JPH0157105B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for synthesizing phenoxycarboxylic acid derivatives, particularly phenoxyacetic acid derivatives, more specifically, the general formula: [However, one of R ₁ and R ₃ is a hydroxyl group and the other is a hydrogen atom or Rp {However,
Rp is

[Formula] (n means a prenoxy group or a polyprenoxy group represented by 0 or an integer from 1 to 19)}, or both of them mean a hydroxyl group, and R ₂ is an alkyl group or

【formula】

【formula】

【formula】

【formula】

【Formula】also For details

[means a group represented by the formula] (where Rp is as above)] A phenol derivative represented by the general formula Cl(CH ₂ ) _n COOR ₄ ... () (where R ₄ is a hydrogen atom or an alkyl basis,
(m means an integer of 1 to 5) is reacted with a monochlorocarboxylic acid derivative represented by the following in the presence of a base, and the general formula or

【formula】

[Formula] (However, the symbols in both formulas are as above) In producing the phenoxycarboxylic acid derivative, the reaction is carried out in the presence of iodine or inorganic iodide as a catalyst. Phenoxycarboxylic acid derivatives represented by the general formula or are extremely useful compounds for the production of pharmaceuticals, and in particular, chalcone derivatives and dihydrochalcone derivatives exhibit strong anti-peptic ulcer effects (Chem
Pharm Bull., 27 , 2943 (1979)) is a very useful compound. That is, the present invention mainly relates to a method for producing chalcone derivatives, dihydrochalcone derivatives, or intermediates thereof useful as anti-peptic ulcer agents. It is known that when producing phenoxyacetic acid derivatives among compounds represented by the general formula or, the reaction generally proceeds in high yield when the phenol derivative and monobromoacetic acid derivative represented by the general formula are used as raw materials. ing. For example, as in Reference Example 1 below, when 2-hydroxy-4-prenoxyacetophenone is reacted with monobromoacetate in the presence of potassium carbonate, 2-ethoxycarbonylmethyloxy-4-prenoxyacetophenone is produced. Obtained with a high yield of 79.6 mol%. However, the raw material monobromoacetic acid derivative is significantly more expensive than the monochloroacetic acid derivative, which not only poses an economical problem, but also has high lachrymatory properties and many difficulties in manufacturing operations. For this reason, it may be possible to replace the monobromoacetic acid derivative with a monochloroacetic acid derivative (Japanese Patent Application Laid-open No. 116355/1982), but simply changing to the chloride would result in a poor yield of the target product, as shown in Comparative Examples 1 and 2 below. 8.9mol% each
and 27.7 mol%, which is extremely low and cannot be an industrially effective method. In view of the above circumstances, the present inventors have conducted extensive research into effective synthetic methods using chlorides, and have found that the effectiveness of the presence of iodine or inorganic iodide as a catalyst when using monochloroacetic acid derivatives. After further investigation, it was discovered that the present invention is not limited to acetic acid derivatives. That is, in the present invention, by allowing iodine or an inorganic iodide to exist as a catalyst in the reaction system,
Using monochlorocarboxylic acid derivatives, which are cheaper and easier to handle than brominated compounds, as one of the raw materials, it is possible to obtain the desired product in high yield despite a short reaction time. This provides an economical method for producing enoxycarboxylic acid derivatives. The inorganic iodides used in the method of the present invention include ammonium iodide and group a of the periodic table of the elements.
and b, families a and b, families a and b,
It refers to compounds of various elements belonging to groups a and b, groups V and b, groups a and b, group b, and iodine, such as lithium iodide, sodium iodide, potassium iodide, and iodine. rubidium chloride, copper iodide, calcium iodide,
Cesium iodide, strontium iodide, manganese iodide, cobalt iodide, chromium iodide, cerium iodide, iron iodide, barium iodide, tin iodide, zinc iodide, nickel iodide, magnesium iodide, iodide Examples include bismuth, silver iodide, yttrium iodide, aluminum iodide, boron iodide, etc., but are not limited to the compounds listed here, and these compounds are not limited to single use, but can be used in combination of two or more. It may be beneficial to use them together. In the present invention, the phenol derivative has the general formula

