158681-13-1

Basic information

• Product Name: Rimonabant hydrochloride
• Synonyms: RIMONABANT HYDROCHLORIDE;5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-n-1-piperidinyl-1h-pyrazole-3-carboxamide monohydrochloride;ACOMPLIA;ACOMPLIA (RIMONABANT;RIMONABANT HCL;Rimonabant(Acomplia);RimonabantConsultedStandard;Acomplia, SR141716
• CAS NO: 158681-13-1
• Molecular Formula: C₂₂H₂₁Cl₃N₄O*ClH
• Molecular Weight: 500.25
• EINECS: 233-720-0
• Product Categories: API;Cnbio;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics;Heterocycles;SR141716
• Mol File: 158681-13-1.mol

Chemical Properties

• Melting Point: 230-240°C
• Boiling Point: 627.6 °C at 760 mmHg
• Flash Point: 333.3 °C
• Appearance: white to beige/
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: soluble20mg/mL, clear
• CAS DataBase Reference: Rimonabant hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Rimonabant hydrochloride(158681-13-1)
• EPA Substance Registry System: Rimonabant hydrochloride(158681-13-1)

Safety Data

• Hazard Codes: T,Xi
• Statements: 25-36
• Safety Statements: 26-45
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 158681-13-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Rimonabant hydrochloride is used as an anti-obesity agent for its ability to modulate the endocannabinoid system, which plays a role in regulating energy balance and appetite.
Used in Research and Development:
Rimonabant hydrochloride is used as a CB1 receptor antagonist for studying its effects on various cellular and physiological processes. This includes its application in analyzing protein synthesis in C2C12 myotubes, examining its effects on human astroglia in combination with methanandamide (mAEA), and studying its impact on murine gastric vagal afferent mechanosensitivity.

Hazard

A poison.

Biochem/physiol Actions

Rimonabant acts as a mycobacterial membrane protein large 3 (MMPL3) inhibitor. Rimonabant hydrochloride exhibits therapeutic activity against weight reduction and smoking cessation.

InChI:InChI=1/C22H21Cl3N4O.ClH/c1-14-20(22(30)27-28-11-3-2-4-12-28)26-29(19-10-9-17(24)13-18(19)25)21(14)15-5-7-16(23)8-6-15;/h5-10,13H,2-4,11-12H2,1H3,(H,27,30);1H

Synthetic route

N-aminopiperidine hydrochloride (63234-70-8) + rimonabant acid (162758-35-2) + rimonabant (168273-06-1) → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Stage #1: rimonabant acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 6h; Stage #2: N-aminopiperidine hydrochloride With triethylamine In tetrahydrofuran at 60℃; for 1.5h; Stage #3: rimonabant With hydrogenchloride	92.7%

1-Aminopiperidine (2213-43-6) + 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (168273-05-0) → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Stage #1: 1-Aminopiperidine; 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 10 - 25℃; for 2 - 3.5h; Stage #2: With hydrogenchloride In water; acetone at 20 - 25℃; for 0.5h;
Stage #1: 1-Aminopiperidine; 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride With triethylamine In dichloromethane at 10 - 20℃; for 1h; Stage #2: With hydrogenchloride pH=1;	33 g
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 0 - 20 °C 2: hydrogenchloride / diethyl ether / pH 1 View Scheme
With TEA In dichloromethane at 0 - 20℃; for 0.5h;

rimonabant (168273-06-1) → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
With hydrogenchloride In methanol; water at 20℃;
With hydrogenchloride In water; acetone at 0 - 55℃; for 0.25 - 1.25h; Product distribution / selectivity;
With hydrogenchloride In methanol; butyl methyl ether at 20℃; for 2h; pH=1.0;

4'-chloropropiophenone (6285-05-8) → rimonabant hydrochloride (158681-13-1)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: triethylamine; methyl iodide / acetonitrile / 24 h / 20 - 45 °C / Inert atmosphere 2.1: tetrahydrofuran / 5 h / 10 - 20 °C 3.1: triethylamine / toluene / 12 h / 20 °C 4.1: toluene-4-sulfonic acid / toluene / 12 h / Reflux 5.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C / Cooling with ice 6.1: triethylamine / dichloromethane / 1 h / 10 - 20 °C 6.2: pH 1 View Scheme

