JPH02255672A - New chromone derivative and antiallergic agent comprising same derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A 5-methoxy-7-isopropoxy-2-methylchromon-4-one shown by formula I [R1 is H or acetyl) R2 is H, 1-6C alkyl, alkyl containing OH at the 1-position or group shown by formula II (n is 1-6; X is OH, alkoxy, carboxyl, dimethoxymethyl, methylpiperazinyl, etc.); R3 is H, methoxymethyl, 1-7C alkyl or group shown by formula II]. EXAMPLE:3-Acetyl-5-hyiroxy-7-isopropoxy-2-methyl-chromone. USE:An antiallergic agent. PREPARATION:3-Acetyl-5,7-dihydroxy-2-methylchromone and 5,7-dihydroxy-2- methylchromone synthesized from fluoroacetophenone as starting raw materials are subjected to combination of alkylation, acylation, introduction of protecting group, deprotection, ester exchange, hydrolysis, etc., to give a compound shown by formula I. Optionally, a corresponding compound shown by formula I is reduced to give a compound shown by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention provides an antiallergic therapeutic agent useful as a pharmaceutical for the treatment of immediate allergic diseases.

[Conventional techniques and issues] Allergic diseases are said to have reactions of type ■ to ■, but the pathology of one disease cannot be explained by one allergic reaction alone, and it is said that the pathology of one disease cannot be explained by one allergic reaction alone, but is a combination of several allergic reactions. This often happens as a result.

For treatment, radical therapy or symptomatic therapy is performed, and antihistamines and/or adrenocortical hormones are frequently used depending on the patient's symptoms. Therefore, various anti-allergic drugs are more effective.
Moreover, the development of drugs with fewer side effects is progressing.

[Means for Solving the Problems] As a result of intensive research to solve the above problems, it was discovered that chromone derivatives, including new chromone derivatives, have anti-allergic effects, leading to the completion of the present invention. That is, the present invention is based on this knowledge, and is based on the following formula I (where Rt represents a hydrogen atom or an acetyl group, and R2
is the number of hydrogen atoms and carbon atoms! -7 alkyl group, alkyl group having a hydroxyl group in the 1st position or formula A(CHt)nX
A (In formula A, n represents 1 to 6, and X is a hydroxyl group, a lower alkoxyl group, a carboxyl group, a sodium carboxyl group, an alkoxycarbonyl group, a methoxymethoxyl group, a dimethoxymethyl group, a 3(4-methylpiperazyl) group, (2-carboquinphenyl)aminocarbonyl group, (2-ethoxyphenyl)aminocarbonyl group, or (2-phenoxyphenyl)aminocarbonyl group.), and R3 is a hydrogen atom, a methoxymethyl group, and has 1 to 1 carbon atoms. 7 or formula A.

However, when RI represents a hydrogen atom, R8 represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a methoxymethyl group, or a propyl group, and when R1 represents an acetyl group, R1 represents a hydrogen atom or a methyl group. and R3
excludes compounds showing hydrogen atoms or methyl groups. ) and anti-allergic agents containing the chromone derivatives as active ingredients; are collectively referred to as the compound of the formula.).

Compounds of formula can be obtained, for example, by several methods shown below.

Alkylation, acylation, and introduction of protective groups using 3-acetyl-5,7-dihydroxy-2-methylchromone and 5,7-cyhydroxy-2-methylchromone, which are synthesized from commercially available fluoroacetophenone, as starting materials, respectively. , deprotection, transesterification, hydrolysis, etc., compounds of formula I can be obtained,
A compound of formula (2) can be obtained by reducing the compound of formula (1) if necessary.

Specific examples of alkylating agents for alkylation include methyl iodide, isopropyl bromide, chloromethyl methyl ether, 4-bromobutylmethoxymethyl ether, 6-bromohexylmethoxymethyl ether, bromoacetaldehyde dimethyl acetal, 8-bromoocta tools, alkyl halides such as 5-(3-chloropropyl)-4-methylpiperazine and l-bromo-2-methoxymethoxyethane, alkyl sulfate esters such as dimethyl sulfate and dipropyl sulfate, ethyl bromoacetate, methyl bromoacetate, etc. Examples include epoxides such as halogenated esters, 1,2-epoxybutane, and 1,2-epoxyoctane. Examples of the base include sodium methylate, sodium hydride, calcium carbonate, diisopropylethylamine (DIEA), etc., and examples of the catalyst include trimethylbenzylammonium hydroxide. Examples of the solvent include dimethylformamide and acetone.

The reaction is accelerated by adding a catalytic amount of potassium iodide or sodium iodide.

Specific examples of the acylating agent used in acylation include ethyl anthranilate, phenyl anthranilate, etc., specific examples of the solvent include dichloromethane, and specific examples of the dehydrating agent include dicyclohexylcarbodiimide.

Transesterification can be carried out by allowing an alkyl alcohol to act in the presence of a catalyst. Examples of the catalyst include sulfuric acid, hydrochloric acid, mercury acetate, and mercury oxide. Examples of the alkyl alcohol include n-propyl alcohol.

Hydrolysis can be carried out by reacting an alkali such as sodium hydroxide or potassium hydroxide in a lower alcohol such as methanol or ethanol.

In each reaction, a protecting group can be introduced for the purpose of protecting the hydroxyl group. The introduction of a protecting group into a compound of formula I:
This can be carried out by reacting the halide of the protecting group to be introduced in the presence of a base. Examples of the base include potassium carbonate, sodium hydride, diisopropylethylamine, and the like. Examples of the solvent include acetone and dimethylformamide. Specific examples of protective groups include methyl group, ethyl group, n-propyl group, methylacetyl group,
Examples include ethylacetyl group, methoxyethyl group, methoxymethoxybutyl group, methoxymethoxyhexyl group, methoxymethoxyoctyl group, and the like. The protecting group is also deprotected if necessary, and can be removed by the action of a mineral acid such as hydrochloric acid or sulfuric acid in a lower alcohol such as methanol or ethanol.

Although the reaction temperature described above is carried out at room temperature, the reaction may be carried out by heating or heating under reflux as appropriate. 3-, one of the starting materials
Acetyl-5,7-dihydroxy-2-methylchromone can generally be obtained by the following method.

Commercially available fluoroacetophenone was refluxed with acetic anhydride and sodium acetate to give 3-acetyl-5,7-diacedoxy-2-methylchromone, which was hydrolyzed with hydrochloric acid to give 3-acetyl-5,7-cyhydroxy-2-methyl. You can get Chromon.

Specific examples of the production of 3-acetyl-5,7-cyhydroxy-2-methylchromone and 5,7-cyhydroxy-2-methylchromone are shown below.

Specific Example 1 Commercially available fluoroacetophenone (99.39 g) and sodium acetate (106.09 g.
℃, added 600 d of 6N hydrochloric acid, and further reacted at 100°C for 1 hour. After cooling, the precipitate was filtered and washed with water.

The obtained crystals were dried in a vacuum dryer 4 to obtain 112.139 (yield: 81.5%) of 3-acetyl-5,7-cyhydroxy-2-methylchromone, one of the starting materials.

Infrared absorption spectrum ν2:;α゛1:3150 (br
), 1642,1626°1510.1494,145
0.1412゜1380.13B0,1290,118
4°115B, 1130.844 Proton nuclear magnetic resonance spectrum (δ ppra in acetone-da):
2.43 (3H, s), 2.52 (3H, s).

2.85 (LH,s).

6.27 (IH, d, J-2Hz).

6.39 (IH, d, J-2Hz).

9.70 ([H,s) Mass spectrum (El) M/Z (%): 234 (M'8
1.8), 220(12,1).

219 (100,0), 216 (29,8).

192(13,9), 153(84,3) Next, 5,7-dihydroxy 2-methylchromone, which is one of the starting materials, can generally be obtained by the following method.

Commercially available fluoroacetophenone was refluxed with acetic anhydride and sodium acetate to obtain 3-acetyl-5,7-diacedoxy-2-methylchromone, which was reacted with an aqueous sodium carbonate solution, and after the reaction was completed, it was precipitated under acidic conditions. 5,7-cyhydroxy-2-methylchromone can be obtained.

A specific example of the production of 5,7-cyhydroxy-2-methylchromone is shown below.

Specific Example 2 Commercially available 70-acetophenone 84.19% sodium acetate anhydride 82.09% and acetic anhydride 561.59%
was added and refluxed for 6 hours. This reaction solution was left in water for 1 day and night, and the resulting precipitate was filtered and thoroughly washed with water and methanol to form white needle-shaped crystals of 3-acetyl-5.7-diacedoxy-2-methylchromone 118. I got 09.

3.2 g of the compound was added to 10% aqueous sodium carbonate solution.
After cooling, the pH was adjusted to 5 using 3N hydrochloric acid, and the resulting precipitate was filtered, washed with water, and then dried. This residue was recrystallized from methanol to obtain 1.3 g (yield: 68.0%) of 5,7-hydroxy-2-methylchromone, one of the starting materials.

[Effects of the Invention] Next, it will be explained with reference to experimental examples that the compound of formula H exhibits antiallergic action.

Experimental Examples Animals used Wistar male rats (body weight 150-70y/animal) purchased from Kiwa Experimental Animal Research Institute were used in groups of five.

Preparation of anti-ovalbumin rat serum Rats were treated with ovalbumin (1019/rat, i, m
), altv (10119/rat, i, +a,) and pertussis vaccine (2X l O + o Bordet
ella pertussts/rat, i, p), and 14 days later, serum was collected and diluted 10 to 20 times.

Method for inducing 0.057 of the anti-ovalbumin rat serum prepared as described above was injected into the dorsal cortex of rats for passive sensitization. 0.2 containing 28g ovalbumin 48 hours after sensitization
PCA was induced by intravenously injecting 5% Evans blue 1d.

Method for determining PCA reaction A piece of skin in the PCA induction triad was dissolved in 2N sodium hydroxide at 37°C overnight, extracted with an acetone-phosphoric acid mixture, and the absorbance (620 nM) of the centrifuged supernatant was measured. It was measured.

Using this absorbance as an index, the PCA reaction inhibition rate was calculated using the following formula.

Experimental Example 1 Using a 20-fold dilution of anti-ovalbumin serum, the compound of the formula was administered at a dose of 9 to 100 Q/A: Absorbance of pigment spots on the skin when the compound of the formula was not administered B: Absorbance of pigment spots on the skin when the compound of the formula was administered.Method of the compound of the formula PCA induction 1. The compound of the formula was dissolved in Agamum physiological saline and orally administered. As a control, only 5% gum arabic physiological saline was orally administered, and the same operation as above was performed.

Experimental Example 2 When a 10-fold dilution of anti-ovalbumin serum was used and the dose of the compound of the formula was set to lo 0 19/9, the following results were obtained.

Experimental Example 3 When a 10-fold dilution of anti-ovalbumin serum was used and the dose of the compound of the formula was 1019/9, the following results were obtained.

Next, an acute toxicity test of the compound of the formula was conducted using ddY mice, and there was no death in either case after oral administration up to 2000 my/9 days.

From the above results, the compound of the formula suppressed the PCA reaction and was found to have an antiallergic effect. Furthermore, acute toxicity tests showed extremely low toxicity, confirming its usefulness as an anti-allergy agent.

Next, the dosage and formulation of the compound of formula will be explained.

The compounds of the formula can be administered to animals and humans neat or with conventional pharmaceutical carriers.

The dosage form is not particularly limited and may be selected and used as required, including tablets, capsules, granules, fine granules,
Examples include oral preparations such as powders, parenteral preparations such as injections, and Zentai.

In order to exert the desired effect as an oral agent, it is usually necessary for an adult to take 30 to 700 190 mg of the compound of the formula divided into several doses a day, although this will vary depending on the age, weight, and severity of the disease of the patient. It seems appropriate to take this drug.

