KR810000289B1 - Process for preparing gamma-pyrone - Google Patents

Abstract

Gamma-pyrones(I; R = H, C1-4 alkyl, phenyl, benzyl; R1 = H, C1-4 alkyl, COR2; R2 = methyl, ethyl phenyl; R3 = H, C1-4 alkyl; X = Cl, Br), useful as sweetening and aromatic component, were prepd. by hydrolysis of 4-halodihydropyrane(II) or 6,6'-oxy bis-[4-halo-2H-pyrane-3(6H)-one (III) in acidic aq. soln. Thus, 1-(2-furyl)-1-ethanol 0.089 mole in tetrahydrofuran was added in the tetrahydrofuran and water at 0-10≰C, distillated for eliminating tetrahydrofuran, refluxed at 105≰C for 2 hr, filtered, adjusted to pH 2.2, cooled, filtered, extracted with chloroform, and recrystallized to give pure maltol 5.5 g (m. p 159.5-160.5≰C).

Description

Method for producing gamma-pyrones

The present invention relates to a method for producing gamma-pyrones, and more particularly, to producing gamma-pyrones by hydrolysis of intermediate compounds. Some of these intermediates are novel and are prepared from suitable furfuryl alcohols using halogen-containing oxidants.

The invention also relates to a one-pot process for producing gamma-pyrones from furfuryl alcohols. The present invention further relates to novel 4-halo-dihydropyran intermediates and their preparation.

Maltol (2-methyl-3-hydroxy-4H-pyran-4-one) is a naturally occurring substance found in the bark of young larch trees, conifers of pine and chicory. . Previous commercial products were obtained by cracking and distilling wood. A method for synthesizing maltol from 3-hydroxy-2- (1-piperidyl methyl) -1,4-pyron is known, and it is also known to obtain maltol by alkali hydrolysis of the sotreptomycin salt. It is also known to synthesize maltol from protected hydrocarbon derivatives and to synthesize maltol five steps using methyl furfuryl alcohol as starting material.

It is known to isolate 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one from the final refined molasses as one of the characteristic sweet-aromatic components and this compound has been previously synthesized. It has been.

Synthesis of gamma-pyrones such as pyrromethic acid, maltol, ethyl maltol and other 2-substituted-3-hydroxy-sweet-pyrones is also known.

Maltol and Ethyl Maltol enhance flavor and aroma in many foods. In addition, these compounds are used as ingredients in perfumes and essential oils. 2-alkenyl pyrromethiconic acid and 2-arylmethylpyromenoic acid inhibit the growth of bacteria and fungi and are useful as flavor and fragrance enhancers in foods and beverages and as fragrance enhancers in perfumes.

The present invention relates to 4-halo-dihydropyrane of general formula (II) or 6, of general formula (V) until the hydrolysis is substantially completed in an acidic aqueous solution, preferably in the temperature range of 70 ° -160 ° C. Provided is a method of preparing gamma-pyrone of formula (I) by heating 6'-oxybis [4-halo-2H-pyran-3 (6H) -one].

Wherein R is hydrogen, C ₁ -C ₄ alkyl, phenyl or benzyl, R 'is hydrogen, C ₁ -C ₄ alkyl or -COR' wherein R 'is methyl, ethyl or phenyl and R' ＂Is hydrogen or C ₁ -C ₄ alkyl and X is chlorine or bromine.

Acids required for hydrolysis can be added to the reaction mixture, for example dissolving intermediates of formula (II) or formula (V) in an aqueous inorganic or organic acid before heating; Alternatively, the acid may be generated in situ during the preparation of the intermediate as described below.

The intermediate compound of formula (II) is a compound of formula (IV) at a temperature of -50 ° to 50 ° C. in a solvent, preferably at room temperature, such as chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or mixtures thereof. It can be prepared by reacting with at least one equivalent of the halogen-containing oxidant selected from 때 until substantially the reaction is complete.

Wherein R, R 'and R' are as defined above.

Examples of suitable solvents for this reaction include water, C _{1 to} C ₄ alkanols or diols, preferably methanol, C _{2 to} C ₁₀ ethers, preferably tetra hydrofuran or isofurophyll ethers, Ketones, preferably acetone, low molecular weight nitriles, esters or amides.

The intermediate compound of formula (IV) is selected from chlorine, bromine, bromine chloride, hypochlorous acid, chibromic acid or mixtures thereof of furfuryl alcohol of formula (III) at a temperature of -50 ° to 50 ° C. in an aqueous solution. It can be prepared by reacting at least one equivalent of the halogen-containing oxidant until the reaction is substantially complete.

Wherein R and R '' are as defined above. This reaction may suitably be carried out in the presence of an O-solvent, which may be one of the solvents described above in the preparation of intermediate compounds of general formula (II).

