55937-99-0

Basic information

• Product Name: Beclobrate
• Synonyms: Beclobrate;Beclipur;Ethyl(±)-2-[[α(-(4-chlorophenyl)-4-tolyl]oxy]-2-methylbutyrate;Sgd-24774;Turec;2-[4-(4-Chlorobenzyl)phenoxy]-2-methylbutyric acid ethyl ester;Butanoic acid, 2-[4-[(4-chlorophenyl)Methyl]phenoxy]-2-Methyl-, ethyl ester;Ethyl 2-(4-(4-chlorobenzyl)phenoxy)-2-Methylbutanoate
• CAS NO: 55937-99-0
• Molecular Formula: C₂₀H₂₃ClO₃
• Molecular Weight: 346.852
• EINECS: 259-912-4
• Mol File: 55937-99-0.mol

Chemical Properties

• Boiling Point: bp0.01-0.1 200-204°
• Flash Point: 149.6°C
• Appearance: /
• Density: 1.128g/cm³
• Vapor Pressure: 7.43E-08mmHg at 25°C
• Refractive Index: 1.541
• Storage Temp.: 2-8°C
• CAS DataBase Reference: Beclobrate(CAS DataBase Reference)
• NIST Chemistry Reference: Beclobrate(55937-99-0)
• EPA Substance Registry System: Beclobrate(55937-99-0)

Safety Data

• Hazardous Substances Data: 55937-99-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Beclobrate is used as a hypolipidemic agent for managing types IIa-V hyperlipoproteinemias, helping to normalize the atherogenic index and reduce the risk of atherosclerosis and related cardiovascular diseases.

Originator

Siegfried AG (Switzerland)

Manufacturing Process

87.0 g (0.4 mol) of 4-chloro-4'-hydroxydiphenylmethane are heated together with 27.0 g (0.2 mol) of anhydrous potassium carbonate in 350 ml of anhydrous xylene for 30 min to reflux temperature, whereafter a solution of 83.5 g (0.4 mol) of 2-bromo-2-ethyl-2-methyl acetic acid ethyl ester in 50 ml of anhydrous xylene is added. The mixture is kept for 24 hours and with vigorous stirring at reflux temperature. After filtering off the precipitated potassium bromide and evaporating the solvent in a Buchi rotary evaporator, the residue is taken up in ether and extracted with normal sodium hydroxide solution. The ether extracts are washed with water, dried over MgSO4 and concentrated by evaporation. The brown oil (82.0 g) thereby obtained is dissolved in n-hexane and filtered through a column of 200 g of basic Al2O3. After evaporating the solvent and distillation at reduced pressure, 34.7 g of pure ethyl (+/-)-2-((α-(p-chlorophenyl)-p-tolyl)oxy)-2-methylbutyrate are obtained with the boiling point 200-204°C/0.01-0.1 mm Hg.

Therapeutic Function

Antihyperlipidemic

World Health Organization (WHO)

Beclobrate, an antihyperlipidaemic agent, was introduced into medicine in 1985. Although a causal relationship between the use of the drug and hepatic toxicity has not been established, the Intercantonal Office for the Control of Medicines has withdrawn marketing authorization since safer therapeutic alternatives are available. Beclobrate is not registered elsewhere.

InChI:InChI=1/C20H23ClO3/c1-4-20(3,19(22)23-5-2)24-18-12-8-16(9-13-18)14-15-6-10-17(21)11-7-15/h6-13H,4-5,14H2,1-3H3

Upstream product

• 5398-71-0 2-bromo-2-ethyl-2-methyl acetic acid ethyl ester 
• 52890-73-0 4-(4-chloro-benzyl)-phenol 
• 64-17-5 ethanol 
• 67-66-3 chloroform 
• 78-93-3 butanone 
• 5406-33-7 4-chlorobenzyl acetate 
• 7452-79-1 ethyl 2-methylbutyrate 
• 37155-52-5 1-(4-chlorobenzyl)-4-methoxybenzene 
• 622-95-7 4-chlorobenzyl bromide 
• 108-95-2 phenol 
• 100-66-3 methoxybenzene 
• 28139-26-6 ethyl 2-(4-bromophenoxy)-2-methylbutanoate 
• 873-76-7 para-Chlorobenzyl alcohol 
• 57125-30-1 ethyl 2-[4-(4-chlorobenzyl)phenoxy]propanoate 