Oral agents include, for example, starch, lactose, sucrose, mannitol,
It is manufactured using conventional methods using carboxymethyl cellulose, corn starch, inorganic salts, etc.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low substituted hydroxypropyl cellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoters: light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the formula can also be administered as suspensions, emulsions, syrups, and elixirs, and these various dosage forms may contain flavorings and colorants.

In order to exert the desired effect as a parenteral agent, although it varies depending on the age, weight, and severity of the disease of the patient, it is usual for adults to administer the compound of formula 5 to 45,319 times a day by intravenous injection;
Intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, and fully dilated preparations for intrarectal administration, and are manufactured according to conventional methods.

Examples of the preparation of compounds of the formula are shown below. However, the present invention is not limited in any way by the Examples described below.

(Left below) Example 1 3-acetyl-5,7-cyhydroxy-2-methylchromone obtained in Example 1: 20.899, potassium carbonate: 24.
739 and potassium iodide 3.769 were dissolved and suspended in dimethylformamide, and isopropyl bromide 17
．． 1- was added, and the mixture was stirred at 60°C for 3.5 hours. The reaction solution was poured into ice water and extracted three times with ethyl acetate, and the a-layer was washed twice with water. The organic layer was dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. Recrystallized from ethyl acetate and 3-
Acetyl-5-hydroxy-7-ituproboxy-2-
7.649 methyl-chromone was obtained. After concentrating the mother liquor, column chromatography [elution solvent, n-hexane:
Ethyl acetate (5:1)], the elution fraction was 1680. d
~3440d was obtained. The eluted fraction was crystallized from ethyl acetate to obtain 7.69 crystals. Based on the physical and chemical properties shown below, this crystalline substance has the following structural formula: 3-acetyl-
It was determined to be 5-hydroxy-7-ituproboxy-2-methyl-chromone.

Properties: Colorless acicular crystals Ultraviolet absorption spectrum λ22:'m(logε): 294
．． 6 (3,94), 260.7 (4,43).

213.9(4,43) Infrared absorption spectrum ν2::α-1:3068.29
B4, 2936.167B.

1664.1610,1500,1442°1412.
1382,1316.11781162.1132.1
110.836 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.37 (6
H, d, J = 5.982).

2.48 (3H, s), 2.62 (3H, s).

4.60 (I H, Sep Ifke, J = 5.
9 Hz).

6.32 (2H, s), 12.55 (IH, s) Mass spectrum (EI) M/Z (%): 276 (M'', 58.
0), 234(34,5).

220 (12,4), 219 (100,0).

217 (10,5), 216 (61,4).

192 (9,7), 153 (34,2).

69 (12,2), 67 (29,5).

43 (48,5) Example 2 4.09 of 3-acetyl-5-hydroxy-physoproboxy-2-methyl-chromone obtained in Example 1 and 5.59 of potassium carbonate were dissolved and suspended in dimethylformamide, and dimethyl was added thereto. Sulfuric acid! , 7- at room temperature after addition of 2
．． Stirred for 5 hours. The reaction solution was poured into ice water, extracted twice with ethyl acetate, washed with water, and the organic layer was dried over anhydrous sodium sulfate, then concentrated to dryness under reduced pressure. Column chromatography [elution solvent, n-hexane: ethyl acetate = 4:1 from 0 to 312, hexane: ethyl acetate = 1:1 from sc to 612] and elute fraction! ,2
a ~ 1.6 (and 4.4ff ~ 5.1 (gaining 2).

From the elution fraction 1.212 to 1.612, Example 1 Part 3
-acetyl-5-hydroxy-7-itsuproboxy 2
-Methyl-4-oxo-48-benzobin 5-0.7y was obtained from the elution fraction 4.4 (2 to 5.112) as a colorless prismatic substance!, 79. Based on its chemical properties, it was determined to be 3-acetyl-5-methoxy-7-iproboxy-2-methyl-chromone having the following structural formula.

Properties: Colorless prism product Ultraviolet absorption spectrum λ = 2:'m (log ε); 294
．． 2 (4,01), 254.4 (4,45).

214.0 (4,43) Infrared absorption spectrum ν2:, CI-': 307
6.3000.2972, 2920°168B, 164
2,1626,1584゜1554.1410,138
8,1372°1338.1324.1196.116
6゜1130.1114 Proton nuclear magnetic resonance spectrum (δ ppta in CDC13): 1.40 (
6H,d, J = 5.4 Hz).

2.40 (3H, s), 2.60 (3H, s).

3.94 (3H, s).

4.62 (IH, SeP 1ike, J=5.9Hz
).

6.33 (IH, d, J=2.4Hz) 6.39 (L
H, d, J = 2.4 Hz) mass spectrum (
El) M/Z (%): 290 (M'', 100.0).

275 (15,3), 248 (17,8).

247 (31,8), 233 (68,3).

231 (13,1), 230 (28,1).

229(17,1), 219(19,7).

205 (28,,8), 203 (31,9).

202 (50,7), 201 (52,4).

200(14,9), 18B(lG,o).

1 7 4 (10,6), 1 6 7 (39,3).

6 7 (48, 3), 4 3 (52, 9) Example 3 Specific example! 3-acetyl-5,7-cyhydroxy-2-methylchromone 1B, 4y and potassium carbonate 56 obtained in
．． 49 was dissolved and suspended in dimethylformamide, 18.57 g of dimethyl sulfate was added thereto, and the mixture was stirred at room temperature for 9 hours.

The reaction solution was poured into ice water, extracted twice with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. Column chromatography [elution solvent, n-hexane:ethyl acetate = 4:1 from 0 to 2.6e, n-hexane:ethyl acetate = 1:l from 2.6Q to 8.49, and from 8.512 onwards, n-hexane:ethyl acetate = 1:1 Ethyl acetate], elution fraction 5.612 to 8.1 known substance (RN=5275 1-4 3-6 1nd
ian, J. Chem l 2(1), 2 6-8
) 2.79 of 3-acetyl-5,7-simethoxy-2-methyl-chromone and 1.3 (colorless crystalline substance 1, 49 was obtained from the elution fractions from 2 to 2.1Q. This colorless crystalline substance was Based on the physical and chemical properties shown below, 3 has the following structural formula.
-acetyl-5-hydroxy-7-medoxy-2-methyl-chromone.

Properties: Colorless acicular crystals Ultraviolet absorption spectrum λ2' nM (log ε): 29
3.9 (3,90), 259.1 (4,41).

214.0 (4,43) Infrared absorption spectrum 1 = 2984.29
36,2852,1696°1668.1612,15
08.13B6゜1352.1332,1306,12
20゜1166.1080.828 Proton nuclear magnetic resonance spectrum (δ ppvlin CDCl5): 2.49 (3H
, s), 2.62 (3H, s).

3.86(3)(,s), 6.35(2H,s).

1 2.5 8 (I H, s) Mass spectrum (El) M/Z (%): 248 (M',
85.8), 247(11,5).

234 (13,9), 233 (100,0).

230(25,7), 167C70,0).

166 (12,2), 69 (11,9).

67(34,6), 43(32,2) (blank below) Example 4 28.29 of 5,7-hydroxy-2-methylchromone obtained in Specific Example 2 and 43.89 of potassium carbonate were dissolved in acetone 36011Ii. The mixture was made cloudy, and methyl bromoacetite 36.2I11 was added dropwise thereto, followed by stirring at room temperature for 12 hours. The precipitated crystals were collected by filtration, dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a crude crystalline substance. Further, the mother liquor was concentrated to dryness, then dissolved in ethyl acetate, washed with water, dried, and then concentrated to dryness under reduced pressure to obtain a crude crystalline substance. The crude crystal material was recrystallized from ethyl acetate to obtain 21.89 g of a colorless needle-like crystal material. This crystalline substance was determined to be 5hydroxy-7-medoxycarbonylmethoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless needle crystal infrared absorption spectrum ν11+211 cm-': 1
770,1664,1616.1504°1376.1
346.1226.116B.

Proton nuclear magnetic resonance spectrum (δ ppm in CDC1a): 2.35 (
3H,s), 3.82(3H,s).

4.68 (2H, s), 6. ．． 04 (IH, s).

6.31 (IH, d, J = 2.0 Hz).

6.36 (IH, d, J = 2.0 Hz).

12.72 (I H, s) Mass spectrum (El) M/Z (%): 264 (M',
I O0,0), 206(8,8).

205 (50,2), l 77 (36°l).

176 (10,7), 175 (33,8).

163(5,4), 123(5,6).

107 (22,0), 79 (6°0).

43(4,7) Example 5 19.5 g of 5-hydroxy-7-medoxycarbonylmethoxy-2-methylchromone obtained in Example 4 was dissolved in dimethylformamide 300W11 and cooled to 0°C.

3.5 g of sodium hydride was added thereto, and the mixture was stirred for 3 hours. 7.17 g of methyl iodide was added to the reaction solution, and the mixture was stirred at 0° C. to room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, and the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain colorless crystalline substance 16.49.

This colorless crystal substance was determined to be 5-methoxy-7-medoxycarponylmethoxy-2-methylchromone having the following structural formula based on the physical and chemical properties shown below.

Properties: Colorless crystal infrared absorption spectrum ν2::α-1=2996.29
52,29 12.2848°17B,4,1 740
,1 662,1 632°160B,1574,14
70,1432°1394.1336.128B, 12
26°1216.1164,1094.1018° Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 2.27 (
3H, d, J = 7).

3.84 (3H, s), 3.94 (3H, s).

4.70 (2H, s).

6.02 (I H, d 1ike, J = 0.7
Hz).

6.33 (IH, d, J = 2.3 Hz).

6.44 (lH, d, J = 2.3Hz) Mass spectrum (EI) M/Z (%): 279 (M”+ 1.18.8
).

27 B(M”, IO0,0).

277 (34,0), 249 (30,0).

232 (29,5), 205 (53,5).

204 (10,4), 189 (44,5).

176 (11,7), l　61 (7,1).

159 (22,9), 90 (9,2).

15(5,3) Example 6 To 5.6 g of 5-methoxy-7=methoxycarbonylmethoxy-2-methylchromone obtained in Example 5 were added 100 d of propatool and 2.0 d of sulfuric acid, and the mixture was heated under reflux for 1 hour. The reaction solution was cooled to room temperature, 500Id of ethyl acetate was added, washed, dried, and the solvent was distilled off under reduced pressure to obtain pale yellow crystalline product 5.19. This was subjected to column chromatography [elution solvent, ethyl acetate:n-hexane=
2:l.

Elution fraction 4.1
Q~6. 4.89 of a pale yellow crystalline substance was obtained from li2.

This was recrystallized from ethyl acetate to obtain colorless prism substance 4.69. This prism material was determined to be 5=methoxy-7-propoxycarbonylmethoxy-2-methylchromone having the following structural formula from the physicochemical properties shown below.

Properties Nibrism crystal infrared absorption spectrum ν2:, C12-'2296
B, 2932, 1734, 1660° 1614.157
6.1486,1474゜1446.142B, 139
4,1360°1336.1290,1270,125
0゜1216.1194.1182.11B4゜111
4.109B, 1058,960°860.824 Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 0.94 (3H
, t, J=7.4Hz).

1.611.79 (2H, m).

2.26 (3H, s), 3.93 (3H, s).

4.20 (2H, t, J = 6.78Z).

4.68 (2H, s), 6.01 (IH, s).

6.3 4 (I H, d, J = 2.2 Hz
).

6.4 4 (I H, d, J -2, 2) (z)
Mass spectrum (EI) M/Z (%): 307 (13,
M”+1), 306 (62, M”).

305(13, M-1), 263(16).

235(l　l), 219(13).

205(100), 189(33).

177(11), 176(12), l59(17).

