Method for preparing and purifying nebivolol intermediate

A technology for solids and compounds, which is applied in the preparation and purification of nebivolol intermediates, and in the field of improved preparation and purification, can solve the problems of poor purity, uncertain yield and quality, and not too high yield, etc. Simple, green process route, less side reactions

Active Publication Date: 2014-09-03
PHARMA CHANGZHOU PHARMA FACTORY NO 4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] And the prepared intermediate I disclosed in patent US7960572B2 and US2011 / 0237808A1, that is, 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl) ethyl Ketones, the yield is not too high, and it is in the form of oil, the purity is poor, and they are directly put into the next reaction without purification, which brings uncertainty to the yield and quality of the subsequent reaction

Method used

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  • Method for preparing and purifying nebivolol intermediate
  • Method for preparing and purifying nebivolol intermediate
  • Method for preparing and purifying nebivolol intermediate

Examples

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preparation example 1

[0042] Preparation Example 1 Preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester

[0043]In a 500ml reactor equipped with mechanical stirring and condenser, add 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid (50g, 255mmol), methanol 394ml and acid methanol (20.3g / 100ml) 6ml, react at about 45°C for 2 hours, cool to room temperature (about 20°C), add NaHCO3 (2.8g, 33.4mmol) and stir for about 1 hour, distill under reduced pressure, and add ethyl acetate to the residue 200ml was dissolved, and the organic phase was washed once with 200ml of 2% sodium bicarbonate and once with 200ml of saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness to obtain 52.9 g of off-white solid. The purity of the product was determined by HPLC, and the content was 99.46% calculated by the area normalization method.

preparation example 2

[0044] Preparation Example 2 Preparation of 1,-dimethylsulfoxide methylene-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methanone

[0045] In a 250ml reactor equipped with mechanical stirring, a dropping funnel and a reflux condenser, add potassium tert-butoxide (20g, 179mmol) and 175ml tetrahydrofuran at room temperature (20°C), stir, and add trimethyl iodide at room temperature Sulfoxide (39.3g, 179mmol), heated to about 70°C, reacted for 2h, cooled to the internal temperature of about 0°C, added dropwise 6-fluoro-3,4-dihydro-2H-1-benzopyran- Methyl 2-carboxylate (25g, 119mmol) in 25ml of tetrahydrofuran was added dropwise and stirred at about 0°C for 1h. After the reaction is complete, concentrate under reduced pressure to remove most of the THF, then add 100ml of water, and spin again to remove the remaining THF. Add 250ml of ethyl acetate and 125ml of water to extract the residue at about 25°C, filter, stand to separate layers, and the water phase Extract once more with ...

Embodiment 1

[0046] Example 1 Preparation of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethanone

[0047] In a 250ml reactor equipped with mechanical stirring and dropping funnel, add 1,-dimethylsulfoxidemethylene-1-(6-fluoro-3,4-dihydro-2H-1- Benzopyran-2-yl)methanone (20g, 74mmol) and tetrahydrofuran 200ml, add water (0.704g, 39mmol) and thionyl chloride (4.66g, 39mmol) in turn, and keep stirring at about 10°C for 30 minutes, Turn on heating and raise the temperature to about 70°C, react for 2 hours, cool down, concentrate the reaction solution to dryness under reduced pressure (-0.095MPa, water bath 50°C), and then pull it with an oil pump for 10 to 15 minutes after spinning, add 100ml of toluene, 100ml of 2% NaHCO3 Wash once; wash with saturated NaCl100ml*4, add anhydrous Na to toluene 2 SO 4 Let dry for 2 hours. Spin dry the toluene phase (-0.095MPa, water bath 50°C), spin it, and then pull it to a constant weight with an oil pump to obtain 16.16g of oil, add 16ml of iso...

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Abstract

The invention relates to a method for preparing and purifying a nebivolol intermediate and in particular relates to an improved method for preparing and purifying 2-chloro-1-(6-fluro-3,4-dihydro-2H-1-benzopyran-2-yl) acetone shown in a formula (I) as shown in the specification. The 2-chloro-1-(6-fluro-3,4-dihydro-2H-1-benzopyran-2-yl) acetone compound is a key intermediate for synthesizing nebivolol. By adopting the method provided by the invention, a high-purity solid of the key intermediate is obtained with high yield (more than 85%) and high purity (more than 99%), operation is easy, and industrial production can be easily realized.

Description

technical field [0001] The present invention relates to the preparation and purification method of nebivolol intermediate, in particular, relates to the key intermediate 2-chloro-1-(6-fluoro-3,4-dihydro of antihypertensive drug nebivolol hydrochloride -A kind of improved preparation and purification method of 2H-1-benzopyran-2-yl)ethanone. belongs to the field of medicinal chemistry. Background technique [0002] Nebivolol (Nebivolol hydrochloride) is a potent and selective third-generation β-receptor blocker, which can increase the level of nitric oxide and has a vasodilation effect. It is alkaline and can be made into various corresponding salts, and the commercially available products exist in the form of hydrochloride. [0003] The synthesis of this substance has been reported in many documents. For example, patent CN200580025850.6 discloses a group of enantiomers through compound a (containing 2 sets of enantiomers, respectively RR / SS and RS / SR). (eg: RR / SS) as the s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/04
CPCC07D311/04
Inventor 葛纪龙沈征董秀忠屠永锐彭文毛秋霞王艳
Owner PHARMA CHANGZHOU PHARMA FACTORY NO 4
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