JPH07121933B2 - Dihydrobenzofuranone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a dihydrobenzofuranone derivative useful as a drug.

More specifically, the present invention provides a compound of the general formula useful as a therapeutic agent for stomach and duodenal ulcer. (In the formula, R ¹ and R ² may be the same or different and each is a hydrogen atom or a lower alkoxycarbonyl group as a substituent, a 2-oxo-1-pyrrolidinyl group or a lower alkyl group which may have a pyridyl group. Or N-R ¹ R ² together form a 1-pyrrolidinyl group, a piperidino group, a 4-methylpiperidino group, a morpholino group or a 1-perhydroazepinyl group, and R ³ and R ⁴ Represents a hydrogen atom or a lower alkyl group, and Y represents a hydrogen atom, a nitro group, an amino group, a lower acylamino group, a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group). To do.

[Conventional technology]

As the dihydrobenzofuranone derivative as in the present invention,
Some compounds are already known. For example, in Journal of Pharmaceutical Sciences (J.Pharm.Sci.) Vol. 69, p. 164 (1980), an intermediate for producing a metabolite of a compound having an inhibitory action on platelet aggregation and an anti-inflammatory action is described. The compound represented by is reported.

In addition, Japanese Patent Laid-Open Publication No. 58-135877 discloses a general formula for anti-inflammatory, analgesic and antipyretic agents. (Wherein R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are a hydrogen atom or a lower alkyl group, R ¹³ is a hydrogen atom or a halogen atom, and n is 0 or 1) It has been reported.

Furthermore, published patent gazette, Sho 59-31511, published patent gazette,
54-98752, 55-2623, 55-64582, 5
5-147271, 56-5473, 56-154477 and 56-154478 have general formulas having gastric secretion inhibitory action, anti-inflammatory action, analgesic action, etc. (In the formula, ring A represents a benzene ring or a naphthalene ring,
The benzene ring or naphthalene ring is a lower alkyl group, nitro group, halogen atom, optionally substituted amino group, optionally substituted hydroxyl group, acyl group, sulfamoyl group, carboxyl group, lower alkoxycarbonyl group, substituted Optionally substituted carbamoyl group, optionally substituted ureido group, optionally substituted thioureido group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, optionally substituted aminomethyl group, cyano Group, which may be substituted with at least one or more of a group and a phenyl group) have been reported.

[Problems to be Solved by the Invention]

The present inventors have conducted studies to find a compound that is effective against stress-induced ulcers and has few side effects. As a result, certain dihydrobenzofuranone derivatives are effective against experimental ulcers, particularly stress ulcers, and have low toxicity. ,
The present invention was found to be useful as a therapeutic agent for gastric and duodenal ulcers of mammals including humans, and has completed the present invention.

The present invention is based on such knowledge.

[Means for Solving the Problems]

The dihydrobenzofuranone derivative represented by the above general formula (I) of the present invention shows a remarkable inhibitory effect on restraint water immersion stress ulcer in rats, has low toxicity, and is useful as a therapeutic agent for gastric and duodenal ulcers. is there.

The compound of the general formula (I) of the present invention is a novel compound and can be produced as follows.

For example, the general formula (Wherein R ³ , R ⁴ and Y have the same meanings as described above), a carboxylic acid represented by the general formula It can be produced by reacting with an amino compound represented by the formula (R ¹ and R ² in the formula have the same meanings as described above).

Also, the general formula (Wherein Y has the same meaning as described above), a compound represented by the general formula (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.)
It can also be produced by reacting an acrylamide derivative represented by with palladium acetate and triphenylphosphine or tris (2-methylphenyl) phosphine in the presence of a base such as triethylamine.

Furthermore, the general formula It can also be produced by treating a compound represented by the formula (wherein R ¹ , R ² , R ³ , R ⁴ and Y have the same meanings as described above) with a base such as potassium carbonate.

The compound of the general formula (I), wherein R ⁴ is a hydrogen atom, is (Wherein Y has the same meaning as described above), a compound represented by the general formula It can also be produced by reacting with a compound represented by the formula (R ¹ , R ² and R ³ in the formula have the same meanings as described above).

In the case of the method described first among these production methods, in the compound of the general formula (II), the compound in which Y is an amino group is protected with an appropriate protecting group and then reacted, and the protecting group is removed after the reaction. Alternatively, it is preferable to carry out the reaction using a compound in which Y is a substituent capable of converting to an amino group, for example, a nitro group, and after the reaction, convert to an amino group.

The general formulas (II), (IV), (VI) and (VI) used as raw materials for producing the compound of the general formula (I) of the present invention.
The compound represented by I) is also a novel compound and can be produced as follows.

For example, the compound represented by the general formula (II) is represented by the general formula 2-bromo-2-methylpropionyl bromide is reacted with a compound represented by the formula (wherein R ³ , R ⁴ and Y have the same meaning as described above) in the presence of anhydrous aluminum chloride,
General formula (R ³ , R ⁴ and Y in the formula have the same meanings as described above), and then the compound is treated with a base such as potassium carbonate and then the ester is hydrolyzed.

Further, the compound represented by the general formula (II), wherein R ⁴ is a hydrogen atom, is The compound represented by the formula (Y has the same meaning as described above) is oxidized with an oxidizing agent such as manganese dioxide or potassium persulfate, or is brominated with N-bromosuccinimide or the like, and then dimethyl is formed. Oxidation with sulfoxide gives the aldehyde derivative represented by the general formula (VII), which is then added to the general formula It can be produced by reacting a malonic acid derivative represented by the formula (R ³ in the formula has the same meaning as described above).

The compound of the general formula (XI) used as a raw material in this production method is 2-bromo-2-methylpropionyl bromide is reacted with an anisole derivative represented by the formula (Y has the same meaning as described above) in the presence of anhydrous aluminum chloride to give a compound represented by the general formula (Wherein Y has the same meaning as described above), and the compound is treated with a base such as potassium carbonate, or a compound of the general formula The compound represented by the formula (Y has the same meaning as described above) is converted into an acid halide and then ring-closed in the molecule in the presence of anhydrous aluminum chloride.

The compound represented by the general formula (IV) used as a raw material in the second production method of the compound of the general formula (I) is a compound represented by the general formula: The compound represented by the formula (Y has the same meaning as described above) is brominated by an appropriate method, or It can be obtained by reacting a compound represented by the formula (Y has the same meaning as described above) with 2-bromo-2-methylpropionyl bromide in the presence of anhydrous aluminum chloride, and then treating with a base.

Further, Y of the obtained compound of the general formula (IV) can be converted into another derivative by applying an appropriate treatment. For example, by oxidizing a compound in which Y is a methyl group, Y
A compound in which is a carboxyl group is obtained, and then an esterification reaction is performed on this to convert into a compound in which Y is an alkoxycarbonyl group. Further, a compound in which Y is a nitro group can be obtained by nitrating a compound in which Y is a hydrogen atom by an appropriate method, and by reducing this, a compound in which Y is an amino group can be converted. It is also possible to convert the amino group into a compound in which Y is an acylamino group by acylating the amino group by an appropriate method.

The compound of general formula (VI) used as a starting material in the third production method of the compound of general formula (I) of the present invention can be produced as follows.

That is, the general formula (Wherein R ³ , R ⁴ and Y have the same meanings as described above), a carboxylic acid or a reactive functional derivative thereof is reacted with an amine (III) to give a compound represented by the general formula (Wherein R ¹ , R ² , R ³ , R ⁴ and Y have the same meanings as described above), and 2-bromo-2-methyl in the presence of anhydrous aluminum chloride is prepared. It can be produced by reacting propionyl bromide.

The compound of the general formula (VII) used as a starting material in the fourth production method of the compound of the general formula (I) may be prepared by oxidizing the compound of the general formula (XI) as described above. it can.

Further, Y of the obtained compound of the general formula (VII) can be converted into another derivative by appropriate treatment. For example, a compound in which Y is a hydrogen atom can be converted into a compound in which Y is a nitro group by nitration by a suitable method.

General formulas (IX), (XII), (XIII), (XV), (XVI) of the raw materials used in the method for producing the above-mentioned production intermediates,
In addition to the above-mentioned raw materials in the respective production methods of the compounds represented by (XVII) and (XVIII) and the compound of the general formula (I), general formula (III),
The compounds represented by (V) and (VIII) are generally known compounds, and are commercially available, or can be easily produced by a method described in the literature or a method similar thereto.

The compound of the general formula (I) of the present invention has a geometric isomer due to a double bond, but in the present invention, it is not limited to E-form, Z-form or a mixture thereof.

The compound of the general formula (I) of the present invention shows an anti-ulcer action with a suppression rate of about 30 to 70% by oral administration of 100 mg per 1 kg of body weight in a restrained water immersion stress ulcer experiment using Wistar male rats. In an acute single-dose oral toxicity test in male ICR mice, a strong toxic effect was not observed even at a dose of 1000 mg / kg body weight, and it is extremely useful as a therapeutic agent for stomach and duodenal ulcer in mammals including humans. .

When the compound of the general formula (I) of the present invention is used as an agent for treating ulcer, it may be administered in various dosage forms as it is or after being mixed with an appropriate pharmaceutical additive.

Examples of such dosage forms include powders, granules, fine granules, tablets, capsules, syrups, liquids, suppositories, and other oral administration agents and parenteral administration agents.

In addition, the optimal dose for actual treatment is appropriately determined according to the patient's age, body weight, sex, degree of symptoms, etc.
In the case of parenteral administration, the daily dose for adults is from 1 mg to 1000 mg and is divided into 1 to several divided doses.

〔The invention's effect〕

The compound represented by the general formula (I) of the present invention is about 30 to 70 by oral administration of 100 mg per kg body weight in a restrained water immersion stress ulcer experiment using male Wistar rats (8 weeks old).
Shows a suppression effect of about%.

In addition, the compound of the general formula (I) of the present invention has low toxicity and IC
Almost no deaths are observed even when 1000 mg / kg of body weight is orally administered to R male mice (6 to 7 weeks old).

As described above, the compound represented by the general formula (I) of the present invention has a strong anti-stress ulcer action and low toxicity, and is therefore useful as a therapeutic agent for stomach and duodenal ulcer of mammals including humans.

〔Example〕

The contents of the present invention will be described in more detail with reference to the following reference examples and examples.

The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference Example 1 50 ml of 4-methylanisole was added to 100 ml of a dry methylene chloride suspension of 55.0 g of anhydrous aluminum chloride under ice-cooling stirring, and then 50 ml of 2-bromo-2-methylpropionyl bromide was added under stirring with heating under reflux. It was added dropwise and heated under reflux for 16 hours. The reaction solution was poured into ice water, acidified with hydrochloric acid, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 101.0 g of oily 2-bromo-2'-hydroxy-2,5'-dimethylpropiophenone.

IR (neat): ν _CO 1630cm ^-1 NMR (CDCl ₃ ) δ: 2.09 (6H, s), 2.32 (3H, s), 6.93 (1H, d, J = 8.2H)
z), 7.29 (1H, dd, J = 2.2and8.2Hz), 8.26 (1H, d, J = 2.2
Hz), 11.84 (1H, s) 2-Bromo-2'-hydroxy-2,5'-dimethylpropiophenone 100.9 g was dissolved in 300 ml of dry toluene, and 84.0 g of anhydrous potassium carbonate was added, and the mixture was stirred at 16%. Heated to reflux for hours. The insoluble matter was removed by filtration, the liquid was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off to give an oily 2,2,5-
68.7 g of trimethyl-3 (2H) -benzofuranone was obtained.
A portion of this is distilled under reduced pressure, boiling point 77-80 ℃ / 3mmHg, melting point 38-
40 ° C. 2,2,5-trimethyl-3 (2H) -benzofuranone was obtained.

Elemental analysis value: (as C ₁₁ H ₁₂ O ₂ ) C% H% Calculated value 74.98 6.86 Measured value 74.78 6.93 IR (KBr): ν _CO 1715cm ⁻¹ NMR (CDCl ₃ ) δ: 1.45 (6H, s), 2.35 (3H, s), 6.98 (1H, d, J = 8.8H
z), 7.4 to 7.5 (2H, m) 2,2,5-trimethyl-3 (2H) -benzofuranone 20.0 g was suspended in a mixed solution of concentrated sulfuric acid 65 ml and water 130 ml, and manganese dioxide 30.0 g was added. The mixture was stirred at 0 ° C for 20 hours. After cooling, ethyl acetate was added to the reaction solution, the insoluble material was filtered off, the organic layer was washed with an aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: benzene / hexane = 3/1) and then recrystallized from diethyl ether-hexane to give a 5-mp melting point of 63-65 ° C. Formyl-2,
12.8 g of 2-dimethyl-3 (2H) -benzofuranone was obtained.

Elemental analysis value: (as C ₁₁ H ₁₀ O ₃ ) C% H% Calculated value 69.46 5.30 Measured value 69.35 5.30 IR (KBr): ν _CO 1715,1685cm ⁻¹ NMR (CDCl ₃ ) δ: 1.52 (6H, s) , 7.21 (1H, d, J = 8.2Hz), 8.18 (1H, d, J
= 2.2Hz), 8.21 (1H, dd, J = 2.2and8.2Hz), 9.96 (1H,
s) 5-formyl-2,2-dimethyl-3 (2H) -benzofuranone (10.0 g) was dissolved in pyridine (100 ml), malonic acid (11.0 g) and aniline (0.2 ml) were added, and the mixture was stirred at 50 ° C for 16 hr and then refluxed for 1 hr. . The reaction solution was concentrated under reduced pressure, acidified with hydrochloric acid, the precipitated crystals were collected by filtration, washed with water and recrystallized from ethanol, and had a melting point of 194 to 197 ° C. 3- (2,3-dihydro-2,2-dimethyl- 3-oxo-5-benzofuranyl) acrylic acid 8.9 g
Got

Elemental analysis value: (as C ₁₃ H ₁₂ O ₄ ) C% H% Calculated value 67.23 5.21 Actual value 67.33 5.19 IR (KBr): ν _CO 1710,1680 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.50 (6H, s) , 6.40 (1H, d, J = 15.9Hz), 7.13 (1H, d,
J = 8.8Hz), 7.78 (1H, d, J = 15.9Hz), 7.8-7.9 (2H, m) Reference Example 2 5-formyl-2,2-dimethyl-3 (2H) -benzofuranone 0.70g is dried with pyridine. Dissolve in 4 ml, methylmalonic acid
After adding 0.86 g and 0.73 ml of piperidine, the mixture was heated under reflux for 48 hours. The reaction mixture was concentrated under reduced pressure, water was added to acidify the mixture with hydrochloric acid, and the mixture was extracted with chloroform. An aqueous solution of 5% sodium hydroxide was added to this organic layer, and the mixture was shaken well and the aqueous layer was separated, treated with activated carbon, acidified with hydrochloric acid, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from diethyl ether-hexane to give 2-methyl-3- (2,3-dihydro-2,2-dimethyl-3-oxo-) having a melting point of 127 to 129 ° C. 0.60 g of 5-benzofuranyl) acrylic acid was obtained.

Elemental analysis value: (as C ₁₄ H ₁₄ O ₄ ) C% H% Calculated value 68.28 5.73 Measured value 67.96 5.69 IR (KBr): ν _CO 1715,1685cm ⁻¹ NMR (CDCl ₃ ) δ: 1.49 (6H, s) , 2.17 (3H, d, J = 1.7Hz), 7.13 (1H, d, J
= 8.8Hz), 7.70 (1H, dd, J = 2.2and8.8Hz), 7.75 to 7.85
(2H, m) Reference Example 3 3.38 g of m-cresol was dissolved in 160 ml of dry acetone, and after adding 10.53 g of sodium hydroxide under stirring with ice cooling, 22 ml of dry chloroform was added dropwise, and after stirring at room temperature for 3 hours, Two
Heated to reflux for hours. The reaction mixture was concentrated under reduced pressure, water was added to make the mixture acidic, and the mixture was neutralized with sodium hydrogen carbonate and washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid, extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oily 2
-Methyl-2- (3-methylphenoxy) propionic acid 4.
I got 33g.

IR (neat): ν _CO 1710cm ^-1 NMR (CDCl ₃ ) δ: 1.60 (6H, s), 2.31 (3H, s), 6.73 (1H, d, J = 8.2H)
z), 6.76 (1H, s), 6.87 (1H, d, J = 8.2Hz), 7.15 (1H, t,
J = 8.2Hz), 8.95 (1H, br) 2-methyl-2- (3-methylphenoxy) propionic acid
Add 80 ml of dry benzene and 8 ml of thionyl chloride to 4.32 g and add 2
After heating under reflux for an hour, the reaction solution was concentrated to dryness under reduced pressure. To a solution of this residue in 60 ml of dry benzene, 3.87 g of anhydrous aluminum chloride was added under ice-cooling stirring, and the mixture was reacted at room temperature for 1.5 hours. The reaction solution was poured into ice water, acidified with hydrochloric acid, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: gloroform / benzene = 2/1) to obtain an oily 2,2,6-trimethyl-3 (2H) -benzofuranone 1.28. got g.

IR (neat): ν _CO 1710 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (6H, s), 2.43 (3H, s), 6.85 to 6.95 (2H, m), 7.
55 (1H, d, J = 8.8Hz) 2,2,6-trimethyl-3 (2H) -benzofuranone 1.26g, dry carbon tetrachloride 40ml, N-bromosuccinimide 1.91g
And 60 mg of 2,2'-azobisisobutyronitrile were added, and the mixture was heated under reflux with stirring for 6 hours under irradiation with light. After cooling, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is dried with dimethyl sulfoxide 10 ml
1.84 g of silver tetrafluoroborate was added with stirring at room temperature and reacted for 18 hours. After adding 0.9 ml of dry triethylamine to the reaction solution, ice water was added and the mixture was extracted with diethyl ether and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography (eluting solvent: chloroform / benzene =
2/1) and then recrystallized from diethyl ether-hexane to give 6-formyl-2,2-dimethyl-mp, melting point 98-100 ° C.
0.41 g of 3 (2H) -benzofuranone was obtained.

