JPH01242540A - Novel chalcone derivative and antiulcer agent containing said derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1-R6 are H, OH, X or OX (X is straight-chain alkyl which may be substituted by OH, halogen or alkoxyl) or, together with the adjacent groups, represent alkylenedioxy, A is OH or O-Y-Z (Y is straight-chain alkylene; Z is carboxyl, alkoxycarbonyl or OH); B is -CH2-, -CO or -CH(OH)-; the dotted line represents single or unsaturated bond]. EXAMPLE:1-(2,4-6-Trihydroxyphenyl)-3-(3,4,5-trihydroxyphenyl)-1 -propanone. USE:Ad antiulcer agent. PREPARATION:Groups OH of compounds expressed by formulas II and III as raw materials are partially or wholly protected and then reaction is carried out to provide a compound expressed by formula IV, which is subsequently deprotected to afford the aimed substance.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to aromatic compounds, particularly chalcone derivatives, and antiulcer agents containing the derivatives as active ingredients.

The chalcone derivative according to the present invention is a novel substance that has not been described in any literature and is useful as a medicine, for example, it is heavily used in the technical field of anti-ulcer agents.

[Prior art and problems] In recent years, the number of patients with peptic ulcers due to stress, irritation from drugs, excessive secretion of gastric acid, etc. has been increasing. Development of H2 receptor antagonists and the like is progressing. However, these drugs have not reached the level of ideal and excellent drugs from the point of view of completely curing ulcers.

Therefore, there has been a need for substances with better anti-ulcer effects.

[Means for solving problems]

The present inventors conducted intensive research to solve the above-mentioned problems, and as a result, they discovered that the chalcone derivative of the present invention has an antiulcer effect. That is, the present invention relates to the general formula [wherein R1 to R6 are the same or different and represent hydrogen, OH, A represents OH or 0-Y-Z; However, Y represents a straight chain alkylene; Z represents a carboxyl, alkoxycarbonyl or hydroxyl group; -111 means a single bond or an unsaturated bond.

However, this excludes compounds in which B is ゝC<2', A represents OH, and the following (a) or (b) is satisfied: (a) 5'
Compounds substituted with a propyl or 3-isopentyl group at position; (b) Compounds substituted with Olli at the 4'-position (and/or 6'-position), 3-position and 4-position. ] and an antiulcer agent containing it as an active ingredient.

In the compound of general formula (1), straight-chain alkyl groups in X include methyl, ethyl groups, etc., and halogens include bases, bromine, iodine, or fluorine. Examples of the alkylenedioxy group include methylenedioxy and ethylenedioxy groups.

Further, among Y, linear alkylene includes methylene, ethylene, and the like. Among Z, the alkoxycarbonyl group broadly includes, for example, those in which 11 of the carboxyl group is substituted with the various alkyl groups described above.

The unsaturated bond means a double bond.

In addition to the above-mentioned free chalcone derivatives, the present invention includes compounds protected with protective groups, and it is a matter of course that the present invention also includes their salts, esters, and the like.

Compound (1) according to the present invention includes, for example, a hydroxy-substituted acetophenone represented by the following formula (II) and (III)
It can be produced by the following method using the hydroxy-substituted benzaldehyde represented by as a raw material.

1'lH For example, by protecting some or all of the OH groups of these starting compounds to form compounds (II'), (II''), and (Ill'), and reacting both to form compounds having a chalcone skeleton ( IV) or (■'): Reaction formula (A) (
II') (II'') (III') These chalcone derivatives (IV) or (■') are then reduced to convert the double bond in the hydrocarbon chain connecting both phenyl groups into a single bond (V ) or (V′), and then remove the protecting group to obtain the target compound (Vl): Reaction formula (B) (V[) In the above reaction, when a protecting group is added to the starting compound (IIL (I[[) The reaction to be introduced may be, for example, by reacting chloromethyl methyl ether and the starting compound at room temperature or with heating in the presence of diisopropylethylamine, but if necessary, the reaction may be carried out in the presence of a base such as dimethylaminopyridine. Alternatively, other protecting group introduction reactions can be used as appropriate.

In addition, the compound (n
'), (II'') or (■') may be produced.

As reaction formula (A), any reaction can be used as long as it is capable of bonding acetophenone into which a protecting group has been introduced and benzaldehyde.

For this purpose, for example, a reaction to condense the two can be carried out in a conventional manner using various condensing agents such as acid-base condensing agents. Examples of condensing agents include potassium hydroxide or sodium hydroxide. These bases can be used to condense both raw materials in ethanol, dimethyl sulfoxide, or other single or mixed organic solvents.After the reaction is complete, neutralize with acid to remove the chalcone skeleton. Compounds (IV) and (IV') having the following formula are obtained.

In reaction formula (B), the reduction reaction is first carried out using hydrogen in the presence of a catalyst with increased activity, such as a suitable carrier or a catalyst with increased activity such as baradium carbon (ρd-c), Raney nickel catalyst, platinum black, or platinum oxide. Although a catalytic reduction method is used, other catalytic reduction methods can also be used as appropriate. In addition to catalytic reduction, other reduction methods can also be widely used. especially,
For example, a method using an ethyl acetate solution of Pd-C on which hydrogen has been adsorbed is a suitable method for carrying out this reaction.

Next, the protecting group is removed to return it to a hydroxyl group, and for this purpose, conventional methods commonly used for removing protecting groups, such as adding methanol hydrochloric acid to the organic solvent solution of (V) or (V'), are used as appropriate. be done.

In order to change Oll at the 2-position to 0-CIl□-COOC)13, that is, to carry out reaction formula (C) or (C'), anhydrous potassium carbonate and potassium iodide are combined in a nitrogen atmosphere. Methyl 2-bromoacetate may be allowed to act in the presence of sodium hydride or in the presence of sodium hydride.

(Blank below next summer) (■) Then, when the protecting group is removed from the above-mentioned compound (■) or (■) by the method described above and OR' is changed to 011, the target compound according to the present invention can be obtained.

If this is then hydrolyzed, the 2-position ester group -0-CHz-COOCIIi, which is also one of the target compounds, is obtained.
A compound having a free carboxylic acid group -〇-CIl□-COOI+ is obtained. For hydrolysis, for example, a solution of potassium hydroxide or sodium hydroxide dissolved in an organic solvent such as alcohol or water can be used, but the method is not limited to this method, and hydrolysis using an acid or an alkali can be used. The conventional method is used as appropriate.

Further, a compound in which a substituent, for example, an isopentyl group is introduced into the acetophenone moiety of the target compound, can be produced as follows.

That is, a hydroxy-substituted acetophenone having a 3-methyl-2-butenyl group introduced at the 3-position shown in the following reaction formula (D) is alkylated, and then reduced as described above to obtain an isopentyl compound.

The isopentyl compound thus obtained is condensed with protected benzaldehyde to produce a compound having a chalcone skeleton, and the OH at the 2-position of acetophenone is 0-CIl□-
COOCH3 and this compound is hydrolyzed to 0-C1
The target compound (IX) designated as 1z-GOOR can be obtained.

0OH (IX) In addition, the compounds of the present invention in which the carbon chain connecting the acetophenone moiety and the benzaldehyde moiety is changed from the 1-position oxo-substituted product to the hydroxy-substituted or unsubstituted product as described above can be produced as follows. (Next summer and below) All of these reactions are reduction reactions, but by controlling the degree of reduction by changing the type and amount of reducing agent used, reaction (E) or (F) can be achieved. can do.

For example, reaction (E) can be carried out by using aluminum chloride and lithium aluminum hydride together in required amounts, or reaction (F) can be carried out by using lithium aluminum hydride alone.

After completion of these reactions, various target compounds can be freely produced by the methods described above.

In addition, compound (V) can be converted to compound (■
) and then reduction to obtain another target compound (X); (■) (X) In other words, according to reaction (G), the methoxycarboxymethoxy group at the 2-position is changed to a hydroxyethoxy group. At the same time, the oxo at position 1 of the carbonaceous chain that connects the two phenyl groups can be changed to a hydroxyl group.

Above, R3-6. Although we have described the production of compound (I) in which The following compounds have also been produced and are included in the present invention.

(1) 1-(2,4,6-tris(methoxymethoxy)phenyl) -3-(3,4,5-1-lis(methoxymethoxy)phenyl)-1-propanone (2) 1
-(2-carboxymethoxy-3-butyl-4,6-cymethoxyphenyl)-3-(4-methoxyphenyl)propane (3) 1-(2-methoxymethoxy-3-isopentyl-4,6-cymethoxyphenyl) methoxyphenyl)-3-(4-methoxyphenyl)-1-propanol (4) 1-(2-hydroxy-4,6-simethoxyphenyl)-3-(4-methoxyphenyl)-1-propano All of the compounds represented by the general formula ([) are useful as medicines or pharmaceutical intermediates, have particularly excellent anti-ulcer effects, and are used alone or in combination as anti-ulcer agents. Furthermore, if necessary, it can also be used in combination with various medicines including other anti-ulcer agents.

Hereinafter, the anti-ulcer effect of the compound represented by the general formula (r) will be explained with reference to experimental examples.

Experimental Examples 1 to 4 The compound of formula I was added to 0.5% CMC-Na (carboxymethylcellulose sodium solution) to male Wistar rats (10 rats per group) weighing 180 to 200 g that had been fasted for 24 hours. The suspension was administered intraperitoneally or orally, and 30 minutes later, 1 d of a mixture of 150 mM hydrochloric acid and 60% ethanol was administered orally. 150mM hydrochloric acid-60%
One hour after administration of the ethanol mixture, laparotomy was performed, and the length of the single-member wound site on the gastric mucosa was defined as the mucosal damage coefficient, and compared with the control group. A 0.5% CMC-Na solution containing no compound of formula I was administered intraperitoneally or orally to the control group. Tables 1 to 4 show the inhibition rates calculated using the following formula.

A: Value of control group B: Value of compound administration group (1) Results of anti-ulcer test by oral administration (dose: 30 mg/kg) Table 1 (2) Results of anti-ulcer test by oral administration (administration Amount: 30 mg/kg) (3) Results of anti-ulcer test by oral administration (1 dose: 100 mg/kg) Table 3 (4) Results of anti-ulcer test by 1 m intracavitary administration (dose:
100mg/kg) As is clear from the experimental examples in Table 4 and above, the compound of formula I exhibits excellent anti-ulcer activity.

Therefore, the drug of the present invention containing this chalcone derivative as an active ingredient is an excellent anti-ulcer agent.

Furthermore, the compound of formula I was administered to ddY male mice at Ig/kg.
No deaths were observed after oral administration.

Thus, the compound of formula (1) has low toxicity and high safety.

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

-m2 compounds can be administered to animals and humans as such or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, and may include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and suppositories. It will be done.

In order to achieve the desired effect as an oral agent, an adult dose of 100 to 900 mg of the compound of the general formula should be administered in divided doses several times a day, although this will vary depending on the age, weight, and severity of the disease of the patient. It seems appropriate to take it.

Oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, cornstarch, inorganic salts, and the like.

