202189-78-4

Usage

Uses

Used in Pharmaceutical Industry:
BENZENEACETIC ACID, 4-(2-(4-(1-(2-ETHOXYETHYL)-1H-BENZIMIDAZOL-2-YL)-1-PIPERIDINYL)ETHYL-ALPHA, ALPHA-DIMETHYLis used as an antihistamine for the symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria. It provides relief from nasal and nonnasal symptoms associated with these conditions.
Used in Allergy Treatment:
Bilastine is used as a histamine H1 receptor antagonist for preventing microvascular extravasation, bronchospasm, and systemic anaphylaxis induced by histamine in guinea pigs. It also prevents anaphylaxis induced by subcutaneous administration of ovalbumin or dinitrophenylated human albumin (DNP) in sensitized rats.
Brand Name:
Bilastine is marketed under the brand name Bilaxten.

Originator

FAES FARMA, S.A. (Spain)

Clinical Use

Bilastine is a selective histamine H1 antagonist approved for the treatment of allergic rhinoconjunctivitis and urticaria (hives). This drug, which has proven to be well tolerated in toxicology profiling, 46 was discovered by the Spainsh firm FAES Farma and was approved by the European Union in 2010.

Synthesis

In 2011, Collier and co-workers published a communication describing both the original synthesis of bilastine and an improved route which was amenable to gram-scale production. Collier’s second generation route, shown below, relies upon a convergent approach involving the union of piperidinyl benzimidazole 49 with fully functionalized phenethyl electrophile 48.Coupling the commercially available bromophenyl acetate 44 with cyclic trioxatriborinane 45 under conventional Suzuki conditions furnished styrene 46 in good yield. Alternatively, this vinylation reaction was also performed under Stille conditions with tributyl vinyl stannane in 83% yield. Hydroboration–oxidation of 46 delivered phenethyl alcohol 47 which was then immediately mesylated under basic conditions in toluene to produce adduct 48. This sulfonate was then reacted with piperidine 49 (whose preparation is described in Scheme 7) followed by saponification of the resulting ester 50 to arrive at bilastene (VI) in 26% overall yield from 44. For the preparation of bilastine piperidine 49, commercially available piperidine 51 was first protected as the Boc-carbamate 52 prior to alkylation of the benzimidazole nitrogen atom with 1-chloro-2-ethoxyethane 53, providing compound 54. The Boc group of 54 was removed under acidic conditions to give fragment 49. This sequence produced the desired piperidine component in 86% overall yield from 51.

Drug interactions

Potentially hazardous interactions with other drugs Antivirals: concentration possibly increased by ritonavir. Grapefruit juice: concentration of bilastine reduced.

Metabolism

Not significantly metabolised. Almost 95% of the administered dose was recovered in urine (28.3%) and faeces (66.5%) as unchanged bilastine

InChI:InChI=1/C28H37N3O3/c1-4-34-20-19-31-25-8-6-5-7-24(25)29-26(31)22-14-17-30(18-15-22)16-13-21-9-11-23(12-10-21)28(2,3)27(32)33/h5-12,22H,4,13-20H2,1-3H3,(H,32,33)

Upstream product

• 114369-15-2 2-(4-bromophenyl)ethyl methanesulfonate 
• 1493-27-2 ortho-nitrofluorobenzene 
• 95893-88-2 N-(β-ethoxyethyl)-o-nitroaniline 
• 95893-89-3 N-(β-ethoxyethyl)-o-phenylenediamine 
• 1487732-17-1 1-(4-bromophenethyl)piperidine-4-carboxylic acid 
• 1567835-76-0 1-(4-bromophenethyl)-N-(2-((2-ethoxyethyl)amino)phenyl)piperidine-4-carboxamide 
• 1567835-77-1 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-dimethylphenylacetic acid methyl ester hydrochloride 
• 1567835-74-8 2-(1-(4-bromophenethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole 
• 1567835-72-6 ethyl 1-(4-bromophenethyl)piperidine-4-carboxylate 
• 4654-39-1 4-bromophenethanol 
• 57625-74-8 methyl 2-methyl-2-phenylpropionate 
• 95-54-5 1,2-diamino-benzene 
• 498-94-2 isonipecotic acid 
• 36293-05-7 2-methyl-2-phenylpropanoyl chloride 

Relevant academic research and scientific papers

Preparation method of bilastine key intermediate

The invention belongs to the technical field of drug synthesis, and relates to 2 - (4 - (2 - (4 -ethoxyethyl) 1 - benzo [2 -] imidazol - 1H - yl) piperi d-ethyl) phenyl) -2 -methylpropionate (-1 -), and a -2 - complex and II acid are used as a catalyst to condensation the enolate anion with the compound (16 15) to form a target product II Ni Lewis. The invention aims to provide a short synthetic route. The provided route raw material condition is mild, the yield is high, the tedious building quaternary carbon atom method reported in the traditional process is avoided, and the method is suitable for industrial production.

