Preparation method for benzodihydropyran compound

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

Active Publication Date: 2012-01-11
CHENGDU KANGHONG PHARMA GRP
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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 condition

Method used

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  • Preparation method for benzodihydropyran compound
  • Preparation method for benzodihydropyran compound
  • Preparation method for benzodihydropyran compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] 1, the synthesis of formula IIa compound

[0050]

[0051] 1.1 Dissolve 5-fluoro-2-hydroxyacetophenone (30g, 0.195mol) in 500ml of dry tetrahydrofuran, cool in an ice-water bath at 0°C, add potassium tert-butoxide (23.76g, 0.195mol) under vigorous stirring, and stir vigorously After 30 minutes, a solution of D-glyceraldehyde acetonide in dichloromethane (w / w = 0.432, 70.36 g, 0.234 mol) was added. After stirring at 0°C for 3.5 hours, concentrated hydrochloric acid was added dropwise to adjust the pH value to 6, and the solvent was removed by rotary evaporation. Ethyl acetate (300 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 (26 g, 47%).

[0052] 1.2 Referring to Example 1.1, potassium tert-butoxide was replaced by sodium tert-...

Embodiment 2

[0086] 1, the synthesis of formula IIb compound

[0087]

[0088] Dissolve 5-fluoro-2-hydroxyacetophenone (30 g, 0.195 mol) in 500 ml of dry tetrahydrofuran, cool in an ice-water bath at 0°C, add potassium tert-butoxide (23.76 g, 0.195 mol) under vigorous stirring, and stir vigorously for 30 After a few minutes, a solution of D-glyceraldehyde acetonide in dichloromethane (w / w = 0.432, 70.36 g, 0.234 mol) was added. After stirring at 0°C for 3.5 hours, concentrated hydrochloric acid was added dropwise to adjust the pH value to 6, and the solvent was removed by rotary evaporation. Ethyl acetate (300 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 (23 g, 41.6%).

[0089] 2, the synthesis of formula IIIb compound

[0090]

[0091] Suspe...

Embodiment 3

[0113] The synthesis of embodiment three formula VIa compounds

[0114]

[0115] 1. Add oxalyl chloride (524 μL, 0.006 mol) into 30 mL of dry dichloromethane, add N,N-dimethylformamide (538 μL, 0.007 mol) dropwise, and stir at room temperature for 10 minutes. The compound of formula IVa (1 g, 0.004 mol) was added to the reaction liquid, triethylamine (1.67 mL, 0.012 mol) was added dropwise, the reaction was stopped after stirring overnight at room temperature, washed with water and saturated brine, dried and concentrated to obtain the product.

[0116] 2. Dissolve the compound of formula VIIa (0.6g, 2.40mmol) in 5mL of methanol, add palladium carbon (5%, 0.06g), after catalytic hydrogenation under normal pressure at 50°C for 1 hour, remove the palladium carbon by filtration, spin the filtrate to obtain colorless Oily product (0.59 g, 97.6%).

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Abstract

The invention provides a preparation method for 1-(6-fluorobenzopyranyl) ethane-1,2-diol, an intermediate of nebivolol. In the preparation method, 5-fluoro-2-hydroxyacetophenone and glyceraldehyde acetonide are mainly used as raw materials; the raw materials are reacted to obtain a compound of a formula II; the compound of the formula II is then reduced, dehydrated, hydrogenated and cyclized; and a propylidene protection group is removed. The preparation method has the advantages of short entire reaction process, mild reaction conditions, high yield, simple post-treatment after purification and the like and cheap and readily 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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IPC IPC(8): C07D311/58C07D407/04
Inventor 严峻杜小春
Owner CHENGDU KANGHONG PHARMA GRP
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