[Formula] or

[Formula] (where R ₁ , R ₂ , and R ₃ are as described above), and specific examples of these include 2-hydroxyacetophenone, 2-hydroxy- 4-prenoxyacetophenone, 2-hydroxy-4-
Geranoxyacetophenone, 2-hydroxy-
4-phalnesyoxyacetophenone, 2-hydroxy-4-decaprenoxyacetophenone,
2-hydroxypropiophenone, 2-hydroxy-4-prenoxypropiophenone, 2-
Hydroxy-4-geranoxypropiophenone, 2-hydroxy-4-decaprenoxypropiophenone, 2'-hydroxychalcone, 2'-
Hydroxydihydrochalcone, 2'-hydroxy-4'-prenoxychalcone, 2'-hydroxy-4'-prenoxydihydrochalcone, 2'-hydroxy-4'-geranoxychalcone, 2'-hydroxy-4 ′-geranoxydihydrochalcone, 2′-hydroxy-4′-decaprenoxychalcone, 2′-
hydroxy-4,4'-diprenoxychalcone,
2'-Hydroxy-2,4'-diprenoxychalcone, 2'-hydroxy-3,4'-diprenoxychalcone, 2'-hydroxy-4'-geranoxy-4
-Prenoxychalcone, 2'-hydroxy-4'-
Prenoxy-2-decaprenoxychalcone, 2′-
hydroxy-4,4'-digeranoxychalcone,
2'-Hydroxy-4,4'-diprenoxydihydrochalcone, 2'-hydroxy-2,4'-diprenoxydihydrochalcone, 2'-hydroxy-
3,4'-diprenoxy dihydrochalcone, 2'-hydroxy-4'-prenoxy-2-geranoxy dihydrochalcone, 2'-hydroxy-4,4'-digeranoxy dihydrochalcone, 2'-hydroxy -2,4-diprenoxychalcone, 2'-hydroxy-2,3-diprenoxychalcone, 2'-hydroxy-3,4-diprenoxychalcone, 2'-
Hydroxy-2,4,4'-triprenoxychalcone, 2'-hydroxy-2,4-diprenoxy-4'-geranoxychalcone, 2'-hydroxy-
2,4,4'-trigeranoxychalcone, 2'-hydroxy-2,4-prenoxy-4'-decaprenoxychalcone, 2'-hydroxy-2,4-diprenoxydihydrochalcone, 2 ′-Hydroxy-
2,3-diprenoxydihydrochalcone, 2'-hydroxy-3,4-diprenoxydihydrochalcone, 2'-hydroxy-2,4,4'-triprenoxydihydrochalcone, 2'-hydroxy-
2,4-diprenoxy-4'-geranoxydihydrochalcone, 2'-hydroxy-2,4,4'-trigeranoxydihydrochalcone, 2'-hydroxy-2,4-prenoxy-4'-decapre Noxydihydrochalcone, 4-hydroxyacetophenone, 2,4-dihydroxyacetophenone, 4
-Hydroxy-2-prenoxyacetophenone, 4-hydroxy-2-geranoxyacetophenone, 4-hydroxy-2-phalnesioxyacetophenone, 4-hydroxy-2-decaprenoxyaceto Phenone, 4-hydroxypropiophenone, 2,4-dihydroxypropiophenone, 4-hydroxy-2-prenoxypropiophenone, 4-hydroxy-2-geranoxypropiophenone, 4-hydroxy- 2
-decaprenoxypropiophenone, 4'-hydroxychalcone, 4'-hydroxydihydrochalcone, 2',4'-dihydroxychalcone, 2',
4'-dihydroxydihydrochalcone, 4'-hydroxy-4-prenoxychalcone, 4'-hydroxy-2-geranoxychalcone, 2',4'-dihydroxy-3-phalnesioxychalcone,
4'-Hydroxy-4-prenoxydihydrochalcone, 4'-hydroxy-2-geranoxydihydrochalcone, 2',4'-dihydroxy-3-phalnesioxydihydrochalcone, 4'-hydroxy-2 ′,4′-diprenoxychalcone, 4′-hydroxy-2,2′-diprenoxychalcone, 4′-hydroxy-2,2′-digeranioxychalcone,
4'-hydroxy-2',4-digeranioxychalcone, 4'-hydroxy-2',4-diprenoxydihydrochalcone, 4'-hydroxy-2,2'-
Diprenoxydihydrochalcone, 4'-hydroxy-2',4-digeranioxydihydrochalcone,
4'-Hydroxy-2,4-diprenoxychalcone, 4'-hydroxy-2,3-diprenoxychalcone, 4'-hydroxy-3,4-diprenoxychalcone, 4'-hydroxy- 2,4-diprenoxydihydrochalcone, 4'-hydroxy-
2,3-diprenoxydihydrochalcone, 2',
4'-dihydroxy-2,4-diprenoxychalcone, 2',4'-dihydroxy-3,4-digeranoxychalcone, 2',4'-dihydroxy-2,
4-diprenoxydihydrochalcone, 2',4'-dihydroxy-3,4-digeranoxydihydrochalcone, 4'-hydroxy-2',2,4-triprenoxychalcone, 4'-hydroxy- 2'-geranoxy-2,4-diprenoxychalcone, 4'-hydroxy-2'-prenoxy-2,3-digeranoxychalcone, 4'-hydroxy-2',2,4-
trigeranoxychalcone, 4'-hydroxy-
2',2,4-triprenoxydihydrochalcone,
4'-Hydroxy-2'-geranoxy-2,4-diprenoxy dihydrochalcone, 4'-hydroxy-2'-prenoxy-2,3-digeranoxy dihydrochalcone, 4'-hydroxy-2',2 , 4-trigeranoxydihydrochalcone, etc., but it goes without saying that the compound is not limited to only the compounds described herein. Incidentally, in the above-mentioned phenol derivatives, phenol derivatives in which positions 3 and 3' of the aromatic ring are substituted with the above-mentioned R ₁ can also be employed. Further, monochlorocarboxylic acid derivatives include, for example, monochloroacetic acid derivatives represented by the general formula ClCH ₂ COOR ₄ (where R ₄ is as defined above), and specific examples thereof include monochlorocarboxylic acid derivatives. Acetic acid, methyl monochloroacetate, ethyl monochloroacetate, monochloroacetic acid-n-propyl, monochloroacetic acid-iso-propyl, monochloroacetic acid-
