JPH0247453B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for synthesizing phenoxy compound derivatives, and more specifically, the general formula: [However, R ₁ , R ₂ , R ₃ are hydrogen atoms, hydroxyl groups,
Rp {However, Rp is

[Formula] (means a prenoxy group or polyprenoxy group represented by n is 0 or an integer from 1 to 19)} or Rq {however, Rq is a group represented by the general formula -O-(CH ₂ -) _n
COOR (R is a hydrogen atom or an alkyl group, m
means a group represented by }, R ₄ is a hydrogen atom, an alkyl group, or a group represented by the general formula

[Formula] or

[Formula] {However, R ₅ , R ₆ , R ₇ are hydrogen atoms, hydroxyl groups, Rp or Rq (However, Rp,
Rq means a group represented by } which means (as described above). However, at least one of R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , and R ₇ represents a hydroxyl group. ] A phenol derivative represented by and the general formula: (However, n represents 0 or an integer from 1 to 19) Prenyl chloride or polyprenyl chloride represented by the following, or the general formula: Cl(CH ₂ ) _n COOR ... (However, R represents a hydrogen atom or an alkyl group,
m represents an integer of 1 to 5) and a monochlorocarboxylic acid derivative represented by
A group consisting of quaternary ammonium bromide, quaternary ammonium iodide, quaternary phosphonium bromide, quaternary phosphonium iodide, and crown ether compound as a catalyst for producing phenoxy compound derivatives by reacting in the presence of a base. The present invention relates to a method for producing a phenoxy compound derivative, characterized in that the reaction is carried out in the presence of at least one compound selected from the following. Compounds of general formula and phenoxy compound derivatives produced from compounds of general formula or are extremely useful compounds for the production of pharmaceuticals,
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. Conventionally, when producing a phenoxy compound derivative from a certain type of compound represented by the general formula, when a certain phenol derivative represented by the general formula and a prenyl bromide or monobromoacetic acid derivative are used as raw materials, generally high It is known that the reaction proceeds with good yield. For example, as in Reference Example 1 below, when 2,4-dihydroxyacetophenone is reacted with prenyl bromide in the presence of potassium carbonate, 2-hydroxy-4-prenoxyacetophenone is produced.
2-ethoxycarbonylmethoxy -4-prenoxyacetophenone
Obtained with a high yield of 79.6 mol%. However, brominated raw materials are significantly more expensive than chlorinated ones, which is not only economically problematic, but also the stability of (poly)prenyl bromide is much lower than that of (poly)prenyl chloride. Since monobromocarboxylic acid esters are inferior in quality, they are difficult to store, and monobromocarboxylic acid esters are highly lachrymatory, which causes many inconveniences in manufacturing operations. For this reason, it may be considered to replace the brominated compound with a chlorinated compound (JP-A-53-116355); As shown in the comparative data, simply changing to a chlorinated product results in an extremely low yield of the target product (for example, in the comparative data above, the yield of each
38.1 and 27.7 mol%), it cannot be an industrially effective method. In view of these circumstances, the present inventors have conducted extensive research on effective synthetic methods using chlorinated compounds, and have found that when using each of the chlorinated compounds mentioned above, specific quaternary compounds or crown ether compounds are used as catalysts. After discovering the effectiveness of the presence of the compound, and conducting further studies, it was discovered that the present invention is effective not only for these examples but also for all chlorinated compounds represented by the general formula or. That is, the present invention
Selected from the group consisting of quaternary ammonium bromide, quaternary ammonium iodide, quaternary phosphonium bromide, quaternary phosphonium iodide, and crown ether compounds, which are known to have a phase transfer catalyst function in the reaction system. It is characterized by the presence of at least one kind of compound. According to the present invention, in the organic reaction solvent, the ionizability of the reactive species is increased by the action of the phase transfer catalyst, and the solid phase is added to the solvent.
By effectively promoting dehydrogenation by a base dispersed as an aqueous solution phase, a chlorinated compound, which is cheaper and easier to handle than a brominated compound, can be used as one of the raw materials, and the reaction time can be reduced. Regardless, the desired product can be obtained in high yield, and an economical method for producing the desired phenoxy compound derivative can be established. Catalysts that can be used in the present invention are those that act as phase transfer catalysts. (i) Quaternary ammonium bromide: e.g.
