CA1046063A - Process for preparing 2(1h)-quinazolinone derivatives - Google Patents
Process for preparing 2(1h)-quinazolinone derivativesInfo
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- CA1046063A CA1046063A CA231,296A CA231296A CA1046063A CA 1046063 A CA1046063 A CA 1046063A CA 231296 A CA231296 A CA 231296A CA 1046063 A CA1046063 A CA 1046063A
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- Prior art keywords
- quinazolinone
- phenyl
- bromine
- chlorine
- cyclopropylmethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A NOVEL PROCESS FOR PREPARING
2(1H)-QUINAZOLINONE DERIVATIVES
ABSTRACT OF THE DISCLOSURE
2(1H)-Quinazolinone derivatives such as 1-cyclopropylmethyl-4-phenyl-6-chloro-2(1H)-quinazolinone are prepared in high yield with high purity by reacting the corresponding 3,4-dihydro-2(1H)-quinazolinone deri-vative with chlorine or bromine in the presence or absence of an alkali in an inert solvent.
2(1H)-QUINAZOLINONE DERIVATIVES
ABSTRACT OF THE DISCLOSURE
2(1H)-Quinazolinone derivatives such as 1-cyclopropylmethyl-4-phenyl-6-chloro-2(1H)-quinazolinone are prepared in high yield with high purity by reacting the corresponding 3,4-dihydro-2(1H)-quinazolinone deri-vative with chlorine or bromine in the presence or absence of an alkali in an inert solvent.
Description
1 ~his invention relates to a novel process for preparing 2(lH)-quinazolinone derivatives.
There has heretofore been known a process for converting a 3,4-dihydro-2(1H)-quinazolinone derivative to a corresponding 2(1H)-quinazolinone deri-vative-having excellent pharmacological properties, such as anti-inflammatory, analgesic, uricosuric and/or - anti-viral activities, by using a heavy metal oxidizing agent such as a manganese compound, chromium compound or salt thereof (e.g. potassium permanganate, manganese `
dio~ide or chromium trioxide) as described in our Canadian Patent No. 949,570.
These oxidizing agents employed in the prior process are relatively expensive and moreover, they may cause difficult problems of the waste treatment and disposal in terms of environmental pollution, especially in case of adopting large scale manufacture.
In order to improve such inconvenience of the known process, the present inventors have studied earnestly, and have found that 3,4-dihydro-2(1H)-quinazolinone derivatives can readily be converted to the corresponding 2(lH)-quinazolinone derivatives with high purity by the action of chlorine or bromine.
This~invention provides a novel process for preparing a compound of t-he formula, ~ ~ (I) d~
-1046~63 1 wherein Rl and R2 are individually hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, nitro,-trifluoromethyl, di-lower alkyl-amino, or when taken together Rl and R2 form methylene-5. dioxy; R3 is phenyl, halophenyl, nitrophenyl, loweralkylphenyl, lower alkoxyphenyl or pyridyl; and R is lower alkyl, lower cycloalkyl, lo~er cycloalkyl-lower . : alkyl, aralkyl, lower alkoxy-lower alkyl or lower haloalkyl; or pharmaceutically acceptable acid addition salts thereof, which comprises reacting a ~,4-dihydro-
There has heretofore been known a process for converting a 3,4-dihydro-2(1H)-quinazolinone derivative to a corresponding 2(1H)-quinazolinone deri-vative-having excellent pharmacological properties, such as anti-inflammatory, analgesic, uricosuric and/or - anti-viral activities, by using a heavy metal oxidizing agent such as a manganese compound, chromium compound or salt thereof (e.g. potassium permanganate, manganese `
dio~ide or chromium trioxide) as described in our Canadian Patent No. 949,570.
These oxidizing agents employed in the prior process are relatively expensive and moreover, they may cause difficult problems of the waste treatment and disposal in terms of environmental pollution, especially in case of adopting large scale manufacture.
In order to improve such inconvenience of the known process, the present inventors have studied earnestly, and have found that 3,4-dihydro-2(1H)-quinazolinone derivatives can readily be converted to the corresponding 2(lH)-quinazolinone derivatives with high purity by the action of chlorine or bromine.
This~invention provides a novel process for preparing a compound of t-he formula, ~ ~ (I) d~
-1046~63 1 wherein Rl and R2 are individually hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, nitro,-trifluoromethyl, di-lower alkyl-amino, or when taken together Rl and R2 form methylene-5. dioxy; R3 is phenyl, halophenyl, nitrophenyl, loweralkylphenyl, lower alkoxyphenyl or pyridyl; and R is lower alkyl, lower cycloalkyl, lo~er cycloalkyl-lower . : alkyl, aralkyl, lower alkoxy-lower alkyl or lower haloalkyl; or pharmaceutically acceptable acid addition salts thereof, which comprises reacting a ~,4-dihydro-
2(1H)-quinazolinone of the formula, R
R2 ~
~ ~ ~ (II) 1 i O
wherein R, Rl, R2 and R3 are as defined above, wi.th chlorine or bromine in the presence or absence of an alkali in an inert solvent.