Elemental analysis value: (as C ₁₁ H ₁₀ O ₃ ) C% H% Calculated value 69.46 5.30 Measured value 69.29 5.27 IR (KBr): ν _CO 1700cm ⁻¹ NMR (CDCl ₃ ) δ: 1.50 (6H, s), 7.55 ~ 7.65 (2H, m), 7.82 (1H, d, J ＝
8.8Hz), 10.09 (1H, s) 6-formyl-2,2-dimethyl-3 (2H) -benzofuranone (0.39g) is dissolved in 3ml of pyridine, 0.27g of malonic acid and 0.1ml of aniline are added, and the temperature is 60 ° C for 18 hours. After stirring, the mixture was heated to reflux for 1 hour. After cooling, the reaction solution was added to ice-diluted hydrochloric acid with stirring, and the precipitated crystals were collected by filtration and washed with water, and then the crystals with a melting point of 258 to 261 ° C.
0.31 g of (2,3-dihydro-2,2-dimethyl-3-oxo-6-benzofuranyl) acrylic acid was obtained.

Elemental analysis value: (as C ₁₃ H ₁₂ O ₄ ) C% H% Calculated value 67.23 5.21 Actual value 67.02 5.25 IR (KBr): ν _CO 1695cm ^-1 NMR (DMSO-d ₆ ) δ: 1.41 (6H, S) , 6.73 (1H, d, J = 15.9Hz), 7.46 (1H, d,
J = 7.7 Hz), 7.55 to 7.7 (3H, m), 12.64 (1H, br-s) Reference Example 4 o-Cresol 7.5 g was dissolved in dry acetone 230 ml, and sodium hydroxide 27.8 g was added under ice-cooling stirring. After that, 28 ml of dry chloroform was added dropwise, and the mixture was stirred for 2 hours and reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, water was added to make the mixture acidic, and the mixture was neutralized with sodium hydrogen carbonate and washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid, extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 100/1) to give oily 2-methyl-2- (2-methylphenoxy) propionic acid 13.0. got g.

IR (neat): ν _CO 1710cm ^-1 NMR (CDCl ₃ ) δ: 1.62 (6H, s), 2.25 (3H, s), 6.82 (1H, d, J = 7.7H)
z), 6.94 (1H, t, J = 7.7Hz), 7.10 (1H, t, J = 7.7Hz), 7.
17 (1H, d, J = 7.7Hz) 2-Methyl-2- (2-methylphenoxy) propionic acid
To 11.5 g, add 80 ml of dry benzene and 4.3 ml of thionyl chloride,
The mixture was heated under reflux for 2 hours. The reaction solution was concentrated to dryness under reduced pressure,
After 80 ml of dry benzene was added to the residue, 8.0 g of anhydrous aluminum chloride was added with stirring under ice cooling, and the mixture was reacted at room temperature for 30 minutes. After pouring the reaction solution into ice water and acidifying with hydrochloric acid,
The mixture was extracted with diethyl ether, washed with 5% aqueous sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: benzene / hexane = 3/1), and the melting point was 61 to 65 ° C.
2.1 g of 2,7-trimethyl-3 (2H) -benzofuranone was obtained.

Elemental analysis value: (as C ₁₁ H ₁₂ O ₂ ) C% H% Calculated value 74.98 6.86 Measured value 74.70 6.89 IR (KBr): ν _CO 1715 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.47 (6H, s), 2.31 (3H, s), 6.97 (1H, t, J = 7.7H
z), 7.42 (1H, d, J = 7.7Hz), 7.50 (1H, d, J = 7.7Hz) 2,2,7-trimethyl-3 (2H) -benzofuranone 2.00g of concentrated sulfuric acid 20ml and water 40ml Suspend in mixed solution, manganese dioxide
After adding 3.00 g, the mixture was stirred at 70 ° C. for 20 hours. After cooling, ethyl acetate was added to the reaction solution, the insoluble material was filtered off, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel flash column chromatography (eluting solvent: benzene / ethyl acetate =
50/1) and 7-formyl-2,2 with a melting point of 123-126 ° C.
0.44 g of -dimethyl-3 (2H) -benzofuranone was obtained.

Elemental analysis value: (as C ₁₁ H ₁₀ O ₃ ) C% H% Calculated value 69.46 5.30 Measured value 69.53 5.29 IR (KBr): ν _CO 1725,1680 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.55 (6H, s) , 7.21 (1H, t, J = 7.7Hz), 7.92 (1H, dd,
J = 1.6and7.7Hz), 8.13 (1H, dd, J = 1.6and7.7Hz), 10.3
7 (1H, s) 7-formyl-2,2-dimethyl-3 (2H) -benzofuranone 0.40 g is dissolved in 5 ml of pyridine, 0.44 g of malonic acid and 0.02 ml of aniline are added, and the mixture is stirred for 16 hours at 50 ° C for 1 hour. Heated to reflux. The reaction mixture was concentrated under reduced pressure, acidified with hydrochloric acid, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethanol-diethyl ether to give a melting point of 206-209.
3- (2,3-dihydro-2,2-dimethyl-3-oxo-
0.45 g of 7-benzofuranyl) acrylic acid was obtained.

Elemental analysis value: (as C ₁₃ H ₁₂ O ₄ ) C% H% Calculated value 67.23 5.21 Actual value 67.16 5.12 IR (KBr): ν _CO 1715,1675cm ⁻¹ NMR (CDCl ₃ ) δ: 1.54 (6H, s) , 6.87 (1H, d, J = 15.9Hz), 7.13 (1H, t,
J = 7.7Hz), 7.72 (1H, d, J = 7.7Hz), 7.74 (1H, d, J = 7.7
Hz), 7.85 (1H, d, J = 15.9Hz) Reference Example 5 2,3,5-Trimethyl-3 (2H) -benzofuranone was added to a mixture of 33 ml of concentrated nitric acid with a specific gravity of 1.42 and 26 ml of concentrated sulfuric acid under ice-cooling stirring. twenty two.
After adding 5g little by little, it stirred at 60 degreeC for 1 hour. The reaction solution was poured into ice water and extracted with diethyl ether,
It was washed with an aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from diethyl ether-hexane to give the melting point 129.
2,2,5-Trimethyl-7-nitro-3 (2H)-
9.5 g of benzofuranone was obtained.

Elemental analysis value: (as C ₁₁ H ₁₁ NO ₄ ) C% H% N% Calculated value 59.73 5.01 6.33 Measured value 59.44 5.00 6.56 IR (KBr): ν _CO 1715cm ⁻¹ νNO ₂ 1535cm ⁻¹ NMR (CDCl ₃ ) δ : 1.56 (6H, s), 2.46 (3H, s), 7.78 (1H, d, J = 1.1H
z), 8.26 (1H, d, J = 1.1Hz) 2,2,5-Trimethyl-7-nitro-3 (2H) -benzofuranone 9.0g was dissolved in 150ml ethanol and 1N hydrochloric acid 42m
l and 0.9% of 5% palladium-carbon were added and hydrogenated at room temperature under normal pressure. The catalyst was filtered off, the solvent was distilled off under reduced pressure, the residue was washed with diethyl ether, and the melting point was 119 to 122 ° C.
There was obtained 8.1 g of 7-amino-2,2,5-trimethyl-3 (2H) -benzofuranone hydrochloride.

Elemental analysis value: (as C ₁₁ H ₁₄ ClNO ₂ ) C% H% N% Calculated value 58.03 6.20 6.15 Measured value 57.86 6.26 6.23 IR (KBr): ν _CO 1725cm ⁻¹ NMR (DMSO-d ₆ ) δ: 1.40 ( 6H, s), 2.26 (3H, s), 6.1 (3H, br), 6.96 (1
H, s), 7.14 (1H, s) 7-amino-2,2,5-trimethyl-3 (2H) -benzofuranone hydrochloride 5.0 g was added to 20 ml of a 10% aqueous solution of borofluoric acid, and the mixture was stirred under ice cooling. A solution of 1.7 g of sodium nitrite in 9 ml of water was added dropwise, and the mixture was reacted for 40 minutes. The precipitated crystals were collected by filtration, washed successively with a 5% aqueous solution of borofluoric acid, cold methanol and cold ethanol, and the melting point of 230-232 ° C (2,3-
Dihydro-2,2,5-trimethyl-3-oxo-7-benzofuran) diazonium tetrafluoroborate 5.0 g
Got

Elemental analysis value: (as C ₁₁ H ₁₁ BF ₄ N ₂ O ₂ ) C% H% N% Calculated value 45.56 3.82 9.66 Measured value 45.62 3.81 9.51 IR (KBr): ν N ₂ ⁺ 2255cm ^-1 ν _CO 1730cm ^-1 NMR (DMSO-d ₆ ) δ: 1.58 (6H, s), 2.48 (3H, s), 8.46 (1H, d, J = 2.2H
z), 8.66 (1H, d, J = 2.2Hz) (2,3-dihydro-2,2,5-trimethyl-3-oxo-7
-Benzofuran) diazonium Tetrafluoroborate (4.9 g) was dissolved in acetic acid (250 ml) and heated under reflux for 1 hour.
The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with diethyl ether, washed with aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in 120 ml of ethanol, 28 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was washed with diethyl ether, the aqueous layer was treated with activated carbon, acidified with hydrochloric acid, extracted with diethyl ether, washed with aqueous sodium hydrogen carbonate solution and water, It was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from diethyl ether-hexane, and the melting point was 165 to 168 ° C.
1.8 g of 7-hydroxy-2,2,5-trimethyl-3 (2H) -benzofuranone were obtained.

Elemental analysis value: (as C ₁₁ H ₁₂ O ₃ ) C% H% Calculated value 68.74 6.29 Measured value 68.50 6.28 IR (KBr): ν _OH 3175cm ^-1 ν _CO 1675cm ^-1 NMR (CDCl ₃ ) δ: 1.47 (6H , s), 2.31 (3H, s), 5.09 (1H, s), 7.01 (1
H, s), 7.03 (1H, s) To 30 ml of ethanol, 0.48 g of 60% sodium hydride (oil) was added little by little under ice-cooling stirring, and then 7-hydroxy-2,2,5-trimethyl-3 ( 2H) -Benzofuranone 1.22 g
And 0.9 ml of methyl iodide were added, and the mixture was heated under reflux for 14 hours.
The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: benzene), and 7-methoxy-2,2,5-trimethyl-3 (2H)-having a melting point of 46 to 49 ° C. 1.17 g of benzofuranone was obtained.

Elemental analysis value: (as C ₁₂ H ₁₄ O ₃ ) C% H% Calculated value 69.89 6.84 Measured value 69.98 6.89 IR (KBr): ν _CO 1705 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.49 (6H, s), 2.36 (3H, s), 3.94 (3H, s), 6.94 (1
H, s), 7.04 (1H, s) 7-methoxy-2,2,5-trimethyl-3 (2H) -benzofuranone (0.60 g) was dissolved in 36 ml of acetonitrile, and 1.57 g of potassium persulfate in 24 ml of water and anhydrous copper sulfate. After 90 mg was added at room temperature with stirring, the mixture was reacted at 70 ° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with diethyl ether, washed with aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether-hexane to give 5-formyl-7-methoxy-mp having a melting point of 123 to 126 ° C.
0.49 g of 2,2-dimethyl-3 (2H) -bezofuranone was obtained.

Elemental analysis value: (as C ₁₂ H ₁₂ O ₄ ) C% H% Calculated value 65.45 5.49 Measured value 65.53 5.48 IR (KBr): ν _CO 1705,1680 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.56 (6H, s) , 4.03 (3H, s), 7.67 (1H, d, J = 1.7H
z), 7.77 (1H, d, J = 1.7Hz), 9.92 (1H, s) 5-formyl-7-methoxy-2,2-dimethyl-3 (2
H) -benzofuranone 0.48 g was dissolved in pyridine 15 ml, malonic acid 0.48 g and piperidine 0.05 ml were added, and the mixture was stirred at 50 ° C for 14
After stirring for an hour, the mixture was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was acidified with hydrochloric acid, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-hexane to give 3- (2,3-dihydro-
0.30 g of 7-methoxy-2,2-dimethyl-3-oxo-5-benzofuranyl) acrylic acid was obtained.

Elemental analysis value: (as C ₁₄ H ₁₄ O ₅ ) C% H% Calculated value 64.12 5.38 Measured value 63.83 5.64 IR (KBr): ν _CO 1715,1685 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.53 (6H, s) , 4.01 (3H, s), 6.38 (1H, d, J = 15.9H
z), 7.28 (1H, d, J = 1.1Hz), 7.45 (1H, d, J = 1.1Hz), 7.
75 (1H, d, J = 15.9Hz) Reference Example 6 3.28 g of methyl 2,4-dimethoxycinnamate was dissolved in 70 ml of dry methylene chloride, and anhydrous aluminum chloride under ice-cooling stirring 3.
After 68 g was added, 2.1 ml of 2-bromo-2-methylpropionyl bromide was added dropwise with stirring with heating under reflux, and the mixture was heated under reflux for 4 hours. The reaction solution was poured into ice water, acidified with hydrochloric acid, chloroform was added and the mixture was stirred for 1.5 hours, then, the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting solvent: chloroform) to give oily 5- (2-bromo-).
2.19 g of methyl 2-methylpropionyl) -4-hydroxy-2-methoxycinnamate was obtained.

IR (neat): ν _CO 1710,1620cm ^-1 NMR (CDCl ₃ ) δ: 2.08 (6H, s), 3.81 (3H, s), 3.94 (3H, s), 6.47 (1
H, s), 6.48 (1H, d, J = 15.9Hz), 7.84 (1H, d, J = 15.9H)
z), 8.70 (1H, s), 12.70 (1H, s) Methyl 5- (2-bromo-2-methylpropionyl) -4-hydroxy-2-methoxycinnamate 2.18 g was dried 1,2-
Dissolve in 40 ml of dimethoxyethane, anhydrous potassium carbonate 2.20
g and 1.38 g of sodium iodide were added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from chloroform-hexane to give 3- (2,3-dihydro-6) having a melting point of 169 to 171 ° C.
There were obtained 1.29 g of methyl -methoxy-2,2-dimethyl-3-oxo-5-benzofuranyl) acrylate.

Elemental analysis value: (as C ₁₅ H ₁₆ O ₅ ) C% H% Calculated value 65.21 5.84 Actual value 64.89 5.77 IR (KBr): ν _CO 1715,1700cm ⁻¹ NMR (CDCl ₃ ) δ: 1.47 (6H, s) , 3.80 (3H, s), 3.97 (3H, s), 6.45 (1
H, d, J = 15.9Hz), 6.52 (1H, s), 7.84 (1H, s), 7.92 (1
H, d, J = 15.9Hz) 3- (2,3-dihydro-6-methoxy-2,2-dimethyl-3
-Oxo-5-benzofuranyl) methyl acrylate 1.28
g was dissolved in 30 ml of ethanol, 4.7 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and the mixture was extracted with methylene chloride. The aqueous layer was treated with activated carbon, acidified with hydrochloric acid, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was recrystallized from diethyl ether-hexane, and the melting point was 225 to 228 ° C.
3- (2,3-dihydro-6-methoxy-2,2-dimethyl-3
0.81 g of -oxo-5-benzofuranyl) acrylic acid was obtained.

Elemental analysis value: (as C ₁₄ H ₁₄ O ₅ ) C% H% Calculated value 64.12 5.38 Measured value 63.83 5.41 IR (KBr): ν _CO 1705,1685 cm ⁻¹ NMR (DMSO-d ₆ ) δ: 1.40 (6H, s), 3.99 (3H, s), 6.52 (1H, d, J = 15.9H
z), 6.89 (1H, s), 7.75 (1H, d, J = 15.9Hz), 7.94 (1H,
s), 12.24 (1H, br-s) Reference Example 7 To 5.21 g of 2,4-dimethoxycinnamic acid was added 100 ml of dry benzene and 9 ml of thionyl chloride, and the mixture was heated under reflux for 2 hours, and the reaction solution was concentrated to dryness under reduced pressure. did. Dry methylene chloride of this residue
The 70 ml solution was added dropwise to a solution of 3.8 ml of piperidine and 7.0 ml of triethylamine in 30 ml of dry methylene chloride under ice cooling with stirring, and then the mixture was reacted at room temperature for 17 hours. The reaction solution was washed successively with diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The residue was recrystallized from chloroform-hexane, melting point 11
There were obtained 4.83 g of 1- (2,4-dimethoxycinnamoyl) piperidine at 1-112 ° C.

Elemental analysis value: (as C ₁₆ H ₂₁ NO ₃ ) C% H% N% Calculated value 69.79 7.69 5.09 Measured value 69.53 7.77 4.99 IR (KBr): ν _CO 1635cm ⁻¹ NMR (CDCl ₃ ) δ: 1.55 to 1.75 ( 6H, m), 3.55 to 3.7 (4H, m), 3.83 (3H,
s), 3.86 (3H, s), 6.45 to 6.55 (2H, m), 6.91 (1H, d, J =
15.4Hz), 7.42 (1H, d, J = 8.8Hz), 7.83 (1H, d, J = 15.4H)
z) 1.76 g of 1- (2,4-dimethoxycinnamoyl) piperidine is dissolved in 20 ml of dry methylene chloride, 1.88 g of anhydrous aluminum chloride is added under ice-cooling stirring, and then 2-bromo is added while stirring under heating under reflux. -2-Methylpropionyl bromide
After dropwise adding 1.1 ml, the mixture was refluxed for 4 hours. The reaction solution was poured into ice water, acidified with hydrochloric acid, chloroform was added and the mixture was stirred for 1 hour. Then, the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / benzene = 50/1) to give an oil.
1- [5- (2-bromo-2-methylpropionyl) -4-
Hydroxy-2-methoxycinnamoyl] piperidine 1.
Got 49g.

