2-(4-(2-(4-(1-(2-乙氧基乙基)-1H-苯并[D]咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸
BENZENEACETIC ACID, 4-(2-(4-(1-(2-ETHOXYETHYL)-1H-BENZIMIDAZOL-2-YL)-1-PIPERIDINYL)ETHYL-ALPHA, ALPHA-DIMETHYL-
CAS: 202189-78-4
Molecular Formula: C28H37N3O3
2-(4-(2-(4-(1-(2-乙氧基乙基)-1H-苯并[D]咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸 - Names and Identifiers
2-(4-(2-(4-(1-(2-乙氧基乙基)-1H-苯并[D]咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸 - Physico-chemical Properties
| Molecular Formula | C28H37N3O3 |
| Molar Mass | 463.62 |
| Density | 1.16±0.1 g/cm3(Predicted) |
| Melting Point | 202 °C |
| Boling Point | 639.1±55.0 °C(Predicted) |
| Water Solubility | Insoluble in water |
| Appearance | powder to crystal |
| Color | White to Light yellow |
| pKa | 4.40±0.10(Predicted) |
| Storage Condition | Sealed in dry,Room Temperature |
| Physical and Chemical Properties | Bioactive Bilastine is a novel resistant, non-sedating antihistamine directed against H1 receptor. Its effect is rapid and durable. |
| Use | bilastine, an oral non-sedating histamine H1 receptor antagonist developed by the Spanish pharmaceutical company FAES, was approved by the European Union in August 2012 for the treatment of allergic rhinitis and urticaria, A phase II clinical study was also conducted in the United States. This product selectively acts on peripheral histamine receptors, has no effect on other histamine receptors, has no cardiac toxicity, is absorbed rapidly by oral administration, and has good tolerance, safety and high bioavailability. |
2-(4-(2-(4-(1-(2-乙氧基乙基)-1H-苯并[D]咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸 - Synthesis of bilastine
from hownet
Author:
Kong Hao , Geng Haiming , Mei Yudan , Xiaoqi Zhu , Sun Pinghua
Abstract:
methyl α, α-dimethyl-4-(2-bromoethyl) phenylacetate (2) was prepared by Friedel-Crafts acylation and reduction, after nucleophilic substitution reaction with 2-(4-piperidinyl)-1H-benzimidazole and 2-chloroethyl ether, the overall yield was about 54% (calculated as 2).
Key words:
bilastine; Histamine H1 receptor antagonist; synthesis
DOI:
10.16522/j.cnki.cjph.2015.07.003
cited:
year:
2015
Last Update：2024-01-02 23:10:35
2-(4-(2-(4-(1-(2-乙氧基乙基)-1H-苯并[D]咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸 - Preparation Method of 2-(4-haloethyl) phenyl -2-methyl propionate and synthesis method of bilastine
Application (patent) number:
CN201210150701.4
applicant (patent):
Wang Lei
inventor:
Wang Lei , Li Ke , Wang Qian , Liu Wei-feng
cited:
Abstract:
The invention discloses a method for preparing 2-(4-haloethyl) phenyl -2-methyl propionate and a method for synthesizing bilastine, 2-(4-haloacetyl) phenyl -2-methyl propionate is produced by acylation reaction of 2-dimethylphenylacetate with haloacetyl halide under the action of catalyst; then the 2-(4-haloacetyl) phenyl -2-methyl propionate undergoes a reduction reaction with the base-Wolf-huangminglong, and the carbonyl group is reduced to form 2-(4-haloethyl) phenyl -2-methyl propionate. Then with the 2-(4-haloethyl) phenyl-2-methylpropionate as an intermediate is condensed with 1-ethoxyethyl-2-pyridin-4-ylbenzimidazole to give esterified bilastine; Then hydrolyzed to give bilastine. The new method for synthesizing bilastine provided by the invention is easy to obtain raw materials, simple to operate, low in cost, environmentally friendly, and completely suitable for industrial production.
Last Update：2023-08-16 22:05:47
2-(4-(2-(4-(1-(2-乙氧基乙基)-1H-苯并[D]咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸 - Synthesis of key intermediates of bilastine
from VIP Journal Professional Edition
Author:
Korean Zaiqi , Wang Sen , Cui , feng bo , Yao Lu , boom
Abstract:
with 2-[1-(4-bromophenyl)-1-methylethyl]-4, 5-dihydro-4, 4-dimethyl 4-[1-(5, 5-dihydro-4, 4-dimethyl-2-(oxyl) oxazolyl]) was obtained by Grignard reaction with dibromoethane.-1-methylethyl]-2-phenylethyl bromide, with 2-(4-piperidinyl) the Intermediate 2-(2-(4-(2-(4-(1H-benzimidazol-2-yl))) was obtained by nucleophilic substitution of -1H-benzimidazole under alkaline conditions. Piperidine -1-yl) ethyl) phenyl) prop-2-yl)-4, 4-dimethyl4, 5-dihydro( oxazole in 63% overall yield. The new process not only avoids the use of n-butyl lithium, cyclohexane and other dangerous reagents, but also reduces the potential safety hazard and environmental pollution, simplifies the experimental steps, and has the advantages of simple operation, high yield and suitable for industrial production.
