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Bilastine compound and preparation method thereof

A bilastine and compound technology, which is applied in the field of bilastine compounds and their preparation, can solve the problems of poor stability and hygroscopicity, no detailed research and disclosure of the bilastine compound purification method, light sensitivity and the like

Active Publication Date: 2015-04-22
天津梅花生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0027] In the research process, repeating the method of the above-mentioned patent literature, the obtained bilastine crude product is easy to decompose under acidic conditions, sensitive to light, poor in stability, and has hygroscopicity.
In the prior art, there are many different crystal forms of Bilastine. These crystal forms have improved stability or improved impurity control, but their performance improvement has unilateral limitations. Bilastine There is no detailed research and disclosure on the refining method of sting compound. In order to obtain this compound with better performance, the present invention is proposed

Method used

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  • Bilastine compound and preparation method thereof
  • Bilastine compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Synthesis of p-methylphenylethanol p-toluenesulfonate (III)

[0112] A mixture of 13.6g (0.1mol) of p-methylphenylethanol (II), 21.0g (0.11mol) of p-toluenesulfonate, 11.1g (0.11mol) of triethylamine and 80ml of dichloromethane was reacted at room temperature for 1h. Add 80ml of water, stir, separate layers, the organic layer is washed with saturated NaHCO3, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 26.7g of p-methylphenylethanol p-toluenesulfonate (III). 92%, content 93.6% (HPLC normalized).

[0113] 1 H NMR (400MHz, CDCl3) δ7.84–7.74 (m, 2H), 7.40–7.30 (m, 2H), 7.16–7.00 (m, 4H), 4.05 (t, J=15.0Hz, 2H), 2.82 ( t,J=15.0Hz,2H), 2.44(s,3H), 2.19(s,3H).

Embodiment 2

[0115] Synthesis of 1-(2-ethoxyethyl)-2-(1-(4-methylphenylethyl)piperidin-4-yl)-1H-benzo[d]imidazole (V)

[0116] In 100ml of dimethylformamide, add 26g (0.0895mol) p-methylphenylethanol p-toluenesulfonate (III), 24.5g (0.0895mol) 1-(2-ethoxyethyl)-2-( Piperidin-4-yl)-1H-benzo[d]imidazole (IV), 18.6g (0.1343mol) anhydrous potassium carbonate, stirred, heated to 80°C for 14h. The reaction solution was concentrated to dryness under reduced pressure, dissolved in chloroform, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and recrystallized from ethyl acetate to obtain 30.8 g of (V) white solid. Yield 87.9%, content 96% (HPLC normalization).

[0117] 1 H NMR (400MHz, CDCl3) δ7.34–7.22(m,2H),7.28–7.21(m,2H),7.12–7.05(m,4H),4.34(t,2H),3.74(t,2H), 3.41(d,2H),3.13(d,1H),2.98(t,1H),2.81(t,2H),2.64(t,2H),2.20(m,4H),2.01(m,3H),2.19 (s,3H), 1.05(t,3H).

Embodiment 3

[0119] Synthesis of 1-(2-ethoxyethyl)-2-(1-(4-bromomethylphenylethyl)piperidin-4-yl)-1H-benzo[d]imidazole (VI)

[0120] 30.0g 1-(2-ethoxyethyl)-2-(1-(4-methylphenylethyl)piperidin-4-yl)-1H-benzo[d]imidazole (V) (0.0766 mol), the mixture of N-bromosuccinimide 14.3g (0.0804mol) and AIBN 100mg in carbon tetrachloride 100ml, the solution was warmed to reflux for 8h. After cooling the reaction mixture to room temperature, water was added, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product which was recrystallized from ethanol to obtain 29.9 g of solid, 1-(2-ethoxy Ethyl)-2-(1-(4-bromomethylphenylethyl)piperidin-4-yl)-1H-benzo[d]imidazole (VI), content 90% (HPLC normalized), yield The rate is 83%.

[0121] 1 H NMR (400MHz, CDCl3) δ7.34–7.22(m,2H),7.28–7.21(m,2H),7.12–7.05(m,4H),4.34(t,2H),4.25(s,2H), 3.74(t,2H),3.41(d,2H),3.13(d,1H),2.98(t,1H),2.81(t,2H),2.64(t,2H),2.20(m,4H),2.01 (m,3H), 1.05(t,3H)....

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Abstract

The invention belongs to the technical field of medicines, and specifically relates to a bilastine compound and a preparation method of the compound. The bilastine compound is high in stability and not obvious in moisture-absorption weight gain under a high-humidity condition, and related substances are not increased; compared with bilastine in other crystal forms, the bilastine compound is high in solubility and outstanding in physical and chemical performances. The preparation method comprises the following steps: by taking p-methyl phenethyl alcohol as a starting raw material, performing the sulfonylation reaction for hydroxy through sulfonyl chloride to obtain sulfonate; condensing sulfonate with 1-ethoxyethyl-2-piperidyl benzoglioxaline; performing bromination for benzyl; carrying out grignard reaction to introduce carboxyl to the benzyl, and then converting benzyl into ester; performing dimethylation for benzyl through iodomethane; finally hydrolyzing to obtain bilastine. The method involves seven synthesis reactions, and has the advantages that few synthesis steps are carried out, the reaction conditions are mild, the raw materials are easily obtained, the reaction process is simple, the yield is high, the cost is relatively low, the industrialization is easily carried out, and three-waste pollution is less.

Description

technical field [0001] The invention relates to medicines in the field of medicine, in particular to a bilastine compound and a preparation method thereof. Background technique [0002] Bilastine is a new type of second-generation H1 receptor antihistamine for the treatment of seasonal or perennial allergic rhinitis conjunctivitis and urticaria. Bilastine is rapidly absorbed orally, has a long duration of action, is very well tolerated, and is non-sedating without the cardiovascular side effects of some other antihistamines. Applying bilastine 20mg once a day can effectively relieve nasal and eye symptoms such as nasal congestion. [0003] Bilastine [0004] English name: Bilastine; [0005] Chemical name: 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl) Phenyl)-2-methylpropionic acid; [0006] Molecular formula: C 28 h 37 N 3 o 3 ; [0007] Molecular weight: 463.61; [0008] Structural formula: [0009] The synthetic route of bilast...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/454A61P17/00A61P37/08A61P11/02A61P27/02
CPCC07D401/04
Inventor 梅开忠黄欣
Owner 天津梅花生物医药科技有限公司
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