IR (neat): νco 1635 cm ^-1 NMR (CDCl ₃ ) δ: 1.55 to 1.75 (6H, m), 2.08 (6H, s), 3.5 to 3.75 (4H,
m), 3.93 (3H, s), 6.46 (1H, s), 6.98 (1H, d, J = 15.9H
z), 7.72 (1H, d, J = 15.9Hz), 8.64 (1H, s), 12.64 (1H,
s) Reference Example 8 To a solution of 7.40 g of 2,2,5-trimethyl-3 (2H) -benzofuranone in 10 ml of acetic acid was added dropwise a solution of 2.3 ml of bromine in 2 ml of acetic acid with stirring at 70 ° C., and then reacted for 1 hour. . The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from hexane to obtain 5.53 g of 7-bromo-2,2,5-trimethyl-3 (2H) -benzofuranone having a melting point of 140 to 144 ° C.

Elemental analysis value: (as C ₁₁ H ₁₁ BrO ₂ ) C% H% Calculated value 51.79 4.35 Measured value 52.05 4.43 IR (KBr): ν _CO 1705cm ⁻¹ NMR (CDCl ₃ ) δ: 1.50 (6H, s), 2.35 (3H, s), 7.40 (1H, d, J = 1.7H
z), 7.64 (1H, d, J = 1.7 Hz) Reference Example 9 5.85 g of potassium persulfate and 0.51 g of copper sulfate pentahydrate were added to 60 ml of water, and 7-bromo-2,2,2, 5-Trimethyl-3 (2H) -benzofuranone 1.50 g of acetonitrile 60 m
After the solution was added, the mixture was stirred at 70 ° C. for 10 hours, and the reaction solution was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. After washing with water, an aqueous sodium hydrogen carbonate solution was added and the mixture was shaken well. The aqueous layer was separated, acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate.
After distilling off the solvent under reduced pressure, the residue was recrystallized from water-containing ethanol to give 7-bromo-2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofurancarboxylic acid having a melting point of 251 to 253 ° C. Obtained 0.96 g.

Elemental analysis value: (as C ₁₁ H ₉ BrO ₄ ) C% H% Calculated value 46.34 3.18 Measured value 46.15 3.15 IR (KBr): ν _CO 1725,1690 cm ⁻¹ NMR (DMSO-d ₆ ) δ: 1.49 (6H, s), 8.10 (1H, d, J = 1.7Hz), 8.42 (1H, d, J
= 1.7Hz), 13.41 (1H, br-s) 7-Bromo-2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofurancarboxylic acid 0.77g to dry benzene 2
0 ml and 1 ml of thionyl chloride were added, and the mixture was heated under reflux for 2 hours.
The reaction solution was concentrated under reduced pressure, 20 ml of absolute ethanol was added to the residue, and the mixture was heated under reflux for 1 hour. The reaction solution is concentrated under reduced pressure,
An aqueous solution of sodium hydrogen carbonate was added to the residue, which was then extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from diethyl ether-hexane to give 7-mp of melting point 134-136 ° C.
Bromo-2,3-dihydro-2,2-dimethyl-3-oxo-
0.71 g of ethyl 5-benzofurancarboxylate was obtained.

Elemental analysis value: (as C ₁₃ H ₁₃ BrO ₄ ) C% H% Calculated value 49.86 4.18 Found value 50.00 4.21 IR (KBr): ν _CO 1735,1710 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.1Hz), 1.55 (6H, s), 4.39 (2H, q, J
= 7.1Hz), 8.32 (1H, d, J = 1.6Hz), 8.51 (1H, d, J = 1.6H)
z) Reference example 10 5-formyl-2,2-dimethyl-3 (2H) -benzofuranone 6.05 g in a mixed solution of 6.7 ml of fuming nitric acid having a specific gravity of 1.52 and 11 ml of acetic anhydride was cooled with dry ice-acetone and stirred. After adding while maintaining the internal temperature at -10 to 20 ° C, the mixture was reacted at room temperature for 7 hours. The reaction solution was poured into ice water, extracted with benzene, washed successively with water, an aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Dissolve the residue in 100 ml of ethanol and add 15% hydrochloric acid 30 m.
l was added and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with benzene, washed successively with water, aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was treated with benzene.
Recrystallization from hexane gave 3.77 g of 5-formyl-2,2-dimethyl-7-nitro-3 (2H) -benzofuranone having a melting point of 168-171 ° C.

Elemental analysis value: (as C ₁₁ H ₉ NO ₅ ) C% H% N% Calculated value 56.17 3.86 5.96 Measured value 56.17 3.71 6.00 IR (KBr): ν _CO 1730,1680cm ⁻¹ νNO ₂ 1535cm ⁻¹ NMR (CDCl ₃ ) Δ: 1.63 (6H, s), 8.48 (1H, d, J = 1.7Hz), 8.95 (1H, d, J
= 1.7 Hz), 10.05 (1 H, s) Example 1 3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid 0.70g to dry benzene 10ml
And 1.1 ml of thionyl chloride were added and the mixture was heated under reflux for 2 hours.
The reaction mixture was concentrated to dryness under reduced pressure, and a solution of this residue in 20 ml of dry methylene chloride was added to 0.44 ml of triethylamine with stirring under ice cooling.
After dropwise addition of 0.38 ml of pyrrolidine to a solution of 5 ml of dry methylene chloride, the mixture was stirred at room temperature for 16 hours. The reaction solution was washed successively with diluted hydrochloric acid, water, an aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethanol-diethyl ether to give 1- [3- (2,3-dihydro-2,2-dimethyl-3-oxo-5) having a melting point of 172-175 ° C. -Benzofuranyl)
Acryloyl] pyrrolidine (0.47 g) was obtained.

Elemental analysis value: (as C ₁₇ H ₁₉ NO ₃ ) C% H% N% Calculated value 71.56 6.71 4.91 Measured value 71.64 6.83 4.86 IR (KBr): ν _CO 1700,1650 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.49 ( 6H, s), 1.85 to 2.1 (4H, m), 3.55 to 3.7 (4H,
m), 6.69 (1H, d, J = 15.4Hz), 7.09 (1H, d, J = 88Hz), 7.
69 (1H, d, J = 15.4Hz), 7.78 (1H, dd, J = 2.2and8.8Hz),
7.87 (1H, d, J = 2.2Hz) Example 2 3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid 0.84 g and piperidine 0.5
After using 4 ml of the same reaction and treatment as in Example 1,
Recrystallized from water-containing ethanol, 1- [3-
1.00 g of (2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) acryloyl] piperidine was obtained.

Elemental analysis: (C ₁₈ as _{H 21 NO 3) C% H} % N% Calculated 72.22 7.07 4.68 Found 72.17 7.33 4.71 IR (KBr): ν CO 1705,1640cm -1 NMR (CDCl 3) δ: 1.49 ( 6H, s), 1.55 to 1.75 (6H, m), 3.55 to 3.75 (4H,
m), 6.87 (1H, d, J = 15.4Hz), 7.08 (1H, d, J = 8.2Hz),
7.64 (1H, d, J = 15.4Hz), 7.76 (1H, dd, J = 1.7and8.2H
z), 7.85 (1H, d, J = 1.7Hz) Example 3 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-5-
(Benzofuranyl) acrylic acid (0.80 g) and 4-methylpiperidine (0.62 ml) were used and treated in the same manner as in Example 1, followed by recrystallization from chloroform-hexane to give a melting point of 166.
1- [3- (2,3-dihydro-2,2-dimethyl-3 at ~ 168 ° C
-Oxo-5-benzofuranyl) acryloyl] -4-
0.92 g of methylpiperidine was obtained.

Elemental analysis value: (as C ₁₉ H ₂₃ NO ₃ ) C% H% N% Calculated value 72.82 7.40 4.47 Measured value 72.56 7.44 4.33 IR (KBr): ν _CO 1710,1645cm ⁻¹ NMR (CDCl ₃ ) δ: 0.98 ( 3H, d, J = 6.6Hz), 1.05 to 1.25 (2H, m), 1.49
(6H, s), 1.6 to 1.8 (3H, m), 2.6 to 2.8 (1H, m), 3.0 to 3.
2 (1H, m), 3.95 to 4.15 (1H, m), 4.6 to 4.8 (1H, m), 6.87
(1H, d, J = 15.4Hz), 7.09 (1H, d, J = 8.2Hz), 7.63 (1H,
d, J = 15.4Hz), 7.77 (1H, dd, J = 2.2and8.2Hz), 7.85 (1
H, d, J = 2.2 Hz) Example 4 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-5-
(Benzofuranyl) acrylic acid (0.70 g) and perhydroazepine (0.44 ml) were used and treated in the same manner as in Example 1 and then recrystallized from methylene chloride-hexane to give a melting point of 13
1- [3- (2,3-dihydro-2,2-dimethyl-3 at 5 to 138 ° C
0.84 g of -oxo-5-benzofuranyl) acryloyl] perhydroazepine was obtained.

Elemental analysis value: (as C ₁₉ H ₂₃ NO ₃ ) C% H% N% Calculated value 72.82 7.40 4.47 Measured value 72.64 7.57 4.46 IR (KBr): ν _CO 1710,1640cm ⁻¹ NMR (CDCl ₃ ) δ: 1.49 ( 6H, s), 1.55 ~ 1.85 (8H, m), 3.55 ~ 3.7 (4H,
m), 6.83 (1H, d, J = 15.4Hz), 7.09 (1H, d, J = 8.8Hz),
7.69 (1H, d, J = 15.4Hz), 7.77 (1H, dd, J = 1.7and8.8H
z), 7.86 (1H, d, J = 1.7Hz) Example 5 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid 1.10 g and morpholine 0.6
After using 3 ml of the same reaction and treatment as in Example 1,
Recrystallized from methylene chloride-hexane, melting point 208-209 ° C
4- [3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) acryloyl] morpholine 0.97
got g.

Elemental analysis value: (as C ₁₇ H ₁₉ NO ₄ ) C% H% N% Calculated value 67.76 6.35 4.65 Measured value 67.45 6.36 4.55 IR (KBr): νco 1705,1645cm ^-1 NMR (CDCl ₃ ) δ: 1.49 (6H , s), 3.6 to 3.8 (8H, m), 6.80 (1H, d, J = 15.
4Hz), 7.10 (1H, d, J = 8.8Hz), 7.70 (1H, d, J = 15.4H)
z), 7.77 (1H, dd, J = 2.2and8.8Hz), 7.85 (1H, d, J = 2.2)
Hz) Example 6 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid 0.50 g and diethylamine 0.3
After using 4 ml of the same reaction and treatment as in Example 1,
Recrystallized from methylene chloride-hexane, melting point 115-118 ° C
N, N-diethyl-3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) acrylamide.
41g was obtained.

Elemental analysis value: (as C ₁₇ H ₂₁ NO ₃ ) C% H% N% Calculated value 71.06 7.37 4.87 Measured value 71.07 7.58 4.64 IR (KBr): ν _CO 1710,1645cm ⁻¹ NMR (CDCl ₃ ) δ: 1.15〜 1.35 (6H, m), 1.49 (6H, s), 3.4 ~ 3.55 (4H,
m), 6.79 (1H, d, J = 15.4Hz), 7.09 (1H, d, J = 8.8Hz),
7.70 (1H, d, J = 15.4Hz), 7.77 (1H, dd, J = 1.7and8.8H
z), 7.86 (1H, d, J = 1.7Hz) Example 7 3- [2,3-dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid (0.30 g) and 1- (3-aminopropyl) -2-pyrrolidinone (0.20 ml) were used and treated in the same manner as in Example 1 and then treated with silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 50). / 1), melting point 155-159 ℃ 3-
0.43 g of (2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) -N- [3- (2-oxo-1-pyrrolidinyl) propyl] acrylamide was obtained.

Elemental analysis value: (as C ₂₀ H ₂₄ N ₂ O ₄ ) C% H% N% Calculated value 67.40 6.79 7.86 Measured value 67.28 6.75 7.58 IR (KBr): ν _NH 3260cm ⁻¹ ν _CO 1720,1665cm ⁻¹ NMR ( CDCl ₃ ) δ: 1.48 (6H, s), 1.65 ~ 1.85 (2H, m), 2.07 (2H, quint,
J = 7.7Hz), 2.45 (2H, t, J = 7.7Hz), 3.25 to 3.5 (6H,
m), 6.41 (1H, d, J = 15.4Hz), 7.07 (1H, d, J = 7.1Hz),
7.10 (1H, br-s), 7.60 (1H, d, J = 15.4Hz), 7.79 (1H, d,
J = 2.2Hz), 7.81 (1H, dd, J = 2.2and7.1Hz) Example 8 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid (0.20 g) and 2-aminomethylpyridine (0.13 ml) were reacted in the same manner as in Example 1 and treated in substantially the same manner, followed by recrystallization from methylene chloride-diethyl ether to give 3- (mp) 124-126 ° C. (2,3-Dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) -N- (2-pyridylmethyl) acrylamide 0.27 g
Got

Elemental analysis value: (as C ₁₉ H ₁₈ N ₂ O ₃ ) C% H% N% Calculated value 70.79 5.63 8.69 Measured value 70.57 5.60 8.70 IR (KBr): ν _NH 3225cm ^-1 ν _CO 1705,1665,1650cm ^-1 NMR (DMSO-d ₆ ) δ: 1.42 (6H, s), 4.50 (2H, d, J = 6.0Hz), 6.75 (1H, d, J
= 15.9Hz), 7.25 to 7.4 (3H, m), 7.53 (1H, d, J = 15.9H
z), 7.77 (1H, dt, J = 1.7 and 7.7Hz), 7.85 (1H, d, J = 1.7)
Hz), 7.99 (1H, dd, J = 1.7and8.8Hz), 8.52 (1H, dd, J =
1.7 and 3.8 Hz), 8.63 (1H, t, J = 6.0 Hz) Example 9 3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid (0.20 g) and 3-aminomethylpyridine (0.11 ml) were reacted in the same manner as in Example 1 and treated in substantially the same manner, and then recrystallized from methylene chloride-hexane to give 3- ( 2,3-dihydro-2,2-
Cimethyl-3-oxo-5-benzofuranyl) -N- (3
0.25 g of -pyridylmethyl) acrylamide was obtained.

Elemental analysis value: (as C ₁₉ H ₁₈ N ₂ O ₃ ) C% H% N% Calculated value 70.79 5.63 8.69 Measured value 70.70 5.62 8.60 IR (KBr): ν _NH 3300cm ⁻¹ ν _CO 1710,1650cm ⁻¹ NMR ( CDCl ₃ ) δ: 1.48 (6H, s), 4.61 (2H, d, J = 6.1Hz), 6.40 (1H, d, J
= 15.4Hz), 6.45 (1H, br-s), 7.08 (1H, d, J = 8.8Hz),
7.31 (1H, dd, J = 5.0 and 7.7Hz), 7.67 (1H, d, J = 15.4H)
z), 7.7 to 7.85 (3H, m), 8.53 (1H, d, J = 5.0Hz), 8.61
(1H, s) Example 10 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) -2-methylacrylic acid (0.30 g) and piperidine (0.18 ml) were reacted and treated in the same manner as in Example 1 and then recrystallized from diethyl ether-hexane to give 3- [3- (having a melting point of 130 to 132 ° C. 0.33 g of 2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) -2-methylacryloyl] piperidine was obtained.

Elemental analysis value: (as C ₁₉ H ₂₃ NO ₃ ) C% H% N% Calculated value 72.82 7.40 4.47 Measured value 72.78 7.45 4.61 IR (KBr): ν _CO 1715,1635 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.48 ( 6H, s), 1.5 to 1.75 (6H, m), 2.09 (3H, d, J = 1.
7Hz), 3.45 to 3.65 (4H, m), 6.48 (1H, br-s), 7.08 (1H,
d, J = 8.8Hz), 7.57 (1H, dd, J = 1.7and8.8Hz), 7.61 (1
H, d, J = 1.7 Hz) Example 11 3- (2,3-dihydro-2,2-dimethyl-3-oxo-6-
Benzofuranyl) acrylic acid 0.22 g and piperidine 0.1
After reacting and treating in the same manner as in Example 1 using 5 ml,
Recrystallized from methylene chloride-diethyl ether, melting point 13
1- [3- (2,3-dihydro-2,2-dimethyl-3 at 5 to 138 ° C
0.21 g of -oxo-6-benzofuranyl) acryloyl] piperidine was obtained.

Elemental analysis: (C ₁₈ as _{H 21 NO 3) C% H} % N% Calculated 72.22 7.07 4.68 Found 72.10 7.17 4.73 IR (KBr): ν CO 1710,1640cm -1 NMR (CDCl 3) δ: 1.47 ( 6H, s), 1.55 to 1.75 (6H, m), 3.55 to 3.75 (4H,
m), 7.02 (1H, d, J = 15.4Hz), 7.17 (1H, d, J = 1.1Hz),
7.22 (1H, dd, J = 1.1and8.2Hz), 762 (1H, d, J = 15.4H)
z), 7.65 (1H, d, J = 8.2Hz) Example 12 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-7-
Benzofuranyl) acrylic acid 0.43 g and piperidine 0.2
After using 7 ml of the same reaction and treatment as in Example 1,
Recrystallized from ethanol-hexane, melting point 158-159 ℃
1- [3- (2,3-dihydro-2,2-dimethyl-3-oxo-
7-benzofuranyl) acryloyl] piperidine 0.40 g
Got

Elemental analysis: (C ₁₈ as _{H 21 NO 3) C% H} % N% Calculated 72.22 7.07 4.68 Found 72.12 7.12 4.67 IR (KBr): ν CO 1715,1645cm -1 NMI (CDCl 3) δ: 1.51 ( 6H, s), 1.55 ~ 1.8 (6H, m), 3.5 ~ 3.75 (4H,
m), 7.09 (1H, t, J = 7.1Hz), 7.30 (1H, d, J = 15.4Hz),
7.63 (1H, dd, J = 1.7and7.1Hz), 7.68 (1H, d, J = 15.4H)
z), 7.71 (1H, dd, J = 1.7 and 7.1Hz) Example 13 3- (2,3-dihydro-7-methoxy-2,2-dimethyl-3
-Oxo-5-benzofuranyl) acrylic acid (0.28 g) and piperidine (0.16 ml) were used and treated in the same manner as in Example 1 and then recrystallized from diethyl ether to give a melting point of 16
1- [3- (2,3-dihydro-7-methoxy-2,2 at 7-169 ° C
0.25 g of -dimethyl-3-oxo-5-benzofuranyl) acryloyl] piperidine was obtained.

Elemental analysis value: (as C ₁₉ H ₂₃ NO ₄ ) C% H% N% Calculated value 69.28 7.04 4.25 Measured value 68.95 7.18 4.35 IR (KBr): ν _CO 1715,1640cm ⁻¹ NMR (CDCl ₃ ) δ: 1.52 ( 6H, s), 1.55 ~ 1.8 (6H, m), 3.5 ~ 3.75 (4H,
m), 4.00 (3H, s), 6.84 (1H, d, J = 15.4Hz), 7.21 (1H,
d, J = 1.7Hz), 7.47 (1H, d, J = 1.7Hz), 7.61 (1H, d, J = 1)
5.4 Hz) Example 14 3- (2,3-Dihydro-6-methoxy-2,2-dimethyl-3
-Oxo-5-benzofuranyl) acrylic acid (0.40 g) and morpholine (0.20 ml) were used for the same reaction and treatment as in Example 1, and then recrystallized from methylene chloride-hexane.
0.44 g of 1- [3- (2,3-dihydro-6-methoxy-2,2-dimethyl-3-oxo-5-benzofuranyl) acryloyl] morpholine having a melting point of 179-181 ° C was obtained.

Elemental analysis value: (as C ₁₈ H ₂₁ NO ₅ ) C% H% N% Calculated value 65.24 6.39 4.23 Measured value 64.94 6.40 4.12 IR (KBr): ν _CO 1695,1650 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.47 ( 6H, s), 3.6 ~ 3.8 (8H, m), 3.95 (3H, s), 6.52
(1H, s), 6.84 (1H, d, J = 15.4Hz), 7.83 (1H, s), 7.95
(1H, d, J = 15.4Hz) Example 15 3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl] acrylic acid 0.50 g to dry benzene 10 ml
And thionyl chloride (0.8 ml) were added and the mixture was heated under reflux for 2 hours.
The reaction solution was concentrated to dryness under reduced pressure, and a solution of this residue in 15 ml of dry dioxane was added to 5 ml of 25% aqueous ammonia and 5 ml of dioxane.
After being added dropwise to the mixed solution of under ice-cooling stirring, the mixture was reacted for 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from ethanol,
3- (2,3-dihydro-2,2-dimethyl-
3-oxo-5-benzofuranyl) acrylamide 0.45
got g.

Elemental analysis value: (as C ₁₃ H ₁₃ NO ₃ ) C% H% N% Calculated value 67.52 5.67 6.06 Measured value 67.69 5.67 5.80 IR (KBr): ν _NH 3375,3160cm ⁻¹ ν _CO 1705,1660cm ^-1 NMR ( CDCl ₃ ) δ: 1.48 (6H, s), 5.64 (2H, br-s), 6.41 (1H, d, J = 15.4
Hz), 7.10 (1H, d, J = 8.8Hz), 7.65 (1H, d, J = 15.4Hz),
7.77 (1H, dd, J = 2.2and8.8Hz), 7.83 (1H, d, J = 2.2Hz) Example 16 3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid (0.50 g) and 40% aqueous methylamine solution (0.5 ml) were used and treated in the same manner as in Example 15 and then recrystallized from ethanol-diethyl ether to give 3- (2,3) having a melting point of 194-197 ° C. 0.42 g of -dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) -N-methylacrylamide was obtained.

Elemental analysis value: (as C ₁₄ H ₁₅ NO ₃ ) C% H% N% Calculated value 68.56 6.16 5.71 Measured value 68.25 6.28 5.69 IR (KBr): ν _NH 3250cm ⁻¹ ν _CO 1715,1665,1645cm ⁻¹ NMR ( CDCl ₃ ) δ: 1.48 (6H, s), 2.96 (3H, d, J = 4.9Hz), 5.70 (1H, br-
s), 6.34 (1H, d, J = 15.4Hz), 7.08 (1H, d, J = 8.2Hz),
7.62 (1H, d, J = 15.4Hz), 7.75 (1H, dd, J = 1.7and8.2H
z), 7.81 (1H, d, J = 1.7Hz) Example 17 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-5-
(Benzofuranyl) acrylic acid (0.50 g) and 70% aqueous ethylamine solution (0.5 ml) were used for the same reaction and treatment as in Example 15, followed by recrystallization from methylene chloride-hexane and N-ethyl-3- (mp 179-181 ° C. 2,3-dihydro-2,2-
0.44 g of dimethyl-3-oxo-5-benzofuranyl) acrylamide was obtained.

Elemental analysis value: (as C ₁₅ H ₁₇ NO ₃ ) C% H% N% Calculated value 69.48 6.61 5.40 Measured value 69.45 6.69 5.08 IR (KBr): ν _NH 3320cm ⁻¹ ν _CO 1715,1645cm ⁻¹ NMR (CDCl ₃ ) Δ: 1.22 (3H, t, J = 7.1Hz), 1.48 (6H, s), 3.44 (2H, dq,
J = 5.5 and 7.1Hz), 5.70 (1H, br-s), 6.33 (1H, d, J = 15.
4Hz), 7.07 (1H, d, J = 8.8Hz), 7.62 (1H, d, J = 15.4H)
z), 7.75 (1H, dd, J = 1.7and8.8Hz), 7.80 (1H, d, J = 1.7)
Hz) Example 18 3- (2,3-Dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid (0.50 g) and 50% dimethylamine aqueous solution (0.6 ml) were used and treated in the same manner as in Example 15 and then recrystallized from methylene chloride-hexane.
3- (2,3-dihydro-2,2-dimethyl-
0.43 g of 3-oxo-5-benzofuranyl) -N, N-dimethylacrylamide was obtained.

Elemental analysis value: (as C ₁₅ H ₁₇ NO ₃ ) C% H% N% Calculated value 69.48 6.61 5.40 Measured value 69.26 6.73 5.13 IR (KBr): ν _CO 1705, 1645 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.49 ( 6H, s), 3.13 (6H, br-s), 6.85 (1H, d, J = 15.4
Hz), 7.09 (1H, d, J = 8.8Hz), 7.66 (1H, d, J = 15.4Hz),
7.77 (1H, d, J = 1.7 and 8.8Hz), 7.86 (1H, d, J = 1.7Hz) Example 19 3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-
Benzofuranyl) acrylic acid 0.30g to dry benzene 10ml
And thionyl chloride (0.5 ml) were added and the mixture was heated under reflux for 2 hours, and the reaction mixture was concentrated to dryness under reduced pressure. A solution of this residue in 5 ml of dry dioxane was added dropwise to a mixture of 0.54 g of glycine ethyl ester hydrochloride, 0.33 g of sodium hydrogencarbonate, 3 ml of dioxane and 3.9 ml of 1N aqueous sodium hydroxide solution under ice-cooling stirring, and then at room temperature. Stir for minutes. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with methylene chloride, washed successively with diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, it was recrystallized from ethanol and had a melting point of 148 to 150 ° C.
N- [3- (2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) acryloyl] glycine ethyl ester (0.24 g) was obtained.

Elemental analysis value: (as C ₁₇ H ₁₉ NO ₅ ) C% H% N% Calculated value 64.34 6.03 4.41 Actual value 64.20 6.12 4.45 IR (KBr): ν _NH 3360cm ⁻¹ ν _CO 1735,1710,1675cm ⁻¹ NMR ( CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1Hz), 1.48 (6H, s), 4.17 (2H, d, J
= 5.0Hz), 4.26 (2H, q, J = 7.1Hz), 6.13 (1H, br-s), 6.
40 (1H, d, J = 15.4Hz), 7.09 (1H, d, J = 8.8Hz), 7.64 (1
H, d, J = 15.4Hz), 7.78 (1H, dd, J = 1.7and8.8Hz), 7.82
(1H, d, J = 1.7Hz) Example 20 1- [5- (2-Bromo-2-methylpropionyl) -4-
Hydroxy-2-methoxycinnamoyl] piperidine 1.
Dissolve 48 g in 30 ml of dry 1,2-dimethoxyethane, add 0.81 g of sodium iodide and 1.30 g of potassium carbonate, and add 5
Stir for hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 5/1) and then recrystallized from diethyl ether-hexane to give 1-melting point 168-170 ° C. 〔3- (2,
3-dihydro-6-methoxy-2,2-dimethyl-3-oxo-5-benzofuranyl) acryloyl] piperidine 0.
Got 52g.