90(14), 43(32) Example 7 16.49 ml of 5-methoxy-7-medoxylcarbonylmethoxy-2-methylchromone obtained in Example 5 was dissolved in 400 d of methanol, and 200 d of 5% potassium hydroxide aqueous solution was dissolved.
11Ii was added and stirred at room temperature for 15 minutes. Reaction liquid to 0
It was cooled to ℃ and adjusted to pa+ about 2 with 6N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain colorless powder substance 14.29. Based on the physical and chemical properties shown below, this colorless powder substance has the following structural formula: 5-methoxy-7
-carpoxymethoxy-2-methylchromone.

Properties: Colorless microcrystalline infrared absorption spectrum νgas CM −': 354
4.3508,1650,1612゜1582.154
6,1490.145B.

1406, I 352, 1280, 1242゜1190
．． 1172. l IC+2.1066°752.598 Proton nuclear magnetic resonance spectrum (δ ppl in CDC13): 2.27 (3
H,s), 3.88 (3H,s).

4.87 (2H, s), 5.98 (lH, s).

6.52 (2H, s) Mass spectrum (El) M/Z (%): 265 (M”+
1.16.9).

264 (M”, 100.0).

2 63 (39,6), 23 5 (28,8).

2 1 B (37,7), 20 5 (33,7).

204 (11,9), 1 8 9 (47, 2).

+ 7 7 (18,7), 1 7 B (17,7)
.

1 6 1 (10,3), l 6 0 (8,0).

1 5 9 (25, 8), 1 4 9 (7, 6).

1 4 B (7, 4), l 4 7 (9, 1).

9 0 (9,8), 4 3 (7,6) Example 8 751 d of methanol and 2.3 d of sodium methoxide were added to 4.19 d of 5-methoxy-7-carboxymethoxy 2-methylchromone obtained in Example 7. The mixture was added and stirred for 15 minutes. 400 d of tetrahydrofuran was added to the reaction solution to precipitate crystals, which were separated by filtration under reduced pressure and dried under reduced pressure to obtain crude crystals. The crude crystal was recrystallized from methanol:tetrahydrofuran to obtain a colorless powder.3.
I got 69. This colorless powder substance was determined to be 5-methoxy-7-storium carboxylate methoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless powder infrared absorption spectrum ν2': f-': 3092.16
60.1608.1494゜1454.1424,14
02,1336°1270.1224,1186,11
70°1112, l 092,1052,842°82
8.578,698,680,602° Proton nuclear magnetic resonance spectrum (δ ppta in DMSO-ds): 2.24
(3H, s), 3.78 (3H, s).

4.21 (2H, s), 5.91 (lH, s).

6.33 (l H, d, J = 2, OH2).

6.41 (I H,d, J = 2.0 Hz) Example 9 3.19 of 5-methoxy-7-carpoxymethoxy-2-methylchromone obtained in Example 7 was added to 60 d of dichloromethane.
After cooling to 0° C., 2.79 g of dicyclohexylcarbodiimide was added and stirred for 40 minutes. Add 2.4g of phenyl anthranilate to it and keep it at room temperature from 0℃.
Stir for hours. The reaction solution was poured into water, extracted with chloroform, and the organic layer was washed successively with 3N hydrochloric acid, saturated aqueous sodium carbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The mixture was concentrated to dryness under reduced pressure to obtain a crude crystal. This was recrystallized from acetone to obtain colorless needle-like substance 2.19. This crystalline substance was determined to be 5-methoxy-7(2-phenoxycarbonylphenyl)aminocarbonylmethoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

(Ph means phenyl group.) Properties: Colorless needle crystal infrared absorption spectrum ν2::α-1=3172.30
96,3032.2980°1746.172B, 16
94.1652°+606,1566.1530.14
B8゜1444.1396,13B6,1344゜13
30.1286.1268, 1240°1190, +1
64.1140, 1110°1080, +056. I
036,1000°914.844,826,778
, 756° Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 2.27 (3H
, s), 3.62 (3H, s).

4.68 (2H, s).

6.01 (IH, d, J = l, OHz).

6.40 (l H, d, J = 2, OH2).

6.53 (IH, d, J = 2, OH2).

7.15-7.50 (6H, m), 7.68 (l　H.

ddd, J = 1. 5.7.3.8.8 Hz)
.

8.32 (I H, dd, J = 1.5.8.3
H, ) 8.84 (l H, dd, r = 1.0.8.3
8Z).

1 2.1 0 (I H, s) Mass spectrum (EI) M/Z (%): 459 (M”,
0.2), 205 (100,0).

20 s (t 4.3), 204 (3,3).

161 (4,7), 146 (19,2).

132 (8,5), 119 (6,3).

94 (41,7), 90 (11,6).

77 (6,7), 66 (9,2), 65 (8,6).

63 (3,8), 55 (3,3), 51 (3,5).

50(3,1), 43(3,8) Example IO 4.59 d of 5-methoxy-7-carpoxymethoxy-2-methylchromone obtained in Example 7 was added to 60 d of dichloromethane.
The mixture was dissolved in J and cooled to 0°C. A dichloromethane solution of dicyclohexylcarbodiimide (3,99/25
d) was added and stirred for 40 minutes at O''C1, followed by dropwise addition of 2.67 g of ethyl anthranilate and stirred at 0°C for 3 hours.The reaction solution was poured into ice water and extracted with chloroform, and the organic layer was extracted. It was washed, dried, and concentrated under reduced pressure to dryness to obtain a crude crystal.This was recrystallized from methanol to obtain a colorless needle-like substance.
5g was obtained. From the physical and chemical properties shown below, this crystalline substance has the following structural formula: 5-methoxy-7-(2-ethoxycarbonylphenyl)aminocarbonylmethoxy-
It was determined to be 2-methylchromone.

Properties: Colorless acicular crystals Infrared absorption spectrum ν22f-': 3256.1696, 1674, 1614°1590.
1530, 1454, 1426° 1342.129B,
1238,1200°1182.1096.752 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.41 (3H
, d, J=6.8Ha).

2.28(31(,s), 4.00(3H,s).

4.39 (2H, q, J=6.8Hz).

4.71 (2H, s), 6.03 (IH, s).

6.50 (IH, d, J=2.4Hz).

6.68 (IH, d, J=2.4).

7.15 (l)1. dt, J = 1.5.8.3
H2).

7.58 (I H, dt, J = 1.5.8.3
Hz).

8.08 (I H, dd, J = 1.5.8.38
Z).

8.78 (l H, dd, J= 1.5, 8.3H2)
.

12.18 (l H,s) Example 11 5-methoxy-7-(2-ethoxycarbonylphenyl)aminocarbonylmethoxy-2-methylchromone obtained in Example 1O was added to methanol I, and 5 g was added to methanol 70d.
40 d of 5% sodium hydroxide solution was added.
Stirred at 0°C for 40 minutes.

After cooling to room temperature, adjust the pH to approximately 2 with 3N hydrochloric acid,
The precipitated crystals were collected by filtration and washed with water to obtain 1.49 g of crude crystals. This was recrystallized from dimethyl sulfoxide to obtain a colorless microcrystalline substance 835.5j19.

This crystalline substance was determined to be 5-methoxy-7-(2-carboxylphenyl)aminocarbonylmethoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless microcrystalline infrared absorption spectrum ν2: ;α-1°3440.31
92,2924,2596°1696.165B, 16
04,1590°1530.1466.1454.14
3B.

1422.1398, 1382, 1346°1300.
1264, 1220, 1196° 1184.1170,
1t 12,109B.

836.788,764,648 Proton nuclear magnetic resonance spectrum (δ ppva in CDC13): 2.27 (3
H,s), 3.86 (3H,s).

4.90 (2H, s), 5.98 (lH, s).

6.64 (I H, d, J = 2.4 I-tZ
).

6.75 (IH, d, J=2.4Hz).

7.21 (IH, dt 1ike).

7.64 (lH, dt 1ike).

7.54 (lH, dd 1ike).

8.68 (lH, dd 1ike).

12.13 (l H, s) Mass spectrum (El) M/Z (%): 383 (M”
, 0.9), 364 (1,0).

31 B(0,9), 220(2,1).

219(5,5), 217(1,7).

207 (4,2), 206 (13,3).

205 (IO0,0), 204 (2,4).

203(2,0) Example 12 Dimethylformamide 140- and diisopropylethylamine 17II11 were added to 13.59 of 5,7-cyhydroxy-2-methylchromone obtained in Example 2 and stirred for 10 minutes. After cooling to 0°C, 6.4 d of chloromethyl methyl ether was added, and the mixture was further stirred at the same temperature for 2 hours. The reaction solution was poured into 1Q of ice water and stirred for 30 minutes. After the crystals had completely precipitated, they were filtered off. The crystals were dissolved in 50011Ii of ethyl acetate and filtered. The mother liquor was washed with water and dried over sodium sulfate. , the solvent was distilled off under reduced pressure to obtain crude crystals of 5-hydroxy-7-medoxymethoxy-2-methylchromone 22.6
I got a 9. This was subjected to column chromatography [elution solvent, n-hexane:ethyl acetate = 3:l], and from the elution fraction 0.31-112, 5-hydroxy-7-medoxymethoxy-2-methylchromone 14.19 (yield 85%
) was obtained.

Infrared absorption spectrum νIII:X nl −' :1
668.1626.1594, 1506°+446.
凰 432,1 4 1 0,1338°1258,
l 202,1158,1 072°1020.92
4,838,8 10 Proton nucleus magnetic resonance spectrum (δ ppw in CDCl5): 2.3 5
(3H, s), 3.4 9 (3H, s).

5.21 (2H, s), 6.03 (IH, s).

6.45 (IH, d, J = 2.2 Hz).

6.54 (I H, d, J -2,2Hz) Mass spectrum (El) M/Z (%): 236 (M'', 16)
, 204(7), 177(5).

17 B(4), 45(100) Next obtained 5-hydroxy=7-medoxymethoxy2-methylchromone 472 Dimethylformamide 51 in R9
Added d. The reaction solution was cooled to 0° C., sodium hydride 105 R9 was added, and the mixture was stirred at room temperature for 2 hours. Next, 0.67 ml of methyl iodide was added, and the mixture was further stirred for 2 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was diluted with ethyl acetate (2511II
X2), washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 585.1 m9 of crude crystals of 5-methoxy-7-medoxymethoxy-2-methylchromone. This was subjected to column chromatography [elution solvent, n-
Hexane:ethyl acetate-1:5], and the elution fraction 24
5-methoxy-7-medoxymethoxy2-methylchromone 404. INVC yield 8! %) was obtained.

Infrared absorption spectrum νwh': x eel −”16
64.1632, 1612, 1570°+392.13
36,1152,1092°1076.1032.92
0 Proton nuclear magnetic resonance spectrum (δ ppm in CDC1a): 2.27 (3H
, s), 3.50 (3H, s).

3.94(3)1. s), 5.23 (2H, s).

6.01 (LH, s).

6.43 (IH, d, J = 2.2 Hz).

6.63 (lH, d, J = 2.2H2) Mass spectrum (El) M/Z (%): 250 (M”, I 3), 20
5(6), 18 B(7).

177 (5), 58 (8), 45 (100).

44 (14), 4 3 (29) Next, 111.79 of the obtained 5-methoxy-7-nodoxymethoxy-2-methylchromone was placed in an eggplant-shaped flask equipped with a mechanical stirrer, and hydrochloric acid-methanol 5007d was added.
and methanol i were added, and the mixture was stirred at room temperature for 48 hours.

The reaction solution was poured into 8Q of ice water and stirred for 30 minutes to completely precipitate crystals, which were then filtered. Dry the crystals under reduced pressure and
Crude crystals of -hydroxy-5-methoxy-2-methylchromone tot, ay were obtained. This was recrystallized from methanol to obtain 81.09° of 5-methoxy-7-hydroxyl 2-methylchromone (yield: 88%).