Downstream Products

• 70930-64-2 2-methyl-2-[4-(4'-chlorobenzyl)-phenoxy]-butanol 
• 71548-88-4 Beclobric acid 
• 77985-11-6 Beclobrinsaeure-methylester 
• 81126-85-4 Isopropyl 2-methyl-2-[p-(p'-chlorobenzyl)phenoxy]butyrate 
• 94740-32-6 t-Butyl 2-methyl-2-[p-(p'-chlorobenzyl)phenoxy]butyrate 
• 77985-12-7 n-Propyl 2-methyl-2-[p-(p'-chlorobenzyl)phenoxy]butyrate 
• 71548-95-3 2-[4-(4-Chloro-benzyl)-phenoxy]-2-methyl-butyric acid sec-butyl ester 
• 81126-86-5 n-Butyl 2-methyl-2-[p-(p'-chlorobenzyl)phenoxy]butyrate 
• 81126-87-6 2-[4-(4-Chloro-benzyl)-phenoxy]-2-methyl-butyric acid isobutyl ester 
• 71548-99-7 2-[4-(4-Chloro-benzyl)-phenoxy]-2-methyl-butyric acid benzyl ester 
• 77985-10-5 2-[4-(4-Chloro-benzyl)-phenoxy]-2-methyl-butyric acid 2-acetylamino-ethyl ester 
• 71548-98-6 2-[4-(4-Chloro-benzyl)-phenoxy]-2-methyl-butyric acid 3,3,5-trimethyl-cyclohexyl ester 
• 81139-19-7 2-[4-(4-Chloro-benzyl)-phenoxy]-2-methyl-butyric acid 2-phenoxy-ethyl ester 

Relevant articles and documents

Diarylmethane compounds as well as preparation method and application thereof

The invention discloses diarylmethane compounds as well as a preparation method and application thereof. The diarylmethane compounds have a molecular structural general formula as defined by a generalformula (I) in the description. The preparation method of the diarylmethane compounds comprises the steps of adding a benzyl halogenated hydrocarbon compound A and an arylboronic acid B into a reaction system containing an organic small-molecular catalyst, an alkali reagent and a solvent, and performing a reaction to prepare the compounds. The diarylmethane compounds provided by the invention contain electron withdrawing groups and an electron-donating group substituted diarylmethane basic structure, and can be widely used for synthesis of pharmaceutical intermediates, particularly polysubstituted methane compounds, and preparation of functional materials; and the preparation method has a simple process and low requirements for reaction conditions, the reaction process is safe and controllable, the atomic utilization rate and production efficiency are high, the regioselectivity and stereoselectivity of the products are efficiently ensured, a frontier science small-molecule organocatalysis concept is introduced, and the method is friendly to the environment.

Transition-Metal-Free Suzuki-Type Cross-Coupling Reaction of Benzyl Halides and Boronic Acids via 1,2-Metalate Shift

Cross-coupling of organoboron compounds with electrophiles (Suzuki-Miyaura reaction) has greatly advanced C-C bond formation and has been well received in medicinal chemistry. During the past 50 years, transition metals have played a central role throughout the catalytic cycle of this important transformation. In this process, chemoselectivity among multiple carbon-halogen bonds is a common challenge. In particular, selective oxidative addition of transition metals to alkyl halides rather than aryl halides is difficult due to unfavorable transition states and bond strengths. We describe a new approach that uses a single organic sulfide catalyst to activate both C(sp3) halides and arylboronic acids via a zwitterionic boron "ate" intermediate. This "ate" species undergoes a 1,2-metalate shift to afford Suzuki coupling products using benzyl chlorides and arylboronic acids. Various diaryl methane analogues can be prepared, including those with complex and biologically active motifs. The reactions proceed under transition-metal-free conditions, and C(sp2) halides, including aryl bromides and iodides, are unaffected. The orthogonal chemoselectivity is demonstrated in the streamlined synthesis of highly functionalized diaryl methane scaffolds using multi-halogenated substrates. Preliminary mechanistic experiments suggest both the sulfonium salt and the sulfur ylide are involved in the reaction, with the formation of sulfonium salt being the slowest step in the overall catalytic cycle.

B(C6F5)3 catalysed reduction of: Para -quinone methides and fuchsones to access unsymmetrical diaryl- and triarylmethanes: Elaboration to beclobrate

A mild and efficient method for the synthesis of unsymmetrical diaryl- and triarylmethanes through a B(C6F5)3 catalyzed reduction of para-quinone methides and fuchsones respectively, using the Hantzsch ester as a reducing source has been developed. Detailed mechanistic investigations revealed that the reaction actually proceeds through a Lewis acid-base pair complex derived from B(C6F5)3 and the Hantzsch ester.

Benzylation of arenes with benzyl halides synergistically promoted by in situ generated superacid boron trifluoride monohydrate and tetrahaloboric acid

To examine the assembly methodology of diarylmethanes, a benzylation of (hetero)arenes with benzyl halides has been developed and various diarylmethanes were furnished with yields of up to 98% and regioselectivities of up to >99%. The complexation of the by-product halogen hydride with BF3·OEt2 generated the Bronsted acid BF3·HX (HBF3X, X=Cl or Br) in situ to synergistically promote the benzylation.