Elemental analysis value: (as C ₁₉ H ₂₃ NO ₄ ) C% H% N% Calculated value 69.28 7.04 4.25 Measured value 68.99 7.02 4.25 IR (KBr): ν _CO 1700,1640cm ⁻¹ NMR (CDCl ₃ ) δ: 1.47 ( 6H, s), 1.55 to 1.75 (6H, m), 3.5 to 3.7 (4H,
m), 3.94 (3H, s), 6.51 (1H, s), 6.89 (1H, d, J = 15.4H
z), 7.84 (1H, s), 7.90 (1H, d, J = 15.4Hz) Example 21 7-Bromo-2,2,5-trimethyl-3 (2H) -benzofuranone 1.00 g, 1-acryloylpiperidine 0.55 A mixture of g, 0.68 ml of triethylamine, 18 mg of palladium acetate and 48 mg of tris (2-methylphenyl) phosphine was heated at 100 ° C for 13 hours in a stream of argon. After cooling, the mixture was acidified with diluted hydrochloric acid, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: benzene / chloroform = 1/1) and then recrystallized from methylene chloride-diethyl ether, melting point 142-144 ° C. 0.45 g of-[3- (2,3-dihydro-2,2,5-trimethyl-3-oxo-7-benzofuranyl) acryloyl] piperidine was obtained.

Elemental analysis value: (as C ₁₉ H ₂₃ NO ₃ ) C% H% N% Calculated value 72.82 7.40 4.47 Measured value 72.95 7.52 4.71 IR (KBr): ν _CO 1710,1640cm ⁻¹ NMR (CDCl ₃ ) δ: 1.49 ( 6H, s), 1.55 to 1.75 (6H, m), 2.36 (3H, s), 3,
5 to 3,75 (4H, m), 7.28 (1H, d, J = 15.4Hz), 7.42 (1H, d,
J = 1.7Hz), 7.52 (1H, d, J = 1.7Hz), 7.64 (1H, d, J = 15.
4 Hz) Example 22 Ethyl 7-bromo-2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofurancarboxylate 0.58 g, 1-acryloylpiperidine 0.37 g, triethylamine 0.31 m
l, palladium acetate 12 mg and triphenylphosphine 2
8 mg of the mixture was reacted and treated in the same manner as in Example 21, purified by silica gel flash column chromatography (eluting solvent: chloroform / benzene = 2/1), and then recrystallized from methylene chloride-diethyl ether to give a melting point of 144- 1- [3- (5-ethoxycarbonyl-2,3 at 146 ° C
0.31 g of -dihydro-2,2-dimethyl-3-oxo-7-benzofuranyl) acryloyl] piperidine was obtained.

Elemental analysis value: (as C ₂₁ H ₂₅ NO ₅ ) C% H% N% Calculated value 67.91 6.78 3.77 Measured value 67.72 6.79 3.71 IR (KBr): ν _CO 1725,1710,1640cm ⁻¹ NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1Hz), 1.53 (6H, s), 1.55 to 1.75
(6H, m), 3.55 to 3.75 (4H, m), 4.40 (2H, q, J = 7.1Hz),
7.28 (1H, d, J = 15.4Hz), 7.73 (1H, d, J = 15.4Hz), 8.33
(1H, d, J = 1.7Hz), 8.44 (1H, d, J = 1.7Hz) Example 23 5-Formyl-2,2-dimethyl-7-nitro-3 (2H)
-Benzofuranone 2.15 g and morpholino carbonyl acetic acid 3.1
7 g was dissolved in 15 ml of dry pyridine, 1 ml of piperidine was added, and the mixture was stirred at 60 ° C. for 16 hours and then heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, acidified with hydrochloric acid, extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 100/1) and then recrystallized from chloroform-diethyl ether to give a mp of 196-199 ° C. -[3- (2,3-
Dihydro-2,2-dimethyl-7-nitro-3-oxo-
5-benzofuranyl) acryloyl] morpholine 1.73 g
Got

Elemental analysis value: (as C ₁₇ H ₁₈ N ₂ O ₆ ) C% H% N% Calculated value 58,96 5.24 8.09 Measured value 58.71 5.21 8.13 IR (KBr): ν _CO 1725,1650cm ^-1 νNO ₂ 1525cm ^-1 NMR (CDCl ₃ ) δ: 1.60 (6H, s), 3.6-3.8 (8H, m), 6.92 (1H, d, J = 15.
4Hz), 7.71 (1H, d, J = 15.4Hz), 8.10 (1H, d, J = 1.7H
z), 8.58 (1H, d, J = 1.7Hz) Example 24 4- [3- (2,3-dihydro-2,2-dimethyl-7-nitro-
To a suspension of 1.38 g of 3-oxo-5-benzofuranyl) acryloyl] morpholine in 20 ml of acetone, a solution of 0.43 g of ammonium chloride in 12 ml of water was added, and zinc powder was added under stirring at 50 ° C to give 1.5 parts of zinc powder.
After adding 2g little by little, it stirred at 70 degreeC for 1 hour. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, water was added, the mixture was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from methylene chloride-diethyl ether to give 4- [3-
(7-Amino-2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) acryloyl] morpholine
1.10 g was obtained.

Elemental analysis: (C ₁₇ H ₂₀ as _{N 2 O 4) C% H} % N% Calculated 64.54 6.37 8.86 Found 64.82 6.59 8.59 IR (KBr): ν NH 3470,3350cm -1 ν CO 1695,1645cm -1 NMR (CDCl ₃ ) δ: 1.49 (6H, s), 2.8 (2H, br), 3.6 to 3.8 (8H, m), 6.75
(1H, d, J = 15.4Hz), 7.10 (1H, d, J = 1.1Hz), 7.29 (1H,
d, J = 1.1 Hz), 7.62 (1H, d, J = 15.4 Hz) Example 25 4- [3- (7-amino-2,3-dihydro-2,2-dimethyl-
3-oxo-5-benzofuranyl) acryloyl] morpholine 0.68 g in dry benzene 8 ml suspension, acetic anhydride 1.1 m
1 and 0.22 g of sodium acetate were added, and the mixture was heated under reflux for 4 hours. The reaction solution was washed successively with diluted hydrochloric acid, water, an aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was recrystallized from ethyl acetate-diethyl ether, and the melting point was 190 to 192 ° C.
4- [3- (7-acetylamino-2,3-dihydro-2,2-
0.52 g of dimethyl-3-oxo-5-benzofuranyl) acryloyl] morpholine was obtained.

Elemental analysis value: (as C ₁₉ H ₂₂ N ₂ O ₅ ) C% H% N% Calculated value 63.68 6.19 7.82 Actual value 63.36 6.42 7.60 IR (KBr): ν _NH 3250cm ^-1 ν _CO 1720,1660,1645cm ^-1 NMR (CDCl ₃ ) δ: 1.51 (6H, s), 2.29 (3H, s), 3.6-3.8 (8H, m), 6.82
(1H, d, J = 15.4Hz), 7.46 (1H, br-s), 7.50 (1H, d, J =
1.1Hz), 7.69 (1H, d, J = 15.4Hz), 8.87 (1H, d, J = 1.1H
z)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/40 31/44 31/445 31/535 31/55 Examiner Shoei Hoshino (56) Reference References JP-A-1-246271 (JP, A) Pharmaceutical Journal, 109 (10), 718-36 (1989) Pharmaceutical Journal, 109 (10), 737-48 (1989)

Claims (4)

[Claims] 1. A general formula (In the formula, R ¹ and R ² may be the same or different and each is a hydrogen atom or a lower alkoxycarbonyl group as a substituent, a 2-oxo-1-pyrrolidinyl group or a lower alkyl group which may have a pyridyl group. Or N-R ¹ R ² together form a 1-pyrrolidinyl group, a piperidino group, a 4-methylpiperidino group, a morpholino group or a 1-perhydroazepinyl group, and R ³ and R ⁴ Is a hydrogen atom or a lower alkyl group, and Y is a hydrogen atom, a nitro group, an amino group, a lower acylamino group, a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group). 2. General formula The dihydrobenzofuranone derivative according to claim 1, wherein R ¹ , R ² , R ³ , R ⁴ and Y in the formula have the same meanings as described above. 3. General formula (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.)
The dihydrobenzofuranone derivative according to claim 2, which is represented by: 4. A general formula The dihydrobenzofuranone derivative according to claim 3, wherein R ³ and R ⁴ have the same meanings as described above.