Tetraalkylammonium bromide (tetramethylammonium bromide, tetraethylammonium bromide, n-octyltrialkylammonium bromide, n-decyltrialkylammonium bromide, etc.), benzyltrialkylammonium bromide (benzyltriethylammonium bromide, etc.), phenyltrialkylammonium Bromide (phenyltrimethylammonium bromide, etc.), β-bromoalkyltrialkylammonium bromide (β-bromoethyltrimethylammonium bromide, etc.), ferrocenylalkyltrialkylammonium bromide (ferrocenylmethyltrimethylammonium bromide, etc.), Methonium Bromide (hexamethonium bromide, decamethonium bromide, etc.), cyclic ammonium bromide (1-alkylpyridium bromide, 1-
aminopyridium bromide, benzylmethylmorpholium bromide, etc.). (ii) Quaternary ammonium iodide: for example, tetraalkylammonium iodide (tetramethylammonium iodide, tetraethylammonium iodide, n-octyltrialkylammonium iodide, n-decyltrialkylammonium iodide, etc.), benzyl Trialkylammonium iodide (benzyltriethylammonium iodide, etc.), phenyltrialkylammonium iodide (phenyltrimethylammonium iodide, etc.), β-alkylcholine iodide (β-methylcholine iodide, etc.), Ferrocenyl Alkyltrialkylammonium iodide (ferrocenylmethyltrimethylammonium iodide, etc.), methonium iodide (hexamethonium iodide, decamethonium iodide, etc.), cyclic ammonium iodide (1-
alkylpyridium iodide, 1-aminopyridium iodide, benzylmethylmorpholium iodide, etc.). (iii) quaternary phosphonium bromides: e.g.
Alkyltriphenylphosphonium bromide (n-butyltriphenylphosphonium bromide, n-amyltorphenylphosphonium bromide, etc.), tetraalkylphosphonium bromide (tetraethylphosphonium bromide, tetrabutylphosphonium bromide, tributylhexadecylphosphonium bromide, tetraphenylphosphonium bromide, etc.) )etc. (iv) Quaternary phosphonium iodide: for example, alkyltriphenylphosphonium iodide (methyltriphenylphosphonium iodide, n-butyltriphenylphosphonium iodide, etc.), tetraalkylphosphonium iodide (tetraethylphosphonium iodide, tetrabutyl phosphonium iodide, tetraphenylphosphonium iodide, tributylhexadecylphosphonium iodide, etc.). (v) Crown ether compounds: for example, crown ethers (12-crown 4, 15-crown-
5, 18-crown-6, dibenzo-18-crown-6, dicyclohexyl-18-crown-6
etc.), Cryptate (Merck, product name, Crypto Fix 5, Crypto Fix 22, Crypto Fix 222, Crypto Fix
222D, cryptofix 222B polymer, etc.)
etc. Furthermore, the present invention is applicable to cases where amines or phosphine compounds and organic bromides or organic iodides are present in the reaction system to produce quaternary bromides or quaternary iodides, or when quaternary hydroxides are produced. Alternatively, cases in which a quaternary bromide or a quaternary iodide is produced by making a quaternary chloride and an inorganic bromide, an inorganic iodide, an organic bromide, or an organic iodide exist are also included. In the present invention, the above-mentioned compounds can not only be used alone, but also two or more kinds can be used in combination, if desired. Moreover, it goes without saying that the invention is not limited to only the compounds described here. In the present invention, the phenol derivative has the general formula

[Formula] (However, R ₁ , R ₂ , R ₃ , and R ₄ are as defined above.) To give a specific example of these, 2-
Benzaldehyde derivatives such as hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2-hydroxy-4-plexibenzaldehyde, 2-hydroxy-4-geranoxybenzaldehyde, 2-hydroxyacetate Phenone, acetophenone derivatives such as 3-hydroxyacetophenone, 4-hydroxyacetophenone, 2,4-dihydroxyacetophenone, 2-hydroxy-4-prenoxyacetophenone, 2-hydroxypropiophenone , 3-hydroxypropiophenone, 4-hydroxypropiophenone, 2,4-dihydroxypropiophenone, 2-hydroxy-4-prenoxypropiophenone, 2-hydroxy-4-geranoxypropiophenone Propiophenone derivatives such as