Key words:
bilastin key intermediate synthesis
DOI:
10.13822/j.cnki.hxsj.2018.10.018
year:
2018
Last Update：2023-08-16 22:05:47
2-(4-(2-(4-(1-(2-乙氧基乙基)-1H-苯并[D]咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸 - Reference Information
| introduction | bilastine (bilastine) is an oral non-sedative histamine H1 receptor antagonist developed by FAES pharmaceutical company in Spain. it was approved by the European union in August 2012 for the treatment of allergic rhinitis and urticaria, and phase ii clinical study was conducted in the United States. This product selectively acts on peripheral histamine receptors, has no effect on other histamine receptors, has no cardiac toxicity, rapid absorption by oral administration, good tolerance, safety and high bioavailability. |
| safety study | a randomized, triple-simulated, double-blind, five-crossed and placebo and positive drug (moxifloxacin, 400mg) controlled clinical study involving 30 healthy volunteers showed that when the daily dose of bilastine reached 100mg(5 times the therapeutic dose), no specific heart rate-related Q-T(Q-TcNi) or other Q-Tc increase was observed in the subjects, indicating that this product has no significant effect on myocardial repolarization, and it is confirmed that it has low toxicity to the heart. |
| pharmacological research | in vitro research results show that compared with H1 receptor antagonists cetirizine and afenadine, bilastine has higher affinity for H1 receptors in guinea pig cerebellum (Ki of the three are 143.1, 248.1 and 44.1nmol • L-1 respectively); Compared with the other 30 related receptors, bilastine has higher selectivity for histamine H1 receptors. In addition, this product not only has a stronger inhibitory effect on the contraction of isolated guinea pig trachea and ileum caused by H1 receptor activation than cetirizine, but also has an inhibitory effect on the allergic contraction of guinea pig ileal smooth muscle caused by ovalbumin. It is better than cetirizine and non-sofiadine. The IC50 of the three are 95.5, 759 and 282nmol • L-1, respectively. In vitro tests in guinea pig atria and jejunum showed that even if the concentration of this product reached 100 μmol • L-1, it would not interfere with the increase of atrial pulsation induced by H2 receptor agonists and the weakening of smooth muscle contraction caused by H3 receptor agonists. Further in vivo tests showed that oral use of this product in rats can dose-dependently inhibit histamine-induced capillary permeability response (ED50 = 2.45mg kg-1) and bronchospasm (ED50=4.57 μg kg-1), with stronger effect on the latter than cetirizine (ED50=53.32 μg kg-1). In addition, this product also shows potential therapeutic effects on passive skin allergic reaction induced by anti-dinitrophenol IgE monoclonal antibody in rats and auricle swelling of IgG-or IgE-dependent mice (ED50 is 5.96, 3.82 and 4.15mg kg-1 respectively). In addition to antagonizing H1 receptors, this product can also inhibit the release of histamine and IL-4 from mast cells and peripheral granulocytes, while other H1 receptor antagonists such as cetirizine can promote the release of these inflammatory mediators. |