C17H13Cl3N2O3 → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / toluene / 12 h / Reflux 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C / Cooling with ice 3.1: triethylamine / dichloromethane / 1 h / 10 - 20 °C 3.2: pH 1 View Scheme

2,4-dichlorophenyl hydrazine hydrochloride (5446-18-4) → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / toluene / 12 h / 20 °C 2.1: toluene-4-sulfonic acid / toluene / 12 h / Reflux 3.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C / Cooling with ice 4.1: triethylamine / dichloromethane / 1 h / 10 - 20 °C 4.2: pH 1 View Scheme
Multi-step reaction with 3 steps 2.1: propionic acid / 16 h / Heating / reflux 2.2: 20 h / 140 - 145 °C 3.1: hydrogenchloride / water; isopropyl alcohol / 9.08 h / 10 - 20 °C View Scheme

5-(4-chlorophenyl)-4-methyl-2,3-furandione → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / toluene / 12 h / 20 °C 2.1: toluene-4-sulfonic acid / toluene / 12 h / Reflux 3.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C / Cooling with ice 4.1: triethylamine / dichloromethane / 1 h / 10 - 20 °C 4.2: pH 1 View Scheme

[[1-(4-chlorophenyl)-1-propenyl]oxy]trimethylsilane → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 5 h / 10 - 20 °C 2.1: triethylamine / toluene / 12 h / 20 °C 3.1: toluene-4-sulfonic acid / toluene / 12 h / Reflux 4.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C / Cooling with ice 5.1: triethylamine / dichloromethane / 1 h / 10 - 20 °C 5.2: pH 1 View Scheme

4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester (169544-41-6) → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Multi-step reaction with 3 steps 2.1: propionic acid / 16 h / Heating / reflux 2.2: 20 h / 140 - 145 °C 3.1: hydrogenchloride / water; isopropyl alcohol / 9.08 h / 10 - 20 °C View Scheme

rimonabant acid (162758-35-2) → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: thionyl chloride / toluene / 3 h / Heating / reflux 2: triethylamine / dichloromethane / 3 h / 0 - 20 °C 3: hydrogenchloride / diethyl ether / pH 1 View Scheme

ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate (158941-22-1) → rimonabant hydrochloride (158681-13-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium hydroxide; water / methanol / 3 h / Heating / reflux 2: thionyl chloride / toluene / 3 h / Heating / reflux 3: triethylamine / dichloromethane / 3 h / 0 - 20 °C 4: hydrogenchloride / diethyl ether / pH 1 View Scheme

rimonabant hydrochloride (158681-13-1) → rimonabant (168273-06-1)

Conditions	Yield
With methanol; potassium hydroxide; water at 0 - 5℃; for 1h;	93%
With sodium hydroxide In methanol; water pH=8.5;
With sodium hydroxide In methanol; water at 28 - 30℃; for 0.666667h; pH=11;

rimonabant hydrochloride (158681-13-1) → rimonabant hydrochloride ethanolate (1000380-28-8)

Conditions	Yield
In ethanol Product distribution / selectivity; Heating / reflux;

rimonabant hydrochloride (158681-13-1) → rimonabant hydrochloride dichloromethanate

Conditions	Yield
In dichloromethane Product distribution / selectivity; Heating / reflux;

rimonabant hydrochloride (158681-13-1) → rimonabant hydrochloride hemi-isopropanolate

Conditions	Yield
In isopropyl alcohol Product distribution / selectivity; Heating / reflux;
In tetrahydrofuran; ethyl acetate; isopropyl alcohol Product distribution / selectivity; Heating / reflux;

rimonabant hydrochloride (158681-13-1) → 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)pyrazole-3-carboxamide hydrate (945634-91-3)

Conditions	Yield
With ammonia; water In methanol at 25 - 30℃; for 2h; pH=8.0 - 10.0; Product distribution / selectivity;
With water In methanol at -14 - 45℃; for 0.666667h; Product distribution / selectivity;
With water In methanol at 20 - 60℃; under 390.039 Torr; for 12h; Product distribution / selectivity; Heating / reflux;

methanol (67-56-1) + rimonabant hydrochloride (158681-13-1) → 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)pyrazole-3-carboxamide hydrate (945634-91-3) + rimonabant methanol solvate