2'-Hydroxychalcone, 2'-Hydroxy-
4′-prenoxychalcone, 2′-hydroxy-
4′-geranoxychalcone, 2′-hydroxy-
4,4'-diprenoxychalcone, 2'-hydroxy-2,4'-diprenoxychalcone, 2'-hydroxy-3,4'-diprenoxychalcone, 2'-hydroxy-4' -geranoxy-4-prenoxychalcone, 2'-hydroxy-4,4'-digeranoxychalcone, 2'-hydroxy-2,4-diprenoxychalcone, 2'-hydroxy-2,3-di Prenoxychalcone, 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 , 2'-dihydroxychalcone, 2,4'-dihydroxychalcone,
2',3-dihydroxychalcone, 2',4-dihydroxychalcone, 4,4'-dihydroxychalcone, 2',4'-dihydroxychalcone, 4'-
Hydroxy-2-prenoxychalcone, 4'-hydroxy-3-prenoxychalcone, 4'-hydroxy-4-prenoxychalcone, 4'-hydroxy-4-geranoxychalcone, 4'-hydroxy- 4-phalnesioxychalcone, 4'-hydroxy-4-decaprenoxychalcone, 2-hydroxy-4'-prenoxychalcone, 3-hydroxy-4'-geranoxychalcone, 4-hydroxy-4 '-prenoxychalcone, 4-hydroxy-4'-decaprenoxychalcone, 4'-hydroxy-4-carboxymethoxychalcone, 4'-
Hydroxy-2-ethoxycarbonylmethoxychalcone, 4-hydroxy-2'-carboxymethoxychalcone, 4'-hydroxychalcone,
4′-hydroxy-2-geranoxychalcone,
2',4'-dihydroxy-3-phanerushioxychalcone, 4'-hydroxy-2,4'-diprenoxychalcone, 4'-hydroxy-2,2'-diprenoxychalcone, 4 ′-Hydroxy-2,2′-
digeranoxychalcone, 4'-hydroxy-2,
4-diprenoxychalcone, 2',4'-dihydroxy-2,4-diprenoxychalcone, 4'-hydroxy-2,2',4-triprenoxychalcone, 4'-hydroxy-2 '-prenoxy-2,3
-Digeranoxychalcone, 4-hydroxy-
2′-carboxypropoxychalcone, 2,2′,
4'-trihydroxychalcone, 2',3,4'-trihydroxychalcone, 2',4,4'-trihydroxychalcone, 2,2',4-trihydroxychalcone, 2',4'-dihydroxychalcone -2-prenoxychalcone, 2',4'-dihydroxy-3-
Prenoxychalcone, 2',4'-dihydroxy-
4-prenoxychalcone, 2',4'-dihydroxy-4-geranoxychalcone, 2',4'-dihydroxy-4-furnesioxychalcone, 2',
4'-dihydroxy-4-decaprenoxychalcone, 2',4'-dihydroxy-2-methoxycarbonylmethoxychalcone, 2,4'-dihydroxy-4-carboxymethoxychalcone, 2,4-
Dihydroxy-2'-ethoxycarbonylbutoxychalcone, 2,4-dihydroxy-4'-carboxymethoxychalcone, 2,2'-dihydroxy-4'-prenoxychalcone, 2,2'-dihydroxy-4 '-Falnesioxychalcone, 2',4
-dihydroxy-4′-prenoxychalcone,
2',4-dihydroxy-4'-geranoxychalcone, 2',4-dihydroxy-4-decaprenoxychalcone, 2,4'-dihydroxy-2'-carboxymethoxychalcone, 2-hydroxy −
2'-Carboxyethoxy-4'-prenoxychalcone, 3-hydroxy-2'-methoxycarbonylmethoxy-4'-prenoxychalcone, 4-hydroxy-2'-ethoxycarbonylmethoxy-4'-
Chalcone derivatives such as prenoxychalcone, 4-hydroxy-2'-methoxycarbonylmethoxy-4'-geranoxychalcone, 2,2',4,4'-tetrahydroxychalcone: 2'-hydroxydihydrochalcone, 2 ′-Hydroxy-4′-prenoxydihydrochalcone, 2′-hydroxy-4′-
Geranoxydihydrochalcone, 2'-hydroxy-4,4'-diprenoxydihydrochalcone, 2'-
Hydroxy-2,4'-diprenoxydihydrochalcone, 2'-hydroxy-3,4'-diprenoxydihydrochalcone, 2'-hydroxy-4'-geranoxy-4-diprenoxydihydrochalcone,
2'-Hydroxy-4,4'-digeranoxydihydrochalcone, 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, 4'-hydroxydihydrochalcone, 2',4'-dihydroxydihydrochalcone Chalcone, 4'-hydroxy-2-geranoxydihydrochalcone, 2',4'-dihydroxy-
3-phalnesioxydihydrochalcone, 4'-hydroxy-2',4-diprenoxydihydrochalcone, 4'-hydroxy-2,2'-diprenoxydihydrochalcone, 4'-hydroxy-2, 2′−
digeranoxydihydrochalcone, 4'-hydroxy-2,4-diprenoxydihydrochalcone,
2',4'-dihydroxy-2,4-diprenoxydihydrochalcone, 4'-hydroxy-2,2',
4-triprenoxydihydrochalcone, 4'-hydroxy-2'-prenoxy-2,3-digeranoxydihydrochalcone, 2-hydroxy-4'-prenoxydihydrochalcone, 4-hydroxy-
