JPH0347178A - Preparation of 6-fluoro-4-chromanone - Google Patents

Abstract

PURPOSE:To readily prepare the subject compound useful as a synthetic intermediate for a diabetic complication remedy by reacting 4-flurorophenol with acrylonitrile as raw materials in the presence of a catalyst comprising a tertiary amine, treating the prepared intermediate with an acid and subsequently treating the product with sulfuric acid. CONSTITUTION:4-Fluorophenol as a raw material is reacted with acrylonitrile as a raw material, preferably in an excess amount based on the 4-fluorophenol, usually in an amount of 2-3 times moles, in the presence of a tertiary amine catalyst to prepare a 3-(4-fluorophenoxy)proppionitrile. The compound of formula II as an intermediate is treated with an acid to form a 3-(4-fluorophenoxy) propinonitrile acid. The compound of formula II is subjected to a ring-closing reaction in the presence of sulfuric acid to provide the compound of formula III. A compound of formula IV as a diabetic complication remedy is prepared by heating the compound of formula III in the presence of sodium cyanide, etc.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention uses 4-fluorophenol F+OH as a starting material and reacts it with acrylonitrile in the presence of a tertiary amine to produce a compound of formula (1). The shown 3-(4-fluorophenoxy)propionitrile was treated with an acid to obtain 3-(4-fluorophenoxy) represented by formula (IV).
- using fluorophenoxy)propionitrile as a synthetic intermediate, converting it into 5-(4-fluorophenoxy)propionic acid represented by formula (II), and then treating with sulfuric acid, with formula (1) The present invention relates to a method for producing 6-fluoro-4-chromanone represented by the following formula.

6-Fluoro-4-chromanone is a (S)-2,3-dihydro-6-fluoro-spiro compound that has strong aldo-reductase inhibitory activity and is expected to be a new therapeutic agent for diabetic complications. (4H-1-benzobilane-4
,4'-imidazolidine)-2:s'-dione (VSA
N: Sorbinil (5orbinil): Formula (I
II) A method of producing romanone (1) by heating with 6-fluoro-4- is used (US Pat. No. 4).
No. 117230, No. 4130714).

It is an important compound as a synthetic intermediate for (R8)-2, and can be easily synthesized by the so-called Bucherer synthesis, which involves a heating reaction in the presence of sodium cyanide and ammonium carbonate.
3-dihydro-6-fluoro-spiro (4) 1-1-benzopyran-4,4'-imidazolidine) -2',
It can be derived into s'-dione.

(Prior art) Conventionally, as a method for producing 6-fluoro-4-chromanone (Otori), as shown in the following formula, 4-fluorophenol and 3
-chloropropionic acid in the presence of sodium hydroxide,
The so-called Wi 11 iam son synthesized 3-
After forming (4-fluorophenoxy)propionic acid (IV), it was dissolved in polyphosphoric acid, however,
In this method, 3-(4-
In the synthesis of fluorophenoxy)propionic acid (IV), since the side reaction of decomposition of 3-chloropropionic acid to 3-hydroxypropionic acid takes precedence, ether bond formation is hindered, and a large excess of 3-chloropropionic acid is used. However, the synthesis yield of compound ([V) is extremely low [J
.

Amer, Chem, 8oc,, 81.94 (19
59)) Considering the use of expensive 4-fluorophenol as a starting material, this method cannot necessarily be said to be an effective method for industrially producing 6-fluoro-4-chromanone (1).

(Problems to be Solved by the Invention) Therefore, the present inventors have made efforts to establish a new industrial method for producing 6-fluoro-4-chromanone (Iris) that is economical, has excellent operability, and safety. As a result of our investigation, we found that an ether bond was effectively formed through the so-called cyanoethylation reaction, in which 4-fluorophenol was reacted with acrylonitrile as a catalyst in the presence of a tertiary amine.
-fluorophenoxy)propionitrile (1) was obtained,
This was then treated with an acid to give 3-(4-fluorophenoxy)propionic acid (1v), which was then subjected to a dehydration ring-closing reaction in sulfuric acid to efficiently produce 6-fluoro-4-chromanone (!l). They discovered that it can be synthesized and completed the present invention.