Infrared absorption spectrum νwa'::cIIt''l:3
428.1658, 1620, 1574°1352.1
208.1180.1092 Proton nuclear magnetic resonance spectrum (δ ppta in DMSO-d s) 22
．． 24 (3H,s), 3.77 (3H,s).

5.89 (LH, s), 6.35 (2H, s) Mass spectrum (El) M/Z (%): 206 (M”, l OO
), 205(47).

177 (46), 160 (41), 14 B (34).

69(37), 43(26) Next, 5.2 g of potassium carbonate and 7547 dimethylformamide were added to 5.29 of 5-methoxy-7-hydroxy-2-methylchromone, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. Next, methyl iodide 16! d was added, and the mixture was further heated and stirred on an oil bath at 60°C for 1 hour. The reaction solution was cooled to room temperature, extracted, washed, dried, and the solvent was distilled off under reduced pressure to obtain 4.99 g of crude crystals. By recrystallizing this from ethyl acetate with stirring, a colorless needle crystal substance 3 was obtained.
．． I got 29. This crystalline substance was determined to be 7,5-dimethoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless needle crystal Infrared absorption spectrum ν: 2'x cTR-': 16
5B, 1624, 1604, 1454° 1420.14
00.133B, 1318°1274.1226,12
06,1116°1086.984 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 2.27 (3H
, s), 3.87 (3H, s).

3.9 3(3)1. s), 6. Ol(I H,
s).

6.33 (IH, d, J = 2.3 H2).

6.41 (I H,d, J = 2.3 Hz) Mass spectrum (FD) M/Z (%): 221 (15, M
+1).

220 (100, M”), 2 t 9 (38, M+-s
>.

191(47), 189(15), 174(41).

162(20), 150(15), 147(29).

69 (15), 43 (21), 40 (26) Example Summer 3 5-methoxy-7-hydroxy-2-methylchromone, the intermediate of Example 12, 5.29 and potassium carbonate 5.2
9 and dimethylformamide 7011i were added, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. Next, 4.77 g of bromoethyl methyl ether was added, and the mixture was heated and stirred for 2 hours at 80° C. in an oil bath. The reaction solution was cooled to room temperature, extracted, washed, dried, and the solvent was distilled off under reduced pressure to obtain 2.9 g of crude crystals. This was subjected to column chromatography [elution solvent, ethyl acetate: n-hexane = 2
:1,2-5<'w ethyl acetate only] to obtain 2.59 crude crystals from eluted fractions 4.9Q to 9.0 g.

This was recrystallized from ethyl acetate with stirring to obtain colorless powder substance 2.49. This colorless powder substance was determined to be 5-methoxy-7-medoxyethoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless powder infrared absorption spectrum νmix ('$1-':1
664.1604, 1566.1462°1444, +
426.1396,1346゜12B6,1218゜1
198,11721132.1112,1102,85
2°824.562 Proton nuclear magnetic resonance spectrum (δ ppm in CDCIg): 2.27 (3H,d, J = 0.7 H2).

3.78 (l H, dd, J -5,9,3,3Hz
).

3.78 (IH, dd, J=4.6, 4.6Hz).

3.47 (3H, s), 3.92 (3H, s).

4i 8 (I H, dd, J = 5.9.3.3H2)
.

4.18 (l H, dd, J = 4.6.4.68
□).

6.01 (IH, d, J = 0.7 Hz).

6.4 1 (2H,s) Mass spectrum (El) M/Z (%): 265 (17,
M+1).

264 (IOO, M'), 263 (M-1).

205 (78), 1 B 9 (32), 177 (43)
.

160(35), 59(83).

(Left below) Example 14 5-methquine-7-hydroquine-2-methylchromone, an intermediate of Example 12, was added with 5.29% of potassium carbonate.
g and! -bromo 2-methoxymethoxyethane8.
59 was added thereto, and the mixture was heated and stirred on an oil bath at 80°C for 2 hours. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed, dried, and the solvent was distilled off under reduced pressure to obtain 9.69 of a crude crystal. This was subjected to column chromatography [elution solvent.

Ethyl acetate:n-hexane-2:1,1. 6 after sl
:1.1.5&hereinafter using ethyl acetate only] to obtain 6.29 crude crystals from elution fractions 2.5Q to 8.5a.

This was recrystallized from ethyl acetate/n-hexane with stirring to obtain colorless powder 5.59%. Based on the physical and chemical properties shown below, this colorless powder has the following structural formula: 5-methoxy-7-(2-methoxymethoxyethoxy)
It was determined to be -2-methylchromone.

Properties: Colorless powder infrared absorption spectrum ν=:zα゛1:2964.16
64,1608. +568°1460, +428.1
396,1346°126B, l 224,1202.
1188°1176.1148.112B, I l t
o.

1040.1022,912,850,834° Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 2.27 (3H
, d, J=0.7Hz).

3.41 (3H, s), 3.92 (3H, s).

3.90-3.95 (2H, m).

4.19-4.23 (2H, m).

4.73 (2H, s).

6.01 (IH, d, J=0.7Hz).

6.4 0-6.4 3 (2H, s) Mass spectrum (El) M/Z (%): 294 (34,
M”), 249(23).

205 (21), 204 (36), l76 (1B).

45(100), 40(31) Next, 5.99% of 5-methoxy-7, -C2-methoxymethoxyethoxy)-2-methylchromone obtained above, methanol and hydrochloric acid methanol reagent 16In! Add Q,
Stirred at room temperature for 20 hours. After adding 100% of water to the reaction solution, the solvent was distilled off under reduced pressure, further water was added, extracted with ethyl acetate, washed, dried, and the solvent was distilled off under reduced pressure to obtain 5.49 g of crude crystals. I got it. This was recrystallized from ethyl acetate with stirring to obtain colorless powder 4.79. This colorless powder was determined to be 5-methoxy-7-(2-hydroxyethoxy)-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless powder infrared absorption spectrum ν2":x cM-"3492.
3360, 3272, 1686°+614.1592,
1562, 1464° 1400.134B, 1220.
1198°1190.1170.1108.846 Proton nuclear magnetic resonance spectrum (δ ppn+ in CDC13): 1.6 B(
I H,s).

2.75 (3H, d, J=0.7Hz).

3.92 (3H, s).

4.00-4.05 (2H, m).

4.13-4.17 (2H, m).

6.01 (IH, d, J=0.7Hz).

6.37 (LH, d, J=2.4Hz).

6.42 (I H,d, J = 2.4 Hz) Mass spectrum (El) M/Z (%): 251 (16, M
”+ 1), 250 (I OO, Ma.

249(36, M-1), 221(25).

205 (42), 204 (20), l 89 (34).

177 (50), 160 (36), 148 (3'5).

69(18), 45(21) Examples! 5 Potassium carbonate 5.2 to 5.29 5-methoxy/7-hydroxy-2-methylchromone, the intermediate of Example 12
9 and dimethyl formaldehyde 70Rj were added, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. Next, 3.3 d of ethyl bromoacetate was added, and the mixture was further heated and stirred on an oil bath at 80° C. for 1 hour. The reaction solution was cooled to room temperature, water was added, extracted, washed, dried, and the solvent was distilled off under reduced pressure to obtain 7.439 crude crystals. This was subjected to column chromatography [elution solvent, ethyl acetate:n-hexane = 1:12
, 2:lA after Oe, acetic acid after 5Q fI)b], and from the elution fractions 3.5Q to 5.012, 6.4 crude crystals were obtained.
I got a 9. This was recrystallized from ethyl acetate with stirring to obtain a colorless powder of 5.99%.

This colorless powder was determined to be 5-methoxy-7-nitoxycarbonylmethoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless powder infrared absorption spectrum ν2:=α~l:175B, 16
62,1612,1578°1474.1454,14
26,1392°1344, l 206,1196. +
182°1164.1114. l 098,848° proton nuclear magnetic resonance spectrum (δ ppm in CDCIJ + 1.32 (3H, t, J = 7.1 Hz).

2.27 (3H, d, J=0.9Hz).

3.93 (3H, s).

4.30 (2H, q, J-7, 1Hz).

4.6 7 (2H, s).

6.0　1(l)■,d,J=0.9Hz).

6. 3 3 (l H, d, J
= 2. 3 1-12).

6.44 (IH, d, J = 2.3Hz) Mass spectrum (El) M/Z (%): 293 (16, M+ 1), 2
92 (85, M').

291 (2o, M+-1), 2 e 3 (32).

235(IO), 219(15).

205(100), 189(52).

177(15), 176(16).

159(33), 90(26), 62(13).

Example 56 500 d of dimethyl formaldehyde was added to 16.59 g of 5-methoxy-7-hydroxy-2-methylchromone, the intermediate of Example 12, 24.0 g of sodium iodide, and 4.2 g of sodium hydride under a nitrogen atmosphere. Plus, oil bath! The mixture was heated and stirred at 00°C for 2 hours. The reaction solution was cooled to 60°C, 21.59 g of 1-(3-chloropropyl)-4-methylpiperazine was added, and the mixture was heated and stirred on an oil bath at 100°C for 3 hours.

The reaction solution was cooled to room temperature, dimethyl formaldehyde was distilled off under reduced pressure using an evaporator, extracted, dried, and the solvent was distilled off under reduced pressure to obtain a crude crystal product 23.19.
I got it. This was then subjected to column chromatography [elution solvent,
The mixture was subjected to methanol distillation, and 17.99 g of crude crystals were obtained from 1.512 to 5.5 g of the eluted fraction.

By recrystallizing this from ethyl acetate, colorless powder 1
I got 7.79. Based on the physical and chemical properties shown below, this colorless powder has the following structural formula: 5-methoxy 7-[3-
It was determined to be (4-methylpiperazyl)propoxy]2-methylchromone.

Properties: Colorless powder infrared absorption spectrum νMIX c71! -' :2
960.2932.2832.2796°1656.1
604. I 568,1462゜1394.1348,
1216.11B4゜1168.1150, 1110,
1094°822.550 Proton nuclear magnetic resonance spectrum (δ ppIIlin CDCIg): 6.43 (
I H,d, J = 2.3 Hz).

6.33 (IH, d, J=2.3Hz).

4.08 (2H, t, J=6.5Hz).

3.92 (3H, s).

2.57 (2H, t, J=6.5Hz).

2.57-2.50 (8H, m).

2.30 (3H, s), 2.27 (3H, s).

2.00 (2H, m, J-6,5Hz) Mass spectrum (EI) M/Z (%): 346 (9, M+2), 207
(100).

la 9 (22), l 13 (80), 97 (23).

83 (26), 71 (41), 70 (95).

6 9 (28), 5 7 (41), 5 5 (3 g).

4 5 (45), 4 3 (74), 4 2 (40) Examples! 7 5,7-cyhydroxy-2-methylchromone 6.29 obtained in Example 2 was converted into N,N'-dimethylformamide 807
1 at 0°C with 1.69 sodium hydride.
Stir for hours. Then isopropylbromide 16.17
d was added and stirring was continued at room temperature for 15 hours. The reaction solution was diluted with 300 II fl of ethyl acetate, washed three times with water and twice with brine, and the ethyl acetate layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. This reaction mixture was subjected to column chromatography [elution solvent, n-hexane:ethyl acetate = 3:l].
The eluate was separated into 301Ii fractions, the 17th fraction was combined, and the solvent was distilled off to obtain 5-hydroxy-
5.49 physobroboxy-2-methylchromone (yield 71.4%) was obtained.

Next, 7.49 g of the obtained 5-hydroxy-7-itsuproboxy-2-methylchromone was dissolved in 40 g of dimethyl formaldehyde.
After dissolving in 0d and cooling to 0℃, sodium hydride! ,
69 was gradually added while stirring. After hydrogen evolution ceased, the reaction mixture was stirred at room temperature for 2.5 hours. Add 18IRfl of n-propyl iodide to it, and
The mixture was stirred at ℃ for 3 hours.