4'-prenoxydihydrochalcone, 2,2'-dihydroxydihydrochalcone, 2,4'-dihydroxydihydrochalcone, 2',3-dihydroxydihydrochalcone, 2',4-dihydroxydihydrochalcone, 4 , 4'-dihydroxydihydrochalcone, 2',4'-dihydroxydihydrochalcone, 4'-hydroxy-2-prenoxydihydrochalcone, 4'-hydroxy-3-prenoxydihydrochalcone, 4'-hydroxy -4-prenoxydihydrochalcone, 4'-hydroxy-
4-phalnesioxydihydrochalcone, 2-hydroxy-4'-prenoxydihydrochalcone,
4-hydroxy-4'-prenoxydihydrochalcone, 4'-hydroxy-4-carboxymethoxydihydrochalcone, 4-hydroxy-2'-ethoxycarbonylethoxydihydrochalcone,
2,2',4'-trihydroxydihydrochalcone, 2',3,4'-trihydroxydihydrochalcone, 2',4,4'-trihydroxydihydrochalcone, 2,2',4-trihydroxydihydrochalcone , 2',4'-dihydroxy-2-prenoxydihydrochalcone, 2',4'-dihydroxy-4-prenoxydihydrochalcone, 2',4'-dihydroxy-4-geranoxydihydro Chalcone, 2',4'-dihydroxy-2-methoxycarbonylmethoxydihydrochalcone, 2,4'-dihydroxy-4-carboxypropoxydihydrochalcone, 2,4-dihydroxy-2'-ethoxycarbonylmethoxydihydrochalcone, 2,
2'-dihydroxy-4'-prenoxydihydrochalcone, 2,2'-dihydroxy-4'-decaprenoxydihydrochalcone, 2',4-dihydroxy-4'-prenoxydihydrochalcone, 2', 4-
Dihydroxy-4'-geranoxydihydrochalcone, 2,4'-dihydroxy-2'-carboxymethoxydihydrochalcone, 2-hydroxy-
2'-Carboxydiethoxy-4'-prenoxydihydrochalcone, 3-hydroxy-2'-methoxycarbonylmethoxy-4'-prenoxydihydrochalcone, 4-hydroxy-2'-ethoxycarbonylethoxy-4'- Prenoxydihydrochalcone, 4-hydroxy-2'-methoxycarbonylmethoxy-4'-geranoxydihydrochalcone,
Examples include dihydrochalcone derivatives such as 2,2',4,4'-tetrahydroxydihydrochalcone, but it goes without saying that the compound is not limited to the compounds described herein. In addition, polyprenyl chloride has the general formula

[Formula] (where n is as defined above), and specific examples thereof include prenyl chloride, geranyl chloride, neryl chloride, farnesyl chloride, geranylgeranyl chloride, Examples include solanesyl chloride, decaprenyl chloride, etc., but are not limited to these compounds. In addition, monochlorocarboxylic acid derivatives have the general formula Cl
It is represented by (CH ₂ ) _n COOR (where R and m are as defined above), and specific examples thereof include monochloroacetic acid, monochloroethyl acetate, monochloroacetic acid-n-propyl , iso-propyl monochloroacetate, n-butyl monochloroacetate, iso-butyl monochloroacetate, n-hexyl monochloroacetate, 3-chloropropionic acid, ethyl 3-chloropropionate, 4-chlorobutyric acid, 4-chloro Examples include methyl butyrate, 5-chlorovaleric acid, ethyl 5-chlorovalerate, 6-chlorocaproic acid, ethyl 6-chlorocaproate, but are not limited to these compounds. Bases used in the reaction of the present invention include alkali metal and alkaline earth metal hydroxides, carbonates, hydrogen carbonates, oxide hydrides, amides, and alcoholates. Specific examples of these include sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. , barium oxide, sodium hydride, calcium hydride, sodium amide, sodium ethylate,
Potassium ethylate, etc., and these can not only be used alone, but also in combination with two
Seeds or more can be used together. Furthermore, the present invention is not limited to only the compounds described here. Furthermore, if necessary, these bases can also be used as a suspension in a solvent or as an aqueous or alcoholic solution. 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, methyl iso-butyl ketone, diethyl ether, tetrahydrofuran,
Ethers such as 1,2-dimethoxyethane, n
