596-51-0

Basic information

• Product Name: Glycopyrrolate
• Synonyms: 1,1-dimethyl-3-hydroxypyrrolidiniumbromidealpha-cyclopentylmandelate;1-methyl-3-pyrrolidylalpha-phenylcyclopentaneglycolatemethobromide;ahr504;asecryl;gastrodyn;glycopyrrolatebromide;nodapton;pyrrolidinium,1,1-dimethyl-3-hydroxy-,bromide,alpha-cyclopentylmandelate
• CAS NO: 596-51-0
• Molecular Formula: Br*C₁₉H₂₈NO₃
• Molecular Weight: 398.33
• EINECS: 209-887-0
• Product Categories: Amines;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;UVINUL;Inhibitors
• Mol File: 596-51-0.mol

Chemical Properties

• Melting Point: 192-195°C
• Appearance: white to tan/
• Density: 1.3222 (rough estimate)
• Refractive Index: 1.6200 (estimate)
• Storage Temp.: Hygroscopic, -20°C Freezer, Under Inert Atmosphere
• Solubility: H2O: ≥24mg/mL
• Merck: 14,4501
• CAS DataBase Reference: Glycopyrrolate(CAS DataBase Reference)
• NIST Chemistry Reference: Glycopyrrolate(596-51-0)
• EPA Substance Registry System: Glycopyrrolate(596-51-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26
• WGK Germany: 3
• RTECS: UY4337630
• Hazardous Substances Data: 596-51-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Glycopyrrolate is used as an antispasmodic for the treatment of air flow blockage and prevention of worsening chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. It is also used as a preoperative antimuscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions, to reduce the volume and free acidity of gastric secretions, and to block cardiac vagal inhibitory reflexes during induction of anesthesia and intubation.
Used in Medical Applications:
Glycopyrrolate is used as a treatment for sialorrhea, peptic ulcers, and chronic obstructive pulmonary disease (COPD). Formulations containing glycopyrrolate have been developed to target these conditions effectively.
Used in Preoperative Medication:
Glycopyrrolate is used as a preoperative medication to reduce secretions and block cardiac vagal inhibitory reflexes, ensuring a smoother induction of anesthesia and intubation process.
Used in Treatment of Sialorrhea:
Glycopyrrolate is used as a treatment for sialorrhea, a condition characterized by excessive saliva production, by inhibiting salivation in a rat model of sialorrhea induced by pilocarpine.
Used in Treatment of Peptic Ulcers:
Glycopyrrolate is used in the treatment of peptic ulcers by reducing post-prandial gastric antral motility in dogs when administered at a dose of 0.01 mg/kg.
Used in Treatment of Chronic Obstructive Pulmonary Disease (COPD):
Glycopyrrolate is used in the treatment of COPD, a long-term lung disease that causes bronchospasm (difficulty with breathing), by inducing relaxation of precontracted isolated human bronchi when used at concentrations of 0.01, 0.1, or 1 μM.

Originator

Robinul,Robins,US,1961

Manufacturing Process

A mixture of 42.5 grams (0.17 mol) of methyl α-cyclopentyl mandelate and 18 grams (0.175 mol) of 1-methyl-3-pyrrolidinol in 500 ml of heptane was refluxed under a Dean and Stark moisture trap, with the addition of four 0.1 gram pieces of sodium at 1-hour intervals. After 5 hours' refluxing the solution was concentrated to one-half volume, and extracted with cold 3N HCl. The acid extract was made alkaline with aqueous sodium hydroxide and extracted with ether which was washed, dried over sodium sulfate, filtered and concentrated. The residue was fractionated at reduced pressure. Yield 33 grams (64%); BP 151° to 154°C/0.2 mm, nD23= 1.5265. The hydrochloride salt was precipitated as an oil from an ethereal solution of the base with ethereal hydrogen chloride. It was crystallized from butanone; MP 170° to 171.5°C. The methyl bromide quaternary was prepared by saturating a solution of the base in dry ethyl acetate with methyl bromide. After standing for 9 days the resulting crystalline solid was filtered and recrystallized from butanone and from ethyl acetate; MP 193° to 194.5°C.

