JPS5929681A - Preparation of dihydrobenzopyrandiol - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for drugs for circulatory organs, etc. advantageously, by reducing 8-methoxy-3,4-dihydro-2H-1- benzopyran-3-one, followed by demethylating the reduction product. CONSTITUTION:8-Methoxy-3,4-dihydro-2H-1-benzopyran-3-one shown by the formula III is reduced in a solvent in the presence of sodium boron hydride, aluminum lithium hydride, to give 3-ol derivative shown by the formula II. This compound is then demethylated to give a compound shown by the formula I . The compound shown by the formula III is obtained by subjecting o-vanillin to ring closure reaction, for example, a compound shown by the formula IV is reacted with acrylonitrile by well-known Curtius rearrangement, hydrolyzed to give a corresponding carboxylic acid, which is converted into an azide derivative, and hydrolyzed.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 3,8-dihydroxy-6,4-dihydro-2H-1-benzopyran represented by the following formula (I).

H 11 The compound of formula I (hereinafter abbreviated as DDE) is a compound known as an intermediate for the production of cardiovascular drugs, antiallergy drugs, and the like.

Conventionally, dihydro-2H-1-benzopyran has been produced by a method of ring-forming chromone or a method of ring-closing using phenol as a raw material. However, there has been little report on a method for producing 6,4-dihydro-2H-1-pensohyran-3-ol in which a hydroxyl group is introduced at the 6-position.

[V
) as a starting material, applying a ring-closing reaction to this to reduce 8-methquine-6,4-dihydro-2H-1-benzopyran-3-one (I), and then demethylating it. He produced DDE and discovered scales.

These reactions are shown by the following equations.

(IV) (I) (It)
(1) In order to obtain the 6-ol form of the formula (1) by reducing the 6-keto form of the formula (1), a reducing reagent such as a compound of the formula (1), such as boron hydride, sodium chloride, hydrogen Stir in the presence of lithium aluminum chloride or the like.

The demethylation reaction of the compound of formula (1) thus obtained can easily proceed, for example, by heating and stirring the compound of formula (1) in an aqueous solution of hydrobromic acid, and the desired DDE can be obtained.

Various methods are possible for producing the compound of formula (2) by subjecting O-vanillin of formula (1) to a ring-closing reaction. For example, the method shown in the following reaction formula can be mentioned. R and R' in the formula
is a lower alkyl group, preferably an ethyl group.

Each reaction step of these methods is known.

The present inventors investigated these methods for producing compound (I) from compound (IV), and found that method a (Curtius rearrangement) is better than other methods, namely method b (Rossen rearrangement) and method C. It has been found that method a is particularly superior because it can produce the target compound (1) in a higher yield than methods (Tiemann rearrangement), method d (Hoffmann reaction), and method e (Dickmann condensation). The individual reactions in these methods are known and can be carried out by conventional methods. In the case of method a, when O-vanillin (IV) is reacted with acrylonitrile, the ring is closed to form cyano-8-methoxy-2H-
1-benzopyran (V) is obtained, which is hydrolyzed to give the corresponding carboxylic acid (Vl), which is then azidated and then hydrolyzed to yield the compound of formula (1).

Example A) 1.0 kg of 0-vanillin are dissolved in 6.52 kg of dimethylformamide and a solution of 604 g of sodium hydroxide in 2 ml of water is added with stirring. This contains 1 acrylonitrile
．． 314 and reflux with stirring for 1.5 hours at a bath temperature of 165-140°C. Then acrylonitrile 1.31
Drop a mixture of i and 0.7 ml of dimethylformamide,
After reacting for 1 hour, add 0.87 mL of acrylonitrile.
．． , e and 0.4 μg of dimethylformamide was added dropwise, and the mixture was refluxed for 1.5 hours with stirring.

After cooling, the reaction solution was poured into 60ml of water and extracted with ethyl acetate. After washing the extract with 10% sodium hydroxide and saturated brine, the solvent was distilled off. The crystal-containing oil obtained is heated to 120° C. and a solution of 840 g of sodium hydroxide in 3.6 ml of water is added dropwise to it while stirring. 1.
After stirring and refluxing for 5 hours, the mixture was cooled, concentrated hydrochloric acid was added to adjust the pH to about 2.5, and the precipitated crystals were collected. After washing with water, 80
When dried under reduced pressure at ~90°C, pale yellow crystals of 8-methoxy-2H-1-benzopyran-6-carboxylic acid were obtained at 600°C.
9 (yield 44.6%).

B) 8-methoxy-2H-1-benzopyran-6-
103.2 g of carbonic acid was suspended in 360 ml of acetone, 60.9 g of triethylamine was added, and while the internal temperature was maintained at 0 to 5°C while stirring with water cooling, 65 g of ethyl chlorocarbonate was added.
．． Drop 29. After stirring for 20 minutes, an aqueous solution of 39 g of sodium azide was added under water cooling and stirring to an internal temperature of 2 to 5.
Add dropwise at °C.

After stirring for 2.5 hours, the mixture was extracted with benzene and washed with saturated brine. 4001 nl of 10% sulfuric acid was added to the benzene layer, heated and stirred, and then refluxed with stirring at an external temperature of 90°C for 7 hours. After the reaction was completed, the benzene was distilled off after washing with 10% sulfuric acid and saturated brine, and 3,4-dihydro-8
-methoxy-2H-1-benzopyran-3-one is 75
．． 4 fi (yield 84.5%).

C) Dissolve the obtained compound in 500 rnl of methanol, add 10.2.9 ml of sodium borohydride in portions and stir for 30 minutes at room temperature. The pH was adjusted to 4 with 20% sulfuric acid, the solvent was distilled off, the resulting residue was extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off to obtain a brown oil.

When ether is added to this, 6,4-dihydro-3-hydroxy-8-methoxy-2H-1-penzopyranca 26,39 (yield 3
4.5%) obtained.

D) 230 g of the obtained compound was mixed with 1.2 g of 47% hydrobromic acid.
-e and stir at 120°C. After 2 hours, neutralize with aqueous sodium hydroxide solution and extract with ethyl acetate. When ether is added to the residue obtained by distilling off the solvent after treatment with activated carbon, crystals with a melting point of 124-126°C are obtained.
3,4-dihydro-3,8-dihydroxy-2H-1-
197.9 (yield 92.8%) of benzopyran is obtained.

Applicant Kowa Co., Ltd.

Claims (3)

[Claims] 6,8-dihydroxy-6,4-dihydro-2H-, characterized in that 1,8-methoxy-3,4-dihydro-2H-1-benzopyran-3-one is reduced and then demethylated. 1-Production method of benzobilane. 8-methoxy obtained by ring-closing 2.0-vanillin
6, characterized in that 3,4-dihydro-2H-1-benzopyran-3-one is reduced and then demethylated.
．． Method for producing 8-dihydroxy-6,4-dihydro-2H-1-benzopyran. 3. 6-dia-2-8-methoxy-2H-1-benzopyran obtained by reacting 0-vanillin with acrylonitrile is hydrolyzed to form 8-methoxy-2H-1-benzopyran-3-carboxylic acid, and this carboxylic acid By azidizing and then acid hydrolysis, O-vanillin is ring-closed to form 8-methoxy-6,4-dihydro-2H-1-
3. Process according to claim 2, characterized in that benzopyran-6-one is obtained.