(Means for Solving the Problems and Effects) The method of the present invention can be represented by the following reaction formula.

(1) (IV) (1) Sunawachi, 3-(4-
3-(4-fluorophenoxy)propionic acid (IV) obtained by acid hydrolysis of fluorophenoxy)propionitrile (1); - It relates to a method for producing chromanone (1).

Conventionally, the cyanoethylation reaction between phenols and acrylonitrile has been carried out in the presence of a strong base such as Triton B (trimethylbenzylammonium hydroxide), metallic sodium, or sodium methoxide (J.

Chem, 8oc, 920 (1945):
J, Amer, Chem.

Soc, 70.599 (1948); Bu
ll, 8oc.

Chin, France 1288 (1957), etc.] or in the presence of a copper compound (US Pat. No. 2,974,160).
Alternatively, it is carried out in the presence of anhydrous aluminum chloride-dry HCl (J, Org, Chem, 22.1264 (1
Various methods have been used, such as 957)).

The present inventors searched for a catalyst effective for the cyanoethylation reaction between 4-fluorophenol and acrylonitrile, and as a result of investigating various compounds including the above-mentioned catalyst, we found that among copper compounds, cupric hydroxide and copper acetate -We discovered that hydrates and the like are excellent catalysts, and also discovered that organic amines, particularly tertiary amines such as triethylamine, which have not been previously reported, can be specifically effective catalysts for this reaction. An efficient method for using the obtained 5-(4-fluorophenoxy)propionitrile (1) for the synthesis of 6-fluoro-4-chromanone (It) was established. The present invention will be specifically explained below.

In carrying out the method of the present invention, first, 4-fluorophenol and acrylonitrile are subjected to a cyanoethylation reaction in the presence of a suitable catalyst to form an ether bond. As a catalyst, cupric hydroxide, copper acetate, copper acetate hydrate,
Copper compounds and copper powders such as copper carbonate and cupric oxide, or tertiary amines such as trimethylamine, triethylamine, tri-n-butylamine, tri-n-octylamine, and dimethylcyclohexylamine, as well as calcium hydroxide and barium hydroxide. , zinc hydroxide, etc. are effective, but considering the reaction yield, operability of post-treatment such as removal of the catalyst after reaction, and economic efficiency, it is recommended to use tertiary amines such as triethylamine in industrial-scale production. is desirable.

The conditions for this reaction vary depending on the type of catalyst used, so they cannot be uniformly defined.
It is used in an amount of 0.01 times or more, preferably about 0.1 to 0.5 times, based on fluorophenol. Although better results are obtained when acrylonitrile is used in an excess amount relative to 4-fluorophenol, a 2 to 3 times molar amount is usually sufficient.

In the reaction, acrylonitrile is usually used as a solvent, but if necessary, a nonpolar solvent such as benzene or toluene, or a polar solvent such as water or ethanol can also be used. When using acrylonitrile as a solvent, the reaction temperature is preferably around reflux temperature; in this case, the reaction is almost completed in 6 to 16 hours, but if it is below reflux temperature, the reaction rate decreases and it takes even longer to complete the reaction. It takes time. After the reaction, excess acrylonitrile, solvent, tertiary amine, and some unreacted 4-fluorophenol can be removed by vacuum distillation, but if a solid catalyst is used, it can be removed by Operation is required. The 3-(4-fluorophenoxy)propionitrile thus obtained can be used as it is in the next reaction, but if it is further washed with an aqueous sodium hydroxide solution of an appropriate concentration, It is also possible to isolate nearly pure 3-(4-fluorophenoxy)propionitrile (1) in high yields.

