CN102329291A

CN102329291A - Method for preparing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-formaldehyde

Info

Publication number: CN102329291A
Application number: CN201110212552A
Authority: CN
Inventors: 李春刚; 孙一平; 侯建; 党祥玉
Original assignee: Shanghai Modern Pharmaceutical Co Ltd
Current assignee: Shanghai Shyndec Pharmaceutical Co Ltd
Priority date: 2011-07-27
Filing date: 2011-07-27
Publication date: 2012-01-25

Abstract

The invention relates to a method for preparing a key intermediate of a medicine for treating cardiovascular disease. The method for preparing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-formaldehyde comprises the following steps of: adding a reducing agent, namely sodium dihydrobis(2-methoxyethoxy)aluminate which is subjected to passivation treatment into a compound shown as a formula 2, and reacting to obtain a target product 1, wherein R is C1-C5 alkyl. Compared with the conventional preparation method, the preparation method has the advantages that: a reagent is cheap and readily obtained, reaction conditions are mild, and the method is more suitable for industrialized production.

Description

A kind of 6-fluoro-3, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde

Technical field

The present invention relates to a kind of key intermediate 6-fluoro-3 of treating cardiovascular disease medicine, preparing method's technical field of 4-dihydro-2H-1-chromene-2-formaldehyde.

Background technology

Nebivolol is a kind of strong effect, third generation beta-blockers optionally, can improve nitric oxide production level, has the vasodilator effect.As a kind of new antihypertensive drug; Nebivolol in step-down treatment, have effect strong, take medicine conveniently (once a day; Each a slice), advantage such as untoward reaction is few, be mainly used in mild to moderate hypertensive patient's treatment, also can be used for the treatment of stenocardia and congestive heart failure.Technical study for this medicine is significant.6-fluoro-3,4-dihydro-2H-1-chromene-2-formaldehyde are the key intermediates of synthetic nebivolol, and its structure is shown in 1:

European patent EP 334429 has adopted the higher di-isopropyl aluminum hydride of price anhydrous, anaerobic, and directly with 6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid is reduced into 6-fluoro-3 under-78 ℃ of conditions, 4-dihydro-2H-1-chromene-2-formaldehyde:

The reagent that this method adopted is comparatively dangerous, and condition is harsh, and complicated operation is difficult to industriallization.

Summary of the invention

The object of the invention just provides a kind of mild condition, 6-fluoro-3 that cost is low, and the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is to overcome the above-mentioned defective that prior art exists.

For reaching above-mentioned purpose, the technical scheme that the present invention adopts is following:

A kind of 6-fluoro-3, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde, this method add in following formula 2 compounds through two (2-methoxy ethoxy) sodium aluminates (Red-Al) of the reductive agent dihydro of Passivation Treatment, react title product:

Wherein, R is the alkyl of C1-C5.

Described substituent R preferable methyl or ethyl most preferably are methyl.Described 6-fluoro-3,4-dihydro-2H-1-chromene-2-first (second) ester can be optically active, can also be racemic.

The preferred Virahol of described passivator, tetrahydro pyrrolidine, hexahydropyridine or morphine quinoline, most preferably morphine quinoline.

Above-mentioned 6-fluoro-3, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde, preferable temperature of reaction are at-20～10 ℃, and controlled temperature and feed rate were reacted 0.5-18 hour, reacted completely.The solvent that is adopted in the process of reaction is toluene, THF, methylene dichloride, 1,2-ethylene dichloride or diethyl ether hexane etc., preferred toluene.

After reaction finishes, reaction solution is added in the frozen water or in the dilute acid solution or in the dilute alkaline soln, collects after the extracting and separating and obtain title product compound 1.Employed acid can be acetic acid, phosphoric acid, hydrochloric acid or sulfuric acid etc.; Employed alkali can be sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood etc.

Beneficial effect of the present invention:

6-fluoro-3 of the present invention, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde compares with prior preparation method, and reagent is cheap and easy to get, and reaction conditions is gentle, is more suitable for suitability for industrialized production.

Description of drawings

Fig. 1 is a 6-fluoro-3, the nuclear-magnetism spectrum of 4-dihydro-2H-1-chromene-2-formaldehyde

Fig. 2 is a 6-fluoro-3, the mass spectrum of 4-dihydro-2H-1-chromene-2-formaldehyde

Embodiment

Embodiment 1

Under nitrogen protection, (toluene solution (content 70%) of two (2-methoxy ethoxy) sodium aluminates of dihydro adds in the reaction flask, adds the dilution with toluene of 15ml, reduces temperature to 0 ℃ with the reductive agent of 12.8ml; To the morphine quinoline 3.97g that wherein slowly drips equivalent, holding temperature is 0-5 ℃, dropwises, and temperature is risen to room temperature; React and after 4 hours this reaction solution slowly is added drop-wise to raw material 6-fluoro-3, in the 40ml toluene solution of 4-dihydro-2H-1-chromene-2-methyl esters 8.0g, this process heats up, and holding temperature is-15～-5 ℃; After dropwising, reacted 4 hours, reaction solution is added in the frozen water solution of 60ml, stirred 15 minutes; Separatory, organic layer is with the salt washing twice of 50ml, and behind the separatory, organic layer is dry; Obtain product 6-fluoro-3 behind the evaporate to dryness, 4-dihydro-2H-1-chromene-2-formaldehyde 5.8g, yield 85%.