- Hydrocarbons such as hexane, benzene, toluene, water, alcohols such as methanol, ethanol, polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. This is an example of what you can get. Furthermore, when this reaction is carried out in an inert gas atmosphere such as nitrogen or argon, the production of by-products that occur when it comes into contact with air can be suppressed, and the quality of the target phenoxy compound derivative can be improved. However, this does not in any way mean that the reaction in an air atmosphere is inhibited. In this case, ascorbic acid, erythorbic acid, hydroquinone monomethyl ether, vitamin E, dibutylhydroxytoluene, butylhydroxyanisole, p-tert-butylcatechol, formic acid, sulfite, acid sulfite, thiosulfate, Of course, antioxidants such as sulfites may be used in combination. In carrying out the present invention, stirring may be carried out by ordinary stirring, but it is also efficient to carry out continuous shear pulverization type stirring. In other words, if the reaction system is heterogeneous, the chloride produced by the reaction of the phenol derivative and prenyl chloride, polyprenyl chloride, or monochlorocarboxylic acid derivative will adhere to the surface of the base and reduce the activity of the base. By carrying out continuous shear pulverization, the active surface of the base can be maintained at all times, thereby shortening the reaction time.
However, this does not normally interfere with stirring in any way. A typical example of a continuous shear grinding type stirrer used for this purpose is a homogenizer such as "Polytron" manufactured by Kinematica GmBH, Switzerland. To explain the method of the present invention in more detail, per 1 mole of phenol derivative, 0.5 to 10 moles of prenyl chloride or polyprenyl chloride, 0.5 to 5 moles of monochlorocarboxylic acid derivatives, 0.5 to 10.0 moles of base,
A method in which 0.0001 to 0.5 mol of the catalyst of the present invention and 0 to 50 mol of a solvent are added, and the reaction is carried out at a temperature of 0°C to 150°C, preferably 0°C to 100°C, for 1 to 20 hours under normal pressure or increased pressure. It is. In addition, the preparation ratio of raw materials,
The reaction method, reaction temperature, reaction time, etc. are not limited to the above ranges. Further, 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, prenyl chloride, polyprenyl chloride or monochloro It may also be reacted with a carboxylic acid derivative. As detailed above, the method of the present invention is inexpensive,
Moreover, it is an industrially advantageous method because phenoxy compound derivatives can be produced in high yield using a chlorine compound that is easy to handle. Reference Examples and Examples will be given below to further specifically explain the present invention and clarify the effects of the present invention, but the scope of the present invention is not limited by these Examples. Reference Example 1 2,4-
Dihydroxyacetophenone 1.52g
(0.01mol), anhydrous potassium carbonate 1.66g, acetone
20 g and 1.98 g of prenyl bromide were charged, and the reaction was carried out at a temperature of 60° C. for 4 hours under a nitrogen atmosphere while stirring. 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 residue was recrystallized from n-hexane to obtain 1.67 g (yield: 75.8 mol%) of 2-hydroxy-4-prenoxyacetophenone. Reference Example 2 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), monobromoethyl acetate 2.00 g (12.0
mmol), anhydrous potassium carbonate 1.38g (10mmol) and acetone 20g, and under nitrogen atmosphere.