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 1 Starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, low substituted hydroxypropyl heptylulose.

[Surfactant] Sodium lauryl sulfate, soy lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant 1 Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

Furthermore, the compound of General 2 can be administered as a suspension, emulsion, syrup, or elixir, and these various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, it is usually necessary to administer 0.1 to 30 mg of the compound of the general formula per day intravenously for adults, although this will vary depending on the age, weight, and severity of the disease of the patient. , intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and diluents generally include distilled water for injection, physiological saline, Butoki 13 aqueous solution,
Vegetable oils for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. can be used. Furthermore, if necessary,
Bactericides, preservatives and stabilizers may also be added. In addition, from the viewpoint of stability, this parenteral ff1J can also be filled into a vial or the like, 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, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

The present invention will be explained specifically and in detail by Examples regarding the synthesis of the compounds according to the present invention, and Preparation Examples regarding the preparation of drugs, but the present invention is not limited thereto.

Example 1 l-(2,4,6-1-lihydroxyphenyl)-3-
(3,4,5-)lihydroxyphenyl)-1-propanone (1) 2',4',6'-tris(methoxymethoxy)
Acetophenone (2', 4', 6'-) diisopropylethylamine was added dropwise to a dimethylformamide solution of hydroxyacetophenone and dimethylaminopyridine while heating to 50°C, and the mixture was stirred. Next, the reaction mixture was added with water, extracted with diethyl ether, the solvent was distilled off, and 2', 4'
, 6'-1-lis(methoxymethoxy)acetophenone (yield 65%) was obtained.

Molecular formula: C, +12°O, (300) Melting point: 39.
5-40.5"C Infrared absorption spectrum ν□xcm-' (KBr): 2
968, 1710. 1606. 1246. 12
32. 1220°1154, 1114.1078.1
046.1024.924°908,818 Proton nuclear magnetic resonance spectrum (200MZ) δppm
.

J oz, CDCh: 62.49 (3■, S), δ3. , 16(S), 63.
47(S).

65.14 (S), 65.15 (S), δ6.51 (
2+1.5)(2) 3.4.5-tris(methoxymethoxy)benzaldehyde 3,4.5-trihydroxyhenzaldehyde monohydrate I'l1 1.0 g (5.8 mmol) was used as a raw material. , dissolve this compound and 0.1 g of dimethylaminopyridine at night 1.
Diisopropylethylamine was stirred into 5ml. While cooling with water, 6.5 ml of chloromethyl methyl ether was added dropwise to the mixed solution, stirred for about 30 minutes, and then further stirred overnight at room temperature. Water was added to the reaction mixture, extracted with diethyl ether, washed with water, dried (anhydrous sodium sulfate), and then the solvent was distilled off. Hexane was added to the residue, which was solidified in a freezer, washed with cold diethyl ether-hexane system, and collected by filtration to obtain 1.16 g (70%) of the title compound.

Molecular formula: C+x11+sOr<286) Melting point: 53.
5-54.5°C Infrared absorption spectrum v, 1. Xcm-' (KB
r) :2932, 1694, 1494,
1454, 1440, 1382.

1322, 1300.1162.1152, 1138,
1112.

1058, 1050.942 Proton nuclear magnetic resonance spectrum (200 MZ) δpp
m.

Juz. (CDCh): 63, 69 (6+1, S), 63.80 (3+1
,S), δ5.42(21+.S), δ
5.45 (411.S), δ7.56 (2H,S
)(3) 2', 3, 4. 4', 5, 6.
1.0 g of the compound obtained from 6'-hexakis(methoxymethoxy)chalcone (1) and compound 1 obtained from (2),
To 0 g of ethanol iotIi solution, 8 m# of saturated potassium hydroxide in ethanol was added and stirred at room temperature overnight.

The reaction mixture was poured into a large amount of water, neutralized using dilute hydrochloric acid, and the precipitated solid was collected by filtration. The filtered solid was dissolved in ethyl acetate, washed with water, dried, and then the solvent was distilled off. When the concentrate was crystallized from ethyl acetate-diethyl ether-hexane system, the title compound was crystallized as pale yellow needles.
．． 60g (85%) obtained.

Molecular formula: Czyl1360+ * (568) Melting point:
105.0~106.0°C Infrared absorption spectrum I'maxCm-' (KB
r): 1650, 1608, 1156. 1
110, 1080, 1048.

1018, 962 Proton nuclear magnetic resonance spectrum (200 MZ) δpp
m.

'82. (CDCI3); 63, 40 (6H, S), δ3.50 (6H, S)
, δ3.52 (311,S), 63.61 (
3H,S), δ5. 11 (4+1, S)
.

65, 17 (2H, S), δ5.19,
5.20 (S, 6+1).

66, 57 (2H, S), 66, 87 (In, a,
J=16.9).

67,04(LH,S), δ7.23(ill,d
, J・15.9) (4) 1- (2, 4.6
-) lis(methoxymethoxy)phenyl) -3 -
(3,4.5-tris(methoxymethoxy)phenyl]-1-propanone MOM Add 517.5 g of the compound obtained in (3) to 50 ml of ethyl acetate solution of 2.6 g of Pd-C to which hydrogen has been adsorbed in advance. 200d solution was added, and while stirring strongly, hydrogen was further adsorbed.After the adsorption was completed, Pd was added using Celite.
-C was removed and then the solvent was distilled off. The concentrate was diluted with ethyl acetate (
When crystallized from a small amount)-diethyl ether-hexane system, 17.1 g of the title compound was obtained as a white solid (at 10 p.m.
0%) obtained.

Molecular formula: CzJzsO+3 (570) Melting point: 55.
0 to 55.5°C Infrared absorption spectrum νmaxcm-' (KBr):
1696, 1608, 1594, 1156, 1
110, 1080.

1052, 1018. 968, 920 proton nuclear magnetic resonance spectrum (200 MZ) δppm.

J82. (CDCI:l): 62, 9-3.2 (41!, m), δ3.43, 3.
47, 3.49.

3.61. δ5.10. 5.11. 5.14. 5
．． 17. δ6.50(211,S), 66.70
(2H,5) (5) 1-(2,4,6-1-lihydroxyphenyl)-3-(3,4,5-)lihydroxydiphenyl)-1-propanone under argon atmosphere, (4) 80 ml of hydrochloric acid-methanol was added dropwise to a methanol solution of 10.0 g of the compound obtained in step 100, and the mixture was stirred at room temperature for 2 hours and 30 minutes. After the reaction was completed, water was added to the reaction mixture, extracted with diethyl ether, washed with water, dried (anhydrous sodium sulfate), and then the solvent was distilled off.

The precipitated solid was washed with ethyl acetate-diethyl ether and then collected by filtration to obtain 3.6 g (62%) of the title compound as a pale yellow powder.

Molecular formula: C+sll+40't (306) Melting point: 2
71-273 (dec,) Infrared absorption spectrum ν□xcm-' (KBr): 3
500, 3428.3272.1644.1618.1
596° proton nuclear magnetic resonance spectrum (200MZ)
δppm.

J H2, (8ceton-d): δ2.77(
211, m), 63.32 (211, m), δ
5.94 (2+1.S), δ6.32 (2+1.S
) Mass spectrum m/z (χ): 302 (M', 20), 180 (11), 168
(18), 153(100), 126(75) Example 2 l-(2,4,6-)lihydroxyphenyl)-3-(
2,3,4-1-Lihydroxyphenyl)-1-propanone (1) 2,3,4-Tris (methoxymethoxy)benzaldehyde 2.3,4-Trihydroxybenzaldehyde 20. O
To 200 d of a dimethylformamide solution containing 1 g and 2.0 g of dimethylaminopyridine, 1
68 d was added and stirred. 741n1 of chloromethyl methyl ether was added dropwise to the reaction mixture under water cooling, and after stirring for 30 minutes, the mixture was returned to room temperature and further stirred for 5 hours. After the reaction was completed, water was added to the reaction mixture, extracted with diethyl ether, washed with water, dried (anhydrous sodium sulfate), and then the solvent was distilled off. The residue was solidified in the freezer, washed with cold hexane, and collected by filtration, yielding 30.6 g (82%) of the title compound.
Obtained.

Molecular formula: C+zll+5Ot (286) Melting point: <30
°C Infrared absorption spectrum l'saxCm-' (KBr
) :2904, 1'6B4.1594.1494.1
454.1384°1276, 1156.108B,
1034.994.956.922 Proton nuclear magnetic resonance spectrum (200?'lZ) δppm.

J oz, (CDCh): 63.51 (311,5), δ3.57 (311,
S), δ3.62(3)1, S), 65
．． 15 (2+1.S), 65.27 (2H,S)
.

65, 28 (211, S), 67.04 (It
(, d, J.8.8).

δ7.61 (111, d, J・8.8), δ10.
29 (IH, S).

(2) 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone 2',4',6'-trihydroxyacetophenone2.
8,3 ykl of diisopropylethylamine was added to 0 g of 10-g THF solution. Heat the reaction mixture to -20°C.
After cooling to 3.61 chloromethyl methyl ether,
- and stirred for an additional 30 minutes. After stirring the reaction mixture at room temperature for 2 hours, water was added, extracted with diethyl ether, washed with water, dried (anhydrous sodium sulfate), and concentrated. When diethyl ether and hexane were added to the concentrate and crystallized in the freezer, the title compound was obtained as a white powder at 2.30%
g (75%) was obtained.

Molecular formula: C+2H+10a (25G) Melting point: 47.
0~48,0°C Infrared absorption spectrum l'mmxCm-' (KBr
) :1622, 1594. 1270. 1222
．． 1208. 1166°1152. 1080. 1
066, 1028. 946 proton nuclear magnetic resonance spectrum (200MZ) δppm.

J nz, (CDCl2): δ2.65(3H,S), δ3.47(3H,S
), δ3.52(3)1. S), δ5.17
(211,S), 65.25(2+1.S).

66.24(211,5) (3) 2'-hydroxy-2,3,4,4', 6'-
10.0 g of the compound obtained from pentakis(methoxymethoxy)chalcone (2) and compound 1 obtained from (1)
To 1.2 g of 100 g of ethanol solution was added 80 g of saturated potassium hydroxide-ethanol solution, and the mixture was stirred at room temperature overnight.

The reaction mixture was poured into a large amount of water, neutralized using dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and then the solvent was distilled off. The concentrate was subjected to silica gel chromatography (eluent: 20 to 33.1 fractions of ethyl acetate:hexane-1:2 = 300 ml).
, φ-100mm, H-260mm), 18.1g (18.1g) of the title compound was obtained as a red-orange oil.
89%).

Molecular formula: (,5ll=□OI□(524) Melting point: 65
．． 5-67°C Infrared absorption spectrum V maxCm-' (KBr)
:1632, 1586.1562.1494.127
8.1212°1158, 1090.932 Proton nuclear magnetic resonance spectrum (200MZ) δppm
.

J 112. (CDCIff): 63, 48 (38, S), 63.51 (3H
,S), δ3.53(311,S), δ3.
62 (311, S), δ3.63 (311, S)
.

