GB2031424A - 1-Aryl-3-methyl-4-ethyl-6H-2- benzopyran-6-ones - Google Patents
1-Aryl-3-methyl-4-ethyl-6H-2- benzopyran-6-ones Download PDFInfo
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- GB2031424A GB2031424A GB7932418A GB7932418A GB2031424A GB 2031424 A GB2031424 A GB 2031424A GB 7932418 A GB7932418 A GB 7932418A GB 7932418 A GB7932418 A GB 7932418A GB 2031424 A GB2031424 A GB 2031424A
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- methyl
- benzopyran
- ethyl
- acid
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- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 150000007513 acids Chemical class 0.000 claims abstract description 8
- 238000009833 condensation Methods 0.000 claims abstract description 6
- 230000005494 condensation Effects 0.000 claims abstract description 6
- 239000013543 active substance Substances 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- UUDYWELSMJWOIM-UHFFFAOYSA-N isochromen-6-one Chemical compound O1C=CC2=CC(=O)C=CC2=C1 UUDYWELSMJWOIM-UHFFFAOYSA-N 0.000 claims description 6
- 125000001033 ether group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- -1 perchlorate anion Chemical class 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 3
- IHVAVWQKKUPGMC-UHFFFAOYSA-N 3-(2-benzoylphenyl)pentan-2-one Chemical class C(C)C(C(=O)C)C1=C(C(=O)C2=CC=CC=C2)C=CC=C1 IHVAVWQKKUPGMC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 150000008366 benzophenones Chemical class 0.000 claims description 2
- HXEZRGLMVYYPFP-UHFFFAOYSA-N chloric acid nitric acid Chemical compound O[N+]([O-])=O.OCl(=O)=O HXEZRGLMVYYPFP-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- SNLLFFAPVUTMFJ-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-4-ethyl-7-methoxy-3-methylisochromen-6-one Chemical compound C=12C=C(OC)C(=O)C=C2C(CC)=C(C)OC=1C1=CC=C(OC)C(OC)=C1 SNLLFFAPVUTMFJ-UHFFFAOYSA-N 0.000 description 5
- ZWUMDFWFKWDFBI-UHFFFAOYSA-N 3-[2-(3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]pentan-2-one Chemical compound CCC(C(C)=O)C1=CC(OC)=C(OC)C=C1C(=O)C1=CC=C(OC)C(OC)=C1 ZWUMDFWFKWDFBI-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- DTNPXSAFFXFCID-UHFFFAOYSA-N 1-(3,4-dihydroxyphenyl)-4-ethyl-7-methoxy-3-methylisochromen-6-one Chemical compound OC=1C=C(C=CC1O)C=1OC(=C(C=2C1C=C(C(C2)=O)OC)CC)C DTNPXSAFFXFCID-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- HCGZVUHIXCXMPZ-UHFFFAOYSA-N 4-ethyl-1-(3-hydroxy-4-methoxyphenyl)-7-methoxy-3-methylisochromen-6-one Chemical compound COC1=C(C=C(C=C1)C=1OC(=C(C=2C1C=C(C(C2)=O)OC)CC)C)O HCGZVUHIXCXMPZ-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- LWAAZFZRLCRJEB-UHFFFAOYSA-N 4-ethyl-7-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-methylisochromen-6-one Chemical compound COC=1C=C(C=CC1O)C=1OC(=C(C=2C1C=C(C(C2)=O)O)CC)C LWAAZFZRLCRJEB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- RUJBDQSFYCKFAA-UHFFFAOYSA-N Tofisopam Chemical compound N=1N=C(C)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 RUJBDQSFYCKFAA-UHFFFAOYSA-N 0.000 description 1
- RSILXRYLDYZSAA-UHFFFAOYSA-N [4-[5-acetyloxy-4-methoxy-2-(2-oxopentan-3-yl)benzoyl]-2-methoxyphenyl] acetate Chemical compound C(C)C(C(=O)C)C1=C(C(=O)C2=CC(=C(C=C2)OC(C)=O)OC)C=C(C(=C1)OC)OC(C)=O RSILXRYLDYZSAA-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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 (7)
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.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU78GO1422A HU176786B (en) | 1978-10-05 | 1978-10-05 | Process for producing 1-phenyl-3-methyl-4-ethyl-6h-2-benzopiran-6-one derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2031424A true GB2031424A (en) | 1980-04-23 |
| GB2031424B GB2031424B (en) | 1982-11-03 |
Family
ID=10996872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7932418A Expired GB2031424B (en) | 1978-10-05 | 1979-09-19 | 1-aryl-3-methyl-4-ethyl-6h-2-benzopyran-6-ones |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5566575A (en) |
| CH (1) | CH643253A5 (en) |
| DE (1) | DE2940464A1 (en) |
| FI (1) | FI793079A7 (en) |
| FR (1) | FR2438043A1 (en) |
| GB (1) | GB2031424B (en) |
| HU (1) | HU176786B (en) |
-
1978
- 1978-10-05 HU HU78GO1422A patent/HU176786B/en not_active IP Right Cessation
-
1979
- 1979-09-19 GB GB7932418A patent/GB2031424B/en not_active Expired
- 1979-10-03 CH CH890079A patent/CH643253A5/en not_active IP Right Cessation
- 1979-10-03 FR FR7924592A patent/FR2438043A1/en active Granted
- 1979-10-04 FI FI793079A patent/FI793079A7/en not_active Application Discontinuation
- 1979-10-04 JP JP12743779A patent/JPS5566575A/en active Pending
- 1979-10-05 DE DE19792940464 patent/DE2940464A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| CH643253A5 (en) | 1984-05-30 |
| FR2438043A1 (en) | 1980-04-30 |
| FR2438043B1 (en) | 1983-02-04 |
| JPS5566575A (en) | 1980-05-20 |
| DE2940464A1 (en) | 1980-04-24 |
| GB2031424B (en) | 1982-11-03 |
| FI793079A7 (en) | 1981-01-01 |
| HU176786B (en) | 1981-05-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |