129784-12-9

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 
• 19833-96-6 2-Cyclopentyl-2-hydroxy-2-phenylacetic acid methyl ester 
• 15206-55-0 methyl 2-oxo-2-phenylacetate 
• 129784-12-9 (3R)-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide 
• 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

• 873295-46-6 (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate mono(4-methylbenzenesulfonate) 
• 129784-12-9 R,R-glycopyrrolate 
• 873295-45-5 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-pyrrolidinium benzoate 

Relevant academic research and scientific papers

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.

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.

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 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.

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.

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.

CRYSTALLISATION AND PURIFICATION OF GLYCOPYRRONIUM BROMIDE

A method for the production of crystalline glycopyrronium bromide, comprises the reaction of glycopyrronium base with methyl bromide in a solvent, in which the solvent is selected such that the diastereoisomeric ratio of the product favours the R,S and S,