65.15 (211, S), δ5.18 (2) 1.
S), δ5.21(2+1.S), 65
．． 24(2+1.S), 65.28(2+1.S)
S).

66.26 (ILd, J=2.2), 66.3 (IH
, d, J・2.2).

66.99 (ill, d, J=8.8), δ7.38
(ill, d, J=8.8).

δ7.86(1)1. d, J=15.6), δ8.
16(1)1. d, J・15.6) (4) 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl) -3-(2,3,4-tris(
methoxymethoxy)phenyl]-1-propanone Add 18.0 g of the compound obtained in (3) to a solution of 3.0 g of Pd-C (5%) on which hydrogen has been adsorbed in 70 Tnl of ethyl acetate.
A solution of 390g of ethyl acetate was added thereto, and hydrogen was further adsorbed while stirring vigorously. After the adsorption was completed, Pd-C was removed using Celite, and then the solvent was distilled off. The concentrate was dried under reduced pressure to obtain 18.34 g (100%) of the title compound as a colorless and transparent oil.

Molecular formula: CzsHtnO+t (526) Colorless oil Infrared absorption spectrum ν□Xcm-' (Neat)
:1622, 1602.1162.1152.1082
．． 105B.

1042, 1022.924 Proton nuclear magnetic resonance spectrum (200MZ) δppm
.

J H2, (CDC1z): 53.06 (2H, m), δ3.37 (2) 1. m),
δ3.45Cs>.

63.47 (S), δ3.51 (S), δ3.54
(S), δ3.6゜(S), 65.12(S), δ
5.14 (S), δ5.18 (S), δ5, 22
(S), 66.26 (111, d, J・5.4), 6
6.27 (IH.

a, +=5.4), 66.89 (2+1.d, J・0.
4) (5) 1-(2,4,6-1-lihydroxyphenyl)-3-(2,3,4-trihydroxyphenyl)-1-propanone Compound obtained in (4) under argon atmosphere Hydrochloric acid-methanol 50 mf was added to 4.6 g of methanol 80 m/solution, and the mixture was stirred at room temperature for 1 hour and 30 minutes. A large amount of water was added to the reaction mixture, extracted with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and then the solvent was distilled off. Concentrate LH-2
After separation and purification with 0, the title compound was crystallized with acetone-ether-hexane system, and the title compound was obtained as a white powder with 1
．． 36g (51%) was obtained.

Molecular formula: C, sit□0. (306) Melting point: 224.0-225.5Cdec,) Infrared absorption spectrum ν□xcm-' (KBr): 3276,
1640.1616.1570.1524.1472°1304, 1284.1256.1204.1168 Proton nuclear magnetic resonance spectrum (200MZ) δppm.

J IIz, (Aceton-d): 62.90 (
28, m), 63.39 (211, m), δ
5.93 (211, S), 66.32 (III,
d, J・8.3), 66.51 (III, d, J・
8.3) Mass spectrum m/z (χ): 180 (42), 138 (100), 126 (79
) Example 3 l-(2-carboxymethoxy-4,6-simethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)propane (1) 1-(2-hydroxy-4,6-dimethoxy-3
-isopentylphenyl-3-(4-methoxyphenyl)propane -(2-hydroxy-4,6-simethoxy3-isopentylphenyl)-3-(4-methoxyphenyl)-
0.17 g of aluminum chloride and 0.04 g of lithium aluminum hydride were carefully added to a solution of 0.20 g of 1-propanone in tetrahydrofuran (3 mZ) under water cooling, and the mixture was heated under reflux for 60 minutes. Subsequently, ethyl acetate and dilute hydrochloric acid were added to the reaction mixture, extracted with ether, washed with water, dried (anhydrous sodium sulfate), and then the solvent was distilled off. The residue was subjected to silica gel column chromatography (Merck 9385, φ=
25n+n+, H=220 mm, fraction 2~
5150 mf) to obtain 0.17 g (87%) of the title compound as a yellow oil.

Molecular formula: Czs11izO4 (372) Yellow oil Infrared absorption spectrum ν□Xcm-' (Neat)
:3580, 2948.1614.1512.1246
．． 1150° proton nuclear magnetic resonance spectrum (200M
Z) δppm.

(CDCI:l): δ0.93 (61Ld, J・6.6), 61.32
~1.40 (2H.

mL 61.5-1.65 (LH, m), 61
．． 65~1.79 (211, m), 62.50~
2.64 (611, m), δ3.75 (311
,5), 63.77 (3H, S), δ3゜7
7 (3+1.S).

δ4.69 (ill, S), 66.09 (LH, S
), δ6.80 (2H, dd, J=2.0.6.
611z), δ7.11 (2H, dd) Mass spectrum m/z (χ) 372 (M+, 49), 315 (76).

121 (2B) (2) 1-(4,6-Simethoxy2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4
-methoxyphenyl)propane (1) and 1.64 g of the compound obtained with sodium hydride.
48 mf of dimethylformamide was carefully and slowly added dropwise to 25 g of the mixture under water cooling in a nitrogen stream.

After stirring for 20 minutes under water cooling, 3.3 m/ml of methyl α-bromoacetate was added dropwise, and the mixture was further stirred at room temperature for 10 minutes. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ether, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. The residue was subjected to column chromatography (silica gel, Merck 9385, φ=70 cylinder, H=330
mm, 650 g, Pr = 0.4 kgf/cm2, eluent ethyl acetate-hexane = 2572), and after concentration, crystallization with diethyl ether-hexane system.
7.09 g (67%) of the title compound as a white solid
Obtained.

Molecular formula: Cz6]1:+aOa (444) Melting point:
53.5-54.5°C Infrared absorption spectrum v mmXcm-' KBr(D
isc) 2944, 1760.1608.1512.1
462.1242°1156, 1134 Proton nuclear magnetic resonance spectrum (200MZ) δppm
.

JH□, (CDC1ff): 60.92 (6H, d, J・6.6), 61.22
~1.42 (2+1°II+), 61.42~1.65
(IH, n+), 61.65-1.84 (28, m
), 62.49-2.65 (68, m), δ3
．． 77゜3.79.3.80.3.81 (12H, S)
, δ4.30 (211, S).

δ6.28 (111, S), 66.80 (2H, dd,
J=2. Sail 6.6).

δ7.12 (2H, dd) Mass spectrum m/z (X) 444 (M", too), 387 (82), 309
(89), 239(64), 121(82) (3) Obtained with 1-(2-carboxymethoxy-4,6-simethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)propane (2) Compound 7, 09 g of methanol (150
mf) 5% potassium hydroxide 45- was added to the solution and stirred for 15 minutes. Dilute hydrochloric acid was added to the reaction mixture under water cooling to adjust the pH to 2.
The mixture was extracted with ether, washed with water, and dried (anhydrous sodium sulfate). After distilling off the solvent, the title compound was crystallized from diethyl ether (a small amount)-petroleum ether-hexane system, and the title compound was obtained as a white powder with 6.8
g (approximately 100%) was obtained.

Molecular formula: czsuz, o6 (430) melting point = 69-7
0.5°C Infrared absorption spectrum v mmxcm-' KBr(D
isc) 294B, 1740.1606.1510.
1462.1440°1244, 1200. 115
0. 1128 proton nuclear magnetic resonance spectrum (200
MZ) δppm.

J82. (CDC1+): 60.92 (6) 1. d, J=6.4), 61.
36 (21!, m).

61.59 (IH, m), δ1.81 (21LmL
62.47~3.68 (68, m), δ3.7
? (3H,S), δ3.80 (3H,S).

δ3.81 (3H,S), δ4.34 (2H,S)
, δ5.88 (br.

S), 66.30 (IH, S), δ6.81 (2
11, dd, J・2.2゜6.6), δ7-12(
2H+dd, J=2.2+ 6.6) Mass spectrum I
ll/z(χ) 430(M”, 75), 373(66), 295(
95), 225(74), 12H100) Example 4 ■-(2-carboxymethoxy-4,6-simethoxyphenyl)-3-(4-methoxyphenyl)propane (1) 1-(2-hydroxy- 4,6-Simethoxyphenyl)-3-(4-methoxyphenyl)propane U■ 1-(2-Hydroxy-4,6-Simethoxyphenyl)
-3-(4-methoxyphenyl)-1-propanone (4,75 g) in tetrahydrofuran (THF) (1
5+n/)? For each method, aluminum chloride (4.0 g)
T) IP (Ion/) suspension and cooled. Furthermore, a suspension of 1.14 g of lithium aluminum hydride in THF (15-) was added to this reaction mixture under water cooling, and the mixture was heated under reflux for about 2 hours using ultrasound. After the reaction was completed, ethyl acetate and dilute hydrochloric acid were added to the reaction mixture, which was then extracted with ether, washed with water, dried (anhydrous sodium sulfate), and then the solvent was distilled off. The residue was subjected to silica gel column chromatography (Merck 9385, φ70 mm, H=24
0 mm, silica gel 470g, Pr”'0.4kg
f/cm", eluent ethyl acetate-hexane = 13), the title compound (74%
)Obtained.

Molecular formula: C1l+)+2□0. (302) Oily substance infrared absorption spectrum ν□Xcm-' Neat:
3416, 2936.1614.1598.1512.
1244° proton nuclear magnetic resonance spectrum (200MZ
) δppm.

JMZ: 61.74-1.86 (2H, m), 62.59 (
4H,t, J・7.1), δ3.69(3)1.
S), δ3.74.3.75 (S.

611), δ5.55 (LH, S), 65.99 (LH
, d, J=2.2).

66.06 (ill, d, J=2.4), δ6.
80 (2H, dd, J・2.2.6.6Hz), δ7
．． H21+, dd, J=2.2.6.6! lz).

δ8.89 (S) Mass spectrum m/z (χ) 148 (24), 121 (-Oll-@?-0CH3,
17) (2) l-(4,6-Simethoxy2-methoxycarbonylmethoxyphenyl)-3-(4-methoxyphenyl)propane A mixture of 2.81 g of the compound obtained in (1) above and 0.23 g of sodium hydride. While cooling with water, 10 ml of DMF was slowly and carefully added dropwise in a N2 stream. Next, after stirring for 20 minutes under cooling with water, 1.
3 mf was added dropwise, and the mixture was further stirred at room temperature for 10 minutes.

After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ether, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. The residue was subjected to column chromatography (silica gel Merck 9385, φ=70 mm, H=200+
+s, eluent Ac0Et-11ex=l : 5, P
r=0.4 kgf/cn+''), concentrated, and crystallized from diethyl ether-hexane system to obtain 2.23 g (64%) of the title compound as a white powder.

Molecular formula: C! +Hzi06 (374) Melting point: 43-4
4.5°C Infrared absorption spectrum v,,Xcra-' KBr(D
isc) :2956, 1?62. 1612. 1
590. 1514. 1430°1246, 121
8. 1200. 1188. 1174. 1156
Proton nuclear magnetic resonance spectrum (200MZ) δppm
.

JN2. (CDCh): 61.81 (2H, m), 62.56-2.71
(4H, m).

δ3.74.3.75, 3.76 (1211, S),
64, 58' (2II.

