)-2-chloropropane hydrochloride (953789-37-2) → lorcaserin

Conditions	Yield
With aluminum (III) chloride In 1,2-dichloro-benzene at 126℃; for 16h; Temperature; Friedel-Crafts Alkylation; Inert atmosphere; Large scale;

Upstream product

• 1030624-41-9 1-((4-chlorophenethyl)amino)propan-2-ol hydrochloride 
• 847063-13-2 1-[[2-(4-chlorophenyl)ethyl]amino]-2-hydroxypropane 
• 937-20-2 p-chlorophenacyl chloride 
• 1875-88-3 2-(4-Chlorophenyl)ethanol 
• 140-53-4 p-chlorobenzyl cyanide 
• 1030624-36-2 2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide 
• 156-41-2 4-chlorophenylethylamine 

Downstream Products

• 616201-80-0 (+/-)-Lorcaserin 
• 846589-98-8 Lorcaserin hydrochloride 
• 824430-78-6 bis((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) L-(+)-tartarate 
• 824430-78-6 2C₁₁H₁₄ClN*C₄H₆O₆ 
• 1006037-59-7 (S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride 
• 616202-92-7 lorcaserin 

Relevant academic research and scientific papers

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.

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.

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.

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.

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.

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.

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.

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.

PROCESSES FOR THE PREPARATION OF 5-HT2C RECEPTOR AGONISTS

The present invention relates to processes and intermediates useful in the preparation of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin), a serotonin (5-ΗT) receptor modulator that is useful in the treatment of, for example, central nervous system disorders, such as obesity.

PROCESSES FOR THE PREPARATION OF INTERMEDIATES RELATED TO THE 5-HT2C AGONIST (R)-8-CHLORO-1-METHYL-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINE

The present invention provides processes and intermediates useful in the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a serotonin (5-HT) receptor agonist that is useful in the treatment or prophylaxis of, for example, central nervous system disorders, such as obesity.