Examples include n-butyl, iso-butyl monochloroacetate, n-hexyl monochloroacetate, and methyl 3-chloropropionate, ethyl 4-chloro-n-butyrate, methyl 6-chloro-n-caproate, etc. However, it is not limited to these compounds. Further, examples of the base used in the reaction of the present invention include hydroxides, carbonates, hydrogen carbonates, hydrides and alcoholates of alkali metals and alkaline earth metals. Specific examples of these include sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium potassium hydrogen carbonate. , sodium hydride, calcium hydride, sodium ethylate, potassium ethylate, etc., but are not limited to these compounds. Furthermore, these compounds are not limited to single use, and it goes without saying that two or more types can be used in combination. Furthermore, in the reaction of the present invention, a suitable solvent may be used as a diluent, such as ketones such as acetone, methyl ethyl ketone, and methyl-iso-butyl ketone, and ethers such as diethyl ether, tetrahydrofuran, and 1,2-dimethoxyethane. , aromatic hydrocarbons such as benzene, toluene,
Aliphatic hydrocarbons such as n-hexane, N,N-dimethylformamide, dimethyl sulfoxide,
Polar aprotic solvents such as hexamethylphosphoric triamide are examples of those that can be used. Furthermore, when this reaction is carried out in an inert gas atmosphere such as nitrogen or argon, the formation of by-products that occur when it comes into contact with air is suppressed, and the quality of the target phenoxycarboxylic acid derivative is improved. However, this does not in any way imply that the reaction under an air atmosphere is hindered. In addition, in this case, ascorbic acid, if necessary,
Antioxidants such as erythorbic acid, hydroquinone monomethyl ether, vitamin E, dibutylhydroxytoluene, butylhydroxyanisole, p-tert-butylcatechol, formic acid, sulfites, acid sulfites, thiosulfates, hyposulfites, etc.
Of course, more than one species may be used in combination as appropriate. To explain the method of the present invention in more detail, 1 to 5 moles of a monochlorocarboxylic acid derivative, 1 to 5 moles of a base, 0.0001 to 0.5 moles of iodine or inorganic iodide, and 0 to 50 moles of a solvent are added to 1 mole of the phenol derivative. The reaction is carried out at a temperature of room temperature to 140°C, preferably room temperature to 100°C, for 5 to 20 hours under normal pressure or increased pressure. Incidentally, the charging ratio of the raw materials is not limited to the above ranges, such as the reaction method, reaction temperature, reaction time, etc. In addition, in carrying out the present invention, a phenol derivative and a base are reacted in advance to prepare an alkali salt or alkaline earth salt of the phenol derivative, and after isolation or without isolation, monochloride is added to this salt. The reaction may be carried out by charging a carboxylic acid derivative. In this case, the catalyst may be added either before or after the reaction. Furthermore, when this reaction is carried out in the presence of water or in the presence of an alkali metal hydroxide or an alkaline earth metal hydroxide, even if monochlorocarboxylic acid ester is used as a raw material, the phenolic acid produced Cicarboxylic acid derivatives may also be obtained as free carboxylic acids. When this reaction is carried out in the presence of alcohols, even if monochlorocarboxylic acid is used as the raw material,
Some of the phenoxycarboxylic acid derivatives produced may be obtained as esters. Furthermore, although the presence of water is not necessary in the present invention, its presence is acceptable. As detailed above,