If desired, the intermediate 4-halo dihydropyran compound of formula (II) is prepared by the appropriate furfuryl alcohol of formula (III) at least one equivalent of the aforementioned halogen- in a solvent at a temperature of -50 ° to 50 ° C. It can be provided directly by reacting with the containing oxidant until the reaction is substantially complete.

Preferred halogen-containing oxidants in each of the reactions described above are chlorine or bromine chloride.

The intermediate compound of formula (V) can be prepared by dehydrating the compound of formula (II ').

The present invention further provides gamma-pyrones of general formula (I), in particular maltol (2-methyl-3-hydroxy-4H-pyran-4-one) and related compounds to furfuryl alcohols of general formula (III). It provides a novel terminology of synthesis prepared by a single vessel process.

According to this single vessel process, furfuryl alcohol in the aqueous medium is reacted with 2 equivalents of halogen-containing oxidant and the reaction mixture is then heated to hydrolyze the resulting intermediate. The single vessel process can be represented by the following scheme.

Wherein R is hydrogen, C ₁ -C ₄ alkyl, phenyl or benzyl; R '"is hydrogen or alkyl of C ₁ ~C ₄ XY is _{Cl 2, Br 2, CIBr,} HOCI, HOBr or a mixture thereof.

The entire reaction path is represented by the following scheme.

Modified tautomers

In J. Med.chem., Vol. 16, p. 1084 (1973), Lefebvre et al. Described the furfuryl derivatives directly when 6-hydroxy-2H-pyran-3 (6H) was used when an oxidizing agent such as peracetic acid or m-chloroperbenzoic acid was used. It has been shown that it can be converted to warm current. The first step in the Lefebvre study is the use of peracids in organic solvents to produce 6-acetoxy or 6-m-chlorobenzoyloxy pyran derivatives, possibly hydrolyzed to 6-hydroxy compounds during water soluble operation. In the first stage of the reaction water is not used and is actually harmful. However, Lefebvre et al. Did not directly convert furfuryl alcohol to gamma-pyrone.

Important for the process for preparing intermediates of the present invention is the use of aqueous solutions of halogen-containing oxidants. Furfuryl alcohol can be cleanly oxidized to 6-hydroxy-2H-pyran-3 (6H) -one using one equivalent of a halogen-containing oxidant in water or a co-solvent of water / organic solvent. It is an unexpected surprise that 6-hydroxy-2H-pyran-3 (6H)-warm can be converted to gamma-pyrons. 6-hydroxy-2H-pyran-3 (6H) -one can be considered the hemi-acetal of aldehyde, which means that a number of unwanted side reactions such as excess oxidation and aldol-type condensation can occur . The reaction proceeds smoothly from furfuryl alcohol to gamma-pyron by using 2 equivalents of a halogen-containing oxidant in water or a cosolvent of water and an organic solvent. This novel single vessel process offers the advantage of using inexpensive Cl ₂ , Br ₂ , BrCl, HOCI, HOBr and mixtures thereof as halogen-containing oxidant. The isolation of the desired gamma pyron is very simple because the solvent, oxidant and by-product inorganic acid are all volatile and can be removed in vacuo so that the prepared gamma-pyron can be directly obtained in high yield by simple concentration.

The single vessel process is operated by dissolving furfuryl alcohol in water or in a cosolvent with water. The cosolvent may be water miscible or water immiscible, and may be C _{1 to} C ₄ alkanols or diols, such as methanol: C _{2 to} C ₁₀ etets, such as tetrahydrofuran or isofurophyll ether; Low molecular weight ketones such as acetone; Low molecular weight nitrile; A wide range can be selected from solvents such as low molecular weight esters and low molecular weight amides. Preferred cosolvents are C ₁ -C ₄ alkanols and C ₂ -C ₁₀ ethers with methanol, and the choice of solvent depends on its price. The solution is maintained at a temperature of -50 ° to 50 ° C, preferably at -10 ° to 10 ° C.

To this solution is charged the desired furfuryl alcohol, at the same time a halogen-containing oxidant (2 equivalents) is added to the reaction mixture. The reaction temperature is maintained at a temperature of −50 ° to 50 ° C., preferably −10 ° to 10 ° C. during halogen addition. If low boiling cosolvents are used, all are distilled off after the addition is complete. The reaction mixture is then heated to a temperature at which the hydrolysis proceeds at an appropriate rate, for example from 70 ° to 160 ° C. Generally used hydrolysis temperature is 100 degreeC-110 degreeC. Heating continues until substantially hydrolysis of the 4-halo-dihydropyran intermediate formed is substantially complete (usually 1-2 hours). The acid needed to catalyze this final hydrolysis is generated in situ by desorbing the acid from the intermediate formed in the reaction pathway. You can also add more mountains if you wish.