S), 65.98 (IH, a, r=2.2), δ6
．． 19 (LH, d.

J・2.2), 66.80 (2H, dd), 67.
11 (2H, dd) mass spectrum -/z (Z): 374 (M”, 100), 239 (100), 14
8(27).

12H29) (3) 1-(2-carboxymethoxy-4,6-simethoxyphenyl)-3-(4-methoxyphenyl)propane Add 0.5 g of the compound obtained in (2) above to methanol (5 mL solution). 2.5% of 5% potassium hydroxide was added and stirred for 15 minutes. Dilute hydrochloric acid was added to the reaction mixture under water cooling to adjust the pH to about 2, and the precipitated solid was collected by filtration. The title compound obtained was ethyl acetate ( 0.37 g (80%) was obtained by recrystallization from a petroleum ether-hexane system.

Molecular formula: 2C2゜HznOi (360) Melting point: 103-104.5℃ Infrared absorption spectrum v, *xcm-' KBr(Di
sc) :2932, 1748.1606.1588.
1514.1428'.

1256, 1246.1168.1126 Proton nuclear magnetic resonance spectrum (200MZ) δppm.

JH□, (CDCI: 61.78 (2tl, m), 62.59 (2H, t
, J.8.9).

δ2.65 (2H, t, J・7.3), δ3.76
, 3.7? .

3.78 (S, 98), 64.62 (S, ill
), 66.00 (ill.

d, J・2.2L δ6.17 (IH, d, J=
2.2), 66.81 (2H, dd, J・2.2.
6.6), 67.11 (2H, dd) mass spectrum n+/z (χ): 360 (M”, 18), 302 (10), 225 (
100), 167(63), 148(53), 1
2H59) Example 5 l-(2-carboxymethoxy-4,6-simethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanol (1) 1-(2-hydroxy-4,6 -Simethoxy3-isopentylphenyl)-
3-(4-methoxyphenyl)-1-propatool 1-
(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-
0.98 g of lithium aluminum hydride was added to a solution of 10.0 g of propanone in TIIP (lOOmf) under water cooling, and the mixture was returned to room temperature and stirred for an additional 20 minutes. After adding 20 rnl of TIIF-water (1:1) and dilute hydrochloric acid to the reaction mixture, the mixture was extracted with ether. Wash the extract with water and dry it (
After washing (anhydrous sodium sulfate), the solvent was distilled off to obtain 9.1 g (90%) of the title compound as crude crystals. Recrystallization of this compound was carried out in a diethyl ether (minor)-petroleum ether-hexane system under water cooling.

Molecular formula: CBI13□o, (388) Melting point: 76.5-77°C Infrared absorption spectrum l'm*xcm-' (Nea
t) :3304, 2948.1622.1600.
1512.1466°1440, 1384.1320.
1246.1214.1134゜1114, 1086 Proton nuclear magnetic resonance spectrum (200MZ) δppm
.

J82. (CDC13): 60.94 (611, d, J=6.4), δ1.
37(2)1. m).

δ1.58 (LH, m), 61.96-2.18 (
21Lm).

62.46 (ill, d, J・3.4), 62.5
1 to 2.77 (411゜), 63.73 (3+1.S
), δ3.78(311,S), δ3.79(3H
,S), δ5.32(lfl,m), 66.0
0 (Ill, S).

66.8H2L'aa, J=2.2.6.6), 6
7.12 (21Ldd, J・2.2), δ8.62 (I
H, S) Mass spectrum m/z (χ): 370 (M", 388-H, 0, 34), 313 (3
2), 179(50), 121(100) (2) 1-(4,6-Simethoxy2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4
-methoxyphenyl)-1-propatool (1) 1.20 g of the compound obtained and 0 sodium hydride,
Add 10mj of DMF to 074g of the mixture under ice cooling and add 1
After stirring for 5 minutes, methyl α-bromoacetate 0.33
mf was added and further stirred for 5 minutes. Water was added to the reaction mixture, extracted with ether, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. The concentrate was subjected to column chromatography (Merck 9385, Pr=0.35 kgf/c
ffl, 150g of silica gel, φ-50++un, H
=180 nun, eluent ethyl acetate; hexane = 1:
After separation and purification in step 3), 0.92 g (64%) of the title compound was obtained as an oil.

Molecular formula: CzbH: +bOt (460) Colorless oil Infrared absorption spectrum ν□cm-' (Neat)
:2948, 1762.1604.1512.14
66, 1246°1206, 1198.1124.10
90 proton nuclear magnetic resonance spectrum (200MZ) δp
p.m.

J Hz, (CDCl2): 60.92 (611, d, J・6.4), 61.2
0-1.44 (2H.

m), 61.55~1.7(ill, m), δ1.9~
2.1 (ill.

m) +62.18 ~ 2.4 (LH, m), 62.46 ~
2.7 (38゜) + 62.76~2.9 (LH,
m), 63.47 (IH, d, J = 11.2), 6
3.77 (311, S), 63.81 (61(
,S).

63, 84 (311, S), 64.29 (Il
l, d, J・15.6).

64.40 (18, a, J=15.4), 64.9~5
．． 1(ill.

m), 66.30 (IH, S), δ6.80 (2) 1.
dd, J=2.5゜6.6), δ7.11 (21
1, ad) Mass spectrum m/z (χ): 442 (M", 460-1t20.39), 385 (
39), 353(22), 19H42), 145
(40), 121(100)(3) obtained with 1-(2-carboxymethoxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanol (2) 0.92 g of methanol (18 mf
) Add 5% potassium hydroxide aqueous solution (6d) to the solution,
Stirred for 0 minutes. After the reaction was completed, dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 2, followed by extraction with ether, washing with water, and drying (anhydrous sodium sulfate). After evaporating the solvent, the concentrate was crystallized using diethyl ether-hexane system to obtain 0.45 g (50%) of the title compound as a white powder.

Molecular formula: czst+5407 (446) Melting point 269~
70.5°C Infrared absorption spectrum ν,,Xcm-' KBr(Di
sc) :3536, 2952.1754.1606.
1586.1514°1466, 1454.1440.
1324.1246.1200° proton nuclear magnetic resonance spectrum (200MZ) δppm.

J□z, (CDCh): 61.35~1.43 (2H, m), 61.55~
1.62 (01゜m), δ1.97~2. Hllll
, m), δ2.1 ~ 2.40 (lll, m), δ
2.4 ~ 2.62 (311, m), 62.71 ~
2.9 (LH, m), , 63.76 (311, S),
δ3.81, 3.82 (6H, S), δ4.3
4 (III, d, ・15.6), δ4.48 (
ill, d, J=15.6), 65.13(L
H, dd, J・8.6°5.3), 66.28
(Ill, S), 66.78 (2H, dd,
J・2.2. 6.6), 67.08 (211,
dd) Mass spectrum m/z (ri: 428 (M”, 446-11□O), 37H41),
237(13).

19H42), 121(100) Example 6 l-(2-hydroxyethoxy-4,6-simethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propatol Example 3(2) Obtained 1-(
84 ml of diethyl ether was added to a mixture of 5.2 g of 4,6-simethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone and 0.51 g of lithium aluminum hydride under cooling. was added, the temperature was returned to room temperature, and the mixture was further heated under reflux for 60 minutes. After the reaction was completed, ethyl acetate and dilute hydrochloric acid were added to the reaction mixture, followed by extraction with ether. Wash the extract with water,
After drying (anhydrous sodium sulfate) and distilling off the solvent, crystallization from ethyl acetate (a small amount)-diethyl ether-hexane system yielded the title compound as white needle-like crystals. 2g (87%) of L was obtained.

Molecular formula: Cz, HxbObC432>Melting point: 99.
5-100°C Infrared absorption spectrum v 11. xcm-' KBr(
Disc): 3548, 3376, 2948.160
4.1590.1514゜1454, 1246.119
6.1126.1088.10?4゜1038, 100
4 Proton nuclear magnetic resonance spectrum (200) IZ) δpp
m.

J H2, (CDC13): 60.93 (6B, d, J=6.4), 61.31
~1.42 (2+1゜m) + δ1.48~1.70
(IH, m), 61.90-2.10 (III, m
), 62.26-2.42 (Ill, m), δ
2.44~2.82 (5H, m), δ3.76~
3.85 (138), δ4.93 (III, m),
66.29 (IH, S), δ6.89 (28,
dd, J=2.2. 6.6), 67.13 (2H
, dd, J.2.2. 6.6) Mass spectrum m/z
(χ): 414 (M”, 432-H2O, 14), 279 (1
00), 121 Example 7 l-(2-hydroxyethoxy-4,6-simethoxyphenyl)-3-(4-methoxyphenyl)-1-propatol (1) 1=(2-hydroxy-4, 6-Simethoxyphenyl)-3-(4-methoxyphenyl)-1-propanol Lithium aluminum hydride 1.01 g of diethyl ether (15 m
,6-Simethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone (8.0 g) in THF (30 m) was added and stirred for 60 minutes. After the reaction was completed, ethyl acetate and dilute hydrochloric acid were added to the reaction mixture, extracted with ether, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off to give 7.32 g (89%) of the title compound as a white powder.
)Obtained.

Molecular formula: Czs)lzzOs (438) Melting point: 75
．． 5 to 76.5°C Infrared absorption spectrum v +s@Xcm-' KBr(
Dtsc) :3464, 1628.159B, 12
42.1210.1196°1150, 1098.10
48 Proton nuclear magnetic resonance spectrum (200MZ) δppm
.

J engineering z, (CDC1z): δ1.92-2.22 (2H, m), δ2.70 (
d, J=3.9).

62.54-2.83 (3H, m), δ3.69 (
3H,S).

63.74 (311, S), δ3.7? (3+
1. S), 65.27 (ltl, m), δ5.
97 (IH, d, J, 2.2), 66.05 (il
l, d, J・2.2), 66.81 (2H, dd,
J.2.2.6.6).

δ7. IH21+, dd, J, 2.0), 68.74 (
11(,S) Mass spectrum m/z(X): 300(M”, 318-tfzO,67), 283(
18), 191(25), 166(33), 14
7(51), 134(85), 121(2)1-(
4,6-Simethoxy2-methoxycarbonylmethoxyphenyl)-3-(4-methoxyphenyl)-1-propatol was added to a mixture of 5.37 g of the compound obtained in (1) above and 0.41 g of sodium hydride under cooling. After adding 100 ml of DMF and stirring for 20 minutes, methyl α-bromoacetate 2.
14 ml was added and stirred for an additional 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ether, washed with water, dried (anhydrous sodium sulfate), and the solution was distilled off to give the title compound as a colorless and transparent oil almost quantitatively.

Molecular formula: Cz+L6(h(390) Colorless oil infrared absorption spectrum ν.axcIl+-' Neat
:3544, 2952.1?58.1614.15
94.1512°1454, 1438.1246.12
16.1198.1156°1130, 1060.10
36 Proton nuclear magnetic resonance spectrum (200MZ) δpp+
m.

J Hz, (CDC1i)' δ1.97-2.3 (28, m), 52.46-2.8
(2H, m).

