Method for preparing benzodihydropyran compound

A compound, sodium borohydride technology, applied in organic chemistry, bulk chemical production, etc., can solve the problems of harsh reaction conditions, large environmental pollution, and long synthesis steps, and achieve short reaction steps, simple post-treatment, and mild reaction conditions Effect

Active Publication Date: 2013-09-18
四川弘远药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In order to solve the shortcomings of the compound of formula I in the prior art, such as long synthesis steps, harsh reaction conditions, low yield, high cost, and great environmental pollution, the present invention provides a new preparation method of the compound of formula I

Method used

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  • Method for preparing benzodihydropyran compound
  • Method for preparing benzodihydropyran compound
  • Method for preparing benzodihydropyran compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1, the synthesis of formula IIa compound

[0044]

[0045] 1.1 Dissolve 5-fluoro-2-hydroxyacetophenone (80g, 0.519mol) in 1000ml of dry tetrahydrofuran, cool in an ice-water bath at 0°C, add potassium tert-butoxide (66.55g, 0.545mol) under vigorous stirring, and stir vigorously After 30 minutes, add a dichloromethane solution of D-glyceraldehyde acetone (w / w=0.432, 234.5g, 0.779mol), stir at 0°C for 3.5 hours, add concentrated hydrochloric acid dropwise, adjust the pH value to 6, and spin evaporate Solvent was removed. Ethyl acetate (1200 mL) and water (500 mL) were added to the residue, the organic phase was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a yellow solid, which was recrystallized from absolute ethanol to obtain a light yellow powder Crystals (52 g, 35%).

[0046] 1.2 Dissolve 5-fluoro-2-hydroxyacetophenone (10g, 0.065mol) in 100ml of dry tetrahydrofuran, cool in an ice-water bath at 0°...

Embodiment 2

[0075] 1, the synthesis of formula IIb compound

[0076]

[0077] Dissolve 5-fluoro-2-hydroxyacetophenone (30g, 0.195mol) in 300ml of dry tetrahydrofuran, cool in an ice-water bath at 0°C, add potassium tert-butoxide (23.77g, 0.195mol) under vigorous stirring, and stir vigorously for 30 Minutes later, add a dichloromethane solution of L-glyceraldehyde acetone (w / w=0.432, 70.49g, 0.234mol), stir at 0°C for 3 hours, add concentrated hydrochloric acid dropwise, adjust the pH value to 6, and remove by rotary evaporation solvent. Ethyl acetate (400 mL) and water (300 mL) were added to the residue, the organic phase was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a yellow solid, which was recrystallized from absolute ethanol to obtain a light yellow powder Crystals (25 g, 45%).

[0078] 2, the synthesis of formula IIIb compound

[0079]

[0080] Suspend the compound of formula IIb (20 g, 0.07 mol) in 100 mL...

Embodiment 3

[0097] The synthesis of embodiment three nebivolol

[0098] The nebivolol of SRRR and RSSS configuration is prepared by the compound of formula I, can refer to prior art,

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Abstract

The invention provides a method for preparing a nebivolol intermediate benzodihydropyran compound, and particularly relates to a method for preparing 1-(6-fluorine benzopyranyl) ethane-1,2-diol. In the preparation method, 5-fluorine-2-hydroxyacetophenone and glyceraldehyde acetonide are mainly used as raw materials, and reduction, cyclization, hydrogenation and propylidene protective group removal are carried out on a compound as shown in a formula II in the reaction. The method provided by the invention has the advantages of short whole reaction processes, mild reaction conditions, high yield, simple after-treatment such as purification and the like, and cheap and available raw materials.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a nebivolol intermediate chroman compound. technical background [0002] Nebivolol (Nebivolol) is a drug that has an important effect on hypertension, and the research on the synthesis process of Nebivolol has always been a relatively popular field. In the patents and literatures of various synthetic techniques that have been disclosed, many of them adopt the key intermediate chroman compound represented by the compound of formula I for synthesis. However, for the synthesis of the compound of formula I: 1-(6-fluorobenzopyranyl)ethane-1,2-diol, there are generally the following four methods for synthesizing the compound of formula I in the prior art. [0003] [0004] Synthetic process one [S.Chandmsekhar, M.Venkat Reddy, Tetrahedron, 56(2000) 6339-6344]: [0005] [0006] (a) Enyl bromide, K 2 CO 3 (83%); (b) (i) heating, 2...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/58
CPCY02P20/55
Inventor 严峻杜小春
Owner 四川弘远药业有限公司
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