KR840002307B1 - Process for preparing 5-substituted pyranone compounds - Google Patents

Abstract

Pyranones [I; R1 = H, COOR5, CONHR5, cyano, 5-tetrazolyl or 5- tetrazolylamino carbonyl; R5 = H or C1-6 alkyl; R3 = R6=(Z)m; m = 0 or 1; Z = O, S, SO2, or CO; R6 = halogen, C1-4 alkyl or C3-6 cycloalkyl substituted phenyl useful in acute hypersensitivity, were prepd. by the reaction of II and acids. Thus, 8.2 g 1- (4methoxyphenyl)-2-propanone was reacted with 9.5 ml dimethylformamidedimethyl at 95-100≰C and crystallized with ether- petroleum spirit to give 4-dimethylamino-3-(4-methoxyphenyl)-3butene- 2-one.

Description

Method for preparing 5-substituted pyranone compound

The present invention relates to a process for the preparation of new pyranone compounds useful as pharmaceuticals.

Pyran-4-one compounds have already been introduced in the literature and are described, for example, in the form of general compounds Annalen 453, 148 (1927), J. Chem. Soc. 3663 (1956), Arch. Pharm. 308, 489 (1975), Angew. Chem. Internat. Edit. 4,527 (1965) and described in J. Org. Chem. 28, 2266 (1964) 30,4263 (1963).

However, the pharmaceutical properties of these compounds have not been studied, and their biological activity has not been reported.

The pyran-4-one compounds of the present invention have new chemical structures with very different chemical structures and are useful as medicines for treating acute hypersensitivity. The compound of the present invention means a compound of the general formula (I) and salts thereof:

[Wherein R ¹ is COOR ⁵ , CONHR ⁵ cyano, 5-tetrazolyl or 5-tetrazolylaminocarbonyl, wherein R ⁵ is hydrogen or C _1-6 alkyl; R ³ is a group of the formula R ^6- (Z) m-, where m is 0 or 1 and Z is O, S, SO, SO ₂ or CO, and R ⁶ is halogen, C _1-4 alkyl , Cycloalkyl, or phenyl optionally substituted by hydroxy]

C _1-6 alkyls of C _1-6 acyl groups include both straight and branched chain groups, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- Butyl, n-pentyl and n-hexyl, most preferably methyl and ethyl groups and the corresponding acyl groups are derived from them. It can be seen that when R ¹ is COOR ⁵ and R ⁵ is alkyl, a substituted alkyl group is also included, and these groups need to be bonded only to an ester group, and thus cleaved easily to show free acid. , It becomes equal.

Examples of such substituted alkyl are acetoxymethyl, methylthiomethyl, methylsulfinylmethyl and methylsulfonylmethyl.

Halogen means fluorine, chlorine, cancelled or oxo, preferably chlorine and cancelled.

In the case of substituted phenyl, it may have one or more substituents in the nucleus, preferably when it has one substituent.

The C _3-6 cycloalkyl group is preferably cyclopropyl or cyclohexyl, and salts of the compounds contained in the above general formulas include, for example, compounds in which R ¹ is COOH or 5-tetrazolyl or an acidic or basic group to substituent R ⁶ . Salts of the bound compounds are also included in the above general formula.

Its acid addition salts may be inorganic acids such as hydrochloric acid, brittle acid, nitric acid, sulfuric acid or phosphoric acid, but organic carboxylic acids such as glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, salicylic acid, O Pharmaceutically acceptable with acetoxybenzoic acid, nicotinic acid or isnicotinic acid, or suitable acids such as organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid P-toluenesulfonic acid or 2-naphthalenesulfonic acid Non-toxic addition salts are preferred. Salts of acidic compounds are preferably inorganic bases such as alkali metal hydroxides, in particular potassium or sodium salts, or alkaline earth metal hydroxides in particular calcium salts, or pharmaceutically acceptable non-toxic salts of organic bases such as amines. In addition to pharmaceutically acceptable salts, other salts include, for example, salts with picric acid or oxalic acid, which are intermediates in the purification of the compound or in preparation of other salts, for example pharmaceutically acceptable salts. It can be used as a compound, and is useful for determining identity, property, or purification.

In the above formula (I), some preferred groups have one or more of the following features.

(a) R ¹ is COOR ⁵ , CONHR ⁶ or 5-tetrazolyl

(b) R ¹ is COOR ⁵ , where R ⁵ is hydrogen or C _1-6 alkyl

(c) R ³ is the general formula R ^6- (Z) m-, where m is 0 or 1 and Z is 0 or CO

(d) R ⁶ is phenyl optionally substituted with 1-3 substituents selected from halogen, C _1-4 alkyl and hydroxy.

One of the preferred compounds is a compound of formula (II) or a salt thereof:

[Wherein R ¹ is COOR ⁵ or CONHR ⁵ (wherein R ⁵ is hydrogen or C _1-6 alkyl), R ³ is a general formula R ^6- (Z) m-, where m is 0 or 1 and Z is O, S or CO, and R ⁶ is phenyl optionally substituted by halogen, methyl or hydroxy]

More preferably R ³ is a group of the general formula R ^6- (Z) m-, where m is 0 or 1 and Z is 0 or CO and R ⁶ is substituted by salt of halogen, methyl or hydroxy It is a compound of the general formula (II) which is phenyl.

In addition, the present invention relates to a method for preparing a compound represented by formula (I) prepared by reacting a compound of formula (III) with an acid, and if necessary, converts a COOR ⁵ group to another R ¹ substituent, or One or more substituents may be introduced into the ^six groups.

Where R ⁸ is C _1-6 alkyl (R ⁸ ) ₂ N is a saturated heterocycle such as morpholino, piperidino, or pyridino

The reaction is preferably carried out under aqueous and non-aqueous conditions at a temperature of 0-100 ° C., more preferably 10 ° -50 ° C., using an inorganic acid such as hydrochloric acid or sulfuric acid.

The compound of the general formula (III) can be conveniently prepared without isolation by reacting the compound of the general formula (IV) with the dialkyl oxalate of the general formula (COOR ⁵ ) ₂ in the presence of a base.

The reaction product is acidified without isolating the intermediate of general formula (III) and closed. Compounds of general formula (IV) are novel and form part of the invention.

The reaction of the compound of formula (IV) with the dialkyl oxalic acid is preferably carried out at an temperature of 0 ° -100 ° C. under an alcohol or an ether solvent, for example, an organic solvent such as ethanol, ether or dimethoxy ethane. The reaction needs to be carried out in the presence of a base such as an alkali metal alkoxide.

The intermediate of formula (IV) can be easily obtained by two different methods.

In the first method, the ketone of the following general formula (V) is reacted with the dialkylamide dialkylacetal of the following general formula (VI).

R ³ -CH ₂ -CO-CH ₂ -H (Ⅴ)

(R ⁸ ) ₂ NC (H) (OR ⁹ ) ₂ (Ⅵ)

Where R ⁹ is C _1-6 alkyl

It is preferable to perform reaction at the temperature of 0-100 degreeC.

Amide acetal of formula (VI) is, for example, trialkyloxonium fluoroborate of formula (R ⁹ ) OBF ₄ , prepared by a known method of alkylating amides of formula HCON (R ⁸ ) ₂ , and The resulting complex is obtained by treatment with an alkali metal alkoxide.

The second method of preparing the compound of general formula (IV) is to acylate the compound of general formula (VII) at a temperature of 0 ° -150 ° C under typical acylation reaction conditions.

R ³ -CH = CHN (R ⁸ ) ₂ (Ⅶ)

Suitable acylating agents are of the general formula R ⁴ CH ₂ COX or (R ⁴ CH ₂ CO) ₂ O, wherein R ⁴ is hydrogen, wherein X is halogen, in particular chlorine. Enamines can be prepared by reacting a suitable acetaldehyde with a dialkylamine in the presence of a base, for example potassium carbonate.

Compounds prepared by the above process wherein R ¹ is COOR ⁵ , wherein R ⁵ is hydrogen or C _1-6 alkyl, can be readily converted to compounds having other R ¹ substituents as follows:

Compounds wherein R ¹ is COOR ⁵ (wherein R ⁴ is C _1-6 alkyl) are hydrolyzed in the presence of an acid such as an inorganic acid such as hydrochloric acid, boron trihalide in an inert solvent, lithium oxide in DMF, Or by reacting with sodium iodide in a mixture of methylethylketone and pyridine to convert to the corresponding free acid wherein R ¹ is COOR ⁵ . Such methods are known in the art. In addition, compounds in which R ¹ is COOR ⁵ , wherein R ⁵ is C _1-6 alkyl, can be synthesized from the free acid by esterifying the free carboxyl group with a suitable alcohol or by treating with a halogenated alkyl in the presence of a base. The salt of this free acid can be easily synthesized by reacting with alkali.

Compounds wherein R ¹ is CONHR ⁵ can be synthesized by reacting a compound wherein R ¹ is COOR ⁵ , wherein R ⁵ is C _1-6 alkyl, with ammonia or a suitable amine of the general formula R ⁵ NH ₂ , which is also ammonia or The amines of the general formula R ⁵ NH ₂ can be synthesized by reaction with a suitable acyl chloride, which can be derived by inverse reaction with thionyl chloride and an organic carboxyl derivative. Such reactions are known in the art.

Compounds in which R ¹ is CN can be synthesized by dehydrating an amide in which R ¹ is CONH ₂ , and a general dehydrating agent is, for example, a mixture of triphenylphosphine and carbon tetrachloride.

The compound wherein R ¹ is 5-tetrazolyl can be prepared by reacting sodium azide in dimethylformamide with ammonium chloride and the cyano derivative prepared above, and by adding a base by standard method, a 5-tetrazolyl derivative Salts can be synthesized from these.

Various compounds of the general formula (I) can be converted into other compounds by simply introducing a group into the R ⁶ nucleus using known chemical reactions. If nitro substitutions are desired for the R ⁶ group, the unsubstituted compound can be nitrated with a mixture of concentrated nitric acid and sulfuric acid by conventional methods. This nitro compound can be converted to other substituents such as amino or acylamino.

This amino compound can be diazotized and the resulting diazonium salt can be converted into various other products, for example, by decomposition in alcohol to give the corresponding halosubstituted compound. Hydroxy substituted compounds can be cleaved, for example, with boron triturated to synthesize from the corresponding methoxy compounds. The alkylsulfonyl and alkylsulfinyl substituted aryl derivatives can be synthesized by, for example, reacting m-chloroperoxybenzoic acid with a corresponding alkylthio compound to oxidize it. In the general formula (I), a compound in which Z is SO or SO ₂ can be synthesized by oxidizing a similar thio compound. The present invention also encompasses pharmaceutical compositions which are mixed with a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compound of general formula (I) of the present invention is useful as a medicament, and especially has a characteristic useful for treating acute hypersensitivity.

The pyranones of formula (I) and their pharmaceutically acceptable salts are useful for preventing and treating acute hypersensitivity diseases, including asthma, and for alleviating asthma conditions. The compound is also low toxicity.

This activity is described by Monga and Shield in Physiology Journal (London) 131,207 (1956) and "Guinea-Pig Incision Peptide" or Physiology Journal described by Brockkhurst in Physiology Journal (London), 151,416 (1960). (London) Proven in guinea pigs using the "Herxheimer" test described in 177,251 (1952). For example, the compound exhibits inhibition by more than 15 percent of the modulator in the "guinea-pig incision test", and in the "heroxheimer" test based on allergic bronchitis induced by guinea pigs, which is rapidly similar to human asthma, The compound showed activity at a dose of 25-200 mg / kg.

When given orally, the compound exhibits the characteristics of an effective compound, but can be administered in a number of ways. Thus, the compounds may be administered orally and rectally, administered topically and parenterally by injection, and are usually used in the form of pharmaceutical compositions.

Such compositions can be prepared by methods known in the art of pharmacy, and are usually prepared by mixing at least one active compound or salt of the invention with a pharmaceutically acceptable carrier. In the preparation of the composition of the present invention, the active ingredient is usually mixed with the carrier or diluted with the carrier, or they can be used in the form of capsules, shakits, paper or other containers. When the carrier is used as a diluent, it may be a solid, semisolid or liquid substance which acts as a vehicle of excipients, bases or active ingredients. Thus, the compositions can contain tablets, shakits, khakits, elixirs, suspensions, aerosols (as solid or liquid media), ointments, soft gelatin capsules, suppositories, injection suspensions and sterile packaging powders containing up to 10% by weight of active compound. It can be in the form of.

Suitable carriers include, for example, lactose, dextrose, sucrose, sorbitan, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth rubber, gelatin, syrup, methylcellulose, methyl- and propyl-hydride Oxybenzoate, talc, magnesium stearate or mineral oil.

The composition of the present invention can be easily prepared by known methods and can be prescribed so that the active ingredient is released quickly, sustained or delayed after administration of the composition to the patient. The composition is formed in unit dosage form containing 5-500 mg, usually 25-200 mg of active ingredient.

The term “unit dosage form” refers to physically discrete units suitable as human and animal unit dosages, each unit containing a predicted amount of active substance calculated to achieve the desired therapeutic effect by mixing with the necessary pharmaceutical carrier. do.

The active compounds are effective up to a wide range of dosages, for example daily dosages in the range of 0.5-300 mg / kg and typical amounts for treating adults are 5-100 mg / kg. The actual amount of compound to be administered, however, is determined by the physician in accordance with the condition to be treated, the environment involved, including the choice of dosage compound and the method of administration, and therefore the dosage range does not limit the scope of the invention.

The following examples are examples of the invention.

Example 1

4-dimethylamino-3-phenyl-3-butene-2-silver

A stirred mixture of benzyl methyl ketone (26.8 ml) and dimethylformamide dimethyl acetal (30.0 ml) is heated for 1.5 h at 95-100 ° C. in a distillation apparatus on an oil bed and methanol is distilled off. The volatile residue is removed under reduced pressure and the product oil is determined as ether-petroleum spiride (40-60 ° C.) to give the title compound (melting point 66 ° C.).

Example 2-15

The compounds listed below are prepared by methods analogous to those described in Example 1.

Example 16

4-dimethylamino-3- (4-methoxyphenyl) -3-butene-2-silver

A stirred mixture of 1- (4-methoxyphenyl) -2-propanone (8.2 g) and dimethylformamide dimethylacetal (9.5 ml) was heated on an oil bed to 95-100 ° C. for 30 minutes and the volatiles were Removal under reduced pressure and the residue crystallized with ether-petroleum spirits (40-60 ° C.) afforded the title compound (melting point 56-58 ° C.).

Example 17

Ethyl 4-oxo-5-phenyl-4H-pyran-2-carboxylate

A solution of 4-dimethylamino-3-phenyl-3-buten-2-one (30.3 g) and dimethyl oxalate (43.5 ml) dissolved in ethanol (75 ml) was dissolved in sodium (5.5 g) in ethanol (150 ml). Is added to a stirred solution of sodium ethoxide. The stirred mixture is heated at reflux for 1 h, cooled to 20-25 ° C. and acidified by addition of 5N hydrochloric acid (150 ml). The mixture is stirred for another hour, then cooled to 5 ° C. and diluted with water (300 ml).

The title product, which is a solid, is recrystallized from ethanol-water (melting point 110-112 ° C.).

Example 18-26

In the same manner as described in Example 17, the following compounds were prepared.

Example 27

4-diethylamino-3-phenyl-3-butene-2-silver

A solution of diethylstyrylamine (1.75 g) dissolved in acetic anhydride (5 ml) is heated under reflux for one hour and then distilled under reduced pressure (0.02 mm) in a bulb-to-bulb device (150 ° C.). Crystallization of the product at low temperature with ether-petroleum spirits (40-60 ° C.) affords crystals of the title product which dissolves at room temperature.

This compound is reacted with diethyl oxalate by the method described in Example 17 to obtain ethyl 4-oxo-5-phenyl-4H-pyran-2-carboxylate, which is the same product as in Example 17.

Example 28

4-oxo-5-phenyl-4H-pyran-2-carboxylic acid

Ethyl 4-oxo-5-phenyl-4H-pyran-2-carboxylate (4.9 g) is heated with concentrated hydrochloric acid (12 ml) in a vapor bed for 1.5 hours. The mixture is cooled and the solid title product is recrystallized from ethyl acetate-dimethylformamide (melting point 225-227 ° C., decomposition).

Example 29

5- (4-Chlorophenylthio) -4-oxo-4H-pyran-2-carboxylic acid

A solution of ethyl 5- (4-chlorophenylthio) -4-oxo-4H-pyran-2-carboxylate (5.0 g) dissolved in dioxane (40 ml) and concentrated hydrochloric acid (20 ml) was refluxed for 2 hours. Heat and then evaporate under reduced pressure. The solid residue is dried and recrystallized with ethyl acetate-petroleum spirit (60-80 ° C.) to give the title product (melting point 165-167 ° C., decomposition).

Example 30

5- (4-Methylphenylsulfonyl) -4-oxo-4H-pyran-2-carboxylic acid

This compound is prepared by the method described in Example 29 (melting point 210 ° C., decomposition).

Example 31

5- (4-methoxyphenyl) -4-oxo-4H-pyran-2-carboxylic acid

By the method described in Example 17, ethyl 5- (4-methoxyphenyl) -4-oxo-4H-pyran-2-carboxylate (melting point 121-123 ° C.) was synthesized and described in Example 29. Hydrolysis by the method yields the title product (melting point 232-234 ° C., decomposition).

Example 32

5- (2-methoxyphenoxy) -4-oxo-4H-pyran-2-carboxylic acid

By the method described in Example 17, ethyl 5- (2-methoxyphenoxy) -4-oxo-4H-pyran-2-carboxylate (melting point 74-76 ° C) was prepared and described in Example 29. By hydrolysis in the conventional manner, an acid is obtained which is the title product (melting point 202-203 ° C.).

Example 33

4-oxo-5-phenylthio-4H-pyran-2-carboxylic acid

By the method described in Example 17, ethyl 4-oxo-5-phenylthio-4H-pyran-2-carboxylate (melting point 79-81 ° C.) was prepared and hydrolyzed by the method described in Example 29. To give an acid which is the title product (melting point 178-181 ° C.).

Example 34

Propyl 5- (4-methoxyphenylthio) -4-oxo-4H-pyran-2-carboxylate

By the method described in Example 17, ethyl 5- (4-methoxyphenylthio) -4-oxo-4H-pyran-2-carboxylate (melting point 90-92 ° C) was prepared and described in Example 29. Hydrolyzed to the acid (melting point 190-193 ° C.) by the prepared method. A solution of the acid (5.4 g) dissolved in carbon tetrachloride (50 ml), n-propanol (2.9 ml) and triethylamine (2.7 ml) was heated under reflux for 7 hours, cooled, washed with dilute hydrochloric acid and then carbonic acid. Wash with natrup solution and evaporate to dryness. The residue was determined by ethyl acetate-petroleum spirits (60-80 ° C.) to give the title product (melting point 91-93 ° C.).

Example 35

N-methyl-4-oxo-5-phenyl-4H-pyran-2-carboxyamide

A stirred suspension of 4-oxo-5-phenyl-4H-pyran-2-carboxylic acid (4.3 g) suspended in dry benzene (50 ml) and thionyl chloride (10 ml) is heated under reflux for 12 h. The clear solution is diluted with petroleum spirit (60-80 ° C.) (50 ml) and cooled to obtain crystals of acid chloride (melting point 175 ° C.).

A solution of methylamine (0.338 g) dissolved in dry pyridine (4.5 ml) was added to a stirred and cooled suspension in which the acid chloride (2.5 g) was suspended in dry pyridine (15 ml), and the solution was stirred at room temperature for 1 hour. After stirring, it is cooled and diluted with water (50 ml). The title product, which is a solid, is dried and recrystallized from chloroform-petroleum spirit (60-80 ° C.) (melting point 196-198 ° C.).

[Examples 36 and 37]

In a similar manner to the barrier described in Example 35, the following compounds were prepared.

Example 38

4-oxo-5-phenyl-N- (5-tetrazolyl) -4H-pyran-2-carboxyamide

A stirred suspension of 5-aminotetrazole hydrate (0.9 g) suspended in benzene (50 ml) is heated under a Dean and Stark water track until the water no longer evaporates, the mixture is cooled and , Filtered and the solid is immediately dissolved in dry pyridine (20 ml). Solid 4-oxo-5-phenyl-4H-pyran-2-carboxylic acid chloride (2.0 g, prepared as described in Example 35) is added dropwise to the cooled and stirred pyridine solution and the mixture is stirred for 2 hours. Stir at room temperature, cool, and dilute with water (50 ml). The title product, which is a solid, is recrystallized from dimethylformamide (melting point 300 ° C. or higher).

Example 39

N-butyl-4-oxo-5-phenoxy-4H-pyran-2-carboxyamide

Ethyl 4-oxo-5-phenoxy-4H-pyran-2-carboxylate is hydrolyzed by acid (melting point 204-206 ° C., decomposition) by the method described in Example 29. The stirred suspension of the acid suspended in dry benzene (40 ml) and thionyl chloride (7.7 ml) is heated under reflux for 12 h and the resulting clear solution is evaporated under reduced pressure.

The residual oil is dissolved twice in dry benzene and re-evaporated to give crude acid chloride, which is reacted with butylamine (1.5 ml) in dry pyridine by the method described in Example 35 to give the title product (melting point 149-151 ° C.). Get

Example 40

5- (4-methoxyphenyl) -4-oxo-pyran-2-carboxyamide

The cooled ammonia solution (30%, 80ml) was suspended in ethyl 5- (4-methoxyphenyl) -4-oxo-4H-pyran-2-carboxylate suspended in ethanol (120ml) at 5-10 ℃. 12.4 g) was added to the stirred suspension, and the mixture was further stirred at 0-5 ° C. for 30 minutes, followed by washing and drying the title product as a solid (melting point 262-263 ° C., decomposition).

Example 41

5- (4-methoxyphenyl) -4-oxo-4H-pyran-2-carbonitrile

5- (4-methoxyphenyl) -4-oxo-4H-pyran-2-carboxyamide (8.0 g) and triphenyl suspended in carbon tetrachloride (80 ml), methylene chloride (160 ml) and triethylamine (4.55 ml) The suspension of phosphine (17.1 g) is stirred at room temperature for 3.5 hours, 2N hydrochloric acid (100 ml) is added to the stirred mixture while cooling, then the solvent layer is washed with water, dried and evaporated.

The solid residue is determined by chloroform-petroleum spirit (60-80 ° C.) to give the title product (melting point 165-167 ° C.).

Example 42

4-oxo-5-phenyl-4H-pyran-2-carbonitrile

To the stirred suspension of ethyl 4-oxo-5-phenyl-4H-pyran-2-carboxylate suspended in ethanol (40 ml) at 10-15 ° C., ammonia solution (40 ml) is added and the mixture is 10-15 ° C. After stirring for 30 minutes at, the solid product is recrystallized from dimethylformamide-ethanol to give 4-oxo-5-phenyl-4H-pyran-2-carboxyamide (melting point 245-248, decomposition).

A suspension of the amide (3.5 g) and triphenylphosphine (8.54 g) suspended in carbon tetrachloride (10 ml), methylene chloride (20 ml) and triethylamine (2.3 ml) is stirred at room temperature for 4 hours. Ice (60 ml) and 2N hydrochloric acid (30 ml) are added, and then all solids are dissolved by sufficient addition of chloroform.

The solvent layer is washed with water, dried, evaporated and the residue is determined by chloroform-petroleum spirit (60-80 ° C.) and then by ethanol to give the title compound (melting point 177-179).

Example 43

5-phenyl-2-tetrazol-5-yl-4H-pyran-4-one

A mixture of 4-oxo-5-phenyl-4H-pyran-2-carbonitrile (2.2 g), sodium azide (1.0 g) and ammonium chloride (8.0 g) in dimethylformamide (120 ml) was stirred at room temperature for 1 hour. After stirring, ice (20 ml) was added and the transparent solution was acidified with 2N hydrochloric acid (20 ml) to obtain a pale solid, which was recrystallized from ethanol to give the title product (melting point 237-238 ° C., decomposition).

Example 44

5- (4-methoxyphenyl) -2-tetrazol-5-yl-4H-pyran-4-one

This compound is synthesized by the method described in Example 43 (melting point 242-245 ° C., decomposition).

Example 45

Ethyl 5- (2-hydroxyphenyl) -4-oxo-4H-pyran-2-carboxylate

Boron trichloride (3.0 ml) in a stirred solution of ethyl 5- (2-methoxyphenyl) -4-oxo-4H-pyran-2-carboxylate (3.2 g) dissolved in methylene chloride at 5-10 ° C. Is added dropwise, the mixture is stirred at room temperature for 2 hours, then cooled to 5 ° C. and carefully diluted with water (50 ml). The title compound as a solid is recrystallized from ethanol (melting point 187-189 ° C.).

Example 46

Ethyl 5- (4-hydroxyphenoxy) -4-oxo-4H-pyran-2-carboxylate

Ethyl 5- (4-methoxyphenoxy) -4-oxo-4H-pyran-2-carboxylate (melting point 106-107 ° C.) was synthesized by the method described in Example 17, and the method described in Example 45. The methoxy group was cleaved to give the title product (melting point 206-208 ° C.).

Example 47

Ethyl 5- (2-hydroxyphenyl) -4-oxo-4H-pyran-2-carboxylate

This compound is prepared by a method similar to the method described in Example 45 (melting point 111-113 ° C).

Example 48

5- (4-hydroxyphenoxy) -4-oxo-4H-pyran-2-carboxylic acid

To a stirred solution of ethyl 5- (4-methoxyphenoxy) -4-oxo-4H-pyran-2-carboxylate (4.35 g) dissolved in methylene chloride was added dropwise boron trichloride (8.8 ml) under reflux. do. The solution is heated under reflux for another 2 hours, then cooled and carefully diluted with water (25 ml). The title product, which is a solid, is recrystallized from water (melting point 257-258 ° C., decomposition).

Example 49

5- (4-hydroxyphenoxy) -4-oxo-4H-pyran-2-carboxylic acid

This compound is prepared by the method described in Example 48 (melting point 193-194 ° C, decomposition).

Example 50

5- (4-methoxybenzoyl) -4-oxo-4H-pyran-2-carboxylic acid

Under the conditions described in Example 45, treatment of 5- (4-methoxybenzoyl) -4-oxo-4H-pyran-2-carboxylate in boron trisulfide to cleave the ester group preferentially yields the title compound ( Melting point 185-190 ° C., decomposition).

Example 51

3- (3,4-dimethoxyphenyl) -4-dimethylamino-3-buten-2-one

This compound is prepared by the method described in Example 1 (melting point 94 ° C).

Example 52

Ethyl 5- (3,4-dimethoxyphenyl) -4-oxo-4H-pyran-2-carboxylate

This compound is prepared by the method described in Example 17 (melting point 141-14394 ° C).

Example 53

5- (3,4-Dimethoxyphenyl) -4-oxo-4H-pyran-2-carboxylic acid

This compound is prepared by the method described in Example 29.

Example 54

Ethyl 5- (3,4-dihydroxyphenyl (-4-oxo-4H-pyran-2-carboxylate

This compound is prepared by the method described in Example 45 (melting point 206-208 ° C.).

Example 55

5- (3,4-Dihydrophenyl) -4-oxo-4H-pyran-2-carboxylic acid

This compound is prepared by the method described in Example 29 (melting point 284-285 ° C., decomposition).

Example 56

5- (3,4-dimethoxyphenyl) -N-oxo-4H-pyran-2-carboxyamide

5- (3,4-Dimethoxyphenyl) -N-methyl-4-oxo-4H-pyran-2-carboxylate (melting point 130 ° C.) was prepared by the method described in Example 35, and reacted with methylamine. This gives the title product (melting point 213-215 ° C.).

Example 57

5- (3,4-Dibenzyloxyphenyl) -4-oxo-4H-pyran-2-carboxylic acid

Ethyl 5- (3,4-dihydrophenyl) -4-oxo-4H-pyran-2-carboxylate (3.0 g) in dry DMF (30 ml), anhydrous potassium carbonate (6.0 g) and benzyl (3.0 ml) ) Is stirred for 2 hours at room temperature and then filtered. Cool the filtrate, acidify with 2N hydrochloric acid (20 ml) and dilute with water (80 ml).

Recrystallization of the solid product with ethanol yields 5- (3, 4-dibenzyloxyphenyl) -4-oxo-4H-pyran-2-carbosylate (melting point 122-125 ° C).

A stirred solution of ethyl ester (7.5 g) and dry lithium iodide dissolved in dry DMF (120 ml) under nitrogen was heated on an oil bath to 165-170 ° C. for 6 hours under nitrogen. The solution is cooled, acidified with 1N hydrochloric acid (500 ml) and the solid product is recrystallized from ethanol to give the title product (melting point 206-208 ° C.).

Example 58

Ethyl 5- (4-tert-butylbenzoyl) -4-oxo-4H-pyran-2-carboxylate

3- (4-tert-butylbenzoyl) -4-dimethylamino-3-buten-2-one was prepared by the method described in Example 16, and the titled compound (melting point) was obtained by the method described in Example 17 without purification. 82-85 ° C.).

Example 59

5- (4-tert-Butylbenzoyl) -4-oxo-4H-pyran-2-carboxylic acid

This compound is prepared by cleaving ethyl ester as described in Example 48 (melting point 133-145 ° C.).

Example 60

3- (4-tert-butylphenoxy) -4-dimethylamino-3-buten-2-one

This compound is prepared by the method described in Example 1 (melting point 98 ° C).

Example 61

5- (4-tert-butylphenoxy) -4-oxo-4H-pyran-2-carboxylic acid

Ethyl 5- (4-tert-butylphenoxy) -4-oxo-4H-pyran-2-carboxylate (melting point 108-110 ° C.) was synthesized by the method described in Example 17, and in Example 29 Hydrolysis together yields the title product (melting point 190-193 ° C., decomposition).

Example 62

3- [4cyclohexyl) phenoxy] -4-dimethylamino-3-buten-2-one

Clean distilled chloroacetone (31 ml) was added to a solution of sodium oxide (1.0 g) dissolved in dry acetone (50 ml), and the mixture was left at room temperature for 1 hour, and then 4- (cyclohexyl) in dry acetone (100 ml). To the mixture of phenol (52.8 g) and anhydrous potassium carbonate (52 g) was added for 1 hour while stirring and refluxing.

The stirred mixture was further heated at reflux for 5 hours, filtered and evaporated to give a brown oil which was determined to be ether-petroleum spirit (40-60 ° C.) to 1- [4- (cyclohexyl) phenoxy] -2 -Propanone (melting point 58 degreeC) is obtained.

The title compound is prepared from this catone by the method described in Example 1 (melting point 137 ° C.).

Example 63

5- [4- (cyclohexyl) phenoxy] -4-one-4H-pyran-4-carboxylic acid

Ethyl 5- [4- (cyclohexyl) phenoxy] -4-oxo-4H-pyran-2-carboxylate (melting point 159 ° C.) was synthesized by the method described in Example 17, and described in Example 29. Hydrolysis as described above yields the title product (melting point 187-190 ° C.).

Example 64

5- (4-Butylphenyl) -4-oxo-4H-pyran-2-carboxylic acid

A stirred solution of 4-butylbenzoaldehyde (13.5 g), nitroethane (9.0 ml) and butylamine (1.6 ml) dissolved in ethanol (20 ml) was heated under reflux for 6 hours and evaporated. When the residue is distilled off under reduced pressure, 1- (4-butylphenyl) -2-nitropropene is obtained (boiling point 124-125 ° C / 0.15 mm).

Concentrated hydrochloric acid (6.5 ml) was added to the stirred mixture of nitropropene (7.6 g), iron (13.6 g) and ferric chloride (0.1 g) in water (50 ml) for 6 hours. It is heated under reflux with the dropwise addition. The mixture is steam distilled and the effluent is extracted with ether. The distillate is evaporated to dryness, and the residue is distilled under reduced pressure to obtain 1- (4-butylphenyl) -2-propanone.

This canon (4.6 g) was reacted with dimethylformamide dimethylacetal (4.0 ml) as described in Example 1 to obtain 3- (butylphenyl) -4-dimethylamino-3-buten-2-one, which was Using without purification and by the method described in Example 17, ethyl 5- (4-butylphenyl) -4-oxo-4H-pyran-2-carboxylate (melting point 65 ° C.) is prepared. Hydrolysis of this ester in the manner described in Example 29 yields the title product (melting point 193-195 ° C.).

Example 65

Ethyl 3-bromo-4-oxo-5-phenyl-4H-pyran-2-carboxylate

To a stirred suspension of sodium hydride [50% dispersion washed with petroleum spirit (40-60 ° C.), 1.3 g] suspended in ether (50 ml) under nitrogen, ethanol (1.6 ml) was added to give a suspension of sodium ethoxide. Manufacture.

A solution of 4-dimethylamino-3-phenyl-3-buten-2-one (4.8 g) and diethyl oxalate (5.2 ml) dissolved in ether (50 m) was added to a stirred sodium ethoxide suspension at 5-10 ° C. The resulting transparent solution was stirred at room temperature for 2 hours, then cooled and treated with glacial acetic acid (2.5 ml) and water (50 ml). Ethyl acetate is added to dissolve the resulting solid, the solvent layer is washed with water, dried and evaporated.

The solid residue is recrystallized from ethyl acetate-petroleum spirit (60-80 ° C.) to give ethyl 6-dimethylamino-2, 4-dioxo-5-phenyl-5-hexenoate (melting point 110 ° C.).

A solution of cancellation (0.73 ml) dissolved in chloroform (10 ml) was added dropwise to a stirred solution of the nucleic acid ester (4.1 ml) dissolved in chloroform at -20 ° C to -25 ° C, and the solution was stirred at room temperature for 1.5 hours. , Washed with water and evaporated. When the bottom oil is determined as ethanol-water, the title product (melting point 134 ° C.) is obtained.

The following example is an example of a pharmaceutical composition containing a compound of formula (I), wherein the active ingredient used is 4-oxo-5-phenyl-4H-pyran-2-carboxylate. However, this compound can be replaced with other active solid compounds of the present invention.

Example 66

Each tablet containing 50 mg of active ingredient is made as follows.

Active ingredient 50 mg lactose 200 mg

Starch 200mg Polyvinylpyrrolidone (with 10% aqueous solution) 20mg

Sodium starch glycolate 20mg total amount 500

Magnesium Stearate 10mg

Starch, lactose and the active ingredient are passed through a shaker and mixed thoroughly. A solution of polyvinylpyrrolidone is mixed with the resulting mixture and the mixture is mixed with NO. 12 Pass through mesh B. S. The particles thus produced are dried at about 55 ° C. and NO. Pass through 16 mesh B. S., add to the particles, mix, and then press into tablet forming machine to prepare a tablet weighing 500 mg.

Example 67

A capsule containing 50 mg of the drug is prepared as follows.

Active Ingredient 50 mg Magnesium Stearate 3 mg

Starch 42mg total amount 140mg

Lactose 45mg

Lactose, starch, magnesium stearate and active ingredient NO. Pass through 44 mesh B.S. and fill in 140 mg light gelatine capsule.

Example 68

Suppositories containing 25 mg of active ingredient are prepared as follows.

Active ingredient 50 mg saturated fatty acid glyceride 2000 mg

The active ingredient is NO. Pass through 66 mesh B. S. suspension and suspend in pre-melted saturated fatty acid glycerides with minimal required heat.

The mixture is poured into a 2 g suppository mold and cooled.

Claims (1)

A method for producing a compound represented by the following general formula (I), wherein a compound of the general formula (III) is reacted with an acid and introduced with one or more substituents in the R ³ group.

[Wherein R ¹ is hydrogen, COOR ⁵ , CONHR ⁵ , cyano, 5-tetrazolyl or 5-tetrazolylamino carbonyl, where R ⁵ is hydrogen or C _1-6 alkyl, R ³ is a general formula R ⁶ (Z) _m -, a group of wherein m is 0 or 1, Z is O, S, SO ₂ or CO, R ⁶ is a selected from halogen, C _1-4 alkyl, C _3-6 cycloalkyl, or Phenyl group optionally substituted by more than one group]