δ3.75.3.76, 3.78.3.79 (12H,
s), δ3.87 (IH, d, J・11.72
), 64.61 (2H, S), 65.08-5.2
1 (LH, m), 66.00 (1B, d, J=2.
2).

66.15 (IH, d, J・2.0), 66.79 (2
H, dd, J・2.2゜6.6), 67.12 (2
11, dd, J=2.2.6.6) Mass spectrum m/
z (χ): 372 (M”, 390-H2O, 82), 299 (7
2), 283 (35), 145 (75), 121 (1
00)(3)1-(2-hydroxyethoxy-4,6-
cymethoxyphenyl)-3-(4-methoxyphenyl)
-1-Propatool (2) Compound 0.22g diethyl ether (4
/) Lithium aluminum hydride 0.0 in solution under water cooling
After adding 5 g of the mixture and returning it to room temperature, the mixture was refluxed for 2 hours using ultrasound. After the reaction was completed, ethyl acetate and dilute hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ether.

The extract was washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off, followed by column chromatography (Merck
9385, 35g of silica gel, φ=20mm, H=
150 mm, Pr = 0.35 kgf/cJ) to obtain 0.2 g of the title compound as a colorless and transparent oil.
(Quantitative) Obtained.

Example 8 4,4',6'-triethoxy-3'-isobenthyl-2'-carpoxymethoxychalcone (1) 4',6'-jethoxy-2'-hydroxy-3
'-(3-Methyl-2-butenyl)acetophenone 2',4',6'-)lihydroxy-3'-(3-methyl-2-butenyl)acetophenone 2.0g and potassium carbonate 3.0g in acetone (10 mZ) into the suspension solution, add 2.4. d was added and stirred for 20 hours. After the reaction was completed, the solids were removed and the filtrate was concentrated. The precipitated solid was washed several times with cold methanol to obtain 1.51 g (61%) of the title compound as a white powder.

Molecular formula: C+JgiOn (292) Melting point: 98.4-98.2°C Infrared absorption spectrum ν□xcm-' (KBr):
29B4.1624.1592.1430.1272.
1234°1172, 1120.870 Proton nuclear magnetic resonance spectrum (200 Mllz) δC
DCl+' (ppn+, J=Hz): 1.44 (3H, t, J=7.0), 1.48 (3
H, t, J・6.8).

1.66 (311, s), 1.77 (3tl, s)
, 2.63 (3H, s).

3.27 (2H, d, J = 7.3), 4.07 (4
11, q, J・6.8).

5.21 (18, m, J=1.5.7.3), 5
．． 87 (LH, s).

13.94<s) Mass spectrum m/z (χ) [EI-MS] :2
92 (M″, 78), 263 (too),
237(64), 221(2) 4',6'-Jethoxy-2-hydroxy-3'-isopentylacetophenone 0.3 g of Pd-C (5%) preadsorbed with hydrogen in ethyl acetate 100/suspension An ethyl acetate solution of the compound obtained in (1) was added to the solution, and after the completion of the reaction in which hydrogen was adsorbed, Pd-C was removed using Celite, and the solution was distilled off under reduced pressure. Hexane was added to the residue to crystallize it, yielding 1.60 g (79%) of the title compound as white needle-like crystals.

Molecular formula: C1? lft, 04 (294) Melting point: 10
5.1~105.5℃ Infrared absorption spectrum ν,, cm-' (KBr)
:2956, 1632.1592.1426.1272
．． 1142°1078' Proton nuclear magnetic resonance spectrum (200Ml(z)δC
DCI x (ppmong, J=Hz): 0.93 (d, J・6.4), 1.40 (t, J・6
．． 8) + 1.43 (t, J=6.8), 1.28~
1.61 (n+), 2.63 (s).

2.56 (t), 4.05 (q, J・6.8), 4
．． 07 (q, J・6.8).

5.89 (s) Mass spectrum m/z (X) [EI-MS]:
294 (M', 56), 237 (100), 209
(47) (3) 4.4', 6'-) Jetoxy-2
A saturated potassium hydroxide-ethanol solution was added to a solution of 11.54 g of the compound obtained from '-hydroxy-3-isopentylchalcone (2) and 6.15 g of p-ethoxybenzaldehyde in ethanol-dimethyl sulfoxide mixture (100 af) with stirring. 120 ml was added and stirred at room temperature for 20 hours. After completion of the reaction, dilute hydrochloric acid was added to the reaction mixture to make it slightly acidic, and the precipitated solid was collected by filtration. The precipitate was dissolved in ethyl acetate, washed with water, dried, and then the solvent was distilled off. When the concentrate was crystallized from an ethyl acetate-methanol system, the title compound was obtained as red-orange crystals in 14.
95g (90%) was obtained.

Molecular formula: CzJi40s (426) Melting point: 126.3-126.7°C Infrared absorption spectrum! l m*xcm-' (KBr
) :2980, 2952.1622.1576, 1
554.1512°1424, 1288.1256.1
230.1216.1160°Proton nuclear magnetic resonance spectrum (200Ml(z)δCDCDC13(pp J
(llz): 0.94 (6H, d, J・6.4), 1.34-1.
60 (12H, m).

2.59 (2H, m), 4.01-4.15 (611
, m), 5.93 (18, s), 6.89 (211
, dd, J=2.0.6.84), 7.52 (28,
dd, J=2.0.6.8), 7.72(IH, d,
15.6).

7.90 (ltl, d, 15.6) Mass spectrum m/z (χ) [EI-MS].

426 (M”, 66), 369 (39), 221
(100), 165(4B), 135(33) (4) 1.0 g of the compound obtained from 4.4',6'-triethoxy-2'-methoxycarbonylmethoxy-3'-isopentylchalcone (3), Anhydrous potassium carbonate 0.5
A solution of 2 g of potassium iodide and 0.1 g of potassium iodide in DMF (10 m/) was stirred at room temperature for 45 minutes under a nitrogen atmosphere. Subsequently, 0.27 m/m of methyl bromoacetate was added dropwise to the reaction mixture.
The mixture was further stirred for 12 hours. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. After washing the extracted solution with water and drying (anhydrous sodium sulfate), the solvent was distilled off and crystallized with ethyl acetate-diethyl ether-hexane system, yielding 0.91 g (79%) of the title compound as a pale yellow solid.
)Obtained.

Molecular formula: CzJ:+5Qt(49B) Melting point: 84.
2℃ Infrared absorption spectrum ysaxCm-' (KBr)
:2952, 1748.1662.1600.15
74.1224° proton nuclear magnetic resonance spectrum (20
0111z) δCDC1z (ppm, J=Hz)
: 0.94(61(,d,J・6.3), 1.28(3
H, t, J = 7.0).

1.38-1.48(8)1. m), 1.58-1.
67 (IH, m).

2.60 (2H, m), 3.73 (3H, s), 3
．． 94~4.11(6H+m)+4.50(2)1.
s), 6.29 (IH, s), 6.87 (2H, d
d, J・1.9. 6.8), 6.88(IH, d
, J=16.0).

7.31 (111, d, J・16.0), 7.
45 (2Ldd, J・1.9°6.8) Mass spectrum m/z (χ) [EI-MS]: 49
8 (M”, 55), 441 (83), 439 (8
6), 369(39), 265(61), 175
(55), 135(100)(5) A solution of 4.1 g of the compound obtained from 2'-carboxymethoxy-4,4',6-driethoxy-3-isopentylchalcone (4) in methanol (100 ml) at 5% KOH(aq) 50- was added and stirred at room temperature for 20 minutes. After the reaction was completed, dilute hydrochloric acid was added to the reaction mixture to make it weakly acidic, and then a large amount of water was added. The separated solid was collected by filtration and then crystallized with ethyl acetate-hexane system to yield the title compound as a pale yellow solid.
．． 02g (76%) was obtained.

Molecular formula: Cz*HzbOt (484) Melting point 7130.
3-130.9°C Infrared absorption spectrum, □cm-' (K3r)
:2956, 1736.1644.1602.1574
．． 1510. “1276, 1250.1166, 113
8.1116.1100 Proton nuclear magnetic resonance spectrum (200MHz) δCDCl5 (pp+w, J=Hz
): 0.99 (6H, d, J=6.3), 1.24 (3H
, t, J・7.1).

1.38 (t, J・7.1), 1.43 (t, J・6
．． 8), 1.49-1.64 (ltl, m), 2.
64 (211, m), 4.09 (q, J=7.1).

4.14 (q, J=6.8), 4.48 (2H, s)
, 6.54 (III, s).

6.93 (IH, d, J = 16.0), 6.95 (2
1Ldd, J=2. Sail 6.8), 7.34 (IH, d
,, L, 16.0), 7.59 (2B, dd.

2.0.6.8) Mass spectrum.../z(χ)-[EI-MSI:
.

484 (M”, 76), 439 (48), 427
(67), 369(36), 25H52), 22
1 (58), 135 (100) Elemental analysis: Calculated value, C: 69°48 H: 7.41 Actual value, C: 69.40 H: 7.48 Example 9 2'-carboxymethoxy-4', 6'-jetoxy-
4-Methoxy-3'-isobentylchalcone (1) 4'
, 6'-jethoxy-2'-hydroxy-4-methoxy-3'-isopentyl chalcone 4 obtained in Example 8 (2)
',6'-Jethoxy-2'-hydroxy-3'-isopentylacetophenone 9.17 g and p-methoxybenzaldehyde 4.60 g were added to a solution of ethanol-dimethyl sulfoxide mixture (100 ml) while stirring. 100 ml of ethanol solution was added and stirred at room temperature for 20 hours.

After the reaction was completed, dilute hydrochloric acid was added to the reaction mixture to make it slightly acidic, and the precipitated solid was collected by filtration. The precipitate was dissolved in ethyl acetate, washed with water, dried, and then the solvent was distilled off. When the concentrate was crystallized with ethyl acetate-petroleum ether system, 10.97 g (86%) of the title compound was obtained as red-orange crystals.
Obtained.

Molecular formula: CzsTo□O, (412) Melting point: 122
．． 0~122.4°C Infrared absorption spectrum v,,, cm-' (KBr)
:2960, 1626.1606.1558.12
52.1232°1218, 1172.1160.11
34.826 proton nuclear magnetic resonance spectrum (200M
Hz)δCDCI! (ppm, J=)Iz): 0.94 (6H, d, J・6.4), 1.31 to 1.
6 ■ m), 2.59 (2H, m), 3.84 (31
1,s), 4.09(4tl,m), 5.94(I
FI, s), 6.91 (2jl, dd), 7.
54 (2H, dd).

7.73 (III, d, J・15.6), 7.91 (
IH, d, J, 15.6) Mass spectrum m/z (Ri
[EI-MS]: 412 (M”, 63), 35
5 (3B), 221 (100), 165 (2) 4'
, 6-jethoxy-4-methoxy-2'-methoxycarbonylmethoxy-3-isopentylchalcone A mixture of 3.0 g of the compound obtained in (1) and 0.38 g of sodium hydride (55% in oil) under a nitrogen atmosphere. 50 ml of DMF was slowly added dropwise to the mixture under ice-cooling, the mixture was returned to room temperature, and then stirred for 30 minutes. 0.85-methyl α-bromoacetate was added dropwise to the reaction mixture, and the mixture was further stirred for 1 hour.