Cobalt co-catalysis for cross-electrophile coupling: Diarylmethanes from benzyl mesylates and aryl halides

The nickel-catalyzed cross-coupling of aryl halides with alkyl radicals derived from alkyl halides has recently been extended to couplings with carbon radicals generated by a co-catalyst. In this study, a new co-catalyst, cobalt phthalocyanine (Co(Pc)), is introduced and demonstrated to be effective for coupling substrates not prone to homolysis. This is because Co(Pc) reacts with electrophiles by an SN2 mechanism instead of by the electron-transfer or halogen abstraction mechanisms previously explored. Studies demonstrating the orthogonal reactivity of (bpy)Ni and Co(Pc), applying this selectivity to the coupling of benzyl mesylates with aryl halides, and the adaptation of these conditions to the less reactive benzyl phosphate ester and an enantioconvergent reaction are presented.

Unsymmetrical diarylmethanes by ferroceniumboronic acid catalyzed direct friedel-crafts reactions with deactivated benzylic alcohols: Enhanced reactivity due to ion-pairing effects

The development of general and more atom-economical catalytic processes for Friedel-Crafts alkylations of unactivated arenes is an important objective of interest for the production of pharmaceuticals and commodity chemicals. Ferroceniumboronic acid hexafluoroantimonate salt (1) was identified as a superior air- and moisture-tolerant catalyst for direct Friedel-Crafts alkylations of a variety of slightly activated and neutral arenes with stable and readily available primary and secondary benzylic alcohols. Compared to the use of classical metal-catalyzed alkylations with toxic benzylic halides, this methodology employs exceptionally mild conditions to provide a wide variety of unsymmetrical diarylmethanes and other 1,1-diarylalkane products in high yield with good to high regioselectivity. The optimal method, using the bench-stable ferroceniumboronic acid salt 1 in hexafluoroisopropanol as cosolvent, displays a broader scope compared to previously reported catalysts for similar Friedel-Crafts reactions of benzylic alcohols, including other boronic acids such as 2,3,4,5-tetrafluorophenylboronic acid. The efficacy of the new boronic acid catalyst was confirmed by its ability to activate primary benzylic alcohols functionalized with destabilizing electron-withdrawing groups like halides, carboxyesters, and nitro substituents. Arene benzylation was demonstrated on a gram scale at up to 1 M concentration with catalyst recovery. Mechanistic studies point toward the importance of the ionic nature of the catalyst and suggest that factors other than the Lewis acidity (pKa) of the boronic acid are at play. A SN1 mechanism is proposed where ion exchange within the initial boronate anion affords a more reactive carbocation paired with the non-nucleophilic hexafluoroantimonate counteranion.

Gold-catalyzed benzylation of arenes and heteroarenes

Friedel-Crafts type benzylation of arenes and heteroarenes with benzylic acetates, alcohols, and carbonates is effectively promoted under mild reaction conditions using catalytic amounts of gold salts. The resulting 1,1-diarylalkanes and 1-aryl-1-heteroarylalkanes are obtained in high yields and with high selectivity. The utility of the method is demonstrated by a short synthesis of beclobrate {ethyl 2-[4-(4-chlorobenzyl)-phenoxy]-2-methylbutyrate (3)}, a fibric acid derivative.

Phenoxy alkanoic acid derivatives having the ability to lower the level of fatty substances in the blood

Novel compounds of the formula STR1 wherein R1 is hydrogen, halogen, or alkyl or alkoxy containing from 1 to 4 carbon atoms, R2 is hydrogen, halogen, hydroxy or alkyl of alkoxy containing from 1 to 4 carbon atoms, n and m are integers such that the sum (n+m) lies in the range from 3 to 10 inclusive and n differs from m, and x is alkyl containing from 1 to 4 carbon atoms, hydrogen or a cation which is a metal cation of main Groups 1, 2 and 3 of the Periodic System of the Elements, an organic base cation or an ammonium ion. These compounds have pharmaceutical utility by virtue of their considerable ability to reduce the level of fatty substances in the blood.

Beclobrate and eniclobrate hydrochloride, new diphenylmethane derivatives as agents for lowering cholesterol and triglyceride levels. Part I: Synthesis and consideration of structure-activity relationships (author's transl)

Within the course of a research project for finding new lipid-lowering substances with better therapeutic indices than the standard agent in use, various diphenylmethane derivatives were synthesized and tested with respect to their activity and toxicity. On the basis of these results Sgd 24774 (beclobrate) and Sgd 33374 (eniclobrate-hydrochloride) were selected for further investigation and clinical studies.