GB2031424A

GB2031424A - 1-Aryl-3-methyl-4-ethyl-6H-2- benzopyran-6-ones

Info

Publication number: GB2031424A
Application number: GB7932418A
Authority: GB
Original assignee: Egyt Gyogyszervegyeszeti Gyar
Current assignee: Egyt Gyogyszervegyeszeti Gyar
Priority date: 1978-10-05
Filing date: 1979-09-19
Publication date: 1980-04-23
Also published as: CH643253A5; FR2438043B1; DE2940464A1; FR2438043A1; JPS5566575A; FI793079A; GB2031424B; HU176786B

Abstract

The invention relates to novel 1- aryl-3-methyl-4-ethyl-6H-2- benzopyran-6-one derivatives having the general formula (I), <IMAGE> wherein R, R<1> and R<2> each stand for hydrogen atom or methyl group, with the proviso that if R and R<2> stand for hydrogen atom then R<1> may not stand for methyl group, and condensation adducts thereof formed with acids. These compounds can be applied as intermediates in the synthesis of pharmaceutically active substances. Furthermore the invention relates to a process for preparing these compounds. The compounds of the general formula (I) may also exist in the tautomeric 2-benzopyrilium-6-oxido form corresponding to the general formula (Ia), wherein R, R<1> and R<2> are as defined above. The term "a compound of the general formula (I)" embraces each of these tautomers and any mixture thereof.

Description

SPECIFICATION 1 -Aryl-3-methyl-4-ethyl-6H-2-benzopyran-6-one Derivatives and a Process for the Preparation Thereof The invention relates to novel 1 -aryl-3-methyl-4-ethyl-6H-2-benzopyran-6-one derivatives having the general formula (I),

wherein R, R1 and R2 each stand for hydrogen atom or methyl group, with the proviso that if R and R2 stand for hydrogen atom then R1 may not stand for methyl group, and condensation adducts thereof formed with acids.

These compounds can be applied as intermediates in the synthesis of pharmaceutically active substances. Furthermore the invention relates to a process for preparing these compounds.

The compounds of the general formula (I) may also exist in the tautomeric 2-benzopyrilium-6oxide form corresponding to the general formula (la),

wherein R, R1 and R2 are as defined above. The term "a compound of the general formula (I)" embraces each of these tautomers and any mixture thereof.

Up to now 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine, a new type of psychovegetative regulators, is the only known and available 5H-2,3-benzodiazepine compound. This compound can be prepared, among others, from 1 -(3,4-dimethoxyphenyl)-3-methyl- 4-ethyl-6,7-dimethoxy-2-benzopyrilium salts (Hungarian Patent Specification No. 155,572).

1-(3-Methoxy-4-hydroxyphenyl)-3-methyl-4-ethyl-7-hydroxy-6H-2-benzopyran-6-one, i.e. the compound of the general formula (I), wherein Rand R2 are hydrogen and R' is methyl group, and its adducts formed with hydrochloric acid and sulfuric acid [compounds of the general formula (IV), wherein R and R2 are hydrogen, R' is methyl group and X is chloride or hydrosulfate ion] are known as well (Mh. Chem. 96, 369/1965/). This 6H-2-benzopyran-6-one derivative is prepared by heating 2-(1 ethylacetonyl)-41,5-diacetoxy-3',4-dimethoxybenzophenone [a compound of the general formula (II) wherein R3 is CH3-CO- group] at 2400C in glacial acetic acid. A disadvantage of this method is that the reaction proceeds only at high temperatures under superatmospheric pressures.Moreover, this method cannot be applied for the preparation of all compounds corresponding to the general formula (I), since only one of the two methoxy groups splits off under the reaction conditions.

Now it has been found that when a compound of the general formula (II) or (III),

wherein R3 stands for hydrogen atom, acetyl group or methyl group, and X stands for halogen atom or hydrosulfate, nitrate, chlorate or perchlorate anion, is treated with aqueous hydrochloric or hydrobromic acid, both partial and total splitting of the ether bonds can be achieved. It has been observed that in those compounds of the general formula (III) wherein R3 stands for methyl group the ether groups in different positions split off with different rates.

The methoxy group in position 6 reacts first, thereafter the splitting proceeds in positions 4' and 3', and the ether bond in position 7 is the most difficult to attack. Thus a new and advantageous method, applicable for the production of any compound of the general formula (I), was found.

Based on the above, the invention relates to a process for the preparation of 6H-2-benzopyran-6one derivatives of the general formula (I) and condensation adducts thereof formed with acids.

According to the invention the ether groups of a 2-(1 -ethylacetonyl)-benzophenone derivative of the general formula (II) or a 1-aryl-2-benzopyrilium derivative of the general formula (III) formed upon contacting said benzophenone derivative with an acid, wherein R3 stands for hydrogen atom, methyl group or acetyl group and X represents halogen atom or hydrosulfate, nitrate, chlorate or perchlorate anion, are split off partially or totally by treating the starting substance with aqueous hydrochloric or hydrobromic acid optionally in the presence of glacial acetic acid, and, if desired, an acid of the general formula HX, wherein X is as defined above, is removed from the resulting 1-aryl-2-benzopyrilium compound of the general formula (IV),

whereafter, if desired, the resulting 6H-2-benzopyran-6-one anhydrobase of the general formula (I) is treated with a mineral acid to form the respective 2-benzopyrilium salt.

The partial or total splitting of the ether groups is preferably performed with 20 to 38% aqueous hydrochloric acid or 40 to 50% aqueous hydrobromic acid at 80 to 1 300C, optionally in the presence of glacial acetic acid.

To form the 6H-2-benzopyran-6-one compounds of the general formula (I) the compounds of the general formula (IV) are treated preferably with an alkali metal carbonate or hydrocarbonate in an aqueous medium. Of the mineral acids usable to prepare the 2-benzopyrilium salts e.g. hydrohalic acids, sulfuric acid and perchloric acid are mentioned.

The preparation of the starting substances of the general formulae (II) and (III) is described in the following references: Ber. Deut. Chem. Ges. 75, 891 (1942), 76, 855 (1943); 77, 6 (1944); J. Am.

Chem. Soc. 72, 1118 (1950); Hungarian Patent Specification No. 158,091.

The invention is elucidated in detail by the aid of the following non-limiting Examples.

Example 1 Preparation of 1 -(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzopyran-6-one (Formula [I], R=R'=R2=CH3) A mixture of 231.6 g (0.6 moles) of 2-( 1 ethyl-acetonyl)-3',4,4',5-tetramethoxybenzophenone, 1 50 ml of glacial acetic acid and 66 ml of 48% aqueous hydrobromic acid is stirred and boiled at an inner temperature of 105 to 107 OC for 9 hours. After one hour of boiling orange red crystals start to separate from the reaction mixture. At that time further 66 ml of 48% aqueous hydrobromic acid are added to the mixture, and boiling is continued for additional 8 hours.The reaction mixture is allowed to cool, the crystal suspension is cooled to 1 5 to 1 60C, the crystals are filtered off, washed four times with 30 ml each of glacial acetic acid and then five times with 50 ml each of ice-cold 99.5% ethanol, and finally dried. In this way 177.4 g of crude 1-(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-6-hydroxy-7- methoxy-2-benzopyrilium bromide are obtained; the product decomposes at 232 to 2350C.

To liberate the anhydrobase the crystals are suspended in 210 ml of water, a total amount of 40 g of sodium hydrocarbonate are added to the suspension in portions, and the reaction mixture is heated at 800C. At the end of the reaction the mixture is cooled to room temperature, admixed with 20 g of sodium chloride, extracted with 300 ml of chloroform and then five times with 50 ml each of chloroform. The chloroform solutions are combined, drived over anhydrous magnesium sulfate, and the resulting orange red solution is evaporated. The residue is admixed with 500 ml of ethyl acetate, the mixture is heated to boiling, cooled, the separated crystals are filtered off and washed thrice with 50 ml each of ethyl acetate. 120.7 g (57%) of 1 -(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2benzopyran-6-one are obtained as a yellow, crystalline substance melting at 180 to 1 82to.

Similar yields can be attained when 2-(1-ethyl-acetonyl)-3',4,4',5-tetramethoxybenzophenone is replaced e.g. by 1 -(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-6,7dimethoxy-2-benzopyrilium bromide, or when concentrated hydrochloric acid is applied to split the ether bonds, instead of 48% aqueous hydrobromic acid.

The adduct of the end-product formed with hydrochloric acid [(C21H23O5)CI] decomposes at 250 to 2520C, whereas the hydrobromide adduct [(C2,H2305)Br] decomposes at 238 to 2400C.

Example 2 Preparation of 1-(3,4-dimethoxyphenyl)-3-methylXethyl-6-hydroxy-7-methoxy-2-benzopyrilium bromide (Formula [IV], R=R'=R2=CH3, X=Br) 0.1 ml of 48% aqueous hydrobromic acid are added to a hot solution of 0.3 g of 1 -(3,4 dimethoxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzopyran-6-one in 1.2 ml of hot glacial acetic acid, and the mixture is cooled imm-ediately. The pure bromide separates as orange red crystals. The crystals are filtered off and washed with abs. ethanol. 0.21 g of the title compound are obtained; the product decomposes at 238 to 2400C.