The reaction solution was concentrated to dryness under reduced pressure, then dissolved in ethyl acetate, and the organic layer was washed with water. The organic layer was dried and then concentrated. Silica gel column chromatography, elution solvent, ethyl acetate:
n-hexane=1:1] and tsio! I11-3
850I/11 yielded 6.19 colorless oily substances.

This colorless oily substance was determined to be 5-propoxy-7-isoproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: colorless oil 285.6 (3,98), 252.9 (4,30).

24 5.5 (4,31), 229.8 (4,29) Infrared absorption spectrum ν+m::'el-':297
2.2932.1664,1610゜156g, 148
6,1468,1432゜1390.132B, 125
8.1184゜1166.1110.1088,844
Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 1.10 (3H
, t, J=7.3Hz).

1.36 (6H, d, J=5.9Hz).

1.91 (2H, m).

2.26 (3H, d, J = 0.71-iz).

3.98 (2H, t, J = 6.8) (,).

4.60 (lH, sep 1ike, J=5.9Hz)
.

5.95 (IH, d, J = 0.7 H2).

6.29 (IH, d, J-2,2Hz).

6.36 (IH, d, J = 2.2 Hz) Mass spectrum (El) M/Z (%): 276 (21,0, M"), 2
48(13,0).

247 (84,4), 219 (31,2).

206 (12,5), 205 (100,0).

201 (10,7), +93 (11,7).

192 (51,7), 177 (17°3).

176 (82,4), 164 (15,7).

163 (13,5), 148 (34,8).

136 (10,3), 124 (10,0).

123 (11,9), 77 (10,4).

69(30,8), 67(12,2) 55(11,2), 51(10,8) 44(56,3) Example 18 5-Hydroxy-phyisoproboxy, an intermediate of Example 17 14.59 ml of 2-methylchromone was dissolved in 410 d of dimethyl formaldehyde, and after cooling to 0°C, 2.79 ml of sodium hydride was added and stirred for 2 hours. Add 31.6 d of n-hebutyl iodide to this reaction solution and
The temperature was raised to ℃, stirred for 2 hours, and then concentrated under reduced pressure. The resulting reaction mixture was dissolved in ethyl acetate, washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The reaction mixture was subjected to column chromatography [elution solvent, ethyl acetate:n-hexane=l:2], and the elution fraction was 2.0.
14.49 colorless crystals were obtained from Q~4.8f2. This colorless crystal was determined to be 5-hebutoxy-7-iproboxy-2-methylchromone having the following structural formula based on the physical and chemical properties shown below.

3C 285,1 (3,91), 253.1 (4,23).

245.6 (4,25), 229.8 (4,24).

2 0 6.0 (4, 28) Infrared absorption spectrum ν2:; α゛1; 2956.29
24.2860,1666°1608.156B,14
76.14321390.1340,1326,125
6°+190.1168,1116.1086 Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 0. 8
8 (3H, t 1ike, J = 6
．． 6 Hz).

1.38 (6H,d, J = 6.1 Hz)1.
20-2.00 (IOH, m).

2.26 (3H, d, J = 0.7 Hz).

4.01 (2H, t, J=6.8Hz).

4.60 (I H, Sep 1ike, J = 6.
1Hz).

5.95 (l H, d, J = 0.7 Hz).

6.28 (lH, d, J = 2.2 Hz).

6.36 (l H, d, J = 2.2 Hz) mass spectrum (El) M/Z (%); 332 (M", 14.1),
261(24,8).

247 (98,1), 234 (27,2), 219 (5
6,9), 205 (60,5).

193 (37, 25, 192 (100, 0).

1 76 (73,4), 55 (32,2).

It was determined to be 5-methoxyethoxy-7-itubroboxy-2-methylchromone having 4 3 (38,7) and 4 1 (56,4).

Example 19 Dimethyl formaldehyde 75 Ili and sodium hydride 156 to 5.99 5-hydroxy-7-itsuproboxy-2-methylchromone, the intermediate of Example 17
9 was added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Next, 7'' of bromoethyl methyl ether was added, and the mixture was further heated and stirred on an oil bath at 80°C for 1 hour. The reaction solution was cooled to room temperature, 300R1 of water was added, extracted with ethyl acetate, washed,
After drying, the solvent was distilled off under reduced pressure to obtain crude oil 1.
3.49 was obtained. This was subjected to column chromatography [elution solvent, ethyl acetate:n-hexane=l:1],
6.69 of an oil was obtained from elution fractions 3.7e-7.5e. This was distilled using a Kugelrohr to obtain 4.49% of a colorless oil. Based on the physical and chemical properties shown below, this oily substance has the following structural formula: Colorless oily infrared absorption spectrum: 2976.2
929,1662,1612゜1568.148B, 1
454,1432°1392.1342,1330,1
260°11B6,1164. l 110.1088°1038.846 Proton nuclear magnetic resonance spectrum (δ ppyi in CDCl5): 1.38 (6
H, d, J = 6.1 Hz).

2.26 (3H, s), 3.52 (3H, s).

3.87 (2H, m), 4.17 (2H, m).

4.60 (IH, m, J = 6.1 Hz).

5.94 (IH, s).

6.33 (IH, d, J = 2.2 Hz).

6.40 (I H, d, J = 2.2 Hz) Mass spectrum (El) M/Z (%): 293 (1, M'+ 1
), 292 (1, M”).

291(1, Mw-1), 260(96).

219(56), 192(100).

190(84), 189(32), 59(28).

= 1:2E, and 6.4 g of oil was obtained from elution fractions 2.1 to 6.012. This oily substance was determined to be 5-methoxymethoxyethoxy-isopropoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Example 20 Dimethyl formaldehyde to 5.99% of 5-hydroxy-7-iproboxy-2-methylchromone, the intermediate of Example 17! 0011i and sodium hydride 1.
69 was added thereto, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Then 1-bromo-2-methoxymethoxyethane 12.79
was added, and the mixture was heated and stirred on an oil bath at 75°C for 1 hour.

The reaction solution was cooled to room temperature, extracted, washed, dried, and the solvent was distilled off to obtain an oily substance 15.09. This was subjected to column chromatography [elution solvent, ethyl acetate:
N-hexane properties: Oily infrared absorption spectrum ν::21α-1:2976.2
932,2824.1660゜1612.1568.1
4B6,1454°1432, Summer 392,134
2.1 330°1302.1260,1186,11
64°1108, J040,916,600 Proton nuclear magnetic resonance spectrum (δ ppm in CDC1*): 1.38 (6H
, d, J=6.1Hz).

2.26 (31-1, d, J=0.7Hz).

3.44 (3H, s).

4.0 1 (2H, t, J=5.1Hz).

4.2 1 (2H, t, J = 5.1 Hz).

4.60 (I H, hept 1ike, J =
6.1 Hz).

4.80 (2H, s).

5.95 (lH,d, J = 0.7)1z)
.

6.32 (IH, d, J=2.2Hz).

6.40 (IH, d, J = 6.40Hz) Mass spectrum (El) M/Z (%): 322 (M", 0.9), 2
91 (8,8).

261 (34,1), 260 (100,0).

259 (18,9), 219 (52,6).

205 (22,8), l　92 (52,1).

190 (50,1), 45 (54,8) Next, add methanol 60- to the obtained 5-methoxymethoxyethoxy-7-isoproboxy-2-methylchromone 6.49, then add 20-hydrochloric acid methanol reagent, Stirred at room temperature for 20 hours. Methanol in the reaction solution was distilled off under reduced pressure, extracted, washed, and dried, and then the solvent was distilled off under reduced pressure to obtain 6.1v of brown crude crystals. This was subjected to column chromatography [elution solvent: n-hexane:ethyl acetate-1 = 2, then ethyl acetate only, elution fractions 9.8Q to 15.51
2.99% of pale yellow crystals were obtained from 2. Further, this was recrystallized from ethyl acetate to obtain 2.59 colorless prism crystals. Based on the physical and chemical properties shown below, this colorless prism product has the following structural formula: 5-hydroxyethoxy-7-
It was determined to be isoproboxy-2-methylchromone.

3C Properties: Colorless prism infrared absorption spectrum ν2Iα-1 = 3352.2980, 1658, 1610°1562.
1434.1394, 1344°1332.1182.
1110,1182°1110.1092.1064 Proton nuclear magnetic resonance spectrum (δ ppm in CDC1*): 1.39
(6H,d, J = 6, IH*).

2.29 (3H, s).

3.92 (2H, t, J=4.3Hz).

4.19 (2H, t, J=4.3Hz).

4.61 (IH, m, J = 6.1 Hz).

4.82 (IH,br,), 5.99 (IH,s).

6.33 (IH, d, J=2.3H2).

6.45 (IH, d, J = 2.3 Hz) Mass spectrum (E[) M/Z (%): 27 B (1, M'), 261
(19).

260 (100), 232 (24).

219(42), 218(37), 217(27).

205 (62), 203 (23), 192 (91).

190(67), 189(31), 176(37).

161 (20), 160 (26), 69 (25) Example 21 27.09 of 5-hydroxy-7-iproboxy-2-methylchromone, the intermediate of Example 17, and 112.09 of potassium carbonate were added to 350 d of acetone. The mixture was dissolved and suspended in water, and 31.97 g of methyl bromoacetite was added dropwise. After stirring for 20 hours at room temperature and 18 hours at 30°C, potassium carbonate 50.39 and methylbumoacetate 15-
was added and stirred at 40°C for 6 hours. Extract the reaction solution,
The organic layer was washed with water, dried, and concentrated to dryness to obtain 48.29 g of a colorless oil. This colorless oil was determined to be 5-methoxycarbonylmethoxy-7-isoproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless oil Infrared absorption spectrum νCHCl″a-■: 1762.
1742, 1658, 1612゜1574.1520,
1422,1392゜1344.1332,1225,
1200°1188, 1 1 64. l 1 38,
1114゜1042.926,848 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.37 (
6H,d, J = 6.1 Hz).

2.27 (3H, d, J = 0.7 Hz).

3.80 (3H, s).

4.51-4.75 (IH, m).

4.75 (2H, s).

5.98 (l H, d, J = 0.7 Hz).

6.25 (lH, dj = 2.4 Hz).

6.46 (IH, d, J = 2.4H2) Mass spectrum (El) M/Z (%): s o 6 (i 7.2), 2
48(11,0).

247 (68,1), 21 B (11,5).

206 (13,3), 205 (100,0).

1 7 7 (10,6), 凰 76 (56,6).

148 (16,7) Example 22 To 5.9 g of 5-hydroxy-physobroboxy-2-methylchromone, which is the intermediate of Example 17, 75 g of dimethyl formaldehyde and 1.69 g of sodium hydride were added, and the mixture was heated to room temperature under a nitrogen atmosphere. The mixture was stirred for 2 hours. Then, 3.9 d of ethyl bromoacetate was added, and the mixture was further stirred for 1 hour. Water 30011i was added to the reaction solution, extracted with ethyl acetate, the ethyl acetate layer was washed, dried, and the solvent was distilled off to obtain 13.89 of a crude crystalline substance. This was subjected to column chromatography [elution solvent, n-hexane:ethyl acetate=
1:2], and 7.49 ml of crude crystal material was obtained from the elution fraction 0.7 yen, 7Q. This was recrystallized from ethyl acetate:n-hexane with stirring to produce a colorless powder of 6°7
I got g. This colorless powder substance was determined to be 5-ethoxycarbonylmethoxy-7-isoproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless powder infrared absorption spectrum νm': x C1-': 174
8.1664.1658, 1634°1614.157
4.14B6,1442゜1388.1350,134
6.1326°1272.1258, 1212.11B
8゜1178.1164,1138,1126゜110
8.814 Proton nuclear magnetic resonance spectrum (δ ppm1n CDCl5): 1.30 (3H,t, J = 7.1 Hz).

1.37 (6H, d, J = 6.1 Hz).

2.27 (3H, d, J=0.7Hz).

4.27 (2H, q, J = 7.1 Hz).

4.58 (IH, m), 4.74 (IH, s).

5.60 (IH, d, J=0.7Hz).

6.25 (IH, d, J=2.3Hz).

6.45 (IH, d, J = 2.3H) Mass spectrum (El) M/Z (%): 320 (8, M
'), 248(11).

247(62), 218(10), 206(13).

205(100), 177(10).

176(53), 148(18) (Hereafter, blank space) Example 23 5-methoxycarbonylmethoxy-7 obtained in Example 21
47.09 g of -isoproboxy-2-methylchromone was dissolved in 700 d of methanol, and 400 d of a 5% aqueous potassium hydroxide solution was added thereto, followed by stirring at room temperature for 1.5 hours. The reaction solution was adjusted to a pi of about 5 with 3N hydrochloric acid, poured into water, and extracted. The aqueous layer was adjusted to pH approximately 2 with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried to produce a colorless prism product.
I got a 9.

This crystalline substance was determined to be 5-carboxymethoxy-7-isobroboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless prism crystal Infrared absorption spectrum ν2: ejx-': 2400-
2900 (br), 1774°1752.1656.1
628.1608°1562.1438. l398. l
382°1364.1352. ! 326,1 22
4゜ttse, t summer 66.1122,944゜8
76.846,834 Proton nuclear magnetic resonance spectrum (δ ppa+ in acetone-da): 1
．． 375 (6H, d, J=5.86Hz).

2.382 (38, d, J=0.74)1z).

4.751.9 (IH, m).

4.844 (3H, s).

6.108 (lH, d, J=0.74Hz).

6.680 (l H, d, J = 2.1982).

6.730 (IH, d, J = 2.19Hz) Mass spectrum (El) M/Z (%): 292 (14, 9), 24
B(20,6).

247 (57,7), 21B (14,5).

206(23,2), 205(I　O0,0).

177 (27,0), 176 (74,2).

180 (l　j3.7), 14　B (37,6).

136(10,5) E, A Calculated value C: 61.6398H: 5
．． 517 Actual value C: 61.60 H: 5.94 Example 24 To 3.2 g of 5-carboxymethoxy-7=isopropoxy-2-methylchromone obtained in Example 23 was added 1 methanol.
Add 50d and 2.37 d of sodium methoxide and add 1
Stir for hours. The reaction solution was distilled off under reduced pressure to give 150% ether.
d was added to precipitate crystals, filtered and dried to obtain a crude crystal material.

By recrystallizing this from water, colorless fine crystals of 2.5
I got g. This crystalline substance was determined to be 5-(sodium carboxylate)methoxy-7-itubroboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

3C Properties: Colorless fine crystal infrared absorption spectrum νmm: e71-': 3410
(br), 1662, 1612° 1606.1490,
1432,1422°1400.1352.132B,
1272°1226.11B4, 1164.113B.

Supervisor 112,1094.1038.828゜700.64
4,612,572 Proton nuclear magnetic resonance spectrum (δ ppm in DJ): 1.349 (6H, d, J=6.1Hz).

2.312(3)(,s), 4.557(2H,s).

4.6-4.8 (l H, m).

6.039 (IH, s).

6.137 (LH, d, J=2.2Hz).

6.523 (IH, d, J = 2.2 Hz) Example 25 5-methoxycarbonylmethoxy-7 obtained in Example 21
-Isopropo, xy-2-methylchromone (5.09 g), propatool (80 Ili), and sulfuric acid (1.57 g.) were placed in a 200 d eggplant flask equipped with a reflux condenser, and heated under reflux for 1 hour. The reaction solution was cooled to room temperature and diluted with 300 ml of ethyl acetate.
After adding d, the mixture was washed, dried, and the solvent was distilled off under reduced pressure to obtain 6.09 g of 7-isopropoxy-5-propoxycarbonylmethoxy-2-methylchromone. This was subjected to column chromatography [elution solvent, n-hexane:ethyl acetate = 1:l], and the eluate fractions were 4.4Q to 8.
, 4.99% of a crude crystal was obtained from Oe. This was recrystallized from ethyl acetate-n-hexane with stirring to obtain colorless powder 3.39. This substance was determined to be 5-proboxycarbonylmethoxy-7-isoproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless powder infrared absorption spectrum ν2::α-1°1752.16
66.1614,1442゜1390.1346,12
06.118B.

1176.1164.1138.1126°1110.
814 Proton-extracted magnetic resonance spectrum (δ ppm in CDCl5): 0.91 (3)
1. t, J=7.3Hz).

1.37(6)(,d,J=6.1Hz).

1.62-1.73 (2H, m).

2.27 (3H, d, J = 0.7 Hz).

4.16 (2H, t, J=6.8H2).

4.58 (IH, m, J=6.1Hz).

4.75 (IH,s).

6.00 (LH, d, J -0.7Hz).

6.25 (l H, d, J = 2.28Z).

6.44 (l H,d, J = 2.2 Hz) Mass spectrum (EI) M/Z (%): 334 (M”, 8
), 248(13).

2 4 7 (72), 2 1 B (12), 2 0
6 (凰 5) 9205 (I 00), 177 (10)
.

176 (57), 148 (16), 43 (22) Example 26 5.09 of 5-carboxymethoxy-7-isopropoxy-2.methylchromone obtained in Example 24 was dissolved in 60 d of dichloromethane and heated to 0°C. Cooled.

After adding 4.09 d of dicyclohexylcarbodiimide there and stirring for 40 minutes, 2.5 d of ethyl anthranilate was added.
was added and stirred at 0°C for 4 hours. The reaction solution was poured into ice water and extracted with chloroform, and the nine organic layers were washed, dried, and concentrated to dryness under reduced pressure.

This was subjected to column chromatography [elution solvent: ethyl acetate = rI-hexane = 2:l], and the eluate fraction was 1.9
3.19 of colorless crystals of 7-isopropoxy-2-methyl-5-(2-ethoxycarbonylphenyl)aminocarbonylmethoxychromone were obtained from 50d-2550-.

The obtained compound 2.59 was dissolved in methanol cap 20-, and 5% sodium hydroxide solution 6011i was added.
The mixture was stirred at 40°C for 40 minutes.

The reaction solution was adjusted to pH approximately 2 with 6N hydrochloric acid, and the resulting precipitate was collected by filtration, washed, and dried under reduced pressure to obtain a starting material. The parent material was recrystallized from ethanol to produce colorless prism product 942.
．． 8R9 was obtained. This crystalline substance was determined to be 5-(2-carboxyphenyl)aminocarbonylmethoxy-7-isoproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

, Properties: Colorless prism crystal infrared absorption spectrum ν2:: 1ff-King 2972.
2928, 2596, 1698° 1650.1 822
,1 594,1 562°151B,1494,14
48,1434°1390.1348.133B, 12
96゜1270.1 256,1220.11B2゜1
142.1110.10B6,840° proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.29 (
6H, d, J = 5.9Hz).

2.30 (3H,!!), 4.79 (l H,s
).

4.70-4.84 (IH, m).

6.02(l　)(,s).

6.54 (IH, d, J = 2.4 H2).

6.73 (IH, d, J = 2.4 Hz).

7.23 (l H, dt 1ike).

7.62 (lH, dt 1ike).

7.94 (IH, dd 1ike).

8.30 (IH, d1ike).

11.55 (lH, s) Mass spectrum (El) M/Z (%): 411 (M”,
1.4), 393(21,9).

247 (17,1), 234 (33,5).

218 (24,3), 205 (24,4).

203(18,4), 193(14,6).

192 (100,0), l77 (23,2).

176 (88,4), 164 (16,7).

16 f(11,1), 148(17,3).

146 (16,8), 119 (31,9).

92 (13,4), 90 (13,7).

77 (11,3), 43 (17,0).

41(12,8) Example 27 4.29 of 5-carboxymethoxy-physoproboxy-2-methylchromone obtained in Example 23 was dissolved in 60 d of dichloromethane and cooled to 0°C. After adding 3.29% of dicyclohexylcarbodiimide there and stirring for 40 minutes, 2.99% of dicyclohexylcarbodiimide was added and heated to 0°C for 50 minutes.
Stir for hours. The reaction solution was poured into ice water, extracted with chloroform, dried, and concentrated to dryness under reduced pressure to obtain crude crystals.

The crude crystals were subjected to column chromatography [elution solvent, ethyl acetate:n-hexane=1:1], and the eluate fraction 28
Crystalline powder 3.29 was obtained from 50d-4950I11. The material was crystallized from ethanol to yield 2.79 colorless prism crystals. This crystalline substance was determined to be 5-(2-phenoxycarbonylphenyl)aminocarbonylmethoxy-7-isoproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

(Ph means phenyl group.) Properties: Colorless prismatic crystal infrared absorption spectrum νa: HeIl −': 317
2.3096, 3032.2980°1746.172
B, 1694, 1652° 1606.1 566.1
530,1488°1444.1396,1386,1
344°13301286.1268,1240°1
190.1164,1140,1110゜1 080.
1 056,1036,1 000゜9 14.844
．． 826,778,756° proton nuclear magnetic resonance spectrum (δ ppm+ in CDC13): 1.35 (
6H, d, J = 5.9 Hz).

2.25 (3H, s).

4.56 CI H, q, J = 5.9 Hz).

4.71 (2H, s), 5.91 (lH, s).

6.32 (l H, d, J = 2.4 Hz).

6.44 (l H, d, J = 2.4 Hz).

7.16-7.38 (6H, m).

6.72 (IH, dt, J=1.5, 7.3H,).

8.17 (l H, dd, J = 1.5.7.8
Hz).

8.24 (I H, dd, J -1,5,7,3Hz
).

11.36 (I H,s) Example 2B 4.79 of 5-hydroxy-7-iproboxy-2-methylchromone, the intermediate of Example 17, and 1.19 of sodium hydride to 1001 of dimethyl formaldehyde
1Ii was added, and the mixture was heated and stirred on an oil bath at 90° C. for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to 60° C., 4.99 g of 1-(3-chloropropyl)-4-methylbiperazine was added, and the mixture was heated and stirred on an oil bath for 3 hours. The reaction solution was cooled to room temperature, dimethylformamide was distilled off, and 150% of ethyl acetate was added.
and 200 d of water were added, extracted with ethyl acetate (100 W 1 x, +1=3), washed, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude oil tt, sy. This was distilled under reduced pressure using a Kugelrohr distillation apparatus to obtain 5.29 g of pale yellow oil (yield: 69%). This substance has the following structural formula based on the physical and chemical properties shown below.
[Determined to be 3-(4-methylpiperazyl)proboxyco-7-isoproboxy-2-methylchromone.

Properties: Pale yellow oily infrared absorption spectrum νcwa'a4" el -'
:2980.2940,2804.1658°160B
, 1568, 1462, 1432° 1390.1344
,1330,1180゜1 1 64.1 1 10,
1 090, 1 036°848.826 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 6.37 (I
H, d, J = 2.2 Hz).

6.32 (IH, d, J=2.2Hz) 5.95 (I
H, d, J = 0.7 Hz).

4.60 (IH, m).

4.09 (2H, t, J=6.8Hz).

2.62 (2H, t, J = 6.88.).

2.47 (8H, m), 2.28 (3H, s).

2.25 (3H, d, J-0.7Hz).

2.07 (2H, m).

1.38 (6H, d, J = 6.0 Hz).

Mass spectrum (El) M/Z (%): 374 (1, M
”), 304(21).

234(35), 193(15).

192 (I OO), 1 ” 13 (12), 97 (30
).

It was determined to be 70(73), 43(26), 42(17) methylpiperazyl)propoxy]-7-ituproboxy 2-methylchromone simalate.