The method of the present invention is an industrially advantageous method because phenoxycarboxylic acid derivatives can be produced in high yield using monochlorocarboxylic acid derivatives that are inexpensive and easy to handle. EXAMPLES The present invention will be described in more detail below with reference to examples to further clarify the effects of the present invention, but the scope of the present invention is not limited by these examples. Example 1 2.20 g of 2-hydroxy-4-prenoxyacetophenone was placed in a 100 ml four-necked flask equipped with a reflux condenser, thermometer, nitrogen gas inlet tube, and stirring device.
(10 mmol), 1.68 g of methyl monochloroacetate, 2.76 g of anhydrous potassium carbonate, 0.16 g of sodium iodide, and 20 g of acetone, and heated to 60 g under a nitrogen atmosphere.
The reaction was carried out at a temperature of 0.degree. C. while stirring for 10 hours. After the reaction was completed, the inorganic substances were separated, and the cake was washed with acetone and combined with the liquid, and then the acetone was distilled off under reduced pressure. The residual liquid was recrystallized from a mixture of n-hexane and toluene to obtain 2-methoxycarbonylmethoxy-4-prenoxyacetophenone 2.31
g (yield 79.0 mol%) was obtained. NMR ( _CDCl3 ),
δ: 1.77, 1.81 (3H, 3H, S, S, CH ₃ X ₂ ),
2.69 (3H, S, COCH ₃ ), 3.80 (3H, S,
COOCH ₃ ), 4.54 (2H, d, J = 7.5, O-CH ₂ -
CH=), 4.68 (2H, S, O-CH ₂ .COOCH ₃ ),
5.47 (1H, t, J=7.5, O- _CH2 -CH=), 6.34
(1H, d, J=1.5, C-3-H), 6.57 (1H, dd,
J=9.0, 1.5, C-5-H), 7.84 (1H, d, J=
9.0, C-6-H). mp78~79.5℃. Reference example 1 2.20 g of 2-hydroxy-4-prenoxyacetophenone in a 100 ml four-necked flask equipped with a reflux condenser, thermometer, nitrogen gas inlet tube, and stirring device.
(10 mmol), monobromoethyl acetate 2.00 g
(12.0mmol), anhydrous potassium carbonate 1.38g
(10 mmol) and 20 g of acetone were charged, and the reaction was carried out under a nitrogen atmosphere at a temperature of 60°C for 10 hours while stirring. After the reaction was completed, the inorganic substances were separated, the cake was washed with acetone, and the cake was combined with the liquid, after which the acetone was distilled off under reduced pressure. The residual liquid was recrystallized from a mixture of n-hexane and toluene to obtain 2.44 g of 2-ethoxycarbonylmethoxy-4-prenoxyacetophenone.
(yield 79.6 mol%) was obtained. Example 2 In Example 1, 2.76 g of anhydrous potassium carbonate was added to 50
The reaction was carried out in the same manner except that 2.5 g of % aqueous sodium hydroxide solution was used. After the reaction was completed, the mixture was neutralized with 2% hydrochloric acid, extracted with ether, and the ether layer was washed with water and dried over anhydrous sodium sulfate. The crystals obtained by distilling off the ether were recrystallized from an ether-n-hexane mixture,
2.07 g (yield 74.4 mol%) of 2-carboxymethoxy-4-prenoxyacetophenone was obtained.
NMR, δ10.89 (1H, s, -COOH). mp138.2~139.8℃. Example 3 In Example 1, sodium iodide was replaced with copper iodide (2), and 2-methoxycarbonylmethoxy-4-prenoxyacetophenone was prepared in the same manner as in Example 1.
2.25g (yield 77.0mol%) was obtained. Comparative Example 1 1.1 g (5 mmol) of 2-hydroxy-4-prenoxyacetophenone and hydroxide were placed in a 100 ml four-necked flask equipped with a reflux condenser, thermometer, nitrogen gas inlet tube, dropping funnel, and stirring device. 