Preparation and purification method of nebivolol intermediate

A solid and compound technology, applied in the preparation and purification of nebivolol intermediates, improved preparation and purification fields, can solve the problems of not too high yield, uncertainty of yield and quality, poor purity, etc., to achieve The process route is green and environmentally friendly, with less side reactions and easy operation

Active Publication Date: 2016-01-27
PHARMA CHANGZHOU PHARMA FACTORY NO 4
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  • 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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  • Preparation and purification method of nebivolol intermediate
  • Preparation and purification method of nebivolol intermediate
  • Preparation and purification method of nebivolol intermediate

Examples

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preparation example 21

[0044] Preparation Example 21, Preparation of -Dimethylsulfoxidemethylene-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 1...

Embodiment 12

[0046] Preparation of Example 12-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 for washing 1 time; saturated NaCl100ml*4 wash, 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 ...

Embodiment 22

[0048] Preparation of Example 22-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethanone

[0049] 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, and concentrate the reaction solution to dryness under reduced pressure (-0.095MPa, water bath 50°C), after spinning, use an oil pump to pull for 10 to 15 minutes, add ethyl acetate 100ml, 2% Wash once with NaHCO3100ml; wash with saturated NaCl100ml*4, add ethyl acetate to anhydrous Na 2 SO 4 Let dry for 2 hours. Spin-dry the ethyl acetate phase (-0.095MPa, water bath 50°C), and then use an oil pump to pull to constant weight to obtain 16.26g of oil, add 16ml of methy...

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Abstract

The present invention relates to a method for preparing and purifying a nebivolol intermediate, in particular to a method for preparing and purifying 2-chloro-1-(6-fluoro-3,4-dihydro- An improved method for 2H-1-benzopyran-2-yl)ethanone, which is a key intermediate for the synthesis of nebivolol. The high-purity solid of the key intermediate is obtained through the method of the present application with high yield (over 85%) and high purity (over 99%), and is easy to operate and suitable for industrial production.

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 (Nebivololhydrochloride) 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 st...

Claims

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Application Information

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Patent Type & Authority Patents(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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