The reaction was carried out at a temperature of 60° 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-ethoxycarbonylmethoxy-4-prenoxyacetophenone 2.44
g (yield 79.6 mol%) was obtained. Example 1 2,4-
Dihydroxyacetophenone 1.52g
(0.01mol), anhydrous potassium carbonate 1.66g, tetraethylammonium iodide 0.13g, acetone
20 g and 1.64 g of prenyl chloride (purity 76.5%) were charged and the reaction was carried out at a temperature of 60° C. for 3 hours while stirring in a nitrogen atmosphere. 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 residue was recrystallized from n-hexane to obtain 2.01 g of 2-hydroxy-4-prenoxyacetophenone (yield: 91.3 mol%).
mp43~44℃, NMR ( _CDCl3 )δ: 1.78, 1.83
(6H, s, 2-CH ₃ ), 2.54 (3H, s, COCH ₃ ),
4.60 (2H, d, J = 6.8, O-CH ₂ -), 5.59 (1H,
t, J=6.8, -O-CH ₂ -CH=), 6.37 (2H,
dd, J=2.2, J=9.5, C-3-H, C-5-
H), 7.57 (1H, d, J=9.5, C-6-H),
12.69 (1H, s, C-2-OH). This product was the same as the recrystallized product obtained in Reference Example 1. For comparison, the same reaction and treatment was carried out without using tetraethylammonium iodide, and the obtained 2-hydroxy-4-prenoxyacetophenone was 0.84 g (yield 38.1 mol%). Ta. In addition, in this reaction, 1.01 g of crystals insoluble in n-hexane were obtained, and this compound was found to be a potassium salt of 2,4-dihydroxyacetophenone based on NMR spectroscopy. Example 2 In Example 1, tetraethylammonium iodide was replaced with benzyltrimethylammonium iodide and the same reaction and treatment were carried out to give 2.05 g of 2-hydroxy-4-prenoxyacetophenone (yield: 93.1 mol%) was obtained. For comparison, benzyltrimethylammonium iodide was replaced with benzyltrimethylammonium chloride and the reaction and treatment were carried out in the same manner. The obtained 2-hydroxy-4-prenoxyacetophenone was 0.71g (yield: 32.2 The yield was very low (mol%). Example 3 Into the same flask as in Example 1, 2.56 g (0.01 mol) of 2',4,4'-trihydroxychalcone, 2.33 g of anhydrous sodium carbonate, 0.19 g of ferrocenylmethyltrimethylammonium iodide, 1.
20 g of 2-dimethoxyethane and 2.34 g of prenyl chloride (purity 98.5%) were charged, and the reaction was carried out at a temperature of 60° C. while stirring for 3 hours. 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 solvent was distilled off under reduced pressure. The residue was recrystallized from an acetone-methanol mixture to give 2'-hydroxy-4,4'-
3.63 g (yield 92.5 mo%) of prenoxychalcone was obtained. mp85.8~86.9℃. Example 4 In a 500 ml flask similar to Example 1, 24.4 g (0.20 mol) of 4-hydroxybenzaldehyde,
30.4 g of anhydrous potassium carbonate, 2.63 g of phenyltrimethylammonium iodide, and 300 g of tetrahydrofuran were charged, and 30.06 g of prenyl chloride (purity 76.5%) was added dropwise over 30 minutes while stirring and refluxing. After the dropwise addition was completed, the reaction was continued for an additional 4 hours under reflux. After the reaction was completed, the inorganic substances were separated, the cake was washed with tetrahydrofuran, and after being combined with the liquid, tetrahydrofuran was distilled off under reduced pressure. The residual liquid was distilled under reduced pressure to obtain 4-prenoxybenzaldehyde.
34.1g (yield: 89.6mol%) was obtained. bp 150.0-154.5℃/8mmHg. NMR (CCl ₄ ) δ: 1.82 (6H, s, 2CH ₃ ), 4.58
(2H, d, J=7.0, -O-CH ₂ ), 5.48 (1H,
t, J=7.0, -O- _CH2 -CH=). Example 5 1.52 g (0.01 mol) of 2,4-dihydroxyacetophenone was placed in a four-necked flask equipped with a reflux condenser, a thermometer, a nitrogen gas inlet tube, and a Polytron ST high-speed continuous shear homogenizer at the center neck. 1.66 g of anhydrous potassium carbonate, 0.13 g of tetraethylammonium iodide, 20 g of acetone, and 1.64 g of prenyl chloride (purity 76.5%) were charged, and the homogenizer was continuously rotated for 2 hours while maintaining the temperature at 60°C under a nitrogen atmosphere. The reaction was carried out. After the reaction was completed, the same treatment as in Example 1 was carried out,
2.09 g (yield 94.9 mol%) of 2-hydroxy-4-prenoxyacetophenone was obtained. Example 6 In a flask similar to Example 1, 1.52 g (0.01 mol) of 2,4-dihydroxyacetophenone, 20 g of acetone, and 1.0 g of 50% aqueous sodium hydroxide solution.
and stirred at room temperature for 30 minutes under nitrogen atmosphere.