Halogen-containing oxidants are selected from chlorine, bromine, bromine chloride, hypochlorous acid or hypobromic acid or mixtures thereof. Bromine chloride is a gas that can be used as a commodity. It can preferably be prepared in situ by adding chlorine to a sodium bromide or potassium solution or by adding bromine to a sodium chloride or potassium solution.

Hypochlorous acid or hypobromic acid is conveniently generated in situ by adding a water soluble acid (HCI, H ₂ SO ₄ or HBr) to an alkali or alkaline earth metal hypohalogenate such as NaOCl, KOCl or Ca (OCl) ₂ . Preferred halogen-containing oxidants use in situ chlorine and bromine chloride based on price factors.

As noted above, the 6-hydroxy-2H-pyran-3 (6H) -one intermediate of formula (IV) can be prepared by reacting a suitable furfuryl alcohol with one equivalent of a halogen-containing oxidant. The isolated intermediate is reacted with additional equivalents of halogen oxides and the desired gamma- by hydrolysis of the 4-halo-6-hydroxy-2H-pyran-3 (6H) -one of formula (II) formed as described above. You can easily switch to pyron.

As an alternative, furfuryl alcohol in aqueous solution with any cosolvent may be reacted with 2 equivalents of halogen-containing oxidant at -10 ° to 10 ° C. After stirring for 30 minutes at room temperature, the pH of the reaction mixture is adjusted to 2 using a strong base and the reaction mixture is extracted with a solvent such as ethyl acetate. Removal of the solvent yields 4-halo-6-hydroxy-2-pyran-3 (6H) one of formula (II ′), which can be hydrolyzed to the desired gamma-pyron. 4-halo-dihydro pyran is dehydrated by heating in vacuo to give 6,6'-oxybis [4-halo-2H-pyran-3 (6H) -one]. This dimer produces the desired gamma-pyron upon hydrolysis, with the addition of acid as desired.

Some of the 4-halo-dihydropyran intermediates and the 6,6'-oxybis [4-halo-2H-pyran-3 (6H) -one] intermediates are novel, and therefore the present invention is of general formula (II '). Provided are a compound, a compound of formula (VI) and a compound of formula (V).

The above formula, R, R R a "'and X are as defined above, R ⁴ is alkyl, or -COR a C ₁ ~C _4" where "is a methyl, ethyl or phenyl.

Gamma-pyrones of formula (I) may also be prepared by reacting at least one equivalent of halogen-containing oxidant with a compound of formula (IV) in an acidic aqueous solution.

Wherein R, R 'and R' are as defined above.

6-Alkoxy-2H-pyran-3 (6H) -one can be prepared by the method described in Tetrahedon Letters No. 17, 1363-1364 (1976). Furfuryl alcohol is anoly alkoxylated to become 2- (1-hydroxyalkyl) -2,5-dialkoxy-dihydrofuran. Treatment with ferrous organic acids yields the desired 6-alkoxy compound.

The 6-acyl compound can be prepared by conventional methods of treating the 6-hydroxy compound with a suitable anhydride in the presence of pyridine.

6-acyl or 6-alkoxy-2H-pyran-3 (6H) -one is acetic acid, formic acid, trifluoroacetic acid, halogenated solvents, ethers, C ₁ -C ₄ alkanols or diols, or low molecular weight ketones, nitriles, Dissolve in a solvent selected from esters or amides. One equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or mixtures thereof is added at room temperature until the reaction mixture is nearly complete to the desired gamma-pyrone (about 1 -3 hours) heated to 70 ° to 160 ° C, generally 100 ° to 110 ° C. Gamma-pyrone can be obtained by standing the cooled and neutralized reaction mixture or by extracting and concentrating the reaction mixture with a solvent such as chloroform. Organic acids and other amphoterics such as formic acid, acetic acid, other organic acids and alkanols that were not completely dried were added to the reaction without adding water.

However, for aprotic assets, water is needed and added to convert the intermediate 4-halo-6-substituted-2H-pyran-3 (6H) -one into pyrone. When a low boiling point solvent is used in the reaction, the solvent is distilled off just before the reaction mixture is heated to 100-110 ° C. to hydrolyze the intermediate 4-halo-dihydropyran to convert to gamma-pyron.

If desired, 4-halo-dihydropyrans can be prepared and isolated by performing halogenation at a temperature of -20 ° to 20 ° C, preferably 5 ° to 10 ° C, in the presence of an organic base such as triethylamide.

After about 30 minutes the reaction mixture was allowed to warm to room temperature and filtered to triethyl amide. The hydrochloride is removed and then the solvent is removed in vacuo to give 4-halo-dihydropyran. This compound is readily hydrolyzed to gamma-pyron by heating under an acid addition (preferably at a temperature of from 70 ° C. to 160 ° C., more preferably from 100 ° to 110 ° C.) in aqueous solution for about 1 hour.