Conditions	Yield
With water at 20℃; for 72h; Product distribution / selectivity; Heating / reflux;

Upstream product

• 158941-22-1 ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate 
• 162758-35-2 rimonabant acid 
• 169544-41-6 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester 
• 63234-70-8 N-aminopiperidine hydrochloride 
• 168273-06-1 rimonabant 
• 5446-18-4 2,4-dichlorophenyl hydrazine hydrochloride 
• 6285-05-8 4'-chloropropiophenone 
• 2213-43-6 1-Aminopiperidine 
• 168273-05-0 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride 

Downstream Products

• 945634-91-3 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)pyrazole-3-carboxamide hydrate 
• 168273-06-1 rimonabant 
• 1000380-28-8 rimonabant hydrochloride ethanolate 

Relevant articles and documents

"Photo-Rimonabant": Synthesis and Biological Evaluation of Novel Photoswitchable Molecules Derived from Rimonabant Lead to a Highly Selective and Nanomolar " Cis-On" CB1R Antagonist

Human cannabinoid receptor type 1 (hCB1R) plays important roles in the regulation of appetite and development of addictive behaviors. Herein, we describe the design, synthesis, photocharacterization, molecular docking, and in vitro characterization of "photo-rimonabant", i.e., azo-derivatives of the selective hCB1R antagonist SR1411716A (rimonabant). By applying azo-extension strategies, we yielded compound 16a, which shows marked affinity for CB1R (Ki (cis form) = 29 nM), whose potency increases by illumination with ultraviolet light (CB1R Kitrans/cis ratio = 15.3). Through radioligand binding, calcium mobilization, and cell luminescence assays, we established that 16a is highly selective for hCB1R over hCB2R. These selective antagonists can be valuable molecular tools for optical modulation of CBRs and better understanding of disorders associated with the endocannabinoid system.

Preparation method for rimonabant hydrochloride

The invention discloses a preparation method for rimonabant hydrochloride, belonging to the field of chemical pharmacy. An ester is used as an initial raw material and undergoes hydrolysis, condensation and salt formation so as to obtain the rimonabant hydrochloride. The preparation method is simple and convenient to operate and has low cost and high yield.

Preparation of crystalline polymorphs of rimonabant hydrochloride

This invention relates to three novel solvate forms of crystalline rimonabant hydrochloride (Form A, B, and C) and two novel crystalline polymorphic forms of rimonabant hydrochloride anhydrous (Form D and E), to processes for preparing such polymorphic forms or solvate forms, to pharmaceutical compositions containing them and to the use of them in medicine.

POLYMORPHS OF RIMONABANT

Crystalline form C of rimonabant and amorphous rimonabant, processes for their preparation and pharmaceutical compositions thereof.

POLYMORPHS OF RIMONABANT

Crystalline form C of rimonabant and amorphous rimonabant, processes for their preparation and pharmaceutical compositions thereof.

PROCESS FOR PREPARATION OF PYRAZOLE DERIVATIVES

A process for preparation of Pyrazole derivatives adapted for one pot reaction involving the use of a pyclizing agent and involving the step of amidation in the presence of a catalyst. The steps for isolation and purification of found Pyrazole derivatives are also disclosed.

POLYMORPHIC FORM OF RIMONABANT HYDROCHLORIDE AND PROCESSES FOR PREPARATION THEREOF

Provided is a crystalline form of Rimonabant hydrochloride, processes for its preparation and pharmaceutical compositions containing such crystalline form of Rimonabant hydrochloride.

IMPROVED PROCESS FOR RIMONABANT

The present invention provides an improved and commercially viable process for the preparation of rimonabant substantially free of amide impurity, namely 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl-4-methyl-pyrazole-3-carboxamide and its pharmaceutically acceptable acid addition salts thereof. Thus, for example, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl-4-methyl-pyrazole-3-carboxylic acid chloride is reacted with 1-minopiperidine in the presence of a base and optionally using a phase transfer catalyst such as tetra-butylammonium bromide in a biphasic reaction medium containing water and a water-immiscible solvent to obtain pure rimonabant.

POLYMORPHIC FORMS OF RIMONABANT

Polymorphic crystalline Forms III, IV, V, and VI of rimonabant, amorphous rimonabant, and amorphous rimonabant in an intimate dispersion with a pharmaceutically acceptable carrier.