Asymmetric syntheses method of ophthalmologic drug bepotastine besilate

A synthesis method and technology of benzenesulfonic acid, applied in the direction of organic chemistry and the like, can solve problems such as limited industrial application and sensitivity, and achieve the effects of convenient operation, low price and simple synthesis

Active Publication Date: 2017-07-11
YICHANG HUMANWELL PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the complexes of chiral bisphosphine ligands and ruthenium used in this method are sensitive to air and water, and flammable and explosive hydrogen gas and high-pressure reaction equipment are required, which limits its industrial application.
At present, there is no domestic manufacturer capable of large-scale production of bepotastine besilate API products, mainly relying on imports

Method used

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  • Asymmetric syntheses method of ophthalmologic drug bepotastine besilate
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  • Asymmetric syntheses method of ophthalmologic drug bepotastine besilate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: Preparation of (4-chlorophenyl) (2-pyridyl) ketone-N-oxide (formula (III))

[0042] Dissolve 0.2g of (4-chlorophenyl)(2-pyridyl)methanone in 2mL of hydrogen peroxide (30% aqueous solution), add 1.0mL of acetic acid, heat to 85°C for 12h, and check the progress of the reaction by TLC until After the reaction of the raw materials was complete, saturated sodium bicarbonate solution was added, extracted with dichloromethane, washed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 0.21 g of a white solid with a yield of 95%. 1 H NMR (400MHz, CDCl 3 ):δ=7.46-7.50(m,5H),7.82(dt,J 1 =4.4Hz,J 2 =2.4Hz, 2H), 8.27-8.29 (m, 1H)ppm.

Embodiment 2

[0043]Embodiment 2: Preparation of (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide (formula (IV))

[0044]

[0045] In a 20 mL Schlenk test tube, add 33 mg catalyst 1a, 0.23 g (4-chlorophenyl) (2-pyridyl) ketone-N-oxide, 5 mL formic acid / triethylamine mixture (formic acid / triethylamine molar ratio 1.1 / 1), seal the test tube, replace the gas with nitrogen for 3 times, react at 40°C for 24 hours, add water after the reaction, extract 3 times with ethyl acetate, combine and concentrate to dryness, and purify to obtain 0.22 g of white solid with a yield of 95%. The enantiomeric excess ee value of the product (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide determined by HPLC was 92%. HPLC separation conditions: OD-H chiral column, mobile phase: n-hexane / isopropanol=90:10 (volume ratio), flow rate: 1.0mL / min, wavelength: 220nm, column temperature: 30°C, retention time: t R =9.0min,t S = 11.5min; 1 H NMR (400MHz, CDCl 3 ): δ=6.08(d, J=4.4Hz, 1H), 6.42(d, J=4.8Hz, 1H), 7.00(t,...

Embodiment 3

[0046] Embodiment 3: Preparation of (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide (formula (IV))

[0047]

[0048] In a 20 mL Schlenk test tube, add 67 mg of catalyst 2a, 0.45 g of (4-chlorophenyl)(2-pyridyl)methanone-N-oxide, 3.35 g of sodium formate, seal the test tube, replace the gas with nitrogen 3 times, and add by syringe 5mL EtOH / H 2 O(EtOH / H 2 (2 volume ratio is 1:1) mixed solvent, reacted for 24 hours at 50 DEG C, extracted 3 times with ethyl acetate after the completion of the reaction, combined and concentrated to dryness, purified to give white solid 0.43g, productive rate 92%, HPLC assay product (S )-(4-Chlorophenyl)(2-pyridyl)methanol-N-oxide has an enantiomeric excess ee of 94%.

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Abstract

The invention relates to an asymmetric synthesis method of an ophthalmologic drug pylistramine besylate. The method concretely comprises the following steps: oxidizing (4-chlorophenyl)(2-pyridyl)methanone to obtain (4-chlorophenyl)(2-pyridyl)ketone-N-oxide; carrying out asymmetric transfer hydrogenation reduction on the (4-chlorophenyl)(2-pyridyl)ketone-N-oxide through using a complex of monosulfonyl chiral diamine and metallic ruthenium, rhodium and iridium as a catalyst and a sodium formate or formic acid and triethylamine mixture or isopropanol as a hydrogen source in order to prepare (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide; reducing the (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide to prepare (S)-(4-chlorophenyl)(2-pyridyl)methanol; and condensing the (S)-(4-chlorophenyl)(2-pyridyl)methanol and ethyl 4-(4-bromopiperidine-1-yl)butyrate to obtain the ophthalmologic drug pylistramine besylate. The total yield is 61.6%.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a new asymmetric synthesis method of ophthalmic medicine bepotastine besylate. Background technique [0002] Bepotastine besilate (formula (I)), the English name is bepotastine besilate, the chemical name is 4-[4-[(S)-[(4-chlorophenyl)pyridin-2-yl]methoxy ]piperidin-1-yl]butanoic acid monobenzenesulfonate. The histamine H1 receptor antagonist developed by Ube Industries, Japan, was first launched in Japan in 2000, and was approved by the US FDA in September 2009. It is mainly used for the treatment of ocular itching associated with allergic conjunctivitis. The S configuration of bepotastine besilate is pharmacologically more effective and less toxic than the corresponding R enantiomer (JP10-237070 or JP1998237070). [0003] [0004] The original research manufacturer used the first racemic compound to obtain 2-[4-[(S)-4-chlorophenyl)(4-piperidinyloxy)m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 符义刚吕金良周海峰王百贵曹路郑华章田峦鸢李仕群李莉娥杜文涛
Owner YICHANG HUMANWELL PHARMA
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