0.3 g of potassium (fine powder) and 20 g of acetone were charged, and 1.0 g of methyl monochloroacetate was added dropwise with stirring. After the dropwise addition was completed, the reaction was carried out at room temperature for 2 hours with stirring. After the reaction was completed, inorganic substances were separated, the cake was washed with acetone, and the cake was combined with the liquid and analyzed by gas chromatography using an internal standard method. As a result, the target product, 2-methoxycarbonylmethoxy-4-prenoxyacetophenone, was 0.13 g (yield: 8.9 mol%). In addition, 1.00 g (recovery rate: 90.9 mol%) of 2-hydroxy-4-prenoxyacetophenone, a raw material, was recovered. Reference Example 2 In Example 1, the same treatment was performed without using sodium iodide, and the obtained 2-methoxycarbonylmethoxy-4-prenoxyacetophenone was 0.81 g (yield 27.7 mol%). Example 4 1.96 g of 2'-hydroxy-4,4'-diprenoxychalcone was placed in the same four-necked flask as in Example 1.
(5.0 mmol), monochloroacetic acid 0.71 g, anhydrous sodium carbonate 1.06 g, barium iodide dihydrate 0.21
g and 10 g of tetrahydrofuran were charged, and the reaction was carried out under reflux in a nitrogen atmosphere while stirring for 10 hours. After the reaction was completed, the inorganic substances were separated, the cake was washed with tetrahydrofuran, and after combining with the liquid, the tetrahydrofuran was distilled off under reduced pressure. The residue was recrystallized from ethanol to give pale yellow crystals of 2'-carboxymethoxy-4,4'-diprenoxychalcone.
1.23g (yield 54.6mol%). mp143.5-145.0℃ NMR (CDCl ₃ ), δ11.50 (1H, s, -COOH) Example 5 In a flask similar to Example 1, 0.2 g of sodium hydride (60%) was suspended in 5 g of n-hexane. A mixture of 1.44 g of 2-hydroxy-4-geranoxyacetophenone dissolved in 10 g of N,N-dimethylformamide was added dropwise over 30 minutes under ice-cooling while passing nitrogen gas. . After the addition was completed, the mixture was stirred at room temperature for 30 minutes, and then a solution of 0.08 g of potassium iodide and 0.92 g of ethyl monochloroacetate dissolved in 10 g of N,N-dimethylformamide was added dropwise over 30 minutes, and the mixture was further stirred at room temperature for 5 minutes. Allowed time to react. After the reaction was completed, dilute hydrochloric acid was added to make the mixture acidic, ether extraction was performed, and the ether layer was washed with water and dried over anhydrous sodium sulfate. The residue after distilling off the ether was recrystallized from a mixture of ether and n-hexane, yielding 1.33% of 2-ethoxycarbonylmethoxy-4-geranoxyacetophenone.
I got g. On the other hand, when potassium iodide was not used, the amount of 2-ethoxycarbonylmethoxy-4-geranoxyacetophenone obtained was 0.24 g. Examples 6 to 21, Comparative Examples 2 to 3 Reactions were carried out in the same manner as in Example 1 using various phenol derivatives, catalysts, solvents, and bases. The results are shown in Table 1. In addition, as a monochloroacetic acid derivative, 7.5 mmol of methyl monochloroacetate
Using. Analysis was performed using high performance liquid chromatography using an internal standard.

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Claims (1)

[Claims] 1. General formula [However, one of R ₁ and R ₃ is a hydroxyl group and the other is a hydrogen atom or Rp {However,
Rp means a prenoxy group or a polyprenoxy group represented by the formula (n is 0 or an integer from 1 to 19)}, or both of them mean a hydroxyl group, and R ₂ is an alkyl group or [Formula] [Formula] [Formula] [Formula] means a group represented by [Formula] or [Formula] (where Rp is as above)] A phenol derivative represented by the general formula Cl(CH ₂ ) _n COOR ₄ ...() (However, R ₄ is a hydrogen atom or an alkyl group,
(m means an integer of 1 to 5) is reacted with a monochlorocarboxylic acid derivative represented by the following in the presence of a base, to obtain the general formula or [formula] [formula] (however, the symbols in both formulas are as above) A method for producing a phenoxycarboxylic acid derivative, characterized in that the reaction is carried out in the presence of iodine or an inorganic iodide as a catalyst.