JPH0344384A - Production of 6-fluoro-4-chromanone-2-carboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound, having aldose reductase inhibitory action and useful as an intermediate for remedy against diabetic complications by subjecting an optically active fluorochromonecarboxamide or ester thereof to catalytic hydrogenating reaction in the presence of a strong acid using a metal catalyst. CONSTITUTION:An optically active 6-fluorochromone-2-carboxamide or ester thereof expressed by formula I [Y is -OR (at least one of R is alkyl having asymmetric carbon atom) or formula II (at least one of R<1> is alkyl having asymmetric carbon atom)] is subjected to catalytic hydrogenating reaction in the presence of a strong acid (e.g. hydrochloric, sulfuric, perchloric, methanesulfonic or trichloroacetic acid) using a metal catalyst (preferably platinum-carbon, palladium-carbon or rhodium-carbon) to afford the objective compound expressed by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing intermediates. More specifically, the present invention relates to a method for producing optically active 6-fluoro-4-chromanone-2-carboxylic acid derivatives.

Prior art 6-fluoro-4-chroma/7- which is the object of the present invention
2-Carphonic acid derivatives are optically active 6-fluoro-2,3-dihydro-2',5'-dioxo-spiro (4H-1-benzubiran- It is useful as an intermediate for the production of 4,4'-imidazolidine)-2-carboxylic acid derivative (II) (Japanese Patent Application No. 61-199924).

Several methods are already known for producing optically electroconductive 4-chromanone-2-carboxylic acid derivatives that do not involve chiral induction at the Chaos C2 position.

For example, according to Japanese Patent Application Laid-Open No. 61-200991, 4-
After converting the chromanone derivative into a chromone derivative, a cyano group is introduced by the action of trimethylsilyl cyanide, and the 2-carboxyl compound is produced by hydrolysis with concentrated hydrochloric acid. Furthermore, according to JP-A No. 63-250373, Fr1e of P-fluoroanisole and maleic anhydride
A del-Crafts acylation reaction followed by an intramolecular Michael reaction using sodium bicarbonate as a base produces the 2-carboxyl compound, which is further treated with thionyl chloride to give the acid chloride and then reacted with an amine to form the 2-carboxyl compound. A □ad body is manufactured.

Note that 4-chromanone derivatives can also be produced by catalytic reduction of chromone derivatives.

For example, J, Am, Chem, Soc, 68.
According to No. 697 (I947), eriodiethiol is prepared from ruthioline as shown in the following formula.

In conventional techniques, 6-fluoro-4-chromatur 2-carboxylic acid derivatives can be produced using methods such as those disclosed in Japanese Patent Application Laid-open No. 6
The method described in No. 1-200991 requires the use of expensive trimethylsilyl cyanide during the process, and the number of steps becomes extremely large if the process for producing the 4-chromanone derivative as a starting material is also included. Also, JP-A No. 63-25037
The method described in Publication No. 3 cannot be said to be an advantageous method for industrial production in that the 2-carboxyl form is partially converted into tar in the process and the reaction and treatment operations are troublesome.

On the other hand, the production of 4-chromanone derivatives by catalytic reduction of chromone derivatives generally has low yields and low reaction selectivity.

That is, according to the method described in J. Am. Chem.
NDS, Vol. 2. P, 256-257 (I9
According to 51), when a chromone derivative is reduced using platinum, palladium, or copper chromite as a catalyst, the reaction proceeds nonselectively, and 4 is produced as one of several reduction products.
-It is known that chromanone derivatives can be obtained.

(R: alkyl, aryl) Furthermore, the 4-chromanone-2-carboxylic acid derivative obtained by the above-mentioned conventional technique is an optically inactive substance that does not involve asymmetric induction at the C2 position.

Therefore, ff = useful as a therapeutic agent for diabetic complications
Scientifically active 6-fluoro-2,3-dihydro-2',5'
-dioxo-spiro(4H-1-benzobilane-4,4
'-Imidazolidine)-2-carbo/acid derivative (I[)
In order to use it as a production intermediate, unnecessary optical isomers must be separated by optical resolution.

Problems to be Solved by the Invention For the reasons mentioned above, optically active 6-
It is desired to establish a method for producing fluoro-4-chromanone-2-carboxylic acid derivatives.