After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. After washing the extracted solution with water and drying (anhydrous sodium sulfate), the solvent was distilled off to obtain 4.03 g of the title compound as an oil.

Molecular formula: C21H310t (484) Melting point: 46.
6℃ Infrared absorption spectrum ν□Xcm-' (KBr):
2952, 174B, 1662.1600.1574
．． 1514°1442, 1422. 1320. 1
290. 1258. 1220°1204, 1174
．． 1136.1098 proton nuclear magnetic resonance spectrum (
200M)Iz)δCDe13(ppm, J=Hz
): 0.94 (611, d, J=6.6), 1.28 (
3H, t, J・6.9).

1.45 (3H, t, J=6.9), 1.34-1
．． 48 (2tl, m).

1.58-1.78 (1■, m), 2.60 (2f
(, m), 3.74 (31t, s), 3.83
(3H,s), 4.00(2+1.Q, J=6.
9).

4.05 (211,q, J=6.9), 4.51
(2H, s), 6.29 (IH, s), 6.8
8 (LH, d, J = 15.9), 6.88 (2H,
dd.

J・2.0. 7.1), 7.32(111,d,
J・15.9), 7.46 (211, dd, J=2
．． 0. 7.1) Mass spectrum m/z (χ) [EI
-MSI: 484 (M”, 81), 427 (1
00), 355(36), 265(62), 16
H74), 121(87)(3) 2'-carboxymethoxy-4', 6-jethoxy-4-methoxy-3'-
To a solution of 4.03 g of the compound obtained from isopentyl chalcone (2) in 50 ml of methanol-dioxane was added 50 mZ of 5%-KOH (aq), and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, water was added to the reaction mixture, the mixture was made weakly acidic using diluted hydrochloric acid, and then extracted with ethyl acetate. The extracted solution was washed with water, dried, and concentrated, and then crystallized from an ethyl acetate-hexane system to obtain 2.54 g (74%, yield from the compound obtained in (1)) of the title compound as a pale yellow solid. .

Molecular formula: C2? l+3407 (470) Melting point: 1
10.6-111.5℃ Infrared absorption spectrum xcm-' (KBr):
2952, 1?36.1644.1602.1574.
1512°1252, 1168.1138 Proton nuclear magnetic resonance spectrum (200M) Iz) δC
DCh (ppm, J=Hz): 0.94 (6H, d, J=6.6), 1.25 (3)
1. t, J・7.0).

1.43 (311,t, J=7.0), 1.37~1
．． 42 (2H, w).

1.49-1.68 (IH, m), 2.64 (2H,
o+), 3.84 (3B, s), 4.09 (2H,
q, J=7.0), 4.14 (2H, q.

7.0), 4.50(lH,s), 6.53(lt
l, s), 6.93 (lIl, d, J=16.1),
6.96 (2H, dd, J=1.9.6.8).

7.34 (III, d, J, 16.1), 7.59
(2H, dd, J = 1.9°6.8) Mass spectrum mHz (χ) [EI-Packing: 470
(M”, 86), 413 (78), 355 (45
), 221(76), 193(71), 16H59)
, 121 (100) Elemental analysis: Calculated value, C: 68.92 Old 7.28 actual value;
C: 69.10 It: 7.25 Example 10 2-Carboxymethoxy-4-ethoxy-4'.

6'-dimethoxy-3'-isopentyl chalcone (1)
4-ethoxy-2'-hydroxy-4', 6'-dimethoxy-3'-isopentyl chalcone 2', 4', 6'-
To a suspension of 25.0 g of trihydroxy-3-(3-methyl-2-butenyl)acetophenone and 45.0 g of potassium carbonate in acetone (200 ml), 22.0 g of dimethyl sulfuric acid was added and stirred for 20 hours. After the reaction was completed, the solids were removed and the filtrate was concentrated. When the precipitated solid was washed several times with cold methanol, 19.0 g (67%) of the following compound was obtained as a white powder.

4',6-Simethoxy 2-hydroxy-3-(3-methyl-2-butenyl)acetophenone Next, 3.0 g of Pd-C (5%) to which hydrogen had been adsorbed in advance and ethyl acetate (
400rd) A solution of 19.0 g of the above compound in ethyl acetate was added to the suspension to further adsorb hydrogen.

After the reaction was completed, Pd-C was removed using Celite, and the solution was distilled off under reduced pressure. When hexane was added to the residue and crystallized, 17.4g of the following compound was obtained as white needle-like crystals.
(91%) obtained.

2'-Hydroxy-4',6'-dimethoxy-3-isopentylacetophenone and a mixed solution of 2.0 g of the compound obtained above and 1.1 g of p-ethoxybenzaldehyde in ethanol-dimethyl sulfoxide (20 rolls) were stirred. At room temperature, add 20% of saturated potassium hydroxide-ethanol solution.
Stir for hours. After the reaction was completed, dilute hydrochloric acid was added to the reaction mixture to make it slightly acidic, and the precipitated solid was collected by filtration. The precipitate was dissolved in ethyl acetate, washed with water, dried, and then the solvent was distilled off. When the concentrate was crystallized in an ethyl acetate-petroleum ether system, the title compound was crystallized as red-orange needle-like crystals.
6g (85%) obtained.

Molecular formula: Cz<IIs. o, (398) melting point 7131
．． 7-132.1°C Infrared absorption spectrum V @mxcl-' (KBr)
:2948, 1632.1606.1582.155
4.1512°1472.1424,1304,128
8.1260,1230°1174. 1148. 1
140. 824 proton nuclear magnetic resonance spectrum (20
0MHz) δCDCl*(ppm, J=Hz)
: 0.94 (611, d, J・6.4), 1.43 (t
, J・7.0), 1.33-1.61(n+), 2
．． 58 (2H, m), 3.88 (3) 1. s).

3.94 (3H, s), 4.06 (2H, q, J=6
．． 8), 5.98 (IH, s), 6.90<2H,
dd), 7.54 (2H, dd, J=2.2.6.8
), 7.76 (2H, s) mass spectrum m/z (ri [EI-MS]: 398 (M", 5B), 3
41(31), 193(100).

(2) 4-ethoxy-4',6'-dimethoxy-2-methoxycarbonylmethoxy-3'-isopentylchalcone C00CHx 15.0 g of the compound obtained in (1), 7 g of anhydrous potassium carbonate
．． 76 g and 1.5 g of potassium iodide oMF (15(I)
n/) solution was stirred at room temperature for 45 minutes under nitrogen atmosphere.

Subsequently, 4.3 d of methyl bromoacetate was added dropwise to the reaction mixture, and the mixture was further stirred for three days. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The extracted solution was washed with water and dried (anhydrous sodium sulfate), then distilled into a solvent and crystallized from an ethyl acetate-diethyl ether-hexane system, yielding 16.1'g of the title compound as a pale yellow solid.
(91%) obtained.

Molecular formula: CztlhaOt (470) Melting point 789.9
~90,8°C Infrared absorption spectrum ν□xcm-' (KBr):
2952, 1738.1642.1602.1572.
1514°1462, 1318. 1276, 12
52. 1200. 11B0゜1158, 1130.
1102.1076, 1044 proton nuclear magnetic resonance spectrum (200MHz) δCDe13 (ppm, J=
Hz): 0.94(61(,d,J・6.6), 1.42(3
L's 7.0).

1.35-1.45 (2 tl, m), 1.58-1.
67 (IH, m).

2.59 (2B, m), 3.72 (3H, s),
3.78 (38,s).

3.87 (311, s), 4.05 (2H, q, J
=7.0), 4.49 (2tl, s), 6.3
2 (IH, s), 6.86 (2tl, dd, J=1
．． 9°6.7), 6.87 (IH, dd, J・15
．． 9), 7.32 (IH, d.

J=15.9), 7.46(2u, aa,,y・1
．． 9. 6.7) Mass spectrum m/z (χ) [Er
−? lS]: 470 (M”, 38), 452 (55
), 411(100), 193(70), 175(
44), 135(41)(3) 2-carboxymethoxy-4-ethoxy-4',6'-dimethoxy-3'-
The compound obtained with isopentyl chalcone (2) was treated in the same manner as in Example 9 (3) to obtain the title compound in a yield of 74% (yield from the compound obtained in (1)).

Molecular formula: CzhHzOl (456) Melting point: 145
．． 7-146.4°C Infrared absorption spectrum v mmxcm-' (KBr)
:2952, 166B, 1600.1260
．． 1202. 1138 proton nuclear magnetic resonance spectrum (200MHz) δCDCh (ppm, J=Hz)
: 0.93 (611, d, J=6.6), 1.37 (
t, J・6.9), 1.43-1.47(m),
1.5-1.6 (IH, +++), 2.63 (2
H, n+).

3.81 (3H, s), 3.93 (3H, s),
4.09 (2H, q, J = 6.9), 4.48 (
28,s), 6.59(IH,s), 6.90
(ill, d, J・16.1), 6.94 (2H,
dd, J=2.0. 6.8).

7.32 (18, d, J・16.1), 7.57
(2H, dd, J, 1.7°6°8) Mass spectrum I11/2 (χ) [EI-MS]
:456 (M”, 51), 411 (58), 399 (4
1), 193 (100), 135 (47) Elemental analysis: Calculated value, C: 68.40 H: 7.07 Actual value; C: 6B, 17 H: 7.00 Example 11 1-(4,6 -cyhydroxy-2-methoxycarbonylmethoxyphenyl)-3-(4-hydroxyphenyl)
-1-propanone (1) l-(2-methoxycarbonylmethoxy-4,6
-Bis(methoxymethoxy)phenyl]-3-(4-methoxyphenyl)-1-propanone2',4',6'-trihydroxyacetophenone2.
0 g of N,N-diisopropylethylamine 8.3- in TIIF (10+nZ) solution (3.61 ml) of 20'c tetrachloromethyl methyl ether was slowly added dropwise and stirred for 30 minutes, then the mixture was further warmed to room temperature and stirred for 2 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extracted solution was washed with water, dried (anhydrous sodium sulfate), concentrated, and then crystallized with diethyl ether-hexane system, resulting in the following compound as a white solid with 2.3
h (75%) was obtained.

2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone, while 15 g of p-hydroxyhenzaldehyde and N,N
-diisopropylethylamine 31.7mZ in DMF (
13.5 ml of chloromethyl methyl ether was added dropwise to the 100 m/) solution under water cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. After washing the extracted solution with water and drying (anhydrous sodium sulfate), the solvent was distilled off and dried under reduced pressure, yielding 18.8 g of the following compound as a colorless and transparent oil.
(94%) obtained.

p-Methoxymethoxybenzaldehyde In an ethanol (100 mf) solution of 15.0 g of the acetophenone derivative obtained above and 14.7 g of the benzaldehyde derivative,
While stirring, add 1 liter of saturated potassium hydroxide-ethanol solution.
20 mf was added and stirred at room temperature for 16 hours. The reaction mixture was poured into cold water, made weakly acidic with dilute hydrochloric acid, and the precipitated solid was collected by filtration. The filtrate was dried under reduced pressure and subjected to silica gel column chromatography (eluent; ethyl acetate:hexane=
1:3). Subsequently, after distilling off the solvent, crystallization was performed using an ethyl acetate-diethyl ether-hexane system to obtain 18.0 g (75%) of the following compound as red-orange plate crystals.

