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Bilastine intermediate and preparation and purification methods therefor

A purification method and compound technology, applied in the direction of organic chemistry, etc., can solve problems such as unfavorable storage and transportation, difficulty in purification, etc., and achieve the effects of convenient transportation and storage, reduction of purification steps, and high yield

Inactive Publication Date: 2017-01-11
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

4-[2-[4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-Dimethylphenylacetic acid Esters are oily, not conducive to storage and transportation, and difficult to purify

Method used

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  • Bilastine intermediate and preparation and purification methods therefor
  • Bilastine intermediate and preparation and purification methods therefor
  • Bilastine intermediate and preparation and purification methods therefor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14-

[0020] Example 14-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-dimethylbenzene Preparation and Purification of Ethyl Acetate Oxalate

[0021] Take 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-dimethylphenylacetic acid Add 10g of ethyl ester, add 80mL of acetonitrile, after the solid is dissolved, add 2.2g of oxalic acid, stir at room temperature for 5-7 hours, filter the product, wash with 20mL of acetonitrile, and dry under vacuum at 40°C to obtain 11.2g of white crystals with a yield of 92% . Melting point: 183°C-185°C. 1 H NMR(400MHz,DMSO),δ(ppm):1.08(t,3H),1.12(t,3H),1.51(s,6H),1.46-1.89(m,4H),1.92-2.14(m,2H ),2.54-2.57(m,2H),2.73-2.77(m,2H),3.03-3.09(m,3H),3.04-3.09(q,2H),3.11-3.16(q,2H),3.64-3.67 (t,2H),4.38-4.41(t,2H),7.14-7.21(m,4H),7.26-7.38(m,2H),7.51-7.57(dd,2H).H RMS(EI):m / z calcd.for C 32 h 43 N 3 o 7 :581.3101.Found:581.3102.

[0022] Take 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidin...

Embodiment 24-

[0023] Example 24-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-dimethylbenzene Preparation and Purification of Ethyl Acetate Oxalate

[0024] Take 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-dimethylphenylacetic acid Add 10g of ethyl ester, add 80mL of ethanol, after the solid is dissolved, add 2.2g of oxalic acid, stir at room temperature for 5-7 hours, filter the product, wash with 20mL of acetonitrile, and dry under vacuum at 40°C to obtain 10.7g of white crystals with a yield of 88% . Melting point: 183°C-185°C. 1 H NMR(400MHz,DMSO),δ(ppm):1.08(t,3H),1.12(t,3H),1.51(s,6H),1.46-1.89(m,4H),1.92-2.14(m,2H ),2.54-2.57(m,2H),2.73-2.77(m,2H),3.03-3.09(m,3H),3.04-3.09(q,2H),3.11-3.16(q,2H),3.64-3.67 (t,2H),4.38-4.41(t,2H),7.14-7.21(m,4H),7.26-7.38(m,2H),7.51-7.57(dd,2H).H RMS(EI):m / z calcd.for C 32 h 43 N 3 o 7 :581.3101.Found:581.3102.

[0025] Take 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]eth...

Embodiment 34-

[0026] Example 34-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-dimethylbenzene Preparation and Purification of Ethyl Acetate Hydrochloride

[0027] Take 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-dimethylphenylacetic acid 10g of ethyl ester, add 80mL of methanol, after the solid dissolves, add excess HCl gas, stir at room temperature for 3-5 hours, filter the product, wash with 20mL of methanol, and dry under vacuum at 40°C to obtain 10.5g of white crystals, the yield 97%. Melting point: 168°C-170°C. 1 HNMR(400MHz,DMSO),δ(ppm):1.05(t,3H),1.10(t,3H),1.48(s,6H),1.50-1.87(m,4H),1.97-2.10(m,2H) ,2.55-2.59(m,2H),2.77-2.80(m,2H),2.99-3.04(m,3H),3.05-3.11(q,2H),3.13-3.17(q,2H),3.54-3.61( t,2H),4.31-4.36(t,2H),7.16-7.23(m,4H),7.27-7.39(m,2H),7.55-7.59(dd,2H).H RMS(EI):m / z calcd.for C 30 h 42 ClN 3 o 3 :527.2915. Found: 527.2915.

[0028] Take 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α-dimet...

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Abstract

The invention discloses an intermediate, i.e., a 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidyl]ethyl]-alpha,alpha-dimethyl phenylacetate salt for synthesizing Bilastine and preparation and purification methods therefor. The intermediate is solid and is not prone to moisture absorption, and thus the defect that oily matters are adverse to storage and transportation is overcome. A product with high purity can be obtained through recrystallizing the intermediate by adopting a mixed solvent of an organic solvent and water, so that the product is suitable for serving as the intermediate for preparing Bilastine, and impurities in Bilastine final products are effectively reduced.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to bilastine intermediate 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine Pyridine]ethyl]-α,α-dimethylphenylacetic acid ester salt and its preparation and purification methods. Background technique [0002] Bilastine is a second-generation oral non-sedative histamine H1 receptor antagonist, developed by Spanish FAES pharmaceutical company, approved by the European Union in 2010 for the treatment of allergic rhinitis and chronic idiopathic urticaria . The required dose of this product is small, the safety range is large, and it does not have the sedative effect on the central nervous system and the toxic and side effects on the cardiovascular system that commonly used antihistamines have. Its chemical structure is shown in formula II: [0003] [0004] Patent applications WO2009102155, CN101952273A and CN102675101A disclose bilastine intermediate 4-[2-[4-[1...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 赵磊王晓林辉王正泽张丽林谢少斐
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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