13118-11-1

Basic information

• Product Name: 1-methylpyrrolidin-3-yl cyclopentylphenylglycolate
• Synonyms: 1-methylpyrrolidin-3-yl cyclopentylphenylglycolate;N-Methyl-3-pyrrolidinyl Cyclopentylmandelate;α-Cyclopentyl-mandelic Acid 1-Methyl-3-pyrrolidinyl Ester;α-Cyclopentyl-α-hydroxy-benzeneacetic Acid 1-Methyl-3-pyrrolidinyl Ester;a-Cyclopentyl-a-hydroxy-benzeneacetic Acid 1-Methyl-3-pyrrolidinyl Ester;a-Cyclopentyl-mandelic Acid 1-Methyl-3-pyrrolidinyl Ester;α-Cyclopentyl-α-hydroxybenzeneacetic acid 1-methylpyrrolidin-3-yl ester;Glycopyrrolate Related Compound B (75 mg) (1-Methylpyrrolidin-3-yl 2-cyclopentyl-2-hydroxy-2-phenylacetate)
• CAS NO: 13118-11-1
• Molecular Formula: C₁₈H₂₅NO₃
• Molecular Weight: 303.396
• EINECS: 236-047-0
• Product Categories: Aromatics Compounds;Aromatics;Heterocycles
• Mol File: 13118-11-1.mol

Chemical Properties

• Boiling Point: 434.6°Cat760mmHg
• Flash Point: 216.7°C
• Appearance: /
• Density: 1.17±0.1 g/cm3 (20 ºC 760 Torr)
• Refractive Index: 1.5256 (589.3 nm 23℃)
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 12.19±0.29(Predicted)
• CAS DataBase Reference: 1-methylpyrrolidin-3-yl cyclopentylphenylglycolate(CAS DataBase Reference)
• NIST Chemistry Reference: 1-methylpyrrolidin-3-yl cyclopentylphenylglycolate(13118-11-1)
• EPA Substance Registry System: 1-methylpyrrolidin-3-yl cyclopentylphenylglycolate(13118-11-1)

Safety Data

• Hazardous Substances Data: 13118-11-1(Hazardous Substances Data)

Usage

Chemical Properties

Light-Yellow Oil

Uses

Glycopyrrolate impurity.

InChI:InChI=1/C18H25NO3/c1-19-12-11-16(13-19)22-17(20)18(21,15-9-5-6-10-15)14-7-3-2-4-8-14/h2-4,7-8,15-16,21H,5-6,9-13H2,1H3

Upstream product

• 13220-33-2 1-methyl-3-pyrrolidinol 
• 19833-96-6 2-Cyclopentyl-2-hydroxy-2-phenylacetic acid methyl ester 
• 427-49-6 2-cyclopentyl-2-hydroxy-2-phenylacetic acid 
• 5763-56-4 2-Cyclopentyl-2-oxoacetic acid 
• 611-73-4 Benzoylformic acid 
• 25726-04-9 phenylglyoxylyl chloride 
• 137-43-9 Cyclopentyl bromide 
• 108-86-1 bromobenzene 
• 15206-55-0 methyl 2-oxo-2-phenylacetate 
• 530-62-1 1,1'-carbonyldiimidazole 
• 60499-30-1 toluene-4-sulfonic acid 1-methylpyrrolidin-3-yl ester 
• 91832-73-4 1-methylpyrrolidin-3-yl methanesulfonate 

Downstream Products

• 129784-12-9 (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1, 1-dimethylpyrrolidinium bromide 
• 129784-12-9 (3RS,2'RS)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1-dimethylpyrrolidinium bromide 
• 65976-16-1 1-benzyl-3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1-methylpyrrolidinium bromide 
• 129784-12-9 (3R,2'S)-3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium bromide 
• 129784-12-9 (3S,2'R)-3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium bromide 
• 596-51-0 glycopyrronium bromide 
• 873295-31-9 [(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium chloride 
• 873295-31-9 [(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium chloride 

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.

PROCESS FOR PREPARATION OF GLYCOPYRROLATE INTERMEDIATE

The present invention discloses an improved process for preparation of highly pure cyclopentyl mandelic acid derivative of formula (I), an intermediate of glycopyrrolate, without using hazardous chemicals.

Substitutes of glycopyrronium bromide as well as preparation method and medical application thereof

The invention discloses glycopyrronium bromide substitutes shown as a formula (I) and a formula (II), a preparation method of the glycopyrronium bromide substitutes and application of the glycopyrronium bromide substitutes in preparation of medicines for treating myopia, medicines for regulating ciliary muscle paralysis, medicines for preventing, treating and delaying juvenile myopia and medicinesfor treating chronic obstructive pulmonary disease (COPD), bronchitis or asthma. The compounds provided by the invention have excellent water solubility, powder flowability and suitable pH value stability of ophthalmic preparations and injections, and are in excellent medicinal alternative forms of glycopyrronium bromide.

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.

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.

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 PRODUCTION OF GLYCOPYRRONIUM TOSYLATE

Provided herein are methods for the production of glycopyrronium tosylate and glycopyrronium tosylate compositions. Also provided herein are compositions useful in the production of glycopyrronium tosylate. Additionally provided herein are glycopyrronium tosylate compositions. Glycopyrronium tosylate is useful for the treatment of, among other conditions, hyperhidrosis.

Carry over of impurities: A detailed exemplification for glycopyrrolate (NVA237)

The original synthesis of glycopyrrolate (NVA237) was revised and shortened into an essentially one-pot process. Without isolating the intermediates, their purification became obsolete, thereby increasing the possibility of the carry over of impurities. For that reason, the actual, potential, and theoretical impurities of the starting materials cyclopentyl mandelic acid and 1-methyl-pyrrolidin-3-ol as well as byproducts which may occur during the synthesis were thoroughly investigated; furthermore, their transformation to possible impurities in the drug substance along the new synthetic route was performed to exclude them as actual impurities in the drug substance with certainty. The question is raised how detailed such investigation-which are fairly manageable for a simple product like glycopyrrolate-need to be.

PROCESS FOR PREPARING PYRROLIDINIUM SALTS

A two step process for preparing a compound of formula (I) in salt or zwitterionic form, wherein R1 and R2 are each independently C3-C8-cycloalkyl or C6-C10-aryl; and R3 and R4 are each independently C1-C8-alkyl. The process minimizes variation in the relative proportions of diastereoisomers.

SOFT ANTICHOLINERGIC ESTERS

Soft anticholinergic esters of the formulas: wherein R1 and R2 are both phenyl or one of R1 and R2 is phenyl and the other is cyclopentyl; R is C1-C8 alkyl, straight or branched chain; and X- is an anion with a single negative charge; and wherein each asterisk marks a chiral center; said compound having the R, S or RS stereoisomeric configuration at each chiral center unless specified otherwise, or being a mixture thereof.