Example 3 Preparation of 1 -(4-methoxy-3-hydroxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzopyran- 6-one (Formula [I], R1=H, R=R2=CH3) A mixture of 50 g (0.13 moles) of 2-(1 -ethylacetonyl)-3',4,4',5-tetramethoxybenzophenone and 110 ml of 48% aqueous hydrobromic acid is boiled under stirring for 6 hours. The mixture is cooled to 500C, 200 ml of ethanol are added, the mixture is cooled, the solids are filtered off and washed four times with 20 ml each of ethanol.The resulting 45.7 g of orange red product, which decomposes at 240 to 2430C, is treated with 10 g of sodium hydrocarbonate in 450 ml of water, the separated solids are filtered off, and then washed with ethanol and dimethyl formamide. 20.3 g of the crude anhydrobase are obtained; the product darkens from 2600C and decomposes at 280 to 2860C. 10 g of the crude product is admixed with 45 ml of dimethyl formamide, the mixture is heated to boiling and filtered when hot. 4.2 g of crude 1 -(4-methoxy-3-hydroxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2benzopyran-6-one separates from the solution. This crude substance is admixed with 12.6 ml of dimethyl formamide, the mixture is heated to boiling and filtered when hot.The resulting precipitate is boiled in 25 ml of abs. ethanol for 10 minutes, the mixture is cooled, and the solids are separated by filtration. The precipitate is washed thrice with 3 ml each of abs. ethanol. 2.8 g of the title compound are obtained; m.p.: 280-2820C (under decomposition).

This product can also be prepared from 1 -(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-7-methoxy- 6H-2-benzopyran-6-one or its hydrobromide adduct, in this instance, however, the time of splitting should be decreased.

The hydrobromide adduct of the title compound [(C20H2,05)Br] decomposes at 237 to 283"C.

Example 4 Preparation of 1 -(3,4-dihydroxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzopyran-6-one (Formula [I]. R=CH3, R1 =R2=H) A mixture of 3.54 g (0.01 moles) of 1-(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H- 2-benzopyran-6-one and 10 ml of 48% aqueous hydrobromic acid is boiled for 10 hours. The mixture is cooled, the precipitate is filtered off and washed four times with 2 ml each of ethanol. 2.97 g of crude 1 -(3,4-dihydroxyphenyl)-3-methyl-4-ethyl-6-hydroxy-7-methoxy-2-benzopyrilium bromide, decomposing at 255 to 2580C, are obtained. This crude product is treated with 0.7 g of sodium hydrocarbonate in 15 mi of water at 800C.The solids are filtered off at 250C, admixed with 7 ml of dimethyl formamide, heated to boiling, and then filtered at 200C. In this way 1.98 g (61%) of the pure anhydrobase are obtained; the yellow substance decomposes at 302 to 3040C. The highest purity grade can be attained by recrystallizing the product from dimethyl formamide.

When 2-( 1 -ethylacetonyl)-3',4,4',5-tetramethoxybenzophenone or 1 -(3,4-dimethoxypheny1)-3- methyl-4-ethyl-6,7-dimethoxy-2-benzopyrilium bromide is applied as starting substance, the period of splitting must be prolonged. In a trial performed with a splitting period of 20 hours the title compound was obtained with a yield of 30%, whereas additional 13.7% of the completely demethylated anhydrobase appeared in the mother liquor.

The hydrobromic acid adduct of the title compound [(C,9H,g05)Br] decomposes at 269 to 2700C, whereas the sulfuric acid adduct [(C19H19O)HSO4. 2H20] decomposes at 1 92 to 1 950C.

Example 5 Preparation of 1 -(3,4-dihydroxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzopyran-6-one (Formula I, R=CH3, R1=R2=H) A mixture of 50 g (0.13 moles) of 2-(1-ethylacetonyl)-31,4,4',5-tetramethoxybenzophenone and 110 ml of 48% aqueous hydrobromic acid is boiled for 6 hours under stirring. The mixture is cooled to 500C, and 200 ml of ethanol are added. The solids separated upon cooling are filtered off, and the filter cake is washed four times with 20 ml each of ethanol. The resulting 45.7 g of orange red product, decomposing at 240 to 2430C, is treated with 10 g of sodium hydrocarbonate in 450 ml of water.The separated precipitate is filtered off and washed with ethanol and dimethyl formamide. 20.3 g of a crude anhydrobase are obtained; the product darkens from 2600C and decomposes at 280 to 2860C.

10 g of this crude substance are admixed with 45 ml of dimethyl formamide, the mixture is heated to boiling, filtered when hot, and the precipitate which separates from the filtrate is washed thrice with 5 ml each of abs. ethanol. In this way 4.88 g of 1 -(3,4-dihydroxyphenyl)-3-methyl-4-ethyl-7-methoxy- 6H-2-benzopyran-6-one are obtained; m.p.: 302 to 3040C (under decomposition).