Properties: Colorless powder infrared absorption spectrum ν: % HE elf''l: Example 29 5-[3-(4-methylpiperazyl)propoxy] to 7-ipropoxy 2-methylchromone obtained in Example 28 was added with diethyl ether to 5.29 Toyo Oo- was added and dissolved. To this was added dropwise 3.29 g of maleic acid dissolved in 200 g of diethyl ether, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was suction-filtered to obtain 11.99 g of crude crystals. A colorless powder 4.49 (yield 52%) was obtained by recrystallizing from methanol-diethyl ether.This substance has the following structural formula based on the following physical and chemical properties.
[3-(4-2976,2680,2596,1666
゜1608.1584.1574,1492゜13B6
,1362.1 190,1 166°1114.87
6.864 Proton nuclear magnetic resonance spectrum (δ ppm in CD5OD): 8.70 (1)
1. d, J=2.2Hz).

6.58 (l H, d, J = 2.2 Hz).

6.24(4)(,s), 4.76(IH,m).

4.23 (2H, t, J = 5.6 Hz).

3.61 (8H, m).

3.5 2 (2H, t, J = 5.6 Hz).

2.83 (3H, m), 2.3 8 (3H, s).

2.3 7 (2H, m).

1.37 (6H, d, J = 6.1 Hz) Based on physical and chemical properties, it was determined to be 5-(4-methoxymethoxybutoxy)-7-ituproboxy-2-methylchromone having the following structural formula.

Example 30 6.0 g of 5-hydroxy-7-iproboxy-2-methylchromone obtained in Specific Example 3 was mixed with 1 part of dimethylformamide.
30d and cooled to 0°C, 1.1y of sodium hydride was added and stirred at 0°C for 2.5 hours. 8.4g of 4-bromobutylmethoxymethyl ether
was added dropwise, the temperature was raised to room temperature, and the mixture was stirred at 80°C for 2.5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed and dried over anhydrous sodium sulfate. This organic layer was concentrated under reduced pressure to obtain a crude oil. Column chromatography [elution solvent, 0-3.3N (n-hexane: ethyl acetate = 1:2), 3.372-(n-hexane: ethyl acetate = 1:3)], 1.812- 4.0
8.0 g of eluted material was obtained from No. 512. This substance has the following properties: colorless oil infrared absorption spectrum ν=::tα-1:2976.2
932°28B0,1664°1610.1568.1
434,1390°1342.1330.11B4,1
164°113B, 1110.1088.1040 Proton nuclear magnetic resonance spectrum (δ ppta in CDCl5): 1.38 (
6H,d, J-6,1Hz).

1.84-2.05 (4H, m).

2.26 (3H, d, J = l, OHz).

3.36 (3H, s), 3.62 (3H, s).

3.62 (2H, t, J = 6, IH2).

4.06 (2H, t, J-6, 1Hz).

4.60 (IH, hept 1ike).

4.63 (2H, s).

5.95 (IH, d, J = l, Ooz).

6.29 (IH, d, J = 2.5 Hz).

6.37 (I H,d, J = 2.5 Hz) Mass spectrum (El) M/Z (%): 350 (M”, 7
．． 1), 305(11,7).

289 (15,1), 287 (27,2).

247 (83,3), 235 (20,8).

219 (29,2), 205 (54,0).

193 (65,0), 192 (51,6).

l゛77 (21,9), 176 (92,2).

14 B (22,3), 71 (20,2).

45 (100,0), 43 (28,8) High MS Calculated value: CtsH□. 0. = 350.17294 Actual value: CtsHtsos = 35.0.17658 Next, the obtained 5-(4-methoxymethoxybutoxy)-7-itsuproboxy 2-methylchromone was mixed with methanol 55111
1. Add hydrochloric acid methanol reagent 18I/Ii.
It was refluxed for 5 hours. Pour the reaction solution into water and dilute with ether for 3
The organic layer was extracted twice, washed, dried, and concentrated under reduced pressure to obtain a syrupy crude oil. Column chromatography [elution solvent, θ to 4.5Q (n-hexane: ethyl acetate = 1:2), ethyl acetate thereafter], and the eluate fraction 9
．． Colorless syrup-like substance 2 from 1512-16.5ff
．． I got 49. Based on the physical and chemical properties shown below, this substance has the following structural formula: 5-(4-hydroxybutoxy)
It was determined to be -7-itubroboxy-2-methylchromone.

Properties: Colorless oil Infrared absorption spectrum ν2;:l Neatα-1=3
4 12.2976.2932,2872゜1 660
, l 608. l 568,1434°1392.
1342, 1330. l 186°1166, I
K 10.1088 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.39 (6
H, d, J = 6, I H2).

1, 79 (2H, quin 1ike).

2, 09 (2H, quin 1ike).

2.28 (3H, d, J = 0.7 Hz).

3. 6 4-3. 8 0 (2H, br,
).

4.07 (2H, t1ike).

4.61 (IH, hept, l1ke).

5.99 (IH, d, J=0.7Hz).

6.28 (I H, d, J = 2.21-12)
.

6.39 (l H,d, J = 2.2 Hz) Mass spectrum (El) M/Z (%): 306 (M”, 1
7.6), 261 (12,5).

24B (10,7), 247 (62,9).

234 (20,8), 219 (42,8).

205 (47,2), 193 (22,1).

192 (100,0), l76 (48,3).

43(21,2) ighMS Calculated value: CI? I(!!05=306.14673 Actual value: C,?I-1..O,=306.14608
Example 3I 5-Hydroxy-7-ituproboxy-2-methylchromone 5.69 and sodium hydride 995 Add dimethylformamide 120 II 11 to JI9 and add 2 at room temperature.
Stir for hours. 6.59% of 6-bromohexylmethoxymethyl ether was added thereto, and the mixture was refluxed for 1 hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (+50dXj4)
After washing and drying with sodium sulfate, the solvent was distilled off under reduced pressure to obtain 12.4 g of an oily substance. This was subjected to column chromatography [elution solvent.

ethyl acetate:hexane-2:l], and the eluted fraction 1.
7.09 of a colorless oil was obtained from 512-4.5e. This substance was determined to be 5-(6-medoxymethoxyhexyloxy)-7-isopropoxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless oil Infrared absorption spectrum ν2*atα-1=2936.1
664.1638.1610°+568.1432. +
390.1340°1330.1184.1164.1
138° proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 6.36 (l
H, d, J = 2.3 Hz).

6.28 (l H, d, J = 2.3 H2).

4.61 (2H,s), 4.61 (lH,m)
.

4.02 (2H, t, J = 6.5 Hz).

3.35 (31-1, s), 2.26 (3H, s).

1. 9 6-1. 8 9 (4H, m)
.

1.68 1.47 (8H, m).

1.38 (6H, d, J = 6.1 Hz).

Mass spectrum (El) M/Z (%): 333 (36)
, 317(58).

247(100), 234(25).

219 (38), 205 (52), +93 (52).

192(71), 176(64) Next obtained 5-(6-medoxymethoxyhexyloxy)-
To 7.3 g of 7-itubropoquine-2-methylchromone and 1207 g of methanol was added 20 g of a hydrochloric acid-methanol solution, and the mixture was heated and stirred for 5 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (200 aQ), dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.2 g of an oil. This was subjected to column chromatography [elution solvent: ethyl acetate], and 5.7 g of a colorless solid was obtained from the elution fractions 3.012 to 95I2. This was crystallized from ethyl acetate to obtain colorless prism crystals of 5.49C (yield: 85%). This substance was determined to be 5-(6-hydroxyhexyloxy)-7-ituproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless prism product Infrared absorption spectrum ν2211 ('I-1: 3480
．． 2948.2924, 1658°160B, l 39
4,1322,1264°1224.117B, 116
4,1112゜oss Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 6.37 (1
)(, d, J = 2.21(z).

6.28 (lH, d, J=2.2Hz).

5.96 (I H, s), 4.60 (l H, m).

4.02 (2H, t, J = 6.4 Hz).

3.66(2)1. dd, J=5.9, 11.5Hz)
.

2.26 (3H, s).

1.96-1.85 (4H, m).

1.66-1.54 (8H, m).

1. 3 8 (6H, d, J -6, 1Hz) Mass spectrum (El) M/Z (%): 334 (M'', 1
8), 247(100).

219(53), 205(55), 193(37).

192 (93),! 76 (65), 41 (41) Example 32 100M1 of dimethylformamide was added to 4.7 g of 5-hydroxy-7-isopropoxy-2-methylchromone and 829 m9 of sodium hydride, and the mixture was stirred at room temperature for 2 hours. To this was added 8-bromooctatool 6,9.9, and the mixture was heated under reflux for 1 hour. Cool the reaction solution to room temperature,
The extract was extracted with ethyl acetate (200ad! x 4), washed, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 13.69% of an oil.

This was subjected to column chromatography [elution solvent, ethyl acetate:n-hexane=2=1, 79. Ethyl acetate], 5.89% of a colorless oil was obtained from the eluate fractions 6.512 to IO, 5ff. Crystallization from acetone yielded 4.79 colorless prisms (yield: 65%). This substance was determined to be 5-(6-hydroxyoctyloxy)-7-iproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

Properties: Colorless prism product Infrared absorption spectrum ν2azc11-'22924.
2848, 1656, 1606° 1394.1336,
1324. l 272°1160.1116.1090 Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 6.36 (IH
, d, J=2.2Hz).

6.28 (IH, d, J = 2.2 Hz).

5.96 (IH, d, 0.7Hz).

4.60 (IH, m).

4.01 (2H, t, J = 6.4 Hz).

3.65 (2H, dd, J = 6.1.l f, 8Hz
).

2.2 5 (3H, d, 0.7Hz).

2.2 5-2.1 7 (2H, m).

1. 9 3-1. 8 5 (4H, m).

1.61-1. 4 3 (101 (, m).

1.38 (6H, d, J = 6.1Hz) Mass spectrum (El) M/Z (%): 362 (M”, 13), 261
(24).

248(19), 247(100).

234(10), 219(51), 205(53).

193(41), l 92(81), 176(61)(
Example 33 6.09 of 5-hydroxy-7-isopropoxy-2-methylchromone, which is the intermediate of Example 17, was dissolved in dimethylformamide 60, and 1.2-epoxyoctane 2
2- and trimethylbenzylammonium hydroxide2. Od was added and stirred at 80°C for 24 hours. The reaction mixture was concentrated to dryness under reduced pressure, the resulting reaction mixture was dissolved in ethyl acetate, the organic layer was washed, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The resulting reaction mixture was subjected to column chromatography [elution solvent, n-hexane:ethyl acetate = 1:1], and the elution fraction was 3.75C.
2.09 of a colorless oil was obtained from ~6.5Q.

This crystalline substance was determined to be 5-(2-hydroxyoctoxy)7-iproboxy-2-methylchromone having the following structural formula from the physical and chemical properties shown below.

■(3C Properties: colorless oily infrared absorption spectrum ν ::';' (Wll -'
:33B4,2928.2864,1658°161
0.1568.14B6,1454°1432, +3
94.1344, 13301264.1186, 116
6.1138°1110.1092,1036,914
゜846.826,664 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 0.88 (3H
, t 1ike).

1.38 (6H, d, J=6.1 Hz).

1.40-1.68 (l OI(,m).

2.28 (3H, d, J = 0.7 Hz).

3.79 (JH, t 1ike) 3.92-1.
08 (I H, m).

4.20 (I H, dd, J = 8.8.2.7
Hz).

4.60 (l H, hept 1ike, J =
6, f Hz).

5.98 (I H,d, J = 0.7 Hz)
.

6.34 (IH, d, J=2.4Hz).

6.43 (I H, d, J = 2.4 Hz)
Mass spectrum (C1-MS) M/Z (%) 3 6
3(MH+), 2 3 5Hi g h mass spectrum calculation value Ct+Hs. 0,362.2093°Actual measurement value C1
, IL. 0.362.2089° Example 34 4.09 of 5-hydroxy-physoproboxy-2-methylchromone, the intermediate of Example 17, was dissolved in dimethylformamide 601111, and 4.8 d of 1.2 epoxybutane, ) Limethylbenzylammonium hydroxide 1.2- was added, and the mixture was stirred at 80°C for 24 hours.