The sodium salt of 2,4-dihydroxyacetophenone was prepared. Subsequently, 0.20 g of methylphenylphosphonium iodide and 1.64 g of prenyl chloride (purity 76.5%) were added, and the reaction was carried out while stirring at a temperature of 60° C. for 4 hours. After the reaction was completed, the same treatment as in Example 1 was carried out,
1.99 g (90.3 mol%) of 2-hydroxy-4-prenoxyacetophenone was obtained. Examples 6 to 15 and Comparative Examples 1 to 2 Reactions were carried out according to Example 1 using various phenol derivatives, bases, solvents, and polyprenyl chloride. The results are shown in Table 1. Analysis was performed using gas chromatography or high performance liquid chromatography using an internal standard method.

【table】

【table】

【table】

[Table] Example 16 In a 100 ml four-necked flask equipped with a reflux condenser, thermometer, nitrogen gas inlet tube, and stirring device, add 2.20 g of 2-hydroxy-4-prenoxyacetophenone.
g (10 mmol), methyl monochloroacetate 1.68 g,
Anhydrous potassium carbonate 2.07g, trimethylphenylammonium iodide 0.132g and acetone 20
Prepare g and bring to a temperature of 60℃ under nitrogen atmosphere.
The reaction was carried out for 10 hours with continued stirring. 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 2.52
g (yield: 86.2 mol%). mp78~79.5℃.
NMR (CDCl ₃ ) δ: 1.77, 1.81 (3H, 3H, s,
s, 2・CH ₃ ), 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, C-CH ₂ -
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). For comparison, the same reaction and treatment without using trimethylphenylammonium iodide resulted in 0.81 g of 2-methoxycarbonylmethoxy-4-prenoxyacetophenone (yield: 27.7 mol). %). Example 17 In a four-neck flask similar to Example 16, 1.22 g (10 mmol) of 4-hydroxybenzaldehyde,
1.68g of methyl monochloroacetate, anhydrous potassium carbonate
2.07 g of triethylbenzylammonium iodide, 0.157 g of triethylbenzylammonium iodide, and 20 g of acetone were charged, and the reaction was carried out at a temperature of 60°C for 6 hours under a nitrogen atmosphere while stirring was continued. After the reaction was completed, the same treatment as in Example 1 was carried out,
1.69 g (yield: 87.0 mol%) of 4-methoxycarbonylmethoxybenzaldehyde was obtained. mp39.0~
40.5℃. NMR (CDCl ₃ ) δ: 3.76 (3H, s, -COOCH ₃ ),
4.68 (2H, s, -O-CH ₂ COO-) 6.99 (2H,
d, J=9.0, C-3, 5-H), 7.82 (2H, d,
J=9.0, C-2, 6-H), 9.88 (1H, s, -
CHO). Example 18 In Example 16, 2.07 g of anhydrous potassium carbonate was
% sodium hydroxide aqueous solution, or trimethylphenylammonium iodide
The reaction was carried out in the same manner except that 0.132 g was replaced with 0.129 g of tetraethylammonium iodide and the other components were kept as they were. After the reaction was completed, the mixture was neutralized with 2% hydrochloric acid and ether, and the ether layer was washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the ether was recrystallized from an ether-n-hexane mixture.
2.35 g (yield: 84.4 mol%) of -carboxymethoxy-4-prenoxyacetophenone was obtained. mp138.2
~139.8℃. NMR δ: 10.89 (1H, s, -COOH. Example 19 In Example 16, 0.132 g of trimethylphenylammonium iodide was mixed with trioctyl-n-
Instead of 0.238g of propylammonium bromide,
React and treat in the same manner, 2.45g of 2-methoxycarbonylmethoxy-4-prenoxyacetophenone
(yield: 83.8 mol%). Example 20 In a four-necked flask similar to Example 16, 1.96 g of 2'-hydroxy 4,4'-diprenoxychalcone was added.