Example 6 Preparation of 1-[3,4-dihydroxyphenyl]-3-methyl-4-ethyl-7-hydroxy-6H-2-benzopyran-6-one] Formula [I], R=R1=R2=H] A mixture of 8.84 g [0.02 moles] of 2-[1 -ethylacetonyl]-4',5-diacetoxy-3',4- dimethoxybenzophenone and 17.7 ml of 48% aqueous hydrobromic acid is boiled for 20 hours. After cooling 45 ml of ethanol are added to the mixture, whereupon 7.65 g of the crude bromide separate as an orange red substance. This crude substance is treated with an excess of sodium hydrocarbonate in water. The resulting 5.27 g of brownish-red crude product, melting at 160 to 1 660C, is recrystallized first from 60 ml of 25% aqueous dimethyl formamide and then from 7.5 ml of dimethyl formamide. In this way 2.3 g [36.5%] of the title anhydrobase is obtained as a yellow substance decomposing at 288 to 2900C. No methoxy impurities can be detected in the NMR spectrum of the product.

The hydrobromic acid adduct of the title compound VC,,H,,OrJBrl decomposes at 261 to 2640C.

Example 7 Preparation of 1 -[3,4-dihydroxyphenyli-3-methyl-4-ethyl-7-hydroxy-6H-2-benzopyran-6-onei Formula [I], R=R1=R2=H] 2-[1 -Ethylacetonyl]-3',4,4',5-tetramethoxybenzophenone or a 1 -[3,4-dimethoxyphenyl]-3- methyl-4-ethyl-6,7-dimethoxy-2-benzopyrilium salt is applied as starting substance, and the splitting period is increased to 30 hours. The reaction mixture is processed as described in Example 6 to obtain the pure.6H-2-benzopyran-6-one derivative with a yield of 35 to 50%. The product is free of methoxy contaminations.

Claims

1. A process for the preparation of a 1 -aryl-3-methyl-4-ethyl-6H-2-benzopyran-6-one derivative of the general formula (I)

wherein R, R1 and R2 each represent hydrogen atom or methyl group with the proviso that if R and R2 stand for hydrogen atom then R' may not stand for methyl group, including any tautomeric forms, condensation adducts thereof formed with acids and mixtures of such compounds, wherein the ether groups of a 2-(1-ethylacetonyl)-benzophenone derivative of the general formula (II)

or a 1 -aryl-2-benzopyrilium derivative of the general formula (III) formed upon contacting said benzophenone derivative with an acid,

wherein R3 stands for hydrogen atom, methyl group or acetyl group and X represents halogen atom or hydrosulfate, nitrate chlorate or perchlorate anion, are split off partially or totally by treating the starting substance with aqueous hydrochloric or hydrobromic acid optionally in the presence of glacial acetic acid, and, if desired, an acid of the general formula HX, wherein X is as defined above, and removing from the resulting 1 -aryi-3-benzopyrilium compound of the general formula (IV),

wherein R, R1, R2 and X are as defined above, whereafter, if desired, the resulting 6H-2-benzopyran-6one anhydrobase of the general formula (I) is treated with a mineral acid to form the respective 2benzopyrilium salt.

2. A process as claimed in claim 1, wherein the partial or total splitting of the ether groups is performed with 20 to 38% aqueous hydrochloric acid or 40 to 50% aqueous hydrobromic acid at 80 to 1 300C, optionally in the presence of glacial acetic acid.

3. A process as claimed in claim 1 or 2, wherein the compound of the general formula (I) is liberated from the compound of the general formula (IV) preferably by treating the latter with an alkali metal carbonate or hydrocarbonate in an aqueous medium.

4. A 1-aryl-3-methyl-4-ethyl-6H-2-benzopyran-6-one derivative of the general formula (I)

wherein R, R' and R2 each represent hydrogen atom or methyl group, with the proviso that if R and R2 stand for hydrogen atom then R1 may not stand for methyl group, a tautomeric form thereof or condensation adducts thereof formed with acids.

5. 1 -Aryl-3-methyl-4-ethyl-6H-2-benzopyran-6 derivatives, ta utomers or condensation adducts thereof formed with acids when produced by a process as claimed in any one of claims 1 to 3.

6. A pharmaceutically active substance when produced from a compound as claimed in claim 4 or claim 5.

New Claims or Amendments to Claims filed on 26 September 1979.

New or Amended Claims:

7. A process according to Claim 1 substantially as herein described with reference to any one oi the Examples; and a product whenever produced by such a process.