TITLE: PROCESS FOR THE PREPARATION OF BILASTINE

The present invention relates to a process for the preparation of bilastine, a compound of formula I. The present invention relates to p-xylene solvate of bilastine and process for its preparation. The present invention relates to a process for the prepar

Method for preparing bilastine

The invention particularly relates to a method for preparing bilastine, which comprises the following steps of reacting 2-(4-{2-[4-(1H-benzimidazole-2-yl)-piperidine-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid serving as a key intermediate with 2-chloroe

Preparation method of bilastine

The invention provides a preparation method of bilastine. Specifically the method comprises the following steps: oxidizing 4-hydroxyethyl phenyl methyl tert-butyrate to obtain 4-acetaldehyde phenyl methyl tert-butyrate, and carrying out a reductive aminat

Preparation method of bilastine

The invention belongs to the technical field of medicines, and discloses a preparation method of bilastine. 4-piperidinecarboxylic acid and methyl alpha,alpha-dimethyl-4-(2-bromoethyl)phenylacetate which are used as raw materials to prepare methyl alpha,alpha-dimethyl-4-[2-[4-formylpiperidyl]ethyl]phenylacetate, the methyl alpha,alpha-dimethyl-4-[2-[4-formylpiperidyl]ethyl]phenylacetate reacts with o-phenylenediamine to generate methyl alpha,alpha-dimethyl-4-[2-[4-[1H-2-benzimidazolyl]piperidin-1-yl]ethyl]phenylacetate, and chloroethyl ether is added into the obtained product to generate bilastine. The method for synthesizing bilastine by a three-step reaction has the advantages of simple route, easily available raw materials, mild reaction conditions, easiness in control, and suitablenessfor industrial production.

Preparation process of bilastine

The invention belongs to the technical field of medicines, and particularly relates to a preparation process of bilastine. According to the process, esterification, deprotection, iodination and hydrolysis reactions are conducted to generate bilastine. The

A process for the preparation of the compared to the russ sandbank method

The invention belongs to the field of medical chemistry, and relates to a preparation method of Bilastine. The preparation method comprises following steps: adding compound 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidine-4-yl]-1-(2-ethoxy-ethyl)-1H-benzimidazole into water containing organic acid, then subjecting the mixture to a thermal-reflux reaction for 1 to 36 hours, and finally obtaining Bilastine after post-processing. The preparation method has the advantages of mild reaction conditions, simple operation and easy industrialization.

A process for the preparation of the compared to the russ sandbank method (by machine translation)

The invention relates to a process for the preparation method compared to the russ sandbank, including I [...] compound added to the water, to add a phase transfer catalyst, paratoluene sulfonyl chloride and sodium hydroxide, after stirring and reacting and filtration to obtain [...] sulfonic acid ester. The sulfonic acid ester added to the water, by adding 2 - (4 - piperidinyl) 1 - H - benzimidazole and phase-transfer catalyst, adding sodium carbonate or potassium carbonate, heating suspension reaction 3 - 5 hours, filtering the obtained intermediate II is added to the strong polar non-protic solvent, by adding sodium hydroxide, phase-transfer catalyst, ethylene glycol is added to the toluene sulfonic acid ester, - 20 - 60° stirring reaction after the end of the filter and wash the obtained intermediate III. The intermediate III into the organic acid aqueous solution, refluxing 3 - 5 hours, water addition, adding alkali saturated, solution reflux 3 - 5 hours, generated in the saturated [...] does not dissolve in the alkaline solution, extraction [...]. The method of mild reaction conditions, the operation is simple, environmental protection, high yield, is suitable for industrial production. (by machine translation)

IMPROVED PROCESSES FOR PREPARATION OF BILASTINE USING NOVEL INTERMEDIATES

Provided herein are improved, commercially viable and industrially advantageous processes for the preparation of Bilastine or a pharmaceutically acceptable salt thereof using novel intermediates, in high yield and purity.

A new and competitive synthetic approach for an antihistamine agent, bilastine

Efforts towards the novel synthesis of second generation non-sedating antihistamine drug, Bilastine was described in this manuscript. This competitive synthetic approach involves the convergent synthesis of Bilastine via simple Friedel-Crafts acylation as an alternate for earlier reported Stille and Suzuki couplings. The selectivity in Friedel-Crafts acylation reaction with chloro acetyl chloride on different substituted arenes was studied and employed the best conditions for the synthesis of Bilastine. Further synthetic approach involves the deoxygenation of aryl ketone to corresponding alkane in single step and finally provides Bilastine with 39% of improved overall yields, utilizing simple and cost-effective reagents, suitable for kilogram scale synthesis.