Means for Solving the Problems The present inventors have solved the above problems and have developed an optically active 6-fluoro-4-O'? As a result of research aimed at establishing an industrial production method for non-2-carboxylic acid derivatives, 6-
When a fluorochromone-2-carboxylic acid amide or ester is subjected to a catalytic hydrogenation reaction in the presence of a metal catalyst, by allowing a strong acid to coexist, asymmetric induction occurs in high yield and with high selectivity at the C2 position, resulting in optical activity. The present inventors have discovered that 6-fluoro-4-chromanone-2-carboxylic acid derivatives can be advantageously used, and have completed the present invention.

That is, the present invention provides the formula (I) [In the formula flJ, Y represents an -OR group (R means an alkyl group having a small number (meaning an alkyl group having at least one asymmetric carbon))] A compound represented by is subjected to a catalytic hydrogenation reaction using a metal catalyst in the presence of a strong acid, and C2
Provided is a method for producing an optically active compound represented by the formula (ill 1 (in the formula (■), Y is the same as above), which is characterized by asymmetric induction of positions.

The present invention will be described in detail.

The starting material 6-fluorochromone-2-carboxylic acid derivative represented by the formula (I) can be easily produced as follows. That is, 6-fluorochromone-2-carboxylic acid oxoyl chloride is produced by condensing 5-fluoro-2-human-oxyacetophenone and oxalic acid diester in the presence of a base and then ring-closing with an acid. By reacting with optically active alcohol or amine, various compounds represented by formula (I) can be produced.

Optically active 6-fluoro-4- produced by asymmetric hydrogenation reaction at C2 position of 6-fluorochromone-2-carboxylic acid derivative
The preparation of the chromano/-2-carboxylic acid derivatives is advantageously carried out as follows.

The solvent is one commonly used in catalytic hydrogenation reactions, such as water, ether, tetrahydrocarbon, petroleum ether,
Methanol, ethanol, isopropyl alcohol, acetic acid, ethyl acetate, benzene, toluene, xylene, etc. can be used alone or in combination, but ethanol, inpropyl alcohol, acetic acid,
Use benzene and tetrahydrofuran. The amount used is usually 5 to 60 times (weight ratio) the amount of 6-fluorochromone-2-carboxylic acid derivative (I). In this water bath reaction, strong acids are added, examples of which are mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, υnoic acid, perhalogen acids such as perchloric acid and perbromic acid, methanesulfonic acid, trifluoric acid, etc. Examples include organic sulfonic acids such as lomethanesulfonic acid and benzenesulfonic acids, and logenoacetic acids such as trichloroacetic acid and trifluoroacetic acid.

However, it is not limited to the above. The amount of strong acid used is usually 0.01 to 10 equivalents relative to compound (I). Examples of metal catalysts that can be used include catalysts normally used in the catalytic reduction of alkenes to alkanes, such as metals such as platinum, palladium, nickel, ruthenium, rhodium, iron, and cobalt, or compounds thereof, or carbon, carbon, etc.
Those supported on alumina, barium sulfate, barium carbonate, calcium carbonate, strontium carbonate, silk, carbon dioxide, etc. can be used.

Specific examples include Raney nickel, palladium-carbon, palladium-alumina, palladium-barium sulfate, palladium-barium carbonate, rhodium-carbon, ruthenium-carbon, platinum-carbon, palladium-black, platinum-black, platinum oxide, and chlorotris. (triphenylphosphine) rhodium (IL dichlorotris () IJ phenylphosphine) ruthenium (D
), but platinum-carbon, palladium-carbo/, and rhodium-carbo/ are preferable. The amount of catalyst used is usually 0.01 to 10.0 m in terms of metal.
o1%, but is not particularly limited to these. In addition, the reaction temperature varies depending on the solvent and catalyst used, but
Usually it is -10 to 100°C. The reaction is preferably carried out under a hydrogen atmosphere, but there are no particular pressure limitations.

The reaction is usually carried out at 0.1 to 20 atm, but the reaction proceeds easily even at 0.1 to 10 atm. After the reaction is complete, remove the catalyst by filtration, add water, extract with a conventional extraction solvent such as methylene chloride, ethyl acetate, ether, etc., and distill off the solvent to obtain optically active 6-fluoro-4-chromanone-2-carboxylic acid. Acid derivative (I1) can be obtained. The recovered catalyst can also be reused. The compound of formula (n) obtained by the production method of the present invention has sufficient purity, but if it is desired to further increase the purity, it can be purified, for example, by a recrystallization method. The purity of the compound of formula (I1) and the production ratio of (→ unitary/(+) unitary) can be easily determined by liquid chromatography.

