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A kind of preparation method of nebivolol and intermediate compound thereof

A compound and pharmaceutical technology, applied in the field of drug synthesis, can solve the problems of unfavorable industrial production, high cost of preparation process, long route and the like

Active Publication Date: 2016-06-22
福安药业集团重庆博圣制药有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The total yield of this route can reach 14.1%, which is a great improvement compared with the literature basis, but its preparation process cost is too high, and most of the post-processing of the reaction steps requires column chromatography, which is not conducive to industrial production
[0014] To sum up, it is particularly important to improve the problems of long route, low yield, high cost and unsuitability for industrial production in the existing process.

Method used

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  • A kind of preparation method of nebivolol and intermediate compound thereof
  • A kind of preparation method of nebivolol and intermediate compound thereof
  • A kind of preparation method of nebivolol and intermediate compound thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: Preparation of (R, R)-Compound I and (S, R)-Compound I

[0077] Absolute configuration of 1-[6-fluoro-(2R)-3,4-dihydro-2H-2-benzopyran-4-one]-(1R)-1,2 was obtained by referring to the method disclosed in WO2004041805 -Ethylene glycol, decarbonylation in trifluoroacetic acid / triethylsilane system to give 1-[6-fluoro-(2R)-3,4-dihydro-2H-2-benzopyran]-(1R) -1,2-ethylene glycol. Add 240g of it into 3L of dichloromethane, stir evenly, add 520mL of pyridine, immediately dissolve and clear, cool in an ice-water bath; weigh 236g of p-toluenesulfonyl chloride, add it into a constant pressure funnel, add 800mL of dichloromethane into the constant pressure funnel, It can dissolve completely and form a suspension. Add the suspension dropwise to the reaction bottle under an ice-water bath. After the addition is complete, remove the ice bath and stir at room temperature for 2 days. After the reaction is complete, pour the reaction solution into 3L of water. , stirred and...

Embodiment 2

[0079] Example 2 Preparation of 6-fluoro-(2S)-2-[1-hydroxyl-2-phthalimide-(1R)-ethyl]-3,4-dihydrochroman (S, R) - compound III

[0080] Put 133.2 grams (0.5mol) of S, R-compound I, 166.7 grams (0.9mol) of phthalimide potassium salt (compound II) and 138.2 grams (1.0mol) of anhydrous potassium carbonate into 480ml of DMF, Stir and heat up to 60-70°C, react for 8-10h. Cool to room temperature, add 1200ml of water and stir for 30min, cool to 5°C and filter, rinse the filter cake with 150ml of cold methanol, and dry under reduced pressure to constant weight to obtain compound 146.8g (S,R)-compound III, yield 86%. 1 H-NMR (CDCl 3 ): δ1.86-2.10(m,2H),2.78-2.95(m,2H),3.76-3.82(m,1H),3.86-3.98(m,2H),4.36(m,1H),4.90(d ,1H),6.78(d,1H),6.96-6.98(d,1H),7.01-7.04(d,1H),7.86-7.90(d,2H),7.98-8.02(d,2H),C 19 h 16 NFO 4 HRMS theoretical value 341.3330, measured value 341.3325

Embodiment 3

[0081] Example 3 Preparation of 6-fluoro-(2R)-2-[1-hydroxyl-2-phthalimide-(1R)-ethyl]-3,4-dihydrochroman (R, R) - compound III

[0082] Put 133.2 grams (0.5mol) of R,R-compound I, 166.7 grams (0.9mol) of phthalimide potassium salt (compound II) and 138 grams (1.0mol) of anhydrous potassium carbonate into 480ml of DMF, Stir and heat up to 60-70°C, react for 8-10h. Cool to room temperature, add 1200ml of water and stir for 30min, cool to 5°C and filter, rinse the filter cake with 150ml of cold methanol, and dry under reduced pressure to constant weight to obtain compound 146.5g (R,R)-compound III, yield 85.8%.

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Abstract

The invention discloses a preparation method of nebivolol used for preparing medicines for treating hypertension of slight or medium degrees, and an intermediate compound. The preparation method comprises the following steps: taking 6-fluoro-2-(1-hydroxy-2-paratoluensulfonyl oxygroup-ethyl)-3,4-dihydrobenzopyrans as an initial raw material, introducing amino, then coupling with 6- fluoro-3,4-dihydro-2-epoxy ethyl-2H-1-benzopyran, and preparing (S,R,R,R) and (R,S,S,S)-nebivolol. Compared with a prior art, the preparation method has the advantages of novel design, simple operation and high yield, the usage of hazardous reagent such as ssodium azide and sodium hydride can be avoided, a column chromatography purifying method is avoided, so that the preparation method conforms to industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of nebivolol, a drug for treating mild to moderate hypertension, and an intermediate compound thereof. Background technique [0002] Nebivolol hydrochloride (Nebivololhydrochloride), the chemical name is α,α'-[iminobis(methylene)bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2- Methanol)] hydrochloride (structure shown in the following formula), developed by Johnson & Johnson Company of the United States, was first launched in Germany and the Netherlands in 1997, and is used for the treatment of essential hypertension. -Receptor blockers, which have remarkable curative effect, are convenient to take, and have few adverse reactions. The commercial name of the tablet is Nebilet. [0003] [0004] Nebivolol has 4 chiral centers, and there are 10 isomers in total due to the symmetry of the structure. Its medicinal uses are (S,R,R,R)-form and (R,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/58C07D405/06
CPCC07D311/58C07D405/06
Inventor 梁杰张稳稳李佩杰郭子维洪荣川陈小勇
Owner 福安药业集团重庆博圣制药有限公司
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