320345-99-1

Basic information

• Product Name: Aclidinium bromide
• Synonyms: (3R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide;1-Azoniabicyclo(2.2.2)octane, 3-((hydroxydi-2-thienylacetyl)oxy)-1-(3-phenoxypropyl)-, bromide, (3R)-;Unii-uqw7uf9N91;LAS 34273;LAS-W 330;(3R)-3-(2-Hydroxy-2,2-di(thiophen-2-yl)acetoxy)-1-(3-phenoxypropyl)quinuclidin-1-ium bromide;ACLIDINIUM BROMIDE INTERMEDIATES;1-Azoniabicyclo[2.2.2]octane, 3-[(2-hydroxy-2,2-di-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide (1:1), (3R)-
• CAS NO: 320345-99-1
• Molecular Formula: C13H10BrN
• Molecular Weight: 564.56
• EINECS: 1592732-453-0
• Product Categories: Inhibitors
• Mol File: 320345-99-1.mol

Chemical Properties

• Melting Point: 230 °C(Solv: acetonitrile (75-05-8))
• Appearance: /
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• Solubility: DMSO (Slightly, Heated), Methanol (Slightly)
• CAS DataBase Reference: Aclidinium bromide(CAS DataBase Reference)
• NIST Chemistry Reference: Aclidinium bromide(320345-99-1)
• EPA Substance Registry System: Aclidinium bromide(320345-99-1)

Safety Data

• Hazardous Substances Data: 320345-99-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Aclidinium bromide is used as a selective muscarinic antagonist for the treatment of chronic obstructive pulmonary disorder (COPD). It acts as a bronchodilator by inhibiting the muscarinic AChR M1, M2, M3, M4, and M5 receptors with Ki values of 0.1 nM, 0.14 nM, 0.14 nM, 0.21 nM, and 0.16 nM, respectively. This selective action on the muscarinic M3 receptor, which is primarily responsible for bronchial and tracheal smooth muscle contraction, makes it an effective treatment for COPD.
Additionally, aclidinium bromide is used as a long-acting antimuscarinic bronchodilator in phase II clinical trials for the treatment of chronic obstructive pulmonary disease. Its rapid hydrolysis in human plasma and inhaled administration help limit systemic exposure and reduce the potential for systemic side effects.
Brand Names:
In the United States, aclidinium bromide is marketed under the brand name Tudorza Pressair, while in the European Union, it is known as Eklira, Bretaris, and Genuair.

Originator

Almirall (Spain)

Clinical Use

Aclidinium bromide was approved by the U. S. Food and Drug Administration (FDA) in July 2012 for the treatment of chronic obstructive pulmonary disease (COPD). Marketed by Forest Pharmaceuticals, aclidinium bromide selectively binds to five human muscarinic receptors (M1-M5), and posesses a subnanomolar binding affinity for these particular targets. Administered by inhalation, this medicine has demonstrated favorable onset and duration of action, and its safety profile is an improvement over competitor therapies.

Synthesis

No manufacturing route has been disclosed to date, the most scalable published synthesis is described in the scheme. Dimethyl oxalate (1) was initially treated with two equivalents of Grignard 2 to give bis-thiophenoate 3 in 36% yield. Subsequent transesterification with (R)-quinuclidinol (4) gave rise to the quinuclidine-containing ester 5 in 50% yield. Aclidinium bromide (I) could be accessed by two different methods involving bromoalkyl phenyl ether 6—an excess of bromide in the presence of an acetonitrile/chloroform mixture gave the drug in 89% isolated yield, or with fewer equivalents of electrophile (1.25 eq) during exposure to refluxing acetophenone has reportedly delivered (I) quantitatively on multi-gram scale.17 From commercial 2, the multi-gram synthesis of Aclidinium bromide (I) was completed in 17.8% over three steps.

references

[1] gavaldà a1, ramos i2, carcasona c3, calama e4, otal r5, montero jl6, sentellas s7, aparici m8, vilella d9, alberti j10, beleta j11, miralpeix m12. the in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide. pulm pharmacol ther. 2014 aug;28(2):114-21.

InChI:InChI=1/C13H9N.BrH/c1-3-7-12-10(5-1)9-11-6-2-4-8-13(11)14-12;/h1-9H;1H

Upstream product

• 1619-34-7 3-quinuclidinol 
• 26447-85-8 hydroxy-di-thiophen-2-yl-acetic acid methyl ester 
• 27998-36-3 2,2-di(2-thiophenyl)-2-hydroxyethanoic acid-3-quinine ester 
• 25333-42-0 (R)-quinuclidin-3-ol 
• 320347-97-5 hydroxydithien-2-ylacetic acid 1-aza-bicyclo[2.2.2]oct-3(R)-yl ester 
• 588-63-6 3-phenoxypropyl bromide 
• 4746-63-8 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid 

Downstream Products

• 4746-63-8 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid 

Relevant articles and documents

Choline M receptor anti-caking agent re-crystallization method

The invention provides a choline M receptor anti-caking agent re-crystallization method, which comprises: (1) heating an aclidinium bromide crude product and DMF to a temperature of 90-130 DEG C, stirring, dissolving, and clarifying; (2) cooling the solut

Novel method for synthesis and purification of aclidinium bromide

The invention discloses a novel method for synthesis and purification of aclidinium bromide. According to the method, tetrahydrofuran is used, haloalkane is used as an initiator, and a finished product is obtained through solvent extraction and recrystall

A PROCESS FOR PREPARING ACLIDINIUM BROMIDE AND INTERMEDIATES THEREOF

Provided herein is a process for synthesis of aclidinium bromide and intermediates thereof, wherein the process for the preparation of aclidinium bromide increases the % yield of aclidinium bromide by about 70% to 90%.