| Preparation | α,α-dimethylphenylacetate methyl (2) is obtained by Friedel-Crafts acylation and reduction reaction to obtain α,α-Dimethyl -4-(2-bromoethyl) phenylacetate methyl ester, after nucleophilic substitution reaction with 2-(4-piperidinyl)-1H-benzimidazole and 2-chloroethyl ether in turn, dilastine was hydrolyzed with a total yield of about 54% (calculated by 2). 1)α,α-dimethyl -4-(2-bromoacetyl) methyl phenylacetate (3) 2(5.0g,28mmol) and bromoacetyl bromide (7.4g,36mmol) are dissolved in dichloromethane (20ml), and the solution is dropped into dichloromethane solution (50ml) of aluminum trichloride (11.2g,84mmol) at -30 ℃, and stirred overnight at 0 ℃. Add dichloromethane (50ml) to dilute, the reaction solution is filtered by diatomite, the filtrate is washed with saturated sodium chloride solution (30ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain yellow oil 3(7.1g,85%). ESI-MS(m/z):299[M + H]+;2)α,α-dimethyl -4-(2-bromoethyl) methyl phenylacetate (4) 3(3.0g,10mmol), trifluoroacetic acid (15.0g,130mmol) and triethylsilane (2.2g,19mmol) were dissolved in dichloromethane (20ml) at 0 ℃, stirred for 30min, and refluxed for 72h, the reaction solution was concentrated to remove dichloromethane, saturated sodium carbonate solution (about 70ml) was added, ethyl acetate (30ml × 3) was used to extract and combine the organic phase, and then saturated sodium carbonate solution (10ml × 3), water (20ml) and saturated sodium chloride solution (20ml) were used to wash, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure at 100 ℃ to obtain colorless oil 4(2.6g,91%)(literature: 68%[9]). ESI-MS(m/z):285[M + H]+;3)α,α-dimethyl -4-[2-[4-[1H-2-benzimidazolyl] piperidine -1-yl] ethyl] methyl phenylacetate (6) Dissolve 5(2.4g,12mmol) and diisopropylethylamine (3.9g,30mmol) in THF(20ml), 4(2.8g,0.01mol) THF solution (10ml) was slowly added dropwise at room temperature. After dropping, raise the temperature to 60 ℃ for 7h, add water (10ml) to quench, concentrate the reaction solution, extract with ethyl acetate (30ml × 3), combine organic phases, wash with water (20ml) and saturated sodium chloride solution (20ml) in turn, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to obtain white solid 6(3.4g,85%),mp263~264 ℃. ESI-MS(m/z):406[M + H]+4)4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl] piperidin-1-yl] ethyl]-α,α-dimethylphenylacetate (8) 6(4.1g,0.01mol) and 60% sodium hydride (0.7g,0.03mol) is added to THF(20ml), stirred at room temperature for 2h, 7(1.3g,12mmol) is added, heated to 60 ℃ for 16h, saturated ammonium chloride solution (10ml) is added to quench the reaction, ethyl acetate (30ml × 3) is used for extraction, organic phase is combined, dried with anhydrous sodium sulfate, filtered, filtrate is concentrated to obtain yellow oil 8(4.7g,98%). ESI-MS(m/z):478[M + H]+;5) Bilastine (1) Add 8(4.5g,0.01mol) to methanol (15ml), add saturated sodium hydroxide solution (15ml), reflow reaction for 5h, add 4mol/L hydrochloric acid (about 100ml) to adjust to pH5 ~ 6, precipitate pale yellow solid, filter, the filter cake was washed with ice water (20ml) and ice ethanol (20ml), dried and recrystallized with methanol to obtain light yellow solid 1(3.4g,83%),mp295~296 ℃. |
| biological activity | Bilastine is a new type of tolerant, non-sedative antihistamine, targeting H1 receptor. Its effect is rapid and lasting. |
| Target | Value |
| H1 receptor (in guinea-pig cerebellum) | 44.15 nM(Ki) |
Last Update：2024-04-09 02:00:04
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2-(4-(2-(4-(1-(2-乙氧基乙基)-1H-苯并[D]咪唑-2-基)哌啶-1-基)乙基)苯基)-2-甲基丙酸
甲硝唑EP杂质A
1-(4-CHLOROPHENYL)UREA,CERTIFIED 标准品
[2-(1-哌啶甲基)苯基]溴化镁 0.25M 四氢呋喃
METHYL 4-(4-(BIS(2-CHLOROETHYL)AMINO)PHENYL)BUTYARTE
1-ButylpyridiniuM heptachlorodialuMinate
4-(3-羟基-4-甲酰基苯氧基)丁酸乙酯
1H-苯并[D][1,2,3]三唑-1-基二甲基氨基甲酸酯
1-STEAROYL-2-HYDROXY-SN-GLYCERO-3-PHOSPHO-L-SERINE (SODIUM SALT);18:0 LYSO PS
山梨糖醇糖浆
甲硝唑EP杂质A
1-(4-CHLOROPHENYL)UREA,CERTIFIED 标准品
[2-(1-哌啶甲基)苯基]溴化镁 0.25M 四氢呋喃
METHYL 4-(4-(BIS(2-CHLOROETHYL)AMINO)PHENYL)BUTYARTE
1-ButylpyridiniuM heptachlorodialuMinate
4-(3-羟基-4-甲酰基苯氧基)丁酸乙酯
1H-苯并[D][1,2,3]三唑-1-基二甲基氨基甲酸酯
1-STEAROYL-2-HYDROXY-SN-GLYCERO-3-PHOSPHO-L-SERINE (SODIUM SALT);18:0 LYSO PS
山梨糖醇糖浆