React 6-acyl or 6-alkoxy-2H-pyran-3 (6H) -one in an organic solvent with 1 equivalent of a halogen-containing oxidant and intermediate 4-halo-dihydropyran to the desired gamma-pyron This method of heating until the conversion is complete is carried out by treating 6-alkoxy-2H-pyran-3 (6H) -one with a methanolic solution of hydrogen peroxide containing sodium hydroxide solution to obtain methoxyketone Tetrahedron Letters 17, 1363 ( 1976) is different from the multi-process described by shono and Matsumura. The isolated epoxy ketone is refluxed with DOWEX 50 ionic exchange resin in water to obtain the desired gamma-pyron.

The following examples illustrate the preparation of gamma pyrones and the preparation of various intermediate compounds according to the method of the present invention.

In the examples given spectroscopic data, NMR chemical shifts were reported as common symbols and all shifts were expressed in units of δ from tetramethylsilane.

Example 1

20 ml of tetrahydrofuran and 50 ml of water were added to a three-necked flask equipped with a magnetic stirrer rod, a gas introduction tube, a thermometer, and an additive node. The solution was cooled to 0 ° -10 ° C. The addition node was charged with a solution of 20 (1.2-furyl) -1-ethanol in 20 ml of tetrahydrofuran and then added dropwise to the stirred reaction flask with the addition of chlorine (0.30 mole) through a gas injection tube. The addition was at such a rate (about 30 minutes) that all alcohol was added to the first 1.3-1.5 equivalents of chlorine while maintaining the temperature below 10 ° C. After the reaction mixture was heated to reflux, tetrahydrofuran was distilled off. When the reaction mixture reached about 105 DEG C, reflux was continued for about 2 hours after attaching the cooler. The reaction mixture was filtered when hot and cooled, and then the pH was adjusted to 2.2 and the reaction mixture was cooled to 5 ° C. Crystallization and filtration gave 3.43 g of crude 3-hydroxy-2-methyl-γ-pyrine (maltol). The aqueous filtrate was extracted with chloroform to give 2.58 g of maltol as a secondary product. The combined solid was distilled off and recrystallized from methanol to obtain 5.5 g (49%) of pure white maltol having a melting point of 159.5 ° to 160.5 ° C.

Example 2

The method of Example 1 was repeated using furfuryl alcohols of the following general formula, with different conditions as shown in Table 1.

Table 1 Single vessel process used as chlorine as oxidant

THF = tetrahydrofuran

EtOAc = ethyl acetate

Example 3

Similar results were obtained by repeating the method of Example 2 using the following auxiliary solvents, respectively.

Example 4

To a three-necked flask equipped with a stirring rod, a gas introduction tube, and an additive node was added 20 ml of tetrahydrofuran, 50 ml of water, and sodium bromide (0.20 mol). The solution was cooled to 0-20 ° C. After adding 20 ml of terahydrofuran solution of 1 (2-furyl) -1-ethanol (0.18 mole) to the added noodle, it was added dropwise into a rapidly stirred reaction flask while chlorine gas (0.40 mole) was put through a gas introduction tube. . Alcohol was added at a rate that maintained the orange color. Cooling in an ice bath kept the temperature below 20 ° C. After adding both alcohol and chlorine to the reaction flask, the temperature was raised to reflux to distill off tetrahydrofuran. The isolation method of Example 1 was used to isolate 12.47 g of pure maltol (55% yield). Almost the same result was obtained when potassium bromide was used instead of sodium bromide.

Example 5

The method of Example 4 was repeated with varying conditions as described in Table 2 using furfuryl alcohol of the structure

[Table 2. Short-term technique using BrCl as an oxidizing agent to produce NaBr in situ by addition of chlorine]

THF = tetrahydrofuran

Example 6

To a three-necked round flask equipped with a magnetic stirring rod, a gas introduction tube, a thermometer, and an added nipple, 50 ml of dehydrated furan and 50 ml of water were added. The solution was cooled to 0 ° C. and chlorine (0.10 mol) was slowly added to the reaction flask while dropwise addition of 1 (2-furyl) -1-ethanol (0.09 mol). The temperature of the reaction mixture did not exceed 10 ° C. Bromine (0.10 mol) was added and the reaction mixture was heated to reflux. According to the isolation method of Example 1, yield of 5.7 g of maltol was obtained.

Example 7

50 mL of tetrahydrofuran and 50 mL of water were placed in a four-necked flask equipped with a thermometer, a cooler, and two additional nutmegs, and the solution was cooled to 10 ° C. Bromine (0.20water) and 1 (2-furyl) -1-ethanol (0.09 mol) were added together through two additions to the well stirred solution. The temperature of the mixture was kept at 15 ° C. during the double addition. The reaction mixture was heated to 75 ° C. for 10 hours. Example 1 Maltol was isolated according to the method. (53% yield)

Example 8

The method of Example 7 was repeated with varying conditions as described in Example 3 using furfuryl alcohols of the general formula:

TABLE 3

Example 9

의 차아염소산나트륨 용액을 얻었다. 테트라히드로푸란 15㎖와 물 15㎖에 1(2-푸릴)-1-에탄올(0.05몰)을 녹인 용액을 삼구 플라스크 내에서 제조한후 5℃로 냉각시켰다. 6

HCl을 사용하여 PH를 1.0∼0.8로 유지시키면서, 차아염소산염용액 21.7㎖을 온도 5℃이하로 유지시키면서 약 33분에 걸쳐 반응 플라스크에 적가했다. 농·염산 15㎖를 반응 혼합물에 가해준후 가열하여 증류에 의해 테트라히드로푸란을 제거했다. 가열을 1시간 더 계속했다. 실시예 1에서와 같이 단리시켰다. 차아염소산나트륨 대신 차아브롬산나트륨을 사용했을 때 거의 동일한 결과가 얻어졌다.Chlorine gas (42.9 g) was passed through a solution of 48 g of sodium hydroxide (150 mL) at 0 ° C to give 2.8

Sodium hypochlorite solution was obtained. A solution of 1 (2-furyl) -1-ethanol (0.05 mol) dissolved in 15 ml of tetrahydrofuran and 15 ml of water was prepared in a three-necked flask and cooled to 5 ° C. 6

21.7 ml of hypochlorite solution was added dropwise to the reaction flask over about 33 minutes while maintaining the pH at 1.0 to 0.8 using HCl. 15 ml of concentrated hydrochloric acid was added to the reaction mixture, followed by heating to remove tetrahydrofuran by distillation. Heating continued for another hour. It was isolated as in Example 1. Almost the same result was obtained when sodium hypobromite was used instead of sodium hypochlorite.

Example 10

차아염소산나트륨용액 21.7㎖를 가했다. 온도를 5℃ 이하로 유지시키면서 가스 도입관을 통해 염소(0.05 몰)를 반응플라스크에 가했다. 반응혼합물을 가열환류시킨 후 테트라히드로푸란을 증류제거했다. 1시간 더 가열을 계속했다. 반응혼합물을 냉각시킨 후 실시예 1의 방법에 따라 말톨을 단리시켰다.2.8 in a solution of 1 (2-furyl) -1-ethanol (0.05 mol) in 15 ml of tetrahydrofuran and 15 ml of water at 5 ° C.

21.7 ml of sodium hypochlorite solution was added. Chlorine (0.05 mol) was added to the reaction flask through a gas introduction tube while maintaining the temperature below 5 ° C. After the reaction mixture was heated to reflux, tetrahydrofuran was distilled off. Heating was continued for 1 hour. After cooling the reaction mixture, maltol was isolated according to the method of Example 1.

Example 11

50 ml of water and 20 ml of tetrahydrofuran solution were added to a three-necked flask, and the solution was cooled to 0 deg. After addition of 1 (2-furyl) -1-ethanol (0.89 mol) in tetrahydrofuran (25 mL) solution, the solution was added dropwise to the reaction flask while BrCl was added through a gas introduction tube. It was at such a rate that all furfuryl alcohol was added to the first 1.3-1.5 equivalents of BrCl while maintaining the temperature below 30 ° C. The reaction mixture was heated to reflux and tetrahydrofuran was distilled off. When the temperature reached 105 ° C., a cooler was attached and the reaction mixture was heated at reflux for about 2 hours. The reaction mixture was cooled and maltol was isolated according to the method of Example 1.

Example 12

25 ml of tetrahydrofuran and 50 ml of water were added to a three-necked flask equipped with a magnetic stirring rod, a thermometer, and two additional nutmegs. Tetrahydrofuran (25 mL) solution of 1 (2-furyl) -1-ethanol (0.89 moles) was added to the solution while maintaining the temperature at 15 ° C. or lower and dropwise bromine (0.16 moles). After the addition was completed, chlorine (0.10 mol) was added through a gas introduction tube and heated to reflux. Maltol was isolated from the cooled solution according to the method of Example 1.

Example 13

6-hydroxy-2-methyl-2H-pyran-3 (6H) -one

One equivalent of bromine was added to a solution in which 25 g of 1 (2-furyl) -1-ethanol was dissolved in 125 ml of tetrahydrofuran and 125 ml of water at 5 ° C. The temperature during the addition was kept at 5-10 占 폚. The solution was adjusted to pH 2.1 and extracted with ethyl acetate (3 x 50 mL). The ethyl acetate extract was dried and evaporated to give a yellow oil.

The oil was chromatographed on silica gel and eluted with chloroform-ethyl acetate (3: 1) to give 4.8 g of clear oil, which was spectroscopically determined to give 6-methoxy-2-methyl-2H-pyran-3 (6H) -one. Was prepared by acid hydrolysis and found to be the same as 6-hydroxy-2-methyl-2H-pyran-3 (6H) -one [Tetrahedron 27, 1973 (1971)].

IR (CHCl ₃ ): 3700, 3300, 1700cm ^-1

NMR (CDCl ₃ , δ): 6.8-7.1 (1H, d of d): 6.0-6.2 (1H, 6), 5.6 (substituted with 1H, br.s, D ₂ O); 5.4-5,5 (1H, d); 4.8-5.0 (1H, q); 1.3-1.6 (3H, t).

Example 14

By repeating the method of Example 13 using furfuryl alkyl of the structure

R is hydrogen or ethyl to obtain a compound of the structure

Ethyl Compound: IR (CHCl ₃ ) 3600, 3340, 1706cm ^-1

Hydrogen compound: IR (CHCl ₃ ) 3565, 3300, 1703cm ^-1

Example 15

4-Bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one

2.2 equivalents of bromine were added dropwise to a solution in which 125 g of tetrahydrofuran and 125 ml of water were dissolved in 25 g of 1 (2-furyl) -1-ethanol at 0 ° to 5 ° C. The temperature during the addition was kept at 5 ° to 10 ° C. After bromination was completed, the solution was stirred at room temperature for 30 minutes and the pH was adjusted to 2.1 using 2N NaOH solution. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate extracts were dried over MgSO ₄ , filtered and dried. The residue was chromatographed on silica gel and eluted with chloroform-ethyl acetate (95: 5). The product was orange oil which was rechromatated on silica gel and eluted with chloroform-ethyl acetate (95: 5).

NMR (CDCl ₃ , δ) 7.3 (1H, d); 6.5 (1H, d); 4.7-5.0 (1H, q); 1.1-1.5 (3H, m)

Example 16

Using furfuryl alcohol of the following structural formula

The method of Example 15 was repeated to yield the following structural formulae wherein R is hydrogen or ethyl,

Was obtained.

Ethyl compound 4-bromo-6-hydroxy-2-ethyl-2H-pyran-3 (6H) -one NMR (CDCl ₃ , δ) 7.4 (1H, 6); 4.6-4.9 (1H, m) -1.8-2.2 (2H, m): 1.0-1.3 (3H, t).

Hydrogen compound 4-bromo-6-hydroxy-2H-pyran-3 (6H) -one NMR (CDCl ₃ , δ) 7.4 (1H, d); 5.5 (1H, d); 4.6 (2H, d of d).

Example 17

NaOH은로 2.1로 맞추고 반응혼합물을 클로로포름으로 추출했다. 농축시켜 말톨을 얻었다. 산, 반응시간 및 말톨수율은 다음과 같았다.A 4-bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) one solution was prepared by dissolving a compound in a water-soluble inorganic acid or a water-soluble organic acid. Heat the solution to reflux, cool to room temperature and adjust pH to 6

NaOH was adjusted to 2.1 and the reaction mixture was extracted with chloroform. Concentration gave maltol. Acid, reaction time and maltol yield were as follows.

-톨루엔 설폰산 및 ＂암베르리트＂ IR-120같은 산물질과 함께 번갈아 사용한다.Organic solvents such as benzene and toluene

Alternately with toxins such as toluene sulfonic acid and "amberlite" IR-120.

Example 18

Instead of bromine and chlorine and the appropriate furfuryl alcohol, the method of Example 15 was repeated to yield the following compounds:

Methyl: 4-chloro-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one NMR (CDCl ₃ , δ): 7.1 (1H, d); 5.8 (1 H, d); 4.6-5.0 (1 H, m) 4.4 (1 H, br.s). ; 1.2-1.5 (3H, m).

Ethyl: 4-chloro-6-hydroxy-2-ethyl-2H-pyran-3 (6H) -one NMR (CDCl ₃ , δ): 7.0-7.1 (1H, 6); 5.6-6.0 (2H, m); 4.4-5.0 (1 H, m); 1.6-2.1 (2H, m); 0.9-1.1 (3H, t).

Hydrogen: 4-chloro-6-hydroxy-2H-pyran-3 (6H) -one NMR (CDCl ₃ , δ): 7.1-7.2 (1H, d): 5.6 (1H, d); 4.4-4.9 (2H, d of d) (D ₂ O added).

Example 19

The method of Example 15 was repeated to obtain a compound of the following structural formula.