Therapeutic Function

Spasmolytic

Biochem/physiol Actions

Glycopyrrolate is long-acting muscarinic antagonist (LAMA). It is kinetically selective muscarinic M3 receptor antagonist.

Mechanism of action

Glycopyrrolate exhibits onset of action within 1 minute when given intravenously and an elimination half-life of approximately 50 minutes. Glycopyrrolate undergoes urinary excretion and elimination.

Clinical Use

Glycopyrrolate is used as an adjunct in the management of pepticulcer and other GI ailments associated with hyperacidity,hypermotility, and spasm. In common with other anticholinergics,its use does not preclude dietary restrictions or use ofantacids and sedatives if these are indicated.

Side effects

dry mouthblurred visionvision problemsloss of tasteheadachenervousnessconfusiondrowsiness

Safety Profile

Poison by intravenous and intraperitoneal routes. Moderately toxic by ingestion and subcutaneous routes. Experimental reproductive effects. When heated to decomposition it emits very toxic fumes of NOx and Br-. See also BROMIDES.

Veterinary Drugs and Treatments

Glycopyrrolate injection is approved for use in dogs and cats. The FDA approved indication for these species is as a preanesthetic anticholinergic agent. The drug is also used to treat sinus bradycardia, sinoatrial arrest, and incomplete AV block, where anticholinergic therapy may be beneficial. When cholinergic agents such as neostigmine or pyridostigmine are used to reverse neuromuscular blockade due to non-depolarizing muscle relaxants, glycopyrrolate may be administered simultaneously to prevent the peripheral muscarinic effects of the cholinergic agent.

InChI:InChI=1/C20H30NO3.BrH/c1-21(2)13-12-18(15-21)24-19(22)14-20(23,17-10-6-7-11-17)16-8-4-3-5-9-16;/h3-5,8-9,17-18,23H,6-7,10-15H2,1-2H3;1H/q+1;/p-1

Synthetic route

methyl bromide (74-83-9) + 3-(2-cyclopentyl-2-hydroxy-2-phenylacetyloxy)-1-methylpyrrolidine (13118-11-1) → glycopyrronium bromide (596-51-0)

Conditions	Yield
In butanone at 20℃; Cooling with ice;	22%
In acetonitrile at -10 - 20℃; for 12h;	144 g
In chloroform; acetonitrile at 20℃; for 72h;

1-methyl-3-pyrrolidinol (13220-33-2) + 2-cyclopentyl-2-hydroxy-2-phenylacetic acid (427-49-6) → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / toluene / 0.5 h / 20 °C 1.2: 20 °C 2.1: butanone / 20 °C / Cooling with ice View Scheme

2-cyclopentyl-2-hydroxy-2-phenylacetic acid (427-49-6) → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydroxide / N,N-dimethyl-formamide / 1 h / 60 °C 1.2: 3 h / 110 °C 2.1: sulfuric acid / tetrahydrofuran / 70 °C 3.1: palladium on activated charcoal; hydrogen / methanol / 3 h / 25 °C 4.1: acetonitrile / 12 h / -10 - 20 °C View Scheme

C20H22O3 → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / tetrahydrofuran / 70 °C 2: palladium on activated charcoal; hydrogen / methanol / 3 h / 25 °C 3: acetonitrile / 12 h / -10 - 20 °C View Scheme

phenylglyoxylyl chloride (25726-04-9) → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 12.25 h / 0 - 25 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.5 h / 0 °C 3.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme

Benzoylformic acid (611-73-4) → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 25 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.5 h / 0 °C 3.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme

1-methyl-3-pyrrolidinol (13220-33-2) → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 25 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.5 h / 0 °C 3.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 25 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.5 h / 0 °C 3.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 10.33 h / 0 - 20 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.5 h / 0 °C 3.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 12.25 h / 0 - 25 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.5 h / 0 °C 3.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme

2-cyclopentyl-2-oxoacetyl chloride → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 10.33 h / 0 - 20 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.5 h / 0 °C 3.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme

1-methylpyrrolidin-3-yl 2-cyclopentyl-2-oxoacetate → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.5 h / 0 °C 2.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme

2-Cyclopentyl-2-oxoacetic acid (5763-56-4) → glycopyrronium bromide (596-51-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 25 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.5 h / 0 °C 3.1: acetonitrile; chloroform / 72 h / 20 °C View Scheme

glycopyrronium bromide (596-51-0) → [(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium chloride (873295-31-9)