The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The resulting syrupy reaction mixture was subjected to column chromatography [elution solvent, n-hexane:ethyl acetate=
1=2], a colorless oily substance of 0.799% was obtained from the elution fraction 2.4f2 to 4.35.This substance has the following structural formula based on the physical and chemical properties shown below. -hydroxybutoxy)-7-ituproboxy 2-methylchromone.

3C Properties: Colorless oil infrared absorption spectrum ν::2"C11l-':
33B4, 2976.2932, 2876°1660.
1610, 1568.14B6゜1454.1432,
1392, 13441330, +262.1186.1
1101090.1034,912,844° Proton nuclear magnetic resonance spectrum (δ PPI in CDC13): 1.02 (3
H, t, J = 7.3) (Z).

1.38 (6H, d, J=6.IH2).

1.48-1.78 (2H, m).

2.28 (3H, d, J = 0.7 Hl).

3.81 (IH, t1ike) 3.86-4.02 (l H, m).

4.2 I(l H, dd, J = 8.5, 2.4Hz
).

4.61 (l H, hept 1ike, J = 6
．． 1 Hz).

5.98 (IH, d, J = 0.7 Hz).

6.34 (l H, d, J = 2.4 Hz).

6.44 (IH, d, J = 2.4Hz) Mass spectrum (CI-MS) M/Z (%); 307 (MH+), 2
35 151-1i mass spectrum calculation value C+vH*tOs 306.1467 actual measurement value C,
,H,,0,306,1470.

Example 35 Example! 5-Hydroxy-physoproboxy-2-methylchromone IO,Oy, the intermediate of 7, was dissolved in dimethylpolamide tso, 4, and after cooling to 0°C, 2.09% of sodium hydride was added and stirred for 30 minutes. . Bromoacetaldehyde-dimethyl acetal 7.5d
was added and stirred at 120°C for 6 hours. The reaction solution was poured into ice water and extracted with diethyl ether. The organic layer was washed, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure.

The reaction mixture was subjected to column chromatography [extraction solvent, ethyl acetate], and the elution fraction was 880I/Ii to 1680
- Colorless prism crystals 9,69 were obtained. Based on the physical and chemical properties shown below, this substance has the following structural formula: 5-(2
,2-dimethoxyethoxy)-physoproboxy2-
It was determined to be methylchromone.

Properties: Colorless prism product Infrared absorption spectrum ν2==α−1=2964.29
32,1660,1632゜1612.1570,14
86,1452°1432.1390,1346,13
34゜11'88,1138.1110.1080゜1
042.840 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.37 (6
H, d, J = 5.91-12).

2.26 (3H, d, J = 0.7) (z).

3.58 (6H, s).

4.03 (2H, d, J-5, 1Hz).

4.59 (I H, hept 1ike, J = 5
．． 9 Hz).

4.83 (1)1. t, J = 5, l H2)
.

5.95 (IH, d, J = 0.7 Hz).

6.29 (l)I, d, J = 2.2 Hz)
6.40 (I H, d, J = 2.2 Hz) Mass spectrum (CI-MS) M/Z (%): 383 (
MH+), 235 E, A calculated value, C: 63.34, H: 6.88 actual value,
C: 63.41, I-1: 6.96 Example 36 Example! 5-hydroxy-7-itubroboxy-2-methylchromone, 516.69, which is an intermediate of 7, was dissolved in acetone IOd, and potassium carbonate, 894.319, was dissolved in 4.
The mixture was stirred at 0°C for 1 hour, and 3.3-methyl iodide was further added. After 48 hours, the reaction solution was poured into ice water, extracted with ethyl acetate, the solvent was distilled off from the extract, and the residue was subjected to silica gel chromatography [elution solvent: ethyl acetate].
Colorless prism product 4 from 510d to 900I11
37.7119 (yield 79.9%) was obtained.

The physical and chemical properties of this compound are described in JP-A No. 362, 1988.
5-Methoxy-7-ituproboxy 2- described in No. 74
This was consistent with the physical and chemical properties of methylchromone.

Next, 6.19 ml of 5-methoxy-7-iproboxy-2-methylchromone was dissolved in 200 d of ethanol, and Raney nickel (W2) 6- was added. Catalytic reduction was carried out at normal pressure at 25° C. When the hydrogen of 680111i was absorbed, stirring was stopped and the catalyst was filtered.

Concentration was performed under reduced pressure to obtain a syrupy residue. This residue is n
-4.6g of colorless crystals recrystallized from hexane-ethyl acetate
I got it. This substance was determined to be 5-methoxyfiisoproboxychroman-4·one having the following structural formula based on the physical and chemical properties shown below.

Properties: Colorless crystal ultraviolet absorption spectrum λ (log ε); 283.4 (4
, 27), 212.9 (4, 35) Infrared absorption spectrum ν2a: C1! -':2972.2928.1676
．． 160B.

+572.1424,1272,1262°1218.
1198.1176.115B.

1122.1094.814 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.36 (6
H, dd, J = 1.5.6.1 Hz).

1.46 (3H, d, J = 6.4 Hz).

2.58 (IH, d, J = 5.9Hz) 2.59 (l
H, d, J = 9.5 Hz).

3. 8 6 (3H,s), 4. 5 1 (
l H, ddd, J = 5.9.6.4.9.5
Hz).

4.57 (I H, Sep 1ike, J = 6.
1 Hz).

6.02 (I H,d, J = 2.28Z)6.
04 (I H, d, J = 2.2 Hz) Mass spectrum (c I -MS) M/Z (%): 250 (M
”, 61.6), 208 (39,9).

179 (29,4), l 67 (13,0).

166 (100,0), 138 (28,1).

137 (11,4), 123 (11,0).

69 (33,9), 66 (11,8).

43(22,1) Example 37 ■Corn starch 24.99■Crystalline cellulose 15. Oy■Carboxymethylcellulose calcium 2.09 ■Light anhydrous silicic acid 0.2g ■Magnesium stearate 0.49 Same as in Example 1 8 7
．． 5 Total 50.09 According to the above recipe, ■ to ■ were mixed uniformly and compression molded using a key press to obtain a portion of tablets 200119.

This tablet contains 301 g of the compound,
Adults: Take 1 to 23 tablets a day in several divided doses.

Example 38 ■ Crystalline cellulose 80.59 ■ Magnesium stearate 0.59 ■ Calcium carboxymethyl cellulose 4.09 ■ Compound obtained in test 6 ts, o9 total 50
．． Oy According to the above recipe, mix ■, ■, and part of ■ uniformly, compression mold, crush, add remaining amounts of ■ and 200119 tablets were obtained.

This tablet contains Compound 30q, and adults should take 1 to 23 tablets per day in several doses.

Example 39 ■ Crystalline cellulose 3o, s9 ■ 1O% hydroxypropyl cellulose ethanol solution 50.09 ■ Carboxymethyl cellulose calcium 4.09 ■ Magnesium stearate 0.590 Example 12
Compound obtained in 15.09 total xoo, og Mix ■, ■, and ■ uniformly according to the above recipe, wet it by a conventional method, granulate it with an extrusion granulator, dry and crush it, (1) and (2) were mixed and compressed using a tablet machine to obtain a portion of 20019 tablets.

This tablet contains the compound 5ox9,
Adults: Take 1 to 23 tablets a day in several divided doses.

Example 40 ■Corn starch 39.99■Magnesium stearate 0.49■Calcium carboxymethyl cellulose 2,09 0Light silicic anhydride 0.29■Compound obtained in Example 18 7.59Total 50.09 According to the above recipe (1) to (2) were uniformly mixed, compression molded using a compression molding machine, pulverized using a crusher, and sieved to obtain granules.

This granule 19 contains compound 150119, and is taken by adults in doses of 0.2 to 4.6 g in several doses per day.

Example 4I ■ Crystalline cellulose 249 ■ 10% hydroxypropyl cellulose ethanol solution 189 ■ Product obtained in Example 24 8 g Total 509 According to the above recipe, ■ to ■ were mixed uniformly and made into a paste. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

This granule 19 contains Compound 160 [9, and is administered in doses of 0.2 to 4.3 g in several doses per day for adults.

One capsule of this preparation contains compound 33.219, and adults should take I to 21 capsules in several doses per day.

Example 43 ■ Distilled water for injection Appropriate amount ■ Grape M 200119 ■ Compound obtained in Example 42 20m9 total amount
5- After dissolving ① and ② in distilled water for injection, they were injected into the ampoule of 5- and autoclaved at I 21 'C for 15 minutes to obtain an injection.

Example 42 ■Corn starch 41. ! M ■ Light silicic anhydride 0.29 ■ Compound obtained in Example 30 8.3 g Total 50.09 Mix ■ to ■ uniformly according to the above recipe, and mix at 200 N
9 was filled into a No. 2 capsule.

Example 44 ■ Distilled water for injection ■ Soybean oil ■ Phospholipid ■ Glycerin ■ Total amount of compound obtained in Example 59 R amount 10, d (1 to 3%) Appropriate amount 5 m9 tooM! The compound was dissolved in ① while heating, and then ② was added to completely dissolve it. Separately, add (■) to distilled water for injection heated to the same temperature to make it homogeneous. Add the solution to the soybean oil phase and emulsify it.
A W-type emulsified injection was obtained.

Claims (4)

[Claims] (1) Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, R_1 represents a hydrogen atom or an acetyl group, and R
_2 is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, an alkyl group having a hydroxyl group in the 1st position, or a formula A(CH_2)_nX
A (In formula A, n represents 1 to 6, and X is a hydroxyl group, lower alkoxyl group, carboxyl group, sodium carboxyl group, alkoxycarbonyl group, methoxymethoxyl group, dimethoxymethyl group, methylpiperazyl group,
-carboxyphenyl)aminocarbonyl group, (2-ethoxyphenyl)aminocarbonyl group or (2-phenoxyphenyl)aminocarbonyl group. ), and R_3 represents a hydrogen atom methoxymethyl group, an alkyl group having 1 to 7 carbon atoms, or formula A. However, when R_1 represents a hydrogen atom, R_2 represents a hydrogen atom or a methyl group, R_3 represents a hydrogen atom, a methoxymethyl group, or a propyl group, and when R_1 represents an acetyl group, R_2 represents a hydrogen atom or a methyl group. , excluding compounds in which R_3 represents a hydrogen atom or a methyl group. ) chromone derivatives. (2) Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼II A chroman derivative represented by (3) Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, R_1 represents a hydrogen atom or an acetyl group, and R
_2 is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, an alkyl group having a hydroxyl group in the 1st position, or a formula A(CH_2)_nX
A (In formula A, n represents 1 to 6, and X is a hydroxyl group, a lower alkoxyl group, a carboxyl group, a sodium carboxyl group, an alkoxycarbonyl group, a methoxymethoxyl group, a dimethoxymethyl group, a 3-(4-methylpiperazyl) group) , (2-carboxyphenyl)aminocarbonyl group, (2-ethoxyphenyl)aminocarbonyl group or (2-phenoxyphenyl)aminocarbonyl group.), and R_3 is a hydrogen atom, a methoxymethyl group,
Represents an alkyl group having 1 to 7 carbon atoms or formula A. However, when R_1 represents a hydrogen atom, R_2 represents a hydrogen atom or a methyl group, R_3 represents a hydrogen atom, a methoxymethyl group, or a propyl group, and when R_1 represents an acetyl group, R_2 represents a hydrogen atom or a methyl group. , excluding compounds in which R_3 represents a hydrogen atom or a methyl group. ) An anti-allergic agent whose active ingredient is a chromone derivative. (4) Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼An anti-allergic agent containing a chroman derivative represented by II as an active ingredient.