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Preparation method of nebivolol intermediate, intermediate for preparing nebivolol intermediate, and preparation method of intermediate

An intermediate and molar ratio technology, which is applied in the preparation of intermediate compound I and the intermediate compound I, and the preparation of nebivolol key intermediate compound II, can solve the problem of high pressure and corrosion resistance of equipment, Respond to the problems of high toxicity of raw materials and difficult purification of products, and achieve the effects of stable physical and chemical properties, convenient production and storage, and high yield

Active Publication Date: 2018-12-14
ZHEJIANG HISOAR PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Therefore, it is necessary to develop a new method for the preparation of α-haloketones to overcome the complex operation of existing methods, long reaction steps, poor atom economy, high cost, high toxicity of reaction raw materials, difficult purification of the obtained products, and resistance to equipment. High pressure and corrosion resistance requirements

Method used

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  • Preparation method of nebivolol intermediate, intermediate for preparing nebivolol intermediate, and preparation method of intermediate
  • Preparation method of nebivolol intermediate, intermediate for preparing nebivolol intermediate, and preparation method of intermediate
  • Preparation method of nebivolol intermediate, intermediate for preparing nebivolol intermediate, and preparation method of intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1 utilizes chromanic acid and 1,3-dichloropropane to prepare dichromanic acid ester 1a

[0062]

[0063] Mix 21.0g of chromanic acid (R configuration, 107mmol), 14.8g of potassium carbonate (107mmol), N,N-dimethylformamide (100mL) and toluene (40mL), then heat to 120°C, then 5.8 g 1,3-dichloropropane (51 mmol) was added to the reaction system, and the reaction was continued for 4 hours, and TLC detected that the reaction was complete. The reaction system was lowered to room temperature, acetic acid (2.2g) was added to quench the reaction, most of the solvent was distilled off under reduced pressure, water (100mL) was added, extracted three times with ethyl acetate (150mL), the combined organic phase was water (100mL ), the resulting organic phase was distilled under reduced pressure to viscous oil, recrystallized with isopropanol (40mL) to obtain 20.3g off-white solid, high performance liquid chromatography showed a single peak, the chromatographic purity ...

Embodiment 2

[0066] Embodiment 2 utilizes chromanic acid and 1,3-dichloropropane to prepare dichromanic acid ester 1a

[0067]

[0068] Mix 15.0g chromanic acid (R configuration, 76.5mmol), 12.0g potassium carbonate (87.0mmol), N,N-dimethylformamide (90mL) and toluene (30mL), then heat to 120°C, then 5.8 g of 1,3-dichloropropane (51 mmol) was added into the reaction system, and the reaction was continued for 4 hours, and the reaction was detected by TLC. The reaction system was lowered to room temperature, acetic acid (2.2g) was added to quench the reaction, most of the solvent was distilled off under reduced pressure, water (100mL) was added, extracted three times with ethyl acetate (150mL), the combined organic phase was water (100mL ), the resulting organic phase was distilled under reduced pressure to viscous oil, recrystallized with isopropanol (40mL) to obtain 10.2g off-white solid, high performance liquid chromatography showed a single peak, the chromatographic purity was 90%, an...

Embodiment 3

[0069] Embodiment 3 utilizes chromanic acid and 1,4-dichlorobutane to prepare dichromanic acid ester 1b

[0070]

[0071] Add 2.9g chromanic acid (S configuration, 15mmol), 1.59g sodium carbonate (15mmol), N,N-dimethylformamide (15mL) into the reaction flask, and then add 0.63g 1,4-dichloro Butane (5 mmol) was added into the reaction system, heated to 120° C. for 5 hours, and the reaction was detected by HPLC. The reaction system was lowered to room temperature, acetic acid (0.3g) was added to quench the reaction, most of the solvent was distilled off under reduced pressure, water (15mL) was added, extracted three times with ethyl acetate (15mL), and the combined organic phases were extracted with water (15mL ) was washed, the resulting organic phase was distilled under reduced pressure to viscous oil, beating with isopropanol (10mL) to obtain 1.8g off-white solid, high performance liquid chromatography showed a single peak, the chromatographic purity was 95%, and the yield...

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Abstract

The invention relates to a preparation method of alpha-haloketone of a nebivolol intermediate of a formula II, an intermediate compound I for preparing the alpha-haloketone, and a preparation method of the intermediate compound I. The preparation method disclosed by the invention comprises the following steps: taking chromane-2-carboxylic acid as a raw material, carrying out a reaction with dihalide or disulfonate, so as to obtain chromane-2-carboxylate I; further carrying out a reaction with dihalomethane under the effect of organo-lithium, so as to obtain the nebivolol intermediate alpha-haloketone II. According to the method disclosed by the invention, the defect that the intermediate for producing the alpha-haloketone is high in cost and low in purity is overcome. Moreover, the methoddisclosed by the invention has the advantages of being simple in operation, environmentally friendly, convenient for industrial production and the like.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to the preparation of a key intermediate compound II of nebivolol, an intermediate compound I used to prepare the intermediate II, and a preparation method of the intermediate compound I. [0002] Background technique [0003] Nebivolol hydrochloride is a third-generation adrenergic β-receptor blocker, which is a mixture of equimolar amounts of left-handed and right-handed isomers, of which the right-handed isomer has a strong β1-receptor blocking effect, and the left-handed The isoform has endothelial cell-dependent vasodilator effects. The chemical structure of nebivolol has four chiral centers, a total of ten chiral isomers, and the marketed drug is a racemate composed of nebivolol hydrochloride with equimolar amounts of RSSS and RRRS configurations mixed . [0004] [0005] Patent WO2008 / 010022A2 discloses a method for preparing racemic nebivolol. Whe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/66C07D311/58C07D311/04
CPCC07B2200/07C07D311/04C07D311/58C07D311/66
Inventor 李洪明褚长虎王智勇江俊张奎祚何赖华
Owner ZHEJIANG HISOAR PHARMA
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