EXAMPLES The present invention will be explained in more detail with reference examples and examples below.

Reference Example 1 Preparation of 6-fluorochromo7-2-carboxylic acid 25 g of metallic sodium was added and dissolved in 500 +++ l of ethanol, and 66.3 g of diethyl oxalate and 5-fluorocl
-2~ Add 70.0 g of hydroxyacetophenone,
It was refluxed for 1 hour. After cooling, ethanol was distilled off under reduced pressure, and a 2N aqueous hydrochloric acid solution was added to the residue, followed by extraction with methylene chloride. After drying the methylene chloride layer over anhydrous magnesium sulfate, the methylene chloride was distilled off, and 230 ml of acetic acid and 230 ml of concentrated hydrochloric acid were added to the residue, followed by refluxing for 1.5 hours. After cooling, the precipitate was collected, washed with water, and dried to obtain 6-fluorochromone-2-carbo/acid 81.
g (yield 86%). Purity by liquid chromatography was 99%.

Melting point 252.0-253.00C (decomposition) Reference example 2゜Production of 6-fluorochromone-2-carboxylic acid amide 6-Fluorochromo/-2-carboxylic acid 20. Og 1
The suspension was suspended in 320 nl of 0.2-dichloroethane, several drops of triethylamine and 17.1 g of thionyl chloride were added thereto, and the mixture was refluxed for 5.5 hours. After cooling, 1,2-dichloroethane and excess thionyl chloride were distilled off under reduced pressure, and the resulting acid chloride was dissolved in 40 ml of methylene chloride. Then, this acid o I))'wo(s) -(-1
The mixture was poured into a methylene chloride (I90 m/) solution containing 11.6 g of -1-phenylethylamine and 9.7 g of triethylamine under water cooling, and stirred for 1 hour. After the reaction, the methylene chloride solution is washed with water, the methylene chloride layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain the target product, N-((S)-1-phenylethyl-6-fluoro). Chromone-2-carboxamide 24.2
g (yield 96%). Purity by liquid chromatography was 99%.

Melting point 124.0-125,5°C 'HNMR (CDCl3.) δ1,63 (d, 3H)
, 5.1~5.6 (m, IH), 7.0~
8.0 (m, 10H) Reference Examples 3 to 5 According to Reference Example 2, 1-menthyl-6-fluorochromone-2-carboxylic acid and H-N-((R)-1-phenylethyl)-6-fluoro Chromone-2-carboxamide was obtained. Show the results in a table.

Example 1゜N-((S)-1-phenylethyl-6-fluorochromone-2-carboxamide obtained in Reference Example 2 8.0
g was dissolved in 15 Qu/ethanol, and 0.32 g of methanesulfonic acid and 1.6 g of 5% platinum-carbon were added thereto. The reaction was started at room temperature with a hydrogen pressure of 7.0 atm and continued until hydrogen absorption stopped. After the reaction is completed, the reaction solution is filtered to remove the catalyst, and the F solution is concentrated to obtain water IQQm.
/ and extracted with methylene chloride. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off to obtain the target product, N -C(S) -1-phenylethyl go 6-.
Fluoro-4-chromanone-2-carboxamidro, 8
g (yield 84%) was obtained. The purity of this product by liquid chromatography was 98 or better, and the production ratio of (→ Taichitsu/(Taichitsu) was 80/20.

'HNMR (CDCe5) δ1.46 (d, 3H)
.

2.8~3.3 (m, 2H), 4.6~5
．． 3 (m.

2H), 6.5-7.6 (m, 9H) Examples 2-12 Using the compounds obtained in Reference Examples 2-4 according to Example 1, asymmetric hydrogenation reactions were carried out under various reaction conditions. I did it. Show the results in a table.

Effects of the invention Optically active 6-
A method for obtaining fluoro-4-chromanone-2-carboxylic acid derivatives has been established.

Claims (1)

[Claims] 1. Formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In formula (I), Y is an -OR group (R is an alkyl group having at least one asymmetric carbon ) or ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ group (R^1 means an alkyl group having at least one asymmetric carbon)] A compound represented by the following is subjected to a catalytic hydrogenation reaction using a metal catalyst in the presence of a strong acid. Formula (II) characterized by asymmetric induction of C_2 position ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In formula (II), Y is the same as above) Manufacturing method.