Embodiment 2

Under nitrogen protection, (toluene solution (content 70%) of two (2-methoxy ethoxy) sodium aluminates of dihydro adds in the reaction flask, adds the dilution with toluene of 10ml, reduces temperature to 0 ℃ with the reductive agent of 8.0ml; To the tetrahydro pyrrolidine 2.03g that wherein slowly drips equivalent, holding temperature is 0-5 ℃, dropwises, and temperature is risen to room temperature; React and after 4 hours this reaction solution slowly is added drop-wise to raw material 6-fluoro-3, in the 30ml toluene solution of 4-dihydro-2H-1-chromene-2-ethyl ester 5.0g, this process heats up, and holding temperature is-15--5 ℃; After dropwising, reacted 4 hours, reaction solution is added in the frozen water solution of 50ml, stirred 15 minutes; Separatory, organic layer is with the salt washing twice of 400ml, and behind the separatory, organic layer is dry; Obtain product 6-fluoro-3 behind the evaporate to dryness, 4-dihydro-2H-1-chromene-2-formaldehyde 2.57g, yield 60%.

Embodiment 3

Under nitrogen protection, (toluene solution (content 70%) of two (2-methoxy ethoxy) sodium aluminates of dihydro adds in the reaction flask, adds the dilution with toluene of 10ml, reduces temperature to 0 ℃ with the reductive agent of 8.0ml; To the Virahol 1.74g that wherein slowly drips equivalent, holding temperature is 0-5 ℃, dropwises, and temperature is risen to room temperature; React and after 6 hours this reaction solution slowly is added drop-wise to raw material 6-fluoro-3, in the 40ml toluene solution of 4-dihydro-2H-1-chromene-2-methyl esters 5.0g, this process heats up, and holding temperature is-15--5 ℃; After dropwising, reacted 6 hours, reaction solution is added in the frozen water solution of 40ml, stirred 15 minutes; Separatory, organic layer is with the salt washing twice of 30ml, and behind the separatory, organic layer is dry; Obtain product 6-fluoro-3 behind the evaporate to dryness, 4-dihydro-2H-1-chromene-2-formaldehyde 2.1g, yield 50%.

Embodiment 4

Under nitrogen protection, (toluene solution (content 70%) of two (2-methoxy ethoxy) sodium aluminates of dihydro adds in the reaction flask, adds the dilution with toluene of 15ml, reduces temperature to 0 ℃ with the reductive agent of 12.8ml; To the morphine quinoline 3.97g that wherein slowly drips equivalent, holding temperature is 0-5 ℃, dropwises, and temperature is risen to room temperature; React and after 4 hours this reaction solution slowly is added drop-wise to raw material 6-fluoro-3, in the 40ml toluene solution of 4-dihydro-2H-1-chromene-2-methyl esters 8.0g, this process heats up, and holding temperature is-5～5 ℃; After dropwising, reacted 4 hours, reaction solution is added in the frozen water solution of 60ml, stirred 15 minutes; Separatory, organic layer is with the salt washing twice of 50ml, and behind the separatory, organic layer is dry; Obtain product 6-fluoro-3 behind the evaporate to dryness, 4-dihydro-2H-1-chromene-2-formaldehyde 5.6g, yield 82%.

The comparative example 1

Under protection of nitrogen gas, with the 6-fluoro-3 of 20g, 4-dihydro-2H-1-chromene-2-formic acid adds in the reaction flask, adds the THF of 160ml; The carbonyl dimidazoles that adds 13g stirred one hour under the room temperature, and ice bath is to-70 ℃, to the toluene solution of the diisobutyl aluminium hydride that wherein drips 340ml content 25% then; Dropwise, keep-70 ℃ of reactions 20 minutes, drip the methyl alcohol of 9.58ml, after dropwising; Reaction solution is imported in 10% the salt sour water of 250ml, extract, separatory is dry; Evaporate to dryness obtains the 6-fluoro-3 of product 20g, 4-dihydro-2H-1-chromene-2-formaldehyde 10.65g, and yield is 57.9%.

Claims

1. 6-fluoro-3, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde, this method add in following formula 2 compounds through two (2-methoxy ethoxy) sodium aluminates of the reductive agent dihydro of Passivation Treatment, react title product 1:

Wherein, R is the alkyl of C1-C5.

2. 6-fluoro-3 as claimed in claim 1, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is characterized in that: R is methyl or ethyl.

3. 6-fluoro-3 as claimed in claim 2, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is characterized in that: R is a methyl.

4. 6-fluoro-3 as claimed in claim 2, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is characterized in that: formula 2 compounds have optically active or racemic modification.

5. 6-fluoro-3 as claimed in claim 1, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is characterized in that: the passivator that uses during Passivation Treatment is Virahol, tetrahydro pyrrolidine, hexahydropyridine or morphine quinoline.

6. 6-fluoro-3 as claimed in claim 5, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is characterized in that: passivator is the morphine quinoline.

7. 6-fluoro-3 as claimed in claim 1, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde, it is characterized in that: temperature of reaction is-20～10 ℃.

8. 6-fluoro-3 as claimed in claim 7, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is characterized in that: temperature of reaction is-15～-5 ℃.

9. 6-fluoro-3 as claimed in claim 1, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is characterized in that: the solvent that reaction is used is toluene.

10. 6-fluoro-3 as claimed in claim 1; The preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde; It is characterized in that: the post-processing step after reacting completely is, adds in the frozen water reaction solution or in the dilute acid solution or in the dilute alkaline soln, extracting and separating goes out title product.

11. 6-fluoro-3 as claimed in claim 10, the preparation method of 4-dihydro-2H-1-chromene-2-formaldehyde is characterized in that: employed acid is acetic acid, phosphoric acid, hydrochloric acid or sulfuric acid; Employed alkali is sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood.