KR820002277B1 - Process for preparing 4,5-dihydro-4-oxofuran-2-carboxylic acid dervalives - Google Patents

Abstract

Furan derivs. I (R1,R2 = a1ky1, cycloa1ky1, a1koxy, Ph;R3 = H, a1ky1; R4 = H, a1ky1, etc.) and their salts, effective hypolipemics at 1.0 mmo1/kg-day in rats, were prepd. Thus, a stirred suspension of 10.5 g NaH in mineral oil, 16 g di-Et oxalate, and 16.4 g 3-hydroxy-3-phenyl-2-butanone were mixed in THF, heated 18hr at 55-60oC, cooled, and poured into H2O, NaOH added to pH 11, and the mixt. kept 24hr to give 20g I(R1=Me, R2 = Ph, R3 = R4 =H), which (0.4 g) was esterified with MeOH-H2SO4 to give 0.32 g Me ester(R1 = R4 = Me, R2 =Ph, R3 = H).

Description

Method for preparing 4,5-dihydro-4-oxofuran-2-carboxylic acid derivative

The present invention provides the preparation of 4,5-dihydro-4-oxofuran-2-carboxylic acid derivatives represented by the following general formula (I) and therapeutically acceptable acid addition salts which are useful as therapeutic agents for hyperlipidemia in mammals. It relates to a method and a method for preparing their pharmaceutical composition.

Where

R ¹ and R ² are each lower alkyl, cyclo (lower) alkyl; Lower alkoxy (lower) alkylene; Phenyl; Or phenyl substituted one or two with lower alkyl, lower alkoxy, halogen, nitro or trifluoromethyl; Or R ¹ and R ² together form a-(CH ₂ ) mX- (CH ₂ ) n-chain (m and n each being an integer of 1 to 4, X is methylene, oxa or thiaim); Or R ¹ and R ² together with the carbon atom to which they are attached form spiro [1,2,3,4-tetrahydronaphthalene] -1 or spiro [indane] -1 radical;

R ³ is hydrogen or lower alkyl;

R ⁴ is hydrogen, lower alkyl, cyclo (lower) alkyl, phenyl (lower) alkylene, amino (lower) alkylene, lower alkylamino (lower) alkylene, di (lower alkyl) amino (lower) alkylene or 3 -Pyridyl (lower) alkylene.

More specifically, in the present invention, 4,5-dihydro-4-oxofuran-2-carboxylic acid in which two substituents are substituted in the fifth position and, in some cases, one lower alkyl group is further substituted in the third position A method for producing derivatives and esters thereof.

The derivatives according to the invention are substances useful for treating hyperlipidemia by administering to a mammal at a dose that does not cause side effects.

4,5-dihydro-4-oxofuran is described in various literatures and is also described as 4,5-dihydro-4-oxofuran-carboxylic acid derivative. For example, 4,5-dihydro-2-methyl-4-oxofuran-3-carboxylic acid and its ethyl esters are described in RERosenkranz et al., Helv, Chim Acta 46, 1259 (1963) and cited references. . In this citation reference, the structure of 4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acid is described as the most intermediate in the decarboxylation of 4-methoxy-5-methylfuran-2-carboxylic acid. It is.

The presence of 4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acid cannot be confirmed by separation or other means.

Several furan derivatives have recently been reported as therapeutic agents for hyperlipidemia. In more detail, derivatives of 2,3,4,5-tetrahydro-3-oxo-4-hydroxy-imidofuran, 2,5-dihydrofuran and 2,3,4,5-tetrahydrofuran They are said to have some or moderate antihyperlipidemic activity. [Reference G.B. Bennett et al., J. Med chem 19, 709 (1976). The document also states that furan derivatives are below the desired level of hyperlipidemic activity.

4,5-hydro-4-oxofuran-2-carboxylic acid according to the present invention is a novel compound that does not affect the weight of the liver and has a hyperlipidemic action.

Preferred groups for the compounds of formula (I) or therapeutically acceptable acid addition salts thereof are those wherein R 1 is lower alkyl, phenyl or 1 substituted phenyl;

R ² is lower alkyl or R 1 and R ² are spiro [1,2,3,4-tetrahydronaphthalene] -1 radicals together with the carbon atoms to which they are attached; R ³ is hydrogen; R ⁴ is hydrogen, lower alkyl or 3-pyridinyl (lower) alkylene.

Most preferred for the compound of formula (I) or a therapeutically acceptable acid addition salt thereof is that R ¹ is lower alkyl, phenyl or 4-chlorophenyl; R ² is lower alkyl or R ¹ and R ² together with the carbon atom to which they are attached are spiro [1,2,3,4-tetrahydronaphthalene] -1 radicals; R ³ is hydrogen; R ⁴ is hydrogen, lower alkyl or 3-pyridinylmethyl.

In the general formula (I), a compound in which R ¹ , R ² , R ^3, and R ⁴ are defined above is subjected to a cyclization reaction of the compound of the general formula (X) under acidic conditions to R in the general formula (I). To obtain a compound in which ¹ , R ² , and R ³ are as defined above and R ⁴ is hydrogen, and if necessary, an esterification reaction is carried out to give R ¹ , R ² and R ^{3 in} formula (I). Is as defined above, R ⁴ is lower alkyl, cyclo (lower) alkylene, amino (lower) alkylene, loweralkylamino (lower) alkylene, di (lower alkyl) amino (lower) alkylene or 3- Prepared by obtaining a compound that is pyridinyl (lower) alkylene.

(R ¹ , R ² and R ³ are as defined above)

In more detail, as R ¹ , R ² , R ³ and R ⁴ in the general formula (II) are defined above, the compound may be prepared by the compound of the general formula (II) in the presence of a strong inorganic proton acceptor in anhydrous state. After reacting with di (lower alkyl) oxalate and hydrolyzing the mixture with water at PH 10-12, the mixture was left under acidic condition to give R ¹ , R ² and R ³ in the formula (II) The corresponding compound is as defined and R ⁴ is hydrogen, followed by an esterification reaction in which R ¹ , R ² and R ³ are as defined above in formula (I) and R ⁴ is lower alkyl, cyclo Prepared by obtaining a compound that is (lower) alkyl, phenyl (lower) alkylene, lower alkylamino (lower) alkylene, di (lower alkyl) amino (lower) alkylene, or 3-pyridinyl (lower) alkylene). .

(R ¹ , R ² and R ³ are as defined above)

When the compound of formula (1) or a therapeutically acceptable acid addition salt thereof is administered to a mammal in a therapeutically effective amount for hyperlipidemia, the poor content of the body is lowered.

A convenient form for administering a compound is a pharmaceutical composition combining a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

The term "lower alkyl" as used herein refers to straight chain alkyl groups having 1 to 6 carbon atoms and branched alkyl groups having 3 to 4 carbon atoms, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Pentyl and hexyl.

The term "lower alkoxy" as used herein refers to straight chain alkoxy groups having 1 to 6 carbon atoms and branched alkoxy groups having 3 to 4 carbon atoms, examples of which include methoxy, ethoxy, isopropoxy, butoxy and Hexyloxy and the like.

As used herein, the term " lower alkylene " means divalent free radicals derived from straight and branched aliphatic hydrocarbons having 1 to 6 carbon atoms by removal of two hydrogen atoms, examples of which include methylene, ethylene, 1-methylpropylene, 2-methylpropylene, 2-ethylpropylene, 2-butylethylene and the like.

The term "cyclo (lower) alkyl" as used herein means a saturated cyclic hydrocarbon radical having 3 to 6 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

As used herein, the term "lower alkylol" refers to straight and branched alkanols having 1 to 4 carbon atoms, examples of which include methanol, ethanol, isopropanol and butanol.

The term "strong inorganic proton acceptor" as used herein means an inorganic base, preferably an alkali metal, examples of which are hydrides, amides, hydroxides and alkoxides of alkali metals (e.g. sodium, sodium hydroxide, potassium hydroxide). , Sodium ethoxide, sodium methoxide, sodium hydride), and the like.

As used herein, the term "lower alkanoyl" refers to straight alkanoyl radicals having 2 to 2 carbon atoms and cyclic alkanoyl radicals having 4 carbon atoms, examples of which are acetyl, propionyl, isobutyryl, hexanoyl Etc.

The term "organic proton acceptor" as used herein refers to organic bases or amines (e.g. triethylamine, pyridine, N-emmorpholine, 1,5-diazabicyclo [4,3,0] non-5-ene). it means.

As used herein, the term "therapeutically acceptable addition salt" means that in formula (I) R4 is amino (lower) alkylene, lower alkylamino (lower) alkylene, di (lower alkyl) amino (lower) alkylene Or a pharmaceutically acceptable acid addition salt of a compound that is 3-pyridinyl (lower) alkylene.

Acid addition salts are prepared by reacting a base form with a suitable compound of formula (I) and at least one equivalent, preferably in excess of an appropriate acid, in an organic solvent, such as diethyl ether or an ethanol-diethyl ether mixture. These salts have the same pharmacological activity as the corresponding base when administered to a mammal. For many uses, it is desirable to administer salts rather than base compounds. Suitable acids in the form of these salts are ordinary inorganic acids (e.g. hydrochloric acid, sulfuric acid or phosphoric acid) and organic acids (e.g. formic acid, acetic acid, maleic acid, dried acid, ascorbic acid, succinic acid, fumaric acid, citric acid or tartaric acid, or egg in body fluids). Soluble, acid, which is soluble in pamoic acid, tannic acid or carboxymethyl cellulose and their respective salts The acid addition salts thus obtained have the same function as the original base compounds in terms of therapeutic use. Any acid can be used as long as it is within the range of and forms a therapeutically poisonous salt.

In addition, the term "therapeutically acceptable addition salt" as used herein also means a compound in which R ⁴ in formula (I) is hydrogen, that is, a therapeutically acceptable inorganic or organic base addition salt of an acid compound. Salts thus derived have the same activity as the original acids and are within the scope of the present invention.

Neutralization of the aforementioned acids with suitable inorganic or organic bases converts to the corresponding salts which are therapeutically toxic in good yield. These salts are administered in the same manner as the original acid compound. Examples of suitable inorganic bases for forming such salts are alkali metals or alkaline earth metals such as hydroxides of sodium, potassium, magnesium calcium decay, carbonates, bicarbonates and alkoxides. Suitable organic bases are lower levels having up to three carbon atoms of alkyl groups. Mono-, di- and trialkylamines (e.g. methylamine, dimethylamine, trimethylamine, ethylamine, di- and triethylamine, N-methyl-N-ethylamine, etc.); alkanol groups with up to 3 carbon atoms Individual mono-, di and trialkanolamines (e.g. mono-, di- and triethanolamine); alkalenediamines (hexamethylenediamine) with up to six carbon atoms; phenylacylamines (e.g. benzylamine, phenylethylamine And N-methylphenylethylamine) and cyclic saturated or unsaturated bases having up to six carbon atoms (e.g. pyrrolidine, morpholine, piperazine and their N-hydroxyalkyl derivatives (N-methyl-morpholine and N- (2-hydroxy Yl) -piperidine) and pyridine] etc. In addition, tetraalkyl (e.g., tetramethyl) having a good solvent for water; alkyl-alkanols (e.g., methyl trimethanol and trimethyl-monoethanol) And cyclic ammonium salts such as N-methylpyridium, N-methyl-N- (2-hydroxyethyl) -morpholinium, N, N-dimethyl morpholinium, N-methyl-N- (2- Hydroxyethyl) -morpholinium, NN-dimethyl piperidinium salt], etc. In general, however, any physiologically suitable ammonium salt can be used.

Conversion to these salts can be carried out in a variety of ways known in the art. For example, in the case of inorganic salts, it is preferable to make the acid of general formula (I) into water containing 1 equivalent or more of hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt.

The reaction is preferably carried out in a water-miscible inert organic solvent (methanol, ethanol, diol acid) in the presence of water, for example using sodium hydroxide, sodium carbonate or sodium bicarbonate to give a solution of sodium salt. Or water-miscible organic solvents of moderate polarity such as lower alkanols (e.g. butanol) or lower alkanones (e.g. methylethylketone) are added to this solution to form solid inorganic salts of the desired form. do.

To form amine salts, acidic compounds of formula (I) are dissolved in solvents of intermediate and lower polarity, such as ethanol, methanol, ethyl acetate, diethyl ether and benzene, and then produced. To the resulting solution is added an amine corresponding to the desired cation in an amount of at least 1 equivalent. If the resulting salt does not precipitate, a solid form can be obtained by the addition of a low degree of polarized miscible diluent (eg benzene or petroleum ether) or by evaporation. When the amines used are quite volatile, excess amines can be easily removed by evaporation. However, it is preferable to use a substantial equivalent amount of amines having low volatility.

Salts whose cations are quaternary ammonium are formed by mixing the acid of general formula (I) with one equivalent of the quaternary ammonium hydroxide in aqueous solution.

The present invention also includes stereoisomers of general formula (I) resulting from asymmetric carbon atoms. It goes without saying that diastereomers resulting from asymmetry are also included in the scope of the present invention. Such diastereomers can be obtained in substantially pure form by classical separation techniques and three-dimensional controlled synthesis.

Also included in the scope of the invention are the preferred enantiomers and the left enantiomers, which can be separated by fractional crystallization of diastereomeric salts of the enantiomers.

The compound of formula (I) or a therapeutically nontoxic salt thereof can be used as a therapeutic agent for hyperlipidemia in mammals by oral or parenteral administration.

The hyperlipidemic action of the compounds according to the invention is easily demonstrated by the following test methods; Male rats weighing 140-170 g (8 in each group) are orally administered in a single dose daily with a suspension of 1.0 ml of a 2% Tween-80 ^* aqueous construction compound suspended in water. In the same way, orally administer only 1.0 ml of 2% Tween-80 ^* aqueous solution of water to the control. One week after the treatment, the rats are cut off and blood is collected. Serum was separated by centrifugation to modify the serum content of cholesterol in an automated analyzer (method NP-24) [A. Zlatks et al., J. Lab. Clin. Med. 41, 486 (1953)]. Phospholipids in serum were analyzed by M. Kraml, clin. chim. Measured by the semi-automated technique of Acta, 13,442 (1966), serum triglycerides were determined in M. Kraml and L. Co-syns, Clin. Biochem. Measured by the semi-automatic method of 2,373 (1959). Cholesterol, phospholipids, and triglycerides in the serum of rats and control rats treated with the test compound were analyzed for their activity and their meanings were examined by Student's t-test. The following result treatment showing triglyceride hypertension activity was calculated by subtracting the triglyceride content in serum in rats treated with the test compound from the serum triglyceride content in control rats and expressing the difference as a percentage of the control content. The following compounds of formula (I) were administered at a 1.0 mmol molar weight per kilogram of body weight, which lowered the triglyceride content as a percentage described below: 4,5-dihiro-5-methyl-4-oxo-5- Phenylfuran-2-carboxylic acid (42%, compound of Example 4), 4,5-dihydro-5-) 1-methylethyl) -4-oxo-5-phenylfuran-5-carboxylic acid ( 52%, compound of Example 4), 4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid (37%, compound of Example 4), spiro [furan-5) 1H), 1 ′ (2 ′ ′)-naphthalene] -3 ′, 4 ′, dihydro-4-oxo-2-carboxylic acid (43%, compound of Example 4), 4,5-dihydro -5-Methyl-4-oxo-5-phenylfuran-2-carboxylic acid methyl ester (53%, the compound of Example 5) and 4,5-dihydro-5-methyl-4-oxo-5-phenyl Furan-2-carboxylic acid 3-pyridinylmethylester (62%, compound of Example 6).

The compound of formula (I) or a therapeutically acceptable salt thereof may also be used in combination with known known anti-hypertensive agents (eg clofibrate) to reduce the increased lipid content in mammals. In such a combination, the compound of formula (I) may be administered continuously or subcutaneously in combination with an effective amount of a known hyperlipidemic agent.

For the appropriate method, composition and dosage of Colfibrate (ATROMID-S), see Charles Z. Baker, Jr. "Physician's Desk Regerence" Medical Economics Company, oradell, N.J. 1977, pp 593-594. For example, 0.5-2.0 g divided doses are administered to a daily patient. The combination of a compound of formula (I) or a therapeutically acceptable salt thereof with a known hyperlipidemic agent is by the same method described above for the use of a hyperlipidemic agent.

When the compound of formula (I) according to the present invention is used as a therapeutic agent for hyperlipidemia in mammals (rats and dogs), these compounds are used alone or in combination with a pharmaceutically acceptable carrier, and the ratio of use is equivalent to the solubility of the compounds. And chemical properties, method of administration and biological practice. For example, the compounds are administered orally in solid form (eg tablets or capsules). In addition, the present compounds may be administered orally in suspension or as a liquid, and may also be administered parenterally. In the case of parenteral administration, it can be used as a sterile liquid solution containing other solutes, such as isotonic agent added with saline or glucos.

Tablet compositions for oral administration include a nontoxic pharmaceutical excipient known to be suitable for the formulation of tablets with the active ingredient. Examples of suitable pharmaceutical excipients include starch, lactose, clay and the like. Tablets may be uncoated and may be coated by conventional methods to slow disintegration and absorption in the gastrointestinal tract and to show sustained release.

Oral aqueous suspensions of the compounds according to the invention combine the active ingredients with one or more nontoxic pharmaceutical excipients (eg emulsifiers and suspending agents) which are known to be suitable for the preparation of aqueous suspensions. Examples of suitable excipients include methyl cellulose, sodium alginate, acacia rubber, lecithin and the like. The aqueous suspension may also be blended with at least one preservative, at least one colorant and at least one sweetener.

Oral non-aqueous suspensions may be prepared by suspending the active ingredient in vegetable oils (eg peanut oil, olive oil, sesame oil, coconut oil) or mineral oil. The suspending agent may contain a thickening agent (wax, hard paraffin or cetyl alcohol). These compositions may also be blended with sweeteners, flavors and antioxidants.

In the case of parenteral administration such as intramuscular, intraperitoneal, subcutaneous and intravenous use, a sterile solution in which the compound according to the present invention is appropriately adjusted in pH and buffered is used. Saline or glucose can be added to make an isotonic solution.

The dosage of the general formula (I) compound as a hyperlipidemic agent depends on the method of administration, the age of the patient and the symptoms of the patient. Generally, at the beginning of treatment, a dose that is significantly less than appropriate for the present compound is administered and the dose is increased gradually until an optimal effect is obtained. It is most preferred that the compounds according to the invention generally be administered in an amount which does not exhibit any harmful side effects and a good effect is obtained. The therapeutically effective amount of the hypertension of the compound is usually about 1.0 mg to about 500 mg per kg of body weight per day, but the amount of change may be increased or decreased.

However, in order to obtain an effective effect, it is most preferable to use about 5 to about 300 mg / kg body weight per day.

[Manufacturing method]

A preferred starting material for preparing the 4,5-dihydro-4-oxofuran-2-carboxylic acid derivative of general formula (I) is α-hydroxyketone of general formula (II).

Where

R ¹ and R ² are each lower alkyl; Cyclo (lower) alkyl; Lower alkoxy (lower) alkylene; Phenyl; Or 1 or 2 substituted phenyl of lower alkyl, lower alkoxy, halogen, nitoro or trifluoromethyl; Or R ¹ and R ² together form a-(CH ₂ ) _m -X- (CH ₂ ) _n -chain (m and n are integers from 1 to 4 and X is methylene, oxa or thiaim); Or R 1 and R 2 together with their bonded carbon atoms form a spiro [1,2,3,4-tetorahydronaphthalene] -1 or spiro [andan] -1 radical; R ⁴ is hydrogen or lower alkyl.

In the general formula (II), starting materials in which R ¹ and R ² are as defined above and R ³ is hydrogen can be prepared using a known compound or by the following reaction process formula.

,39(1953)〕. 바람직한 방법으로서는 아세틸렌 가스로 포화시킨 무수 액상 암모니아 용액중의 일바식(Ⅲ)의 화합물과 티튬 또는 나트륨 혼합물을 9시간 반응시킨다음 일반식(Ⅳ)의 상응하는 화합물을 단리시키는 방법이다.In Reaction Process Formula 1, a number of general formula (IV) acetylene carbinols are known and known. In addition, acetylene carbinol is easily obtained by adding metal acetylide to ketones in which R ¹ and R ² are defined above in General Formula (III). [AW Johnson, Acetylene Compound, Vol. 1, Acetylene Alcohol, E. Arnold Co., London, 1946; RA Raphael, Sacetylene Compounds of Organic Synthesis, London, Butterworth's Sci. Publ., 1955; PA Robins and J. Walker, J. Chem. Soc., 177 (1957); And ED Bergmann et al., J. Appl. Chem.

, 39 (1953)]. A preferred method is to react the compound of formula (III) with a titanium or sodium mixture in anhydrous liquid ammonia solution saturated with acetylene gas for 9 hours and then isolate the corresponding compound of formula (IV).

, 42(1953), G.F.Hennian 및 B.R. Fleck, Amer. Chem. Soc., 77, 3253(1955); 및 G.F. Hennian 및 E.J. Watson, J. Org. Chem., 23, 656(1958)〕Acetylenecarbinol of the general formula (IV) is hydrated at 60 to 65 DEG C for 1 to 6 hours in a mixture of mercuric oxidizing agent (red form) or mercuric sulphate, aqueous tetrahydrohydrofuran and sulfuric acid. Is converted to α-hydroxyketone of formula (II). AW Johnson, supra, pp 102-105; EDBergmann and DFHerman, J. Appl. Chem.,

, 42 (1953), GFHennian and BR Fleck, Amer. Chem. Soc., 77, 3253 (1955); And GF Hennian and EJ Watson, J. Org. Chem., 23, 656 (1958)].

In general formula (II), the starting material whose R <^1> and R <^2> is as defined above and R <^3> is lower alkyl can be manufactured using a well-known compound, or can be manufactured and used by following Reaction Formula 2.

[Reaction Process Formula 2]

(1968), 참고 Chem. Abstr.,

, 19233 Z〕.In Reaction Process Formula 2, condensation of the organometallic derivative of Formula (III) with a ketone of Formula (III) yields a corresponding α-hydroxyketone in which R ³ is lower alkyl in Formula (II). II Lapkin and TN Povarnitsyna, Zh. Obshch. Khim.,

(1968), Chem. Abstr.,

, 19233 Z].

,2590(1940); J. Kapron 씨 및 J. Wiemann, Bull. Soc. Chim. 프랑스,

,945(1945); 및 Y.L. Pascal, Ann. Chim. (Paris), 245(1968)에 기재되어 있다.As an alternative to using the compound of formula (V) as starting material, in formula (II), R ¹ or R ² is phenyl; Or α-ketoalcohol which is 1 or 2 substituted phenyls of lower alkyl, lower alkoxy, halogen, natro or trifluoromethyl. Mr. K. Binovic and S. Vrancea, Mr. Chem. Ther., 313 (1968) method is used to obtain compounds of the general formula (VI) which alkylate and correspond to the compounds of the general formula (V), which are described in J.R. Mr. Catch et al., J. Chem. Soc. Bromination under the conditions described in 272 (1948) yields the corresponding bromokenone of the general formula. For the conversion of the bromoketone obtained to the corresponding hydroxy ketone of the general formula (II), see JG Aston and RB Greenberg, J. Amer. Chem. Soc.,

, 2590 (1940); Mr. J. Kapron and J. Wiemann, Bull. Soc. Chim. France,

, 945 (1945); And YL Pascal, Ann. Chim. (Paris), 245 (1968).

,5794(1945)에 서술된 방법에 의하여 일반식(Ⅱ)의 α-히드록시케톤을 제조할 수 있다.In addition to the above-mentioned preparation methods, YL Pascal, supra and P. Kaufmann, J. Amer. Chem. Soc.,

(Alpha) -hydroxyketone of general formula (II) can be manufactured by the method described by (5794) (1945).

Reaction Scheme 3 below shows the conversion of R ¹ , R ² and R ³ to a corresponding compound as defined above in α-hydroxyketone of Formula (II) in Formula (I),

[Reaction Process Formula 3]

As shown in Reaction Process Formula 3, a compound in which R4 is hydrogen in General Formula (I) is produced from the compound of General Formula (II) via step II → Ⅸ → Ⅹ → I. The intermediates of formulas (iii) and (iii) may be isolated to continue the reaction in separate processes, but the compounds of formula (II) may be separated in a single reactor without isolating intermediates and (iii). It may be converted to the corresponding compound of formula (I).

The first step of the conversion reaction of the general formula (II) α-hydroxyketone is that of the animal with α-hydroxyketone and di in the presence of 1 to 4 molar equivalents of a strong inorganic proton acceptor, preferably sodium hydride, in anhydrous inert organic solvent. Condensation reaction of (lower alkyl) oxalate. Preferred inert organic solvents can be selected from di (lower alkyl) ethers and cyclic ethers such as diethyl ether, dioxane and tetrahydrofuran.

The reaction mixture is held at 30 to 70 ° C., preferably at 50 to 60 ° C. for 10 to 30 hours, and the resulting ene is filtered as soon as possible to the ate salt, dissolved in water, and acidified with dilute inorganic acid. The compound of formula (VII) is then extracted with a water immiscible inert organic solvent, preferably diethyl ether.

The hydrolysis of the resulting compound is carried out in a solution of 1 to 3 molar equivalents of potassium or sodium hydroxide in a water miscible organic solvent, preferably in methanol, ethanol, tetrahydrofuran or dioxane aqueous solution at 15 to 30 ° C. under alkaline conditions. It is easily performed for from 40 hours. Next, the resulting solution is extracted with a water immiscible organic solvent, preferably diethyl ether, benzene, chloroform, dichloromethane, etc., and the pH of the required solution is adjusted to 3 to 5 with a strong acid (e.g. hydrochloric acid). Extraction with a water immiscible organic solvent as described above yields the corresponding compound of general formula (X).

Cyclization of the resulting compound under acidic conditions yields the corresponding compound of formula (I) wherein, in formula (I), R ¹ , R ^2, and R ³ are as defined above, and R ⁴ is hydrogen. . One method of carrying out the cyclization reaction is 0.1 to 10 molar equivalents, preferably 0.1 to 0.4 molar equivalents of the general formula (X) compound and an acid catalyst (e.g., hydrogen chloride, hydrogen bromide) in an inert organic solvent, preferably benzene or toluene. , Hydrochloric acid, hydrobromic acid, P-toluenesulfonic acid, sulfuric acid, phosphoric acid, polyphosphoric acid, and the like, preferably P-toluenesulfonic acid or hydrogen chloride) is maintained at 20 to 100 ° C. for 2 to 50 hours. Another method is to cyclize the compound of general formula (X) in an aqueous solution containing an acid catalyst for 10 to 50 hours. Preferred catalysts for use in aqueous conditions are hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid. The aqueous solution usually contains an acid catalyst in an amount sufficient to maintain the pH of the solution at 0.5 to 3.0, preferably 1.0 to 2.0.

As a variant of converting the general formula (II) compound to the corresponding general formula (I) compound, the above separate condensation, alkaline hydrolysis and cyclization reactions are combined in one operation without isolating intermediates and (iii). Way.

This variant is a method of condensing alpha-hydroxyketone of the general formula (II) with di (lower alkyl) oxalate in the same manner as above. However, the reaction mixture is mixed with about equal volume of water without filtration. The resulting aqueous alkali solution is then adjusted to pH 10-12 with sodium hydroxide, if necessary, maintained at pH 10-12 and temperature 15-30 ° C. for 10-40 hours, followed by a water immiscible organic solvent, preferably di The ethyl ether amount is washed with benzene. The acid catalyst, preferably hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid is then added into the aqueous solution until the pH value of the solution reaches 0.5 to 3.0, preferably 1.0 to 2.0. The acidic solution is then kept at 10 to 50 ° C., preferably at 20 to 30 ° C. for 0.5 to 10 hours, followed by water immiscible organic solvents (e.g. ethyl acetate, diethyl ether, benzene, toluene, chloroform, dichloro). Extraction is carried out with methane, etc. The organic extract is evaporated and, if necessary, purification is carried out to obtain the corresponding compound in which R 4 in formula (I) is hydrogen.

In the last method, the pH of the alkaline aqueous solution was maintained at 8 to 9 without maintaining the pH at 10 to 12, and the alkaline aqueous solution was acidified to give R ¹ , R ² and R ³ in the following general formula (V). Isolate intermediates.

In more detail, in the same manner as above, the α-hydroxyketone of the general formula (II) is condensed with di (lower alkyl) oxalate. Without filtration of the reaction mixture, the resulting aqueous solution is mixed with approximately equal volume of water and then maintained at pH 8-9 with dilute hydrochloric acid or sodium hydroxide, if necessary. The resulting aqueous solution is then maintained at pH 8-9 and temperature 15-30 ° C. for 1-5 hours and washed with a water immiscible organic solvent in the same manner as above. Next, the mixture is acidified by the same method as described above in the general formula (II) to the general formula (I), held at 10 to 50 ° C, preferably at 20 to 30 ° C for 1 to 30 minutes, and then extracted. The corresponding intermediate of XI) is obtained.

The intermediate of formula (XI) is reacted under aqueous alkaline conditions at pH 10-12 to give the corresponding compound wherein R ⁴ in formula (I) is hydrogen. In this reaction, a solution of the formula (II) compound in aqueous potassium hydride or sodium is maintained at pH 10 to 12 and at temperature of 15 to 30 ° C. for 10 to 40 hours, and treated with a water immiscible organic solvent in the same manner as described above. Subsequently, the aqueous solution is acidified in the same manner as described above in the general formula (II) → (I), maintained in an acidic solution and then extracted to give the corresponding compound in which R ⁴ is hydrogen in general formula (I).

In general formula (I), esterification of the acidic compound whose R <^4> is hydrogen, In general formula (I), R <^4> is lower alkyl, cyclo (lower) alkyl, phenyl (lower) alkylene, amino (lower) alkyl. Corresponding esters are obtained which are ene, lower alkylamino (lower) alkylene, di (loweralkyl) amino (lower) alkylene or 3-pyridinyl (lower) alkylene. Esterification can be accomplished in a number of ways, for example; Dehydrating binders (dicyclohexylcarbodiimide); Acid catalysts; Diazoalkanes; And acid chlorides.

Preferred variants include acid catalysts, preferably 0.1 to 1.0 molar equivalents of sulfuric anhydride or hydrogen chloride, and 2 to 50 equivalents of lower alkanols, hydroxy cyclo (lower) alkanes, phenyl (lower) alkanols, amino (lower) alkanols, Low alkylamino (lower) alkanol, di (lower alkyl) amino (lower) alkanol or 3-pyridyl (lower) alkanol is a method of esterifying 1 to 10 hours at 50-100 degreeC.

Amino (lower) alkanols, lower alkylamino (lower) alkanols, di (lower alkyl) amino (lower) alkanols or loweralkylamino (lower) alkanols, di (lower alkyl) amino (lower) alkanols or 3 When using pyridinyl (lower) alkanols, the corresponding additional molar amount of acid catalyst must be added to the reactor. When the reactants are mutually soluble, esterification solvents may not be used, but anhydrous inert organic solvents such as dimethylformamide, benzene, toluene, chloroform and the like may be used.

Another preferred esterification method is the use of an acid chloride, in which 50 to 80 solutions of an acidic compound wherein R ⁴ is hydrogen in formula (I) and 5 to 50 molar equivalents of thionyl chloride are used. Heating at 1 ° C. for 1 to 10 hours followed by evaporation yields the corresponding acid chloride. This acid chloride, 1 to 10 molar equivalents of the aforementioned alcohols and organic proton acceptors (e.g. pyridine or triethylamine) are inert organic solvents such as acetone, benzene, dichloromethane, toluene, chloroform or dimethylformamide, preferably Is maintained in acetone at a temperature of 0 to 50 ° C. for 2 to 10 hours, evaporated and purified to give R ¹ , R ² and R ³ as defined above in formula (I) and R ⁴ is lower Alkyl, cyclo (lower) alkyl, phenyl (lower) alkylene, amino (lower) alkylene, loweralkylamino (lower) alkylene, di (loweralkyl) amino (lower) alkylene or 3-pyridinyl (lower) Obtain a compound of alkylene.

The present invention is described in more detail by enumerating the following examples.

Example 1

3-hydroxy-4-methyl-3-phenyl-1-pentin (IV: R ¹ = CH (CH ₃ ) ₂ , R ² = pH)

The dry ice reflux condenser is filled with 700 ml of freshly condensed liquid ammonia into the elongated reaction flask and then ammonia gas is passed through a tower of potassium hydroxide particles. The dehydrated acetylene gas stream in the sulfuric acid wash bottle is introduced into ammonia for 10 minutes with stirring, then the acetylene passage rate is reduced and the acetylene inlet is maintained in the reaction mixture for the next operation (about 9 hours). 9.2 g of sodium fragments are added and 2-methyl-1-phenyl-1-propanone (50 g) is added dropwise after 2 hours. Stirring at −33 ° C. for 6 hours then blocks the inlet of the acetylene stream and evaporates ammonia overnight. Carefully add ice water to dilute the resulting solution with dilute sulfuric acid and extract with diethyl ether. The extracts are combined, washed with saturated brine and dried over magnesium sulfate. Then filtration and evaporation gave 45.5 g of the title compound. ir (CHCl ₃ ) 3600, 3310, 1450 and 1010 (m ^-1 nm (CDCl ₃ ) δ0.85 and 1.07 (d), 2.10 (seven line), 2.35 (S), 2.66 (S), 7.27

Example 2

3-hydroxy-4-methyl-3-phenyl-2-pentanone (II ‥ R ¹ = CH (CH ₃ ) ₃ R ² = Ph, R ³ = H)

To a reflux mixture of tetrahydrofuran (70 mL), mole (5 mL) and concentrated sulfuric acid (1.5 g) was added 1 g of red mercury oxidant and reflux continued for 5 minutes. The internal temperature is then adjusted to 60 ° C. to 62 ° C. and 10 g of 3-hydroxy-4-methyl-3-phenyl-1-pentin (Example 1) is added.

An exothermic reaction (naturally occurring mild reflux) occurs and a clear solution is formed. Again 1 g of mercury oxidant is added and the solution is refluxed for 30 minutes. The reaction mixture is then stirred at 60 ° C. for another 3 hours to form a mercury slurry precipitate. After cooling, the slurry was diluted with 100 ml of diethyl ether and filtered through diatomaceous earth. The filter cake is washed with 200 ml of diethyl ether, the filtrates are combined and washed repeatedly with water. Then dried over magnesium sulfate, filtered and evaporated to give 10.6 g of the title compound. ir (CDCl ₃ ) 3470 and 1775-1710 cm ⁻¹ , nmr (CDCl ₃ ) δ 0.91 (d), 2.15 (s), 2.79 (seven line), 4.39 (s) and 7.20-7.65 (m).

Example 3

3-hydroxy-3-phenyl-2-butanone (II: R ¹ = Me, R ² = Ph, R ³ = H)

The title compound is prepared by a variation of G.F.Hennion and B. R. Fleck. J. Amer. Chem. Soc., 77,3258 (1955). A 3-hydroxy-3-phenyl-1-butyne (2 g) solution in methanol (5 mL) is added at 55 ° C. over 30 minutes. A slightly exothermic reaction occurs and the internal temperature is maintained between 55 and 57 ° C. 50 mg of dilute mercury sulfate is added during the reaction. Next, an acetylene compound is completely added, 50 mg of dihydrogen sulfate is further added, and the mixture is stirred at 55 ° C. for 1 hour. During the stirring operation, water is added and the reaction mixture is poured into ice water and then exported to diethyl ether. The extracts are combined, washed with water and dried over magnesium sulfate. Filtration and evaporation result in chromatography on silica gel using benzene as eluent. Evaporation of the appropriate eluent then yields 0.5 g of the title compound.

ir (CHCl ₃ ) 3450 and 1751 cm ^-1 , nmr (CDCl ₃ ) δ 1.75 (s), 2.08 (s), 4.50 (s) and 7.40 (m)

Equivalent amount of 3-hydroxy-3- (4-chlorophenyl) -1-butyne, 3-hydroxy-3-methyl-1-butyne instead of 3-phenyl-3-hydroxy-1-butyne in the above method , 1-ethynyl-1,2,3,4-tetrahydronaphthalene 3-ethyl-3-hydroxy-1-heptin, 3-hydroxy-3,3-diphenyl-1-propyne, 3-cyclo Hexyl-3-hydroxy-1-hexyne, 4-ethoxy-3- (3-methoxyphenyl) -3-hydroxy-1-butyne, 3- (3,4-diethylphenyl) -3-hydroxy Hydroxy-3- (4-nitrophenyl-1-propyne, 3-ethynyl-3-hydroxytetrahydrofuran, 1-ethynyl-1-hydroxycyclohexane, 1-ethynyl-1-hydroxyindan Or 3-cyclopentyl-5-ethoxy-3-hydroxy-1-pentine to afford the following compound of formula (II): 3-hydroxy-3- (4-chlorophenyl) 2-buta Non, (CHCl ₃ ) 3440 and 1710 cm ^-1 , 3-hydroxy-3-methyl-2-butanone, 1-acetyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene IR (film ) 3450 and 1710㎝ ^-1, 3-ethyl-3-hydroxy-2-heptanone, 3-hydroxy-3,3-di Nyl-2-propaneone, 3-cyclohexyl-3-hydroxy-2-hexanone, 4-ethoxy-3- (3-methoxyphenyl) -3-hydroxy-2-butanone, 3- ( 3,4-diethylphenyl-3-hydroxy-3- (4-nipropenyl) -2-propanone, 3-acetyl-3-hydroxytetrahydrofuran, 1-acetyl-1-hydroxycyclohexane , 1-acetin-1-hydroxyindane and 3-cyclopentyl-5-ethoxy-3-hydroxy-2-pentanone

Example 4

4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (I: R ¹ = Me, R ² = Ph, R ³ and R ⁴ = H)

Sodium hydride (10.5 g, 54% in mineral oil) stirring in anhydrous tetrahydrofuran (400 mL) to diethyloxalate (16 g) and 3-hydroxy-3-phenyl-2 in tetrahydrofuran (50 mL) Butanone (16.4 g, Example 3) solution is added dropwise.

The solution temperature is maintained at 55 to 60 ° C. and the solution is kept at the same temperature for 18 hours after the addition is complete. The cold reaction mixture is poured into water and the pH of the mixture is adjusted to 11 with sodium hydroxide, left for 24 hours and washed with diethyl ether. 6N hydrochloric acid is added and the pH of the aqueous solution is adjusted to 1.

The acidic mixture is kept at 20 to 30 ° C. for 2 hours and then extracted with diethyl ether. Drying the ether extract and evaporating slowly yields 20 g of a crystal having a melting point of 174 to 176 캜.

Elemental Analysis. C ₁₂ H ₁₀ O ₄ (%)

Theoretical, C, 66.06; H, 4.62

Found, C, 66.41; H, 4.69

The title compound solution in dietel ether and the same amount of benzylamine solution in diethyl ether are mixed at 0 ° C. The precipitate is filtered off and crystallized in isofpanol to give the title compound having a melting point of 192 to 193 ° C. In the same manner, 3-hydroxy-3-phenyl-2-butanone was replaced with another compound of the same general formula (II) described in Examples 2 and 3, whereby the following compounds of the general formula (I) Obtained. 4,5-dihydro-5- (1-methylethyl) -4-oxo-5-phenylfuran-2-carboxylic acid (fusion at 151 to 153 ° C) nmr (CDCl ₃ ) δ0.92 (t), 2.55 (Seven lines), 6.33 (s) and 7.15-7.65 (m); 5- (4-chlorophenyl) -4,5-dihydro-5-methyl-4-oxfuran-2-carboxylic acid (melting point 169 ° C) nmr (CDCl ₃ ) δ 1.75 (s), 6.25 (s) and 7.45 (m); 4,5-Dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid (melting point 180-181 degreeC) IR (new sol) 2800 (wide), 1737,1670 and 1600-1, spiro [ Furan-5- (4H), 1 '(2'H) -naphthalene-3', 4-dihydro-4-oxo-2-carboxylic acid (melting point 152-154 ° C), nmr (MeOH-d ₄ ) δ 2.07 (m), 2.84 (+), 6.29 (s) and 6.8-7.4 (m); 5-butyl-5-ethyl-4,5-dihydro-4-oxofuran-2-carboxylic acid; 4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid; 5-cyclohexyl-4,5-dihydro-4-oxo-5-propylfuran-2-carboxylic acid; 4,5-dihydro-5-ethoxymethyl-5- (3-methoxyphenyl) -4-oxofuran-2-carboxylic acid; 4,5-dihydro-5- (3,4-diethylmethyl) -5- (4-nitrophenyl) -4-oxofuran-2-carboxylic acid; 1,7-dioxaspiro [4,4] non-2-ene-4-oxo-2-carboxylic acid; 1-oxaspiro [4,5] -deck-2-ene-4-oxo-2-carboxylic acid, spirofuran-5 (4H), 1'-indane] -4-oxo-2-carboxylic acid; And 5-cyclopentyl-4,5-dihydro-5- (3-ethoxypropyl) -4-oxofuran-2-carboxylic acid.

Example 5

4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid methyl ester (I: R ¹ and R ⁴ = Me, R ² = Ph, R ³ = H)

Mixture of 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (0.4 g, Example 4), anhydrous methanol (50 mL) and sulfuric acid (3 drops) Reflux and evaporate.

The residue is diluted with 50 ml of diethyl ether and the solution is washed quickly with saturated sodium bicarbonate and water and dried over magnesium sulfate. Crystallization of the residue obtained by filtration and evaporation in diethyl ether gave 0.32 g of the title compound having a melting point of 60 to 62 캜. nmr (CDCl ₃ ) δ 1.81 (s), 3.99 (s), 5.25 (s) and 7.42 (m)

In the same way, when 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid is replaced with another compound of the same general formula (I) described in Example 4, The following compounds of general formula (I) are obtained, respectively. 4,5-dihydro-5- (1-methylethyl) -4-oxo-5-phenylfuran-2-carboxylic acid methyl ester; 5- (4-chlorophenyl) -4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acid methyl ester; 45-dihydro = 5,5-dimethyl-4-oxofuran-2-carboxylic acid methyl ester (melting point 66 ° C.) IR (CHCl 3) 1720,1695 and 1575 cm ⁻¹ ; Spiro [furan-5 (4H), 1 '(2'H) -naphthalene] -3', 4'-dihydro-4-oxo-2-carboxylic acid methyl ester; 5-butyl-5-ethyl-4,5-dihydro-4-oxofuran-2-carboxylic acid methyl ester; 4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid methyl ester; 5-cyclohexyl-4,5-dihydro-4-oxo-5-propylfuran-2-carboxylic acid methyl ester; 4,5-dihydro-5-ethoxymethyl-5- (3-methoxyphenyl) -4-oxofuran-2-carboxylic acid methyl ester; 4,5-dihydro-5- (3,4-diethylphenyl) -5- (4-nitrophenyl) -4-oxofuran-2-carboxylic acid methyl ester; 1,7, -dioxaspiro [4,4] non-2-ene-4-oxo-2-carboxylic acid methyl ester; 1-oxaspiro [4,5] tech-2-ene-4-oxo-2-carboxylic acid methyl ester; Spiro [furan-5- (4H), 1′-indane] -4-oxo-2-carboxylic acid methyl ester; And 5-cyclopentyl-4,5-dihydro-5- (3-ethoxypropyl) -4-oxofuran-2-carboxylic acid methyl ester.

Example 6

4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid 3-pyridinylmethyl ester (1: R ¹ = Me, R ³ = pH, R ³ = H, R ⁴ = 3-pyridinylmethyl)

A mixture of 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (8.75 g, Example 4) and thionyl chloride (90 mL) was refluxed for 3 hours and evaporated. Let's do it. The residue is dissolved in 100 mL of benzene) and evaporated (twice).

Infrared spectra of the residue show quantitative conversion of carboxylic acid to thionyl chloride. ir (CHCl ₃ ) 1820 and 1795, 1755 and 7115 cm ^-1 . This material is dissolved in 50 ml of anhydrous acetone and a mixture of 3-pyridinemethanol (4.8 g), pyridine (3.1 g) and acetone (100 ml) is added at 0 ° C. The reaction mixture is stirred for 4 h at 20 ° to 30 ° C. and evaporated under reduced pressure. The residue is partitioned between chloroform and saturated sodium bicarbonate.

The organic layers are combined, dried and evaporated to afford 8.8 g of the title compound. IR (CHCl ₃ ) 1753,1742,1715 (wide), 1595 and 1100 cm ⁻¹ and nmr (CDCl ₃ ) δ 1.78 (s), 5.45 (s), 6.29 (s), 7.24 (m), 7.84 ( Two triplets and 8.60 (m).

The title compound (18 g) is dissolved in acetone (20 mL) and hydrogen chloride solution in diethylether is added until the precipitate is completely formed. The solvent is decanted off and the condensate is treated with diethyl ether. The residue is crystallized in acetone to give 15 g of hydrochloride of the title compound having a melting point of 124 to 125 ° C.

Elemental analysis _{(C 18 H 15 NO 4 ·} Hcl),%

Theoretic: C, 62.52 H, 4.66, N, 4.05

Found: C, 62.30 H, 4.53, N, 3.94

The title compound solution in diethyl ether and the (E) -2-butene diacid (0.5 molar volume) solution in isopropanol are mixed at -10 ° C. The resulting precipitate is filtered and crystallized in acetonitrile to give the hemi- (E) -2-butenedioate salt of the title compound having a melting point of 128 to 130 ° C.

In the same manner, 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid is obtained with the following compounds of the general formula (I) equivalent to 1 equivalent described in Example 4. 4,5-dihydro-1- (1-methylethyl) -4-oxo-5-phenylfuran-2-carboxylic acid 3-pyridinylmethyl ester; 5- (4-Chlorophenyl) -4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acid 3-pyridinylmethyl ester, nmr (CDCl 3) δ 1.77 (s), 5.46 ( s), 6.29 (s), 7.42 (m) and 8.70 (m); 4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid 3-pyridinylmethyl ester (melting point 109 to 110 ° C); Spiro [furan-5 (4H) -1 '(2'H) -naphthalene] -3', 4'-dihydro-4-oxo-2-carboxylic acid 3-pyridinylmethyl ester 5-butyl-5- Ethyl-4,5-dihydro-4-oxofuran-2-carboxylic acid 3-pyridinylmethyl ester; 4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid 3-pyridinylmethyl ester; 5-cyclohexyl-4,5-dihydro-4-oxo-5-propylfuran-2-carboxylic acid-3-pyridinylmethyl enester; 4,5-dihydro-5-ethoxymethyl-5- (3-methoxyphenyl) -4-oxofuran-2-carboxylic acid 3-pyridinylmethyl ester; 4,5-dihydro-5- (3,4-diethylphenyl) -5- (4-nitrophenyl) -4-oxofuran-2-carboxylic acid 3-pyridinylmethyl ester; 1,7-dioxaspiro [4,4] non-2-ene-4-oxo-2-carboxylic acid 3-pyridinylmethyl ester; 1-oxaspiro [4,5] deck-2-ene-4-oxo-2-carboxylic acid 3-pyridinylmethyl ester; Spiro [furan-5 (4H), 1′-indane] -4-oxo-2-carboxylic acid 3-pyridinylmethyl ester; And 5-cyclopentyl-4,5-dihydro-5- (3-ethoxypropyl-4-oxofuran-2-carboxylic acid 3-pyridinyl methyl ester.

Example 7

6-methyl-6-phenyltetrahydropyran-2,3,5-trione (XI: R ¹ = Me, R ² = pH, and R ³ = H)

To a stirred suspension of sodium hydride (10.5 g, 54% in mineral oil) in anhydrous tetrahydrofuran (400 mL), 3-hydroxy-3-phenyl-2-butanone (16.4 g, in 15 mL of tetrahydrofuran) was carried out. Example 3) and diethyloxalate (16 g) solution were added dropwise.

The temperature of the solution is maintained at 55-60 ° C., completely added and the solution is kept at the same temperature for 18 hours.

The cold reaction mixture is poured into water and the mixture is adjusted to pH 8-9 with sodium hydroxide or hydrochloric acid. The mixture of Ph 8-9 is left for 24 hours and extracted with diethyl ether.

The ether extract is dried, evaporated and crystallized in diethyl ether to give the title compound having a melting point of 142 to 144 ° C. Tr (New sol) 3130,1718 and 1640 cm ⁻¹ ; uv (MeOH) λ max 268 mm (ε = 8830) and nmr (MeOH-d ₃ ) δ 1.89 (s), 5.92 (s) and 7.34 (s).

Elemental Analysis Value (C12H9O4),%

Theoretical, C, 66.05 H, 4.62

Found, C, 66.14 H, 4.83

Example 8

4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (I: R ¹ = Me, R ² -ph, R ³ and R ⁴ = H)

The mixture of 6-methyl-6-phenyltetrahydropyran-2,3,5-trione (2.18 g, Example 7) in an aqueous sodium hydroxide solution (15 mL) at pH 11 is stirred for 24 hours and washed with diethyl ether. .

Hydrochloric acid (6N) is added until the pH of the solution is between 1-4. The precipitates are collected and crystallized in diethyl ether to give the title compound (2.0 g) having a melting point of 174 to 176 ° C.

Example 9

Optical Fractionation of 4,5-Dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic Acid

=+110℃(C=2, 메탄올)인 벤질아민염 5.0g을 수득한다. 이 생성염을 물(100㎖) 및 디에틸에테르(100㎖)중에 넣고 교반한 다음 용액이 산성(pH1)이 될때까지 6N 염산을 첨가한다. 에테르층을 모으고, 세척액의 pH가 중성이 될때까지 물로 세척한 다음 건조시킨다. 다음에 증발을 행하고 디에틸에테르에서 재결정하며는 융점이 87내지 89℃인 (+)-4,5-디히드로-5-메틸-4-옥소-5-페닐푸란-2-카르복실산(2,7g)이 수득된다.A (+)-α-methylbenzylamine (3.63 g) solution in diethyl ether (50 mL) was added to 4,5-dihydro-5-methyl-4- in 20 mL of 10% isopropyl alcohol in diethyl ether. It is added to a solution in which oxo-5-phenylfuran-2-carboxylic acid (6,54 g, Example 4) is dissolved. Cool the mixture, separate the mother liquor and store the crystals (6.5 g) simultaneously. The crystals were then recrystallized three times in methanol to give a melting point of 194 to 196 ° C and an optical rotation of

5.0 g of benzylamine salts are obtained at = + 110 &lt; 0 &gt; C (C = 2, methanol). The resulting salt is poured into water (100 mL) and diethyl ether (100 mL), stirred, and 6N hydrochloric acid is added until the solution is acidic (pH 1). The ether layers are combined, washed with water until the pH of the wash solution is neutral and dried. Then evaporated and recrystallized from diethyl ether to give (+)-4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid having a melting point of 87 to 89 캜. , 7 g) is obtained.

=+146.4°(C=2, 메탄올); ir(뉴졸) 3440, 3310, 2540, 1720 및 1669㎝^-1.

= + 146.4 ° (C = 2, methanol); ir (new sol) 3440, 3310, 2540, 1720 and 1669 cm ^-1.

Elemental Analysis Value (C ₁₂ H ₁₀ O ₄ H ₂ O),%

Theoretic value: C 61.01 H 5.12 H ₂ O 7.63

Found: C 61.19 H 5.07 H ₂ O 7.85

=-108°(C=2, 메탄올)인 벤질아민염 2.4g이 수득된다.The residue (4.3 g) obtained by evaporating the mother liquor obtained from the said benzylamine salt was dissolved in a water (50 mL) solution, and 6N hydrochloric acid was added until the aqueous layer became acidic (pH1). Combine the ether layers and wash with water until the wash is neutral. The residue, which is then dried over magnesium sulfate and evaporated is dissolved in 70 ml of 10% isopropyl alcohol-diethyl ether solution. Next, a solution of (1) -α-methylbenzylamine in diethyl ether (30 mL) is added, the solution is cooled and the crystals (3.9 g) are combined. The next recrystallization in methanol three times, the melting point is 198 ~ 199 ℃, optical rotation value

2.4 g of benzylamine salt with = -108 ° (C = 2, methanol) are obtained.

=-144.1°(C=2, 메탄올), Tr(뉴졸) 3440, 3320, 2540, 1720 및 1669㎝^-1.The resulting salt was added to a solution of water (70 mL) and diethyl ether (70 mL), stirred, and 6N hydrochloric acid was added until the aqueous layer became acidic (pH = 1). The ether layer is separated, washed with water until the wash solution is neutral and then evaporated. Recrystallization of the residue from diethyl ether gave 1.2 g of (-)-4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid having a melting point of 87 to 89 占 폚.

= -144.1 ° (C = 2, methanol), Tr (Newsol) 3440, 3320, 2540, 1720 and 1669 cm ^-1 .

Elemental Analysis Value (C ₁₂ H ₁₀ O ₄ ),%

Theoretic value: C 61.01 H 5.12 H ₂ O 7.62

Found: C 61.14 H 5.05 H ₂ O 5.82

Claims (1)

A process for preparing 4.5-dihydro-4-oxofuran-2-carboxylic acid derivative of general formula (I), wherein the compound of general formula (X) is subjected to cyclization under acidic conditions.

In the above formulas, R ¹ and R ² are each lower alkyl; Cyclo (lower) alkyl; Lower alkoxy (lower) alkylene; Phenyl; Or phenyl substituted one or two with lower alkyl, lower alkoxy, halogen, nitro or trifluoromethyl; Or R ¹ and R ² together form a-(CH ₂ ) mX- (CH ₂ ) n-chain (m and n are integers of 1 to 4, X is methylene, oxa or thiaim) or R ¹ and R ² together with the carbon atom to which they are attached form a spiro [1,2,3,4-tetrahydronaphthalene] -1- or spiro [indane] -1 radical; R ³ is hydrogen or lower alkyl; R ⁴ is hydrogen.