High-purity high-yield aclidinium bromide preparation method suitable for industrial production

The invention discloses a high-purity high-yield aclidinium bromide preparation method suitable for industrial production. The preparation method comprises the following steps: 1) adding methyl 2,2-di(2-thienyl)-2-hydroxyacetate and TBDMSCl into solvent,

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.

Choline M receptor antagonist aclidinium bromide and preparation method thereof

The invention relates to choline M receptor antagonist aclidinium bromide and a preparation method thereof. According to the preparation method, 2,2-di(2-thienyl)-2-methyl glycolate reacts with 3-quinuclidinol to obtain 2-hydroxy-2,2-di(2-thienyl) acetic

AN ADVANTAGEOUS PROCESS FOR PREPARING 1-AZONIABICYCLO[2.2.2]OCTANE,3-[(HYDROXYDI-2-THIENYLACETYL)OXY]-1-(3?PHENOXYPROPYL)-, BROMIDE, (3R)- AND ITS NOVEL CRYSTALLINE FORM-I

The present invention discloses the process for preparation of 1- ?Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacety1)oxy]-1-(3?iphenoxypropy1)-, bromide, (3R)- and its novel crystalline form-I

A choline M receptor antagonists arab League bromine ammonium and its preparation method

The invention relates to choline M receptor antagonist aclidinium bromide and a preparation method thereof. The chemical structural formula of the choline M receptor antagonist aclidinium bromide is as shown in the specification. The preparation method comprises the following steps: mixing R-quinine-3 alcohol, alkali and an organic solvent, dripping methyl oxalyl chloride, after the methyl oxalyl chloride is completely dripped, heating, performing heating reflux for 1-20 hours, and separating and purifying, thereby obtaining a substance A; adding iodine into a tetrahydrofuran solution of 2-bromothiophene and magnesium powder to initiate reaction for 1-5 hours, thereby preparing a Grignard reagent of 2-bromothiophene, adding the substance A, stirring to react for 10-30 minutes at the room temperature, performing heating reflux for 4-6 hours, separating and purifying, thereby preparing 2,2-dithienyl-2-glycolic acid-R-quinine-3-base ester, and performing quaterisation reaction with 3-phenoxypropyl bromine, thereby obtaining aclidinium bromide. The aclidinium bromide provided by the invention is simple in reaction operation, high in yield, low in price, short in reaction route, small in waste generation and easy in industrialization production.

PROCESS FOR THE PREPARATION OF ACLIDINIUM BROMIDE

A process for preparing (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1- azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) comprises reacting 2-hydroxy-2,2- dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester and 3-phen

NOVEL QUINUCLIDINE DERIVATIVES AND MEDICINAL COMPOSITIONS CONTAINING THE SAME

A compound according to formula (I) wherein z? is a phenyl ring, a C4 to C9 heteroaromatic compound containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 each independently represent a hydrogen or halogen atom, or a hydroxy group, or a phenyl, —OR4, —SR4, —NR4R5, —NHCOR4, —CONR4R5, —CN, —NO2, —COOR4 or —CF3 group, or a straight or branched lower alkyl group which may optionally be substituted, for example, with a hydroxy or alcoxy group, wherein R4 and R5 each independently represent a hydrogen atom, straight or branched lower alkyl group, or together form an alicyclic ring; or R1 and R2 together form an aromatic, alicyclic or heterocyclic ring; n is an integer from 0 to 4; A represents a —CH2—, —CH═CR6, —CR6═CH—, —CR6122—, —CO—, —O—, —S—, —S(O)—, SO2 or NR6— group, wherein R6 and R2 each independently represent a hydrogen atom, straight or branched lower alkyl group, or R6 and 122 together form an alicyclic ring; m is an integer from 0 to 8; provided that when m=0, A is not —CH2—; p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2,3 or 4 position including all possible configurations of the asymmetric carbons; B represents a group of formula (i) or (ii), wherein R10 represents a hydrogen atom, a hydroxy or methyl group; and R8 and R9 each independently represents formulae (a), (b), (c), (d) and wherein R11 represents a hydrogen or halogen atom, or a straight or branched lower alkyl group and Q represents a single bond, —CH2—, —CH2—CH2, —O—, —O—CH2—, —S—, —S—CH2— or —CH═CH—, and when (i) or (ii) contain a chiral centre they may represent either configuration; X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, which shows high affinity for muscarinic M3 receptors (Hm3).