2'-Hydroxy-4,4',6'-)lis(methoxymethoxy)chalcone 17.0g of the above compound was added to a suspension of 5% Pd-C2, 5g in ethyl acetate (380d) on which hydrogen had been adsorbed in advance. Ethyl acetate solution was added to further adsorb hydrogen. After the reaction is complete,
Pd-C was removed using Celite, and the solvent was distilled off under reduced pressure. The residue was left in the freezer, yielding 16.7 g (98%) of the following compound as a white solid.

1(2-hydroxy-4,6-bis(methoxymethoxyphenyl)-3-(4-methoxymethoxyphenyl)
~1-Propanone 2.0 g of the compound obtained above, potassium carbonate (anhydrous) 1.
4g and potassium iodide 0.28 D? IF (20rn
l) The solution was stirred for 70 minutes at room temperature under nitrogen atmosphere. Subsequently, 0.56 m# of methyl α-bromoacetate was added to the reaction mixture, and the mixture was further stirred for 5 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. After washing the extracted solution with water and drying (anhydrous sodium sulfate), the solvent was distilled off and crystallized from an ethyl acetate-petroleum ether-hexane system, yielding 2.14 g (9.9 g) of the title compound as a white solid.
1%) obtained.

Molecular formula: CBtlzsO+. (464) Melting point: 49
．． 0~50.0°C Infrared absorption spectrum 1/IIIMCIll-'
(KBr) :2952, 1750.170B, 1
614.1592.122B.

1218, 1152.1134.10B6.1038.
1016 proton nuclear magnetic resonance spectrum (200Mz)
δppmJ9□, (CDCI,).

62.93-3.02 (2H, m), 63.09
~3.17 (21+.

m), 63.41 (3H,S), δ3.4
6, 3.46. δ3.77 (311, S), δ4.
57 (21+, S'), 65.07 (2H
,S).

δ5.12 (2+1.S), δ5.14 (2H,S),
66.17 (III.

d, J・2.0), 66.49 (Ill, d, J=
2.0), δ6.95C2H, dd, J=2.0.
6.6), 67.15 (211, dd, J.2.
0. 6.6) (2) 2.0 g of the compound obtained with 1-(4,6-cyhydroxy-2-methoxycarbonylmethoxyphenyl)-3-(4-hydroxyphenyl)-1-propanone (1) in methanol (20+n/ ) To the solution (80-90%) hydrochloric acid-methanol solution 15/1 was added and heated (45-50°C in a water bath) for 20 minutes while stirring. After the reaction was completed, the reaction mixture was returned to room temperature, water was added, and the precipitated solid was collected by filtration. After drying the filtrate under reduced pressure, it was recrystallized from a methanol-chloroform-hexane system, yielding 1.41 g (97%) of the title compound as a white powder.
Obtained.

Molecular formula: CIaH+ sO+ (346) Melting point 719
8.5-199.0°C Infrared absorption spectrum smxCm-' (Br)
:343B, 1730.1622.1514.13
72.1310° proton nuclear magnetic resonance spectrum (20
0MZ) δ (Acetone-d): 62.89 (2H, t, J・7.8), 63.43
(2B, t, J・7.8), 63.70 (3H
,S), δ4.83(2+1.S), δ5.
94 (IH, d, J = 2.5), 66.00 (Il
l, d, r・2.5).

66.75 (2H, dd, J・2.4.6.8), 67
, 10 (2H, dd) mass spectrum m/z (χ): 346 (M”, 19), 225 (30), 19
7 (31).

Example 12 ■-(2-Carboxymethoxy-4,6-cyhydroxyphenyl)-3-(4-hydroxyphenyl)-1-propanone OOH Actually, methanol (1, 5
m1) To the solution was added 0.5% of a 5% aqueous potassium hydroxide solution, and the mixture was stirred at room temperature for 15 minutes. After the reaction was completed, water was added to the reaction mixture, the solution was adjusted to be slightly acidic using diluted hydrochloric acid, and the precipitated solid was collected by filtration. The filtered solid was heated and dried under reduced pressure, and then recrystallized from a methanol-chloroform-hexane system to obtain 29 ml of the title compound as a white powder.

Molecular formula: CI J+ act (332) Melting point: 2
35.5-237.0°C Infrared absorption spectrum v maxCm-' (KBr)
:3408, 1?42.1632.1600.15
14.1454°1252, 1210.1180 Proton nuclear magnetic resonance spectrum (200MZ) δppm
.

J=H2, (Acet, one-d): 62.90 (
2H, t, J = 8.1), δ3.46 (21, t, J
8.1).

64.83(2+1.S), δ5.97(II
I, d, J = 2.3), 66.0 (LH, d, J.
2.3), 66.73 (21+, dd, J・2
．． 1゜6.4), 67.10 (211, dd, J.
2.1.6.4) Mass spectrum m/z (χ): 332 (M'', 21), 211 (26), 1
53(61).

Example 13 1-(4,6-Sihydroxy-2-methoxycarbonylmethoxyphenyl), -3-(3,4-dihydroxyphenyl)-1-propanone C00CI+.

(1) 1-(2-methoxycarbonylmethoxy-4,6
-bis(methoxymethoxyphenyl)]-3-(3,4
-Bis(methoxymethoxyphenyl)]-]Under a stream of 1-propanone, ■-[2-hydroxy-4,6-bis[methoxymethoxyphenyl)-3-(3,4-bis(methoxymethoxyphenyl)]- ]1-propanone 121g
D to a mixture of 1.50 g of sodium hydride and 1.50 g of sodium hydride under water cooling.
MF 100mf was slowly added dropwise, the temperature was returned to room temperature, and the mixture was stirred for 30 minutes. Next, add 3.5% of methyl α-bromoacetate to the reaction mixture at room temperature. Ornl was added and stirred for an additional 60 minutes. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and then separated and purified by column chromatography (silica gel Merck 9385, eluent: ethyl acetate:hexane-1:4). After evaporation of the solvent, the concentrate was crystallized with ethyl acetate-petroleum ether-hexane system, and 12.6 g (90 g) of the title compound was obtained as a white powder.
%)Obtained.

Molecular formula: CzJznO,z (522) Melting point: 68.
5~69.0°C Infrared absorption spectrum ν□Xcm-' (KBr)
:1760, 1708.1608.1594.1512
．． 1256°1150, 1126.1084.103B
, 1012.1002 proton nuclear magnetic resonance spectrum (200MZ) δppm.

J□z, (CDCh): 63.09-3.18 (2H, m), 62.96
~3.00 (211°m), δ3.42 (3) 1. S)
, 63.46 (3H, S), δ3.50 (311,
S), 63.76 (,TI,S),
δ4.59 (2H, S).

65.09<2H,S), δ5.12(2+1.
S), δ5. l8(2H,S), δ5.20
(2H, S), 66.17 (IH, d, J・2.0
), 66.50 (111, d, J・2.0),
66.83 (IH.

dd, J=2.0. 8.3), 67.03 (IH
, d, J=2.0).

67.04 (IH, d, J・8.3) (2) 1-(4,6-cyhydroxy-2-methoxycarbonylmethoxyphenyl)-3-(3,4-dihydroxyphenyl)-1-propanone (1) Compound 3 obtained in
A 50% hydrochloric acid-methanol solution was added to a solution of 8 g of methanol (80 m!), heated to 40-50'C (in a hot water bath), and stirred for about 20 minutes. After the reaction was completed, the reaction mixture was poured into water and the precipitated solid was collected by filtration. Next, the filtered solid was dissolved in ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-petroleum ether to yield 2.07 g (81%) of the title compound as a white solid.

Molecular formula: c, @n, aos (362) Melting point: 170
．． 5-171.5°C Infrared absorption spectrum smaMCm-' (Br)
:3504, 3428. 3244. 1722.
1632. 1598°1526, 144B,
1432. 1316. 1202. 1158°11
28.1108 Proton nuclear magnetic resonance spectrum (200MZ) δppn
+.

J H2, (Ac6ton-d): 62.84 (2
11, t, J・8.1), 63.39 (2tf, t,
J.8.1).

63.69 (311, S), δ4.82 (2H,
S), δ5.93 (III.

d, J・2.3), 66.00(lILd, J・2
．． 3), 66.59 (lH, dd, J・8.1.2
．． 1), δ6.72(1)1. d, J・8.1)
.

δ6.76 (IFI, d, J・2.1) Mass spectrum m/z (χ): 367 (M”, 48), 225 (53), 19
7 (46).

Example 14 4.4'-dihydroxy-2-methoxyluponylmethoxychalcone (1) 2'-methoxycarbonylmethoxy-4,4=bis(methoxymethoxy)chalcone 25 g of 2',4'-dihydroxyacetophenone D?
IP (280mZ)? 13.6 m of N,N-diisopropylethylamine ter in solution g! was slowly added dropwise, and the mixture was allowed to warm to room temperature and stirred for 3 hours. After the reaction was completed, a large amount of water was added to the reaction mixture, and the mixture was extracted with diethyl ether. After washing the extracted solution with water and drying (anhydrous sodium sulfate), the solvent was distilled off under reduced pressure and dried to obtain the following compound almost quantitatively as a deep red-orange oil.

2'-Hydroxy-4'-methoxymethoxyacetophenone The above compound 30. To a solution of 14 g of 4-methoxymethoxybenzaldehyde and 25.1 g of DMSO (too much), add 200 g of saturated potassium hydroxide-ethanol solution.
mf was added and stirred for 12 hours. Next, dilute hydrochloric acid (approximately 3N) was added to the reaction mixture under cooling to make a neutral solution, and the precipitated solid was collected by filtration and dried under reduced pressure. The dried solid was subjected to column chromatography (silica gel, Mer
ck 9385, eluent ethyl acetate:hexane=1:1
) and then crystallized with ethyl acetate-petroleum ether, yielding 25.5 g (49%) of the following compound.
)Obtained.

2-Hydroxy-4,4'-bis(methoxymethoxy)chalcone 10.0 g of the compound obtained above, anhydrous potassium carbonate 6.0
A solution of 1.0 g of potassium iodide in DMF (100 ml) was stirred at room temperature for 60 minutes, then 3.3 d of methyl α-bromoacetate was added, and the mixture was further stirred for 4 hours. After the reaction is complete,
Water was added to the reaction mixture, and the precipitated solid was collected by filtration.

Subsequently, the filtered solid was dissolved in ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and then the solvent was distilled off.
The residue was crystallized from ethyl acetate-diethyl ether-hexane system to obtain the title compound 9 as a white solid.

61 g (80%) was obtained.