3-(4-fluorophenoxy)propionitrile (1
) to 6-fluoro-4-chromanone (1), 3-(4-fluorophenoxy)propionitrile (1) is first acid-hydrolyzed to give 3-(4-fluorophenoxy)propionic acid. (■) (At this time, examples of acids that can be used include hydrochloric acid, hydrobromic acid, and sulfuric acid. To increase the rate of hydrolysis reaction, use a high concentration of hydrobromic acid or sulfuric acid. However, in the case of hydrochloric acid, these side reactions are not observed at all.If the reaction rate and reaction yield are considered, , it is preferable to use concentrated hydrochloric acid, in which case compound (1)
By refluxing the mixture in concentrated hydrochloric acid for about 10 hours, compound (1) can be obtained in quantitative yield.

Next, 3-(4-fluorophenoxy)propionic acid (
The cyclization induction of IV) to 6-fluoro-4-chromanone (K) can be carried out by a known method (US) in which compound (ff) is stirred in polyphosphoric acid at 100°C for 10 minutes to obtain compound (1) Patent cylinder No. 4.117.230, Patent No. 4.130,71
It can be carried out in a good yield by a method such as stirring No. 4) or compound (IV) in concentrated sulfuric acid at room temperature for 1 hour. If the conditions for these acid hydrolysis and ring-closing reactions are adjusted,
3-C4-fluorophenoxy) in almost quantitative yield.
It is also possible to obtain 6-fluoro-4-chromanone (Otori) from propionitrile (1).

(Example) The present invention will be described below with reference to Examples. The present invention is of course not limited to this.

Example 1 A mixed solution consisting of 11.2f of 4-fluorophenol, 10.6y1 of acrylonitrile, and 2.02F of t-ethylamine was refluxed for 16 hours with stirring, and then acrylonitrile, triethylamine, and 4-fluorophenol were removed under reduced pressure. . The resulting residue was diluted with ether and diluted with 10
% sodium hydroxide aqueous solution, then washed with 2N hydrochloric acid,
Dehydrated with anhydrous magnesium sulfate. When the ether was distilled off, 11.51 g of a colorless liquid of 3-(4-fluorophenoxy)propionitrile was obtained (yield: 70%).

Example 2 A mixture of 1.12 f of 4-fluorophenol, 2.65 g of acrylonitrile, and a catalyst was reacted with stirring at the reflux temperature of acrylonitrile for 10 hours.

Reaction L3-(4-fluorophenoxy)propionitrile production yield relative to 4-fluorophenol is determined by GLO
The following results were obtained.

(GLC: Hitachi model 063 gas chromatograph; column,
FAL-M (chromosorb W(A
M-DM C8) l-15PO4,3 cabinets x 1 m
) React in a 60°C autoclave** Cyclohexyl dimethyl a
mine Example 3 3-(4-fluorophenoxy)propionitrile 45
．． A mixed solution of 50y and 12N hydrochloric acid was stirred at about 120°C for 10 hours. After cooling and partitioning between ethyl acetate and water, the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate.

When ethyl acetate was distilled off, white crystals of 5-(+-fluorophenoxy)propionic acid s 0.70 y were obtained.

mp84-85°C (literature value 86°C) j, IR,
The HNM solution was consistent with a standard product synthesized from 4-fluorophenol and 3-chloropropionic acid by a known method.

Example 4 3-(4-fluorophenoxy)propionic acid 30.0
A mixture of f (163.0 mmol) and concentrated sulfuric acid (180 me) was stirred at room temperature for 1 hour and then poured into 700 y of ice, whereupon white crystals precipitated. This white crystal is removed by furnace.
After washing with water, it was air dried.

This was recrystallized from ethanol to obtain 20.551 white crystals of 6-fluoro-4-chromanone (yield 76%).
.

Claims (1)

[Claims] (1) The formula (
I ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 3-(4-fluorophenoxy)propionitrile shown in (I) is treated with acid to form formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( IV) is converted into 3-(4-fluorophenoxy)propionic acid represented by formula (IV), and then treated with sulfuric acid.
II) ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) Method for producing 6-fluoro-4-chromanone shown in (II).