[R is propyl, butyl, phenyl or benzyl; X is bromine or chlorine]

Example 20

4-Bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one was heated under vacuum at 40 ° C. for 16 hours. The resulting oily solid was crystallized from isopropyl alcohol to give 6,6'-oxybis [4-bromo-2methyl-2H-pyran-3 (6H) -one] having a melting point of 125 ° C.

Example 21

The compound of the following structural formula was obtained by repeating the method of Example 20 using the compound of the following structural formula as a starting material.

R is hydrogen, ethyl, propyl, butyl, phenyl or benzyl; X is bromine or chlorine.

Example 22

A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one (0.0025 mol) in 20 ml of 35% phosphoric acid was refluxed for about 5 hours. Maltol (34%) was isolated by the process of Example 1.

Example 23

R is hydrogen, methyl, ethyl, propyl, phenyl or benzyl; X is bromine or chlorine. Is treated by the method of Example 22 to obtain a compound of the structure

R is as defined above.

Example 24

A 6-methoxy-2-methyl 2H-pyran-3 (6H) -one (0.01 mol) solution in 20 ml of acetic acid was treated with chlorine (0.01 mol) gas at room temperature. The reaction mixture was heated to reflux for about 1 hour, cooled to room temperature, diluted with 20 mL of water, adjusted to pH 7.0 with 50% NaOH solution, and the reaction mixture was extracted with chloroform. The chloroform extract was concentrated to give maltol and recrystallized from methanol to give a pure product (56%) with a melting point of 159.5 ° -160.5 ° C.

Example 25

Repeating the process of Example 24 using the compound of the following structural formula as a starting material

R is hydrogen, alkyl of 2-4 carbon atoms, phenyl, or benzyl; R 'is an alkyl and -COR' of 2-4 carbon atoms, where R 'yields a gamma-pyrone of the following structure: methyl, ethyl or phenyl.

R is hydrogen, alkyl of 2-4 carbon atoms, phenyl or benzyl

Example 26

Acetic acid was replaced with each of the following solvents, and the results of Example 24 were repeated to obtain comparable results.

Formic Ethylene Glycol

Methanol trifluoroacetic acid

Ethanol acetone

Tetrahydrofuran acetonitrile

benzene

Example 27

Chlorine prepared on the spot by adding chlorine to bromine, calcium hypochlorite, sodium hypochlorite, potassium hypochlorite, sodium hypochlorite, bromine chloride or chlorine to a solution containing sodium bromide or bromine to sodium chloride solution Substituted with bromine, the process of Example 24 was repeated to obtain a comparison result.

Example 28

4-Chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) -one

Chlorine (0.05 mol) was added to a 6-methoxy-2-methyl-2H-pyran-3 (6H) -one (0.05 water) solution at -10 ° C through a gas introduction tube. After addition, triethylamine (0.05 mol) was slowly added while maintaining -10 ° C. After stirring for 30 minutes, the reaction mixture was covered to room temperature and filtered to remove triethylamine hydrochloride and the solvent was removed in vacuo. The crude product was redissolved in ether-benzene and filtered to remove the last trace of triethylamine hydrochloride. The solvent was removed to give 4-chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) (yield 99%). NMR analysis of the signal at 5.05 to 5.25 clearly shows two doublets in the ratio of 3: 1, corresponding to both at C-6 of the two possible isomers of the compound.

Two optical forms of the trans isomer were synthesized from hydrocarbon electric fields by Paulson, Eberstein and Cobernick in Tetrahedron Letters 4377 (1974).

Example 29

4-Bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one

Chlorine was replaced with bromine to repeat the process of Example 28 to obtain 4-bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one having a yield of 93%. Two broad forms of trans isomers were starred by Paulson and colleagues in Tetrahedron Letters 4377 (1974).

Example 30

The process of Examples 28 and 29 were repeated using starting materials of the following structural formula as starting materials,

R is hydrogen, alkyl of 2-4 carbon atoms, phenyl or benzyl; R 'obtained a compound of the following structure with alkyl of 2-4 carbon atoms.

R and R 'are defined above;

X is chlorine or bromine

Example 31

4-Bromo-6-acetyl-2H-pyran-3 (6H) -one

A 6-acetyl-2H-pyran-3 (6H) -one solution in dichloromethane prepared by the method described in Tetrahedron 27, 1973 (1971) was brominated by the process of Example 6 to have a melting point of 78 ° to 80 ° C. -Bromo-6-acetyl-2H-pyran-3 (6H) -one was obtained. The mass spectra of the compounds showed the parent peaks expected at 234 and 236 mass units.

Example 32

Mass spectroscopy by repeating the process of Example 31 with 4-bromo-6-acetyl-2-methyl-2H-3 (6H) -one 6-acetyl-2-methyl-2H-pyran-3 (6H) -one Showing parent mass 249.96 and 247.96 by the following NMR spectrum:

(δ, CDCl ₃ ): 7.3 (1H, d); 6.4 (1 H, d of d); 4.7 (1H, Q); 2.2 (3H, S); 1,4 (3H, S). 4-bromo-6-acetyl-2-methyl-2H-3 (6H) -one was obtained.

Example 33

The process of Example 25 was repeated using chlorine instead of bromine and starting compound as the starting material.

R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, or benzyl,

R 'is alkyl or -COR' of 1 to 4 carbon atoms, where R 'is methyl, ethyl or phenyl. The compound of the following structural formula was obtained.

R and R 'are defined above and X is chlorine.

Example 34

4-chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) -one and acetic acid were added to a round bottom flask equipped with a stirring bar and a cooler, and the reaction mixture was heated to reflux for 1 hour. I was.

Cooling gave maltol (65%).

Example 35

Formic acid was used instead of acetic acid, and the process of Example 35 was repeated to obtain comparable results.

Example 36

The process of Example 34 was repeated using a compound of the following structural formula as a starting material.

R is hydrogen, alkyl of 1-4 carbon atoms, phenyl or benzyl;

R 'is an alkyl of 1-4 carbon atoms or -COR' where

R ＂is methyl, ethyl or phenyl,

X is bromine or chlorine

The compound of the following structural formula is obtained.

R is hydrogen, alkyl of 1-4 carbon atoms, phenyl or benzyl.

Example 37

28 ml of 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one methanol and 38 ml of water were added to a round bottom three neck flask. The solution was cooled to −15 ° C. and 0.166 mole of 5-ethyl-2- (2-hydroxy-propyl) furan (J. Org. Chem., 26, 1673, (1960)) and chlorine 0.416 were added simultaneously. The temperature was maintained between -16 and -8 ° C. After complete addition, the solution was warmed to 80 ° C. and refluxed for 3 hours The mixture was extracted with chloroform (3 × 100 mL) by cooling to room temperature and adjusting the pH to 2,1. The combined organic layers were washed with water and brine, dried over magnesium sulfate, and the organic solution was filtered and evaporated to give a thick black solid, which was recrystallized twice from methanol to give 8.06 grams (30% yield) of a white solid. It raised and obtained the pure product of melting | fusing point 157 degrees-159 degreeC.

[analysis]

Calcd for C ₈ H ₁₀ 0 ₃ : C, 62.33; H, 6.54

Found: C, 62.05; H, 6.44.

NMR (CDCl ₃ , δ); 6-CH ₃ , 2.33 (3H, s); 2-CH ₃ , 1.30 (3H, t); 2-CH ₂ -2.75 (2H, quadruple), 5H, 6.23 (1H, s).

Example 38

2,6-dimethyl-3-hydroxy-4H-pyran-4-one

28 ml of water and 32 ml of methanol were added to a round three neck flask and the mixture was cooled to -15 ° C. The solution was treated simultaneously with 5methyl-2- (α-hydroxy-ethyl) furan (J.Org.Chem., 26, 1673,1960) 0.167 mol) and 0.416 mol of chlorine. The temperature during the addition was maintained at -15 ° to -10 ° C. The mixture was warmed to room temperature for at least 30 minutes and heated to reflux for 3 hours. The pH of the cooled solution was adjusted to 2.1 and extracted with chloroform (3 x 100 mL). The chloroform extracts were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue of black oil was chromatographed on silica gel developed with methylene chloride / ethyl acetate (95: 5). The product isolated by evaporation was recrystallized from methanol to give a brown solid (yield, 25%). It sublimed and obtained the white solid whose melting | fusing point is 161 degreeC-163 degreeC.

[analysis]

Calcd for C ₇ H ₈ 0 ₂ : C, 59.99; H, 5.75

Found: C, 59.83; H, 5.82

NMR (CDCl ₃ , δ); 6-CH ₃ , 2.33 (3H, s); 2-CH ₃ , 2.26 (3H, s); 5-H, 6.10 (1 H, s).

Claims (1)

Hydrolysis of 4-halo-dihydropyran of formula (II) or 6,6'-oxybis [4-halo-2H-pyran-3 (6H) -one] of formula (V) in acidic aqueous solution Process for preparing gamma-pyrons of formula (I), characterized in that heating until substantially complete:

Wherein R is hydrogen, C ₁ -C ₄ alkyl, phenyl or benzyl, R 'is hydrogen, C ₁ -C ₄ alkyl or COR ＂wherein R' is methyl, ethyl or phenyl, and R ' Is hydrogen or C ₁ -C ₄ alkyl and X is chlorine or bromine.