(5.0 mmol), 0.71 g of monochloroacetic acid, 1.06 g of anhydrous sodium carbonate, 0.127 g of tributylhexadecylphosphonium iodide, and 10 g of tetrahydrofuran, and the reaction was carried out under reflux under a nitrogen atmosphere while stirring for 10 hours. Ta. After the reaction was completed, the mixture was neutralized with 2% hydrochloric acid, and the precipitated crystals were separated and thoroughly washed with water. The obtained pale yellow crystals were recrystallized from acetone to give a pale yellow crystal.
1.37 g (yield: 60.8 mol%) of 2'-carboxymethoxy-4,4'-diprenoxychalcone was obtained. mp
143.5-145.0℃, NMR ( _CDCl3 ) δ: 11.50 (1H,
Example 21 A flask similar to Example 16 was charged with 0.2 g of sodium hydride (60%) suspended in 5 g of n-hexane, and while passing nitrogen gas, 2-hydroxy-4-gelatin was added. Noxyacetophenone 1.44g, N
-Dissolved in 10g of dimethylformamide
It took 30 minutes to drip. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes to prepare the sodium salt. Next, 0.10 g of n-butyltriphenylphosphonium bromide
A solution of 0.92 g of monochloroethyl acetate and 10 g of N,N-dimethylformamide was added dropwise over 30 minutes, and the mixture was further reacted at 60° C. for 5 hours. After the reaction was completed, the reaction mixture was treated in the same manner as in Example 3 to obtain 1.61 g (yield: 86.0 mol%) of 2-ethoxycarbonylmethoxy-4-geranoxyacetophenone. Comparative Example 3 (Additional test to Reference Example 2 of JP-A No. 53-116355) 2-Hydroxy-4- was placed in a 100 ml four-necked flask equipped with a reflux condenser, thermometer, nitrogen gas inlet tube, dropping funnel, and stirring device. 1.1 g (5 mmol) of prenoxyacetophenone, 0.3 g of potassium hydroxide (fine powder), and 20 g of acetone were charged, and while stirring, 1.0 g of methyl monochloroacetate was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the 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. As a result, 0.13 g (yield: 8.89 mol%) of the target product, 2-methoxycarbonylmethoxy-4-prenoxyacetophenone, was obtained.
In addition, the raw material 2-hydroxy-4-prenoxyacetophenone was 1.00 g (recovery rate 90.9 mol%).
Recovered. Examples 22 to 29 and Comparative Examples 4 to 5 Reactions were conducted in the same manner as in Example 16 or Example 18 using various phenol derivatives, catalysts, solvents, and bases. The results are shown in Table 2. Note that 7.5 mmol of methyl monochloroacetate was used. Analysis was performed using gas chromatography or high performance liquid chromatography using an internal standard.

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【table】

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【table】

Claims (1)

[Claims] 1. General formula: [However, R ₁ , R ₂ , R ₃ are hydrogen atoms, hydroxyl groups, Rp
{However, Rp is
[Formula] (means a prenoxy group or polyprenoxy group represented by n is 0 or an integer from 1 to 19)} or Rq {However, Rq is a group represented by the general formula -O-(CH ₂
-) _n COOR (R is a hydrogen atom or an alkyl group,
m means a group represented by an integer of 1 to 5)}, and R ₄ is a hydrogen atom, an alkyl group, or a general formula [formula] or [formula] {however, R ₅ , R ₆ , R ₇ are hydrogen atoms, hydroxyl groups, Rp or Rq (however, Rp,
Rq means a group represented by } which means (as described above). However, at least one of R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , and R ₇ represents a hydroxyl group. ] A phenol derivative represented by and the general formula: (However, n represents 0 or an integer from 1 to 19) Prenyl chloride or polyprenyl chloride, or the general formula: Cl(CH ₂ ) _n COOR ... (However, R represents a hydrogen atom or an alkyl group, m represents an integer of 1 to 5) and a monochlorocarboxylic acid derivative represented by
A group consisting of quaternary ammonium bromide, quaternary ammonium iodide, quaternary phosphonium bromide, quaternary phosphonium iodide, and crown ether compound as a catalyst for producing phenoxy compound derivatives by reacting in the presence of a base. 1. A method for producing a phenoxy compound derivative, comprising carrying out the reaction in the presence of at least one compound selected from the following.