Conditions	Yield
With Amberlite IRA900 Cl In ethanol; water Product distribution / selectivity;	94%
Stage #1: glycopyrronium bromide With silver(I) acetate In methanol at 15 - 25℃; for 2h; Stage #2: With hydrogenchloride In ethyl acetate at 5 - 10℃; for 1h;	72%

glycopyrronium bromide (596-51-0) → [(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium chloride (873295-31-9)

Conditions	Yield
With resin Amberlite IRA900 CI In ethanol; water	94%

glycopyrronium bromide (596-51-0) → 3-hydroxy-1,1-dimethyl pyrrolidinium bromide + 2-cyclopentyl-2-hydroxy-2-phenylacetic acid (427-49-6)

Conditions	Yield
With sodium hydroxide In water at 20℃;	A 3.87 g B 92%

glycopyrronium bromide (596-51-0) → (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate mono(4-methylbenzenesulfonate) (873295-46-6)

Conditions	Yield
With dihydrogen peroxide; toluene-4-sulfonic acid In cyclohexane; cyclohexene at 25 - 30℃; for 12h; Reagent/catalyst;	69.2%

glycopyrronium bromide (596-51-0) → 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium iodide

Conditions	Yield
With sodium iodide In dichloromethane; water for 16h;

silver benzoate (532-31-0) + glycopyrronium bromide (596-51-0) → 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-pyrrolidinium benzoate (873295-45-5)

Conditions	Yield
In water at 92℃;

silver(I) 4-methylbenzenesulfonate (16836-95-6) + glycopyrronium bromide (596-51-0) → (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate mono(4-methylbenzenesulfonate) (873295-46-6)

Conditions	Yield
In water at 40℃; Darkness;
In isopropyl alcohol at 20℃; Darkness;

Reaxys ID: 30758740 + glycopyrronium bromide (596-51-0) → Reaxys ID: 30758741

Conditions	Yield
In 2-methyltetrahydrofuran

Sodium laurate (629-25-4) + glycopyrronium bromide (596-51-0) → glycopyrronium laurate

Conditions	Yield
In water at 20℃; for 96h; Solvent;

glycopyrronium bromide (596-51-0) + stearic acid (57-11-4) → glycopyrronium stearate

Conditions	Yield
With potassium hydroxide In 2-methyltetrahydrofuran; water for 0.5h;

glycopyrronium bromide (596-51-0) + toluene-4-sulfonic acid (104-15-4) → (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate mono(4-methylbenzenesulfonate) (873295-46-6)

Conditions	Yield
With Aliquat 336; sodium hydroxide In dichloromethane; cyclohexane; water at 25 - 30℃; for 24h; Reagent/catalyst; Solvent; Concentration;

sodium tosylate (657-84-1) + glycopyrronium bromide (596-51-0) → (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate mono(4-methylbenzenesulfonate) (873295-46-6)

Conditions	Yield
In water at 40 - 45℃; Green chemistry; Industrial scale;	390 g

Upstream product

• 74-83-9 methyl bromide 
• 13118-11-1 3-(2-cyclopentyl-2-hydroxy-2-phenylacetyloxy)-1-methylpyrrolidine 
• 13220-33-2 1-methyl-3-pyrrolidinol 
• 427-49-6 2-cyclopentyl-2-hydroxy-2-phenylacetic acid 
• 124-40-3 dimethyl amine 
• 5763-56-4 2-Cyclopentyl-2-oxoacetic acid 
• 611-73-4 Benzoylformic acid 
• 25726-04-9 phenylglyoxylyl chloride 

Downstream Products

• 873295-32-0 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium iodide 
• 873295-31-9 [(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium chloride 
• 873295-31-9 [(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium chloride 
• 873295-45-5 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-pyrrolidinium benzoate 
• 873295-46-6 (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate mono(4-methylbenzenesulfonate) 
• 51052-74-5 3-hydroxy-1,1-dimethyl pyrrolidinium bromide 
• 427-49-6 2-cyclopentyl-2-hydroxy-2-phenylacetic acid 

Relevant articles and documents

Synthesis process of glycopyrronium bromide

The invention discloses a synthesis process of a glycopyrronium bromide bulk drug, and the process comprises the following steps: carrying out hydroxyl protection on an a-cyclopentyl mandelic acid compound by using a dihydropyran compound, carrying out esterification reaction, removing a protecting group, and finally carrying out quaternization reaction to obtain glycopyrronium bromide. The method is mild in reaction condition, does not need to introduce a large amount of auxiliaries and solvents, conforms to the green chemistry principle, and is suitable for industrialization.