Molecular formula: C2□lIzaos (416) Melting point: 85.
0~85.5°C Infrared absorption spectrum! '*axCm-' (KBr)
:1770, 1606. 1510, 1428
, 1242, 1212.

1174, 1158, 1128. 10?6. 1
016,994.

Proton nuclear magnetic resonance spectrum (200 MZ) δpp
m.

J82. (Acetone-d): 63, 44 (
3H,S), δ3.45(311,S), 6
3.78 (311, S), δ4.92 (2+1, S
), δ5.25 (21L S).

δ5.27(2+1,S), 66,71(1B,
d, J=2.2), 66, 77 (IH, da,
J=2.2, 8.4), 67, 08 (21+
, dd.

J・2.0, 6.6), δ7.64 (III,
d, J・15.6), 67, 73 (IH, d, J≧8.
8), 67, 73 (2H, dd, J・2.2.

6,6), 67,85(11(,d,J=15.6
) (2) 4.4'-dihydroxy-2-methoxycarbonylmethoxychalcone (1) 0.50 g of methanol (5 rnl
) Add 4 ml of hydrochloric acid-methanol to the solution and heat at 45-50°C.
(in a hot water bath) and stirred for 30 minutes. After the reaction is complete,
After adding water to the reaction mixture and extracting with ethyl acetate,
It was washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. When the residue was crystallized from methanol-ethyl acetate (a small amount)-hexane, the title compound was obtained as a red pine colored powder.
．． 316g (80%) was obtained.

Molecular formula: c, t+,, ob (328) Melting point = 207 ~
208.0"C Infrared absorption spectrum νlIaxcm-' (KBr)
:3408, 3352. 1732. 1722.
1322. 1260.

1240, 1216, 1194, 1186. 1
172 proton nuclear magnetic resonance spectrum (200MZ) δ
ppm.

Joz, (8cetone-d): δ3.78 (3
1LS), 64.88 (211,S), 66.5
0(ill.

d, J・2.2), 66.58(ill, dd, J
・2.2.8.3).

δ6.90 (20, aa, J=2.0.6.8),
67.58-7.71 (4H, m), 67.82 (
IH, d, J = 15.6) Mass spectrum m/z (X)
: (75), 107(41) Example 15 2'-Carboxymethoxy-4,4'-dihydroxychalcone 2.5 g of the compound obtained in the previous example in methanol-dioxane (75 m/-25 m solution with 5% water 50 ml of potassium oxide aqueous solution was added and stirred for 15 minutes.After the reaction was completed, water was added to the reaction mixture, and the solution was diluted with dilute hydrochloric acid under cooling.
The temperature was adjusted to about H6 to 4, and the precipitated solid was collected by filtration. The filtered solid was dried by heating under reduced pressure and crystallized with methanol-chloroform-hexane to obtain 1.46 g (61%) of the title compound as a reddish-orange powder.

Molecular formula: C+ fi11+ 606 (32B) Melting point: 207.0-208.0°C Infrared absorption spectrum □xcm-' (KBr):
3112, 1736. 1634', 1600.
1536. 1514°1256, 1210.119
0.1172.834 proton nuclear magnetic resonance spectrum (
200MZ) δppm.

J H2, (CDt) 2SO: 64.81 (2+1.S), 66.44 (IH, d
, J=2.0), 66.49(III, dd, J
P2. Sail 8.3), 66.8N2+1. d.

, b8.8), δ7.54 (111, d, J・15.6
), 67.62 (Ill.

d, J=8.3), 67.82(ill, d, J=
15.6) Mass spectrum m/z (χ): 314 (M”, 26), 255 (26), 163
(33), 137(100), 107(52) Example 16 1-(4-1:Floxy2-methoxycarbonylmethoxyphenyl)-3-(4-hydroxyphenyl)-1
-Propanone (1) 1-(2-methoxycarbonylmethoxy-4-methoxymethoxyphenyl)-3-(4-methoxymethoxyphenyl)-1-propanone 0OCH3 5% palladium-carbon 1.5 to which hydrogen has been adsorbed in advance
A solution of 10.0 g of the compound obtained in Example 14 (1) in ethyl acetate was added to the suspension of 10.0 g of the compound obtained in Example 14 (1), and hydrogen was further adsorbed. After the reaction was completed, the palladium-carbon in the reaction mixture was removed using Celite, and the filtrate was concentrated under reduced pressure and crystallized from methanol, yielding the title compound 9.
6g (96%) obtained.

Molecular formula: C2411!60t(394)% Formula% Infrared absorption spectrum ν□xcm-' (in Br):
1762, 1666, 1600.1236.1208.
119B.

1178, 1148.1126.1076, 1016.
986 proton nuclear magnetic resonance spectrum (200MZ) δ
ppm.

J engineering 2. (CDC13): 62.97 (2H, t, J・8.1), 63.3
7(211,t, J・8,1), δ3.46(
6)1. S), δ3.74 (3H,S),
δ5.14 (2H, S), δ4.68 (211,
S), δ5.18 (2H.

S), 66.45 (Ill, d, J・2.2), 6
6.71 (in, aa.

J・2.2.8.6), 66.94 (2H, da, J・
2.0.6.6).

δ7.16 (2+1.dd, J=2.0.6.6),
67.79 (LH.

d, J=8.6) (2) 1-(4-hydroxy-2-methoxycarbonylmethoxyphenyl)-3-(4-hydroxyphenyl)
- To a solution of 1.0 g of the compound obtained from 1-propanone (1) in methanol (10 m), add 7.5 - of hydrochloric acid-methanol solution to 40 - 45'
C (in a hot water bath) and stirred for 30 minutes. After the reaction is complete,
Ice water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid obtained by heating and drying under reduced pressure was mixed with methanol-ethyl acetate (a small amount)-
Crystallization from petroleum ether gave 0.75 g (95%) of the title compound as a white powder.

Molecular formula: aft + *Os (380) Melting point: 1
45.5-146.5°C Infrared absorption spectrum I'maxCm-' (KBr
) :3320,1?30.1614.1585.1
514.1254° Proton nucleus 1a gas resonance spectrum (
200FIZ) δppm.

J H2, (Aceton-d): δ2.87 (2
H, t, J=7.7), δ3.33(2)1. t,
J・7.7), δ3.72 (3)1. S)
, δ4.83 (21LS), δ6.45 (II
(, d, J=2.2), δ6.53 (Ill, dd
, J=8.8°2.2), 66.73(2)1. dd
, J・6.6.2.2), δ7,67(ill, d,
J・8.8), 67.08(ill, dd, J=2
．． 2. 6.6) Mass spectrum m/z (χ): 330 (M”, 75χ), 209 (99r)
.

xstoooo；'@ ), x2o(99x), to
7(9+z) Example 17 -(2-carboxymethoxy-4-hydroxyphenyl)-3-(4-hydroxyphenyl)=1-propanone 2.63 g of the compound obtained in the previous example in methanol (30 m
l) Add 30ml of 5% potassium hydroxide aqueous solution to the solution,
Stirred at room temperature for 15 minutes. After the reaction was completed, dilute hydrochloric acid was added to the reaction mixture under water cooling to make the solution slightly acidic, and the precipitated solid was collected by filtration and dried under reduced pressure by heating. Next, the dried solid was crystallized with methanol, cochloroform, and petroleum ether, and the title compound was obtained as a white powder at 2.24%
g (89%) was obtained.

Molecular formula: C+? ll+60b (316) Melting point: 16
0.5-161.0°C Infrared absorption spectrum □Xcm-' (KBr):
3160, 3048.1?38.1630.1602.
1574°1260, 1188. 1126. 10
72.992 proton nuclear magnetic resonance spectrum (200M
Z) δppm.

J oz, (Solo, 8ceton-d): δ2
．． 88 (211, t, J・7.4), δ3.33 (2H
, t, J・7.4).

64.83 (2+1.S), δ6.49 (il
l, d, J=2.0), 66.54 (I
H, dd, J=2.0.8.3tlz), δ6.7
2 (211°dd, J=2.4.6.4), 67.
08(2+1.dd), 67.68(111,d, J=
8.3) Mass spectrum m/z (χ): 316 (M”, 20), 195 (34), 1
37 (100° (margin below next summer) Preparation example 1 Preparation of tablets (2) Nyuu Kyouten
90g (3) Cornstarch Mix 29g (1), (2) and 17g of cornstarch and granulate it with a paste made from 7g of cornstarch.
g of cornstarch and (4) are added and the mixture is compressed in a compression tablet machine to produce 1000 tablets containing (1) 10 +ng per 1i2 tablets.

(Leaving space for next summer) Preparation example 2 Capsule (2) Lactose 150g (3) Cornstarch 100g
(4) Crystalline cellulose 40g (5)
Light anhydrous silicic acid 5g 1000 pieces
500 g According to a conventional method, the above ingredients are mixed and granulated and filled into 1000 capsules, each weighing 500 mg.

Preparation Example 3 Preparation of injection (2) Sodium chloride 9g (3)
Chlorobutanol 5g (4) Sodium bicarbonate Ig all ingredients in distilled water 100%
Dissolve at 0 mf, dispense 1 rnl into 1000 brown ampoules, replace with nitrogen gas, and seal. The entire process is carried out under aseptic conditions.

[Effects of the Invention] As described above, the present invention provides a novel chalcone derivative and an highly effective anti-ulcer agent containing the derivative as an active ingredient.

Claims (1)

[Claims] 1. Chalcone derivative represented by the following general formula: ▲ Formula,
There are chemical formulas, tables, etc. ▼ [In the formula, R_1, R_2, R_3, R_4, R_5, R_6 are
are the same or different and represent hydrogen, OH,
together with adjacent groups represents alkylene dioxy (however, not all represent hydrogen atoms); A represents OH or O-Y-Z (Y represents straight-chain alkylene; Z represents carboxyl, alkoxycarbonyl, or hydroxyl group); B represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ; ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ means a single bond or an unsaturated bond. However, this excludes compounds in which B is a mathematical formula, chemical formula, table, etc.▼, A at the 2' position represents OH, and the following (a) or (b) is true: (a) The 5' position is propyl or Compounds substituted with 3-isopentyl or isopentenyl group, (b) 4'-position (and/or 6'-position), 3- and 4-positions are O
Compounds substituted with H groups. [In the formula, R_1, R_2, R_3, R_4, R_5, R_6 are
are the same or different and represent hydrogen, OH,
together with adjacent groups represents alkylene dioxy (however, not all of them represent hydrogen atoms); A represents OH or O-Y-Z; (Y represents straight-chain alkylene; Z represents carboxyl, alkoxycarbonyl or hydroxyl group); B represents ▲ mathematical formula, chemical formula,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
Or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ means; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ means a single bond or an unsaturated bond. However, this excludes compounds in which B is a mathematical formula, chemical formula, table, etc.▼, A at the 2' position represents OH, and the following (a) or (b) is true: (a) The 5' position is propyl or Compounds substituted with 3-isopentyl or isopentenyl groups, (b) 4'-position (and/or 6'-position), 3- and 4-positions are O
Compounds substituted with H groups. ]