Glycopyrronium bromide intermediate as well as preparation method and application thereof

The invention provides a glycopyrronium bromide intermediate as well as a preparation method and application thereof, and relates to the technical field of chemical synthesis. The preparation method of the glycopyrronium bromide intermediate comprises the step of carrying out transesterification reaction on methyl alpha-cyclopentyl mandelate as a raw material and 1, 4-dibromo-2-butanol under the action of a first base catalyst to obtain a glycopyrronium bromide intermediate, namely a compound 2. The preparation method of glycopyrronium bromide comprises the step of carrying out quaternization reaction on the compound 2 and dimethylamine under the action of a second base catalyst to obtain glycopyrronium bromide. The method has the advantages of cheap and easily available raw materials, avoidance of use of toxic gas bromomethane commonly used in the prior art, small environmental pollution, environment-friendliness, mild reaction conditions, easy control of the reaction process, avoidance of use of metal sodium, safe operation, high safety coefficient, great reduction of the reaction steps, production cost saving, high product yield, and high purity. A process route capable of industrially producing products with higher quality is provided.

A preparation method of the glycopyrrolate

The invention discloses a method for preparation of glycopyrrolate, firstly the α - cyclopentyl mandelic acid for benzyl protected hydroxy, then the conventional method and 1 - methyl - 3 - pyrrolidinol esterification of key intermediate pyrrolidinol ester; in the middle of the invention supplies the key under the condition of Pd/C debenzylation, finally methyl bromide quaternary ammonium formation salting out the solid filter and get the glycopyrrolate crude, refined is obtained when the location of the qualified products. In order to prevent the occurrence of side reactions, the method of using very low cost introduced into hydroxyl protective agent benzyl, greatly improves the yield, simplifying the post-treatment, reduces the amount of waste water. The method of the invention with the production operation is simple, the production cost is low, raw materials are easy, high yield, low pollution and the like, the resulting product in accordance with the pharmaceutical quality standards.

PROCESS FOR SYNTHESIS OF GLYCOPYRRONIUM BROMIDE

Provided herein are processes for preparation of glycopyrronium bromide comprising reaction of N-methylpyrrolidin-3-ol with compounds of Formula I or Formula II followed by additional steps.

Discovery of Novel Potent Muscarinic M3 Receptor Antagonists with Proper Plasma Stability by Structural Recombination of Marketed M3 Antagonists

The marketed long-acting M3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M3 antagonists. As a result, two novel potent M3 antagonists, (R/S)-3-[2-hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1,1-dimethylpyrrolidinium bromides (1 a: Ki=0.16 nm, IC50=0.38 nm, t1/2=9.34 min; 1 b: Ki=0.32 nm, IC50=1.01 nm, t1/2=19.2 min) with proper plasma stability were identified, which (particularly 1 a) hold great promise as clinical drug candidates to overcome the drawbacks caused by the inappropriate stability of the currently marketed M3 antagonists. In addition, structure–activity relationship studies revealed that the R configuration of the pyrrolidinyl C3 atom was clearly better than the S configuration.

PROCESS FOR PREPARING (3RS)-3-[(2SR)-(2-CYCLOPENTYL-2-HYDROXY-2-PHENYLACETYL)OXY]-1,1-DIMETHYLPYRROLIDINIUM BROMIDE

The present invention relates to an efficient and environmentally friendly process for preparing (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide with high yield and purity suitable for industrial scale applications.

CONTINUOUS PROCESS FOR THE ALKYLATION OF CYCLIC TERTIARY AMINES

A continuous process for the alkylation of tertiary amines and, in particular, to a continuous process for the quaternization of cyclic tertiary amines useful for the preparation of cyclic quaternary ammonium salts with high purity is described.