In the compound of the above formula (I) and elsewhere in the specification, the term "alkyl"
means both straight or branched chain saturated aliphatic hydrocarbon radicals, and the term "lower alkyl" may be methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; the term "lower alkoxy" may be methoxy, ethoxy, - n-propoxy, isopropoxy, n-butoxy or isobutoxy; the term "lower cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohcxyl, cycloheptyl or cyclooctyl;
the term "aralkyl" may, for example, be benzyl, .
~og6063 1 halobenY.yl or lower alkylbcnzyl; t~le term "halot~en"
may be fluorine, chlorine, bromine or iodine; and the term "lower haloalkyl" may, for example, be 2-chloro-ethyl, 2,2-dichloroethyi, 2-bromoethyl, 2-fluoroethyl, 2,2-di~luoroethyl, 2,2,2-trifluoroethyl or 2,2,3,3,3-pentafluoropropyl.
- In carrying out the process of the present invention, the reaction may be preferably carried out at a temperature in the range of from room temperature to the boiling point of the solvent employed.
. Examples of the alkali include sodium - hydroxide, potassium hydroxide, sodium carbonate, . . potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, potassium tert-butoxide .and the like.
Suitable inert solvents include, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, methoxyethanol, ethoxyethanol, tetra-hydrofuran, dioxane, water, chloroform, carbon tetra-chloride, 1,2-dichloroethane, l,l,l-trichloroethane, benzene, toluene or a mixture thereof.
Chlorine or bromine is used in at least equimolar amount, more specifically a few.molar amount to the 3~4-dihydro-2(1H)-quinazolinone of the formula (II). For the reaction, chlorine or bromine may be also employed in the form of a hypohalogenous acid derivative such as sodium hypochlorite, sodium hypobromite, potassium hypobromitc or tert-butyl hypochlorite, which can be readily . 104f~63 1 prep~red by adding chlorine or bromine to a coolcd solu-tion of sodium hydroxide or potassium hydroxide according to a known procedure.
In certain conditions, 3-halosubstituted
R2 ~
~ ~ ~ (II) 1 i O
wherein R, Rl, R2 and R3 are as defined above, wi.th chlorine or bromine in the presence or absence of an alkali in an inert solvent.
In the compound of the above formula (I) and elsewhere in the specification, the term "alkyl"
means both straight or branched chain saturated aliphatic hydrocarbon radicals, and the term "lower alkyl" may be methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; the term "lower alkoxy" may be methoxy, ethoxy, - n-propoxy, isopropoxy, n-butoxy or isobutoxy; the term "lower cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohcxyl, cycloheptyl or cyclooctyl;
the term "aralkyl" may, for example, be benzyl, .
~og6063 1 halobenY.yl or lower alkylbcnzyl; t~le term "halot~en"
may be fluorine, chlorine, bromine or iodine; and the term "lower haloalkyl" may, for example, be 2-chloro-ethyl, 2,2-dichloroethyi, 2-bromoethyl, 2-fluoroethyl, 2,2-di~luoroethyl, 2,2,2-trifluoroethyl or 2,2,3,3,3-pentafluoropropyl.
- In carrying out the process of the present invention, the reaction may be preferably carried out at a temperature in the range of from room temperature to the boiling point of the solvent employed.
. Examples of the alkali include sodium - hydroxide, potassium hydroxide, sodium carbonate, . . potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, potassium tert-butoxide .and the like.
Suitable inert solvents include, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, methoxyethanol, ethoxyethanol, tetra-hydrofuran, dioxane, water, chloroform, carbon tetra-chloride, 1,2-dichloroethane, l,l,l-trichloroethane, benzene, toluene or a mixture thereof.
Chlorine or bromine is used in at least equimolar amount, more specifically a few.molar amount to the 3~4-dihydro-2(1H)-quinazolinone of the formula (II). For the reaction, chlorine or bromine may be also employed in the form of a hypohalogenous acid derivative such as sodium hypochlorite, sodium hypobromite, potassium hypobromitc or tert-butyl hypochlorite, which can be readily . 104f~63 1 prep~red by adding chlorine or bromine to a coolcd solu-tion of sodium hydroxide or potassium hydroxide according to a known procedure.
In certain conditions, 3-halosubstituted
3,4-dihydro-2(1H)-quinazolinone derivative may be obtain-ed as an intermediate of this reaction. The intermediate is relatively unstable and can be easily converted to : the end product by heating or treating with an inorganic or organic base such as alkali metal hydroxide, alkali metal alkoxide, ammonia, triethylamine, pyridine or the like.
The reaction may be usually effected with-out isolation of the intermediate. In this reaction, the compounds of the formula (I) may be substantially prepared as a hydrochloride or hydrobromide, which easily liberates the hydrogen halide by contacting with an alkali.
This invention is further disclosed in the following Examples of more preferred embodiments there-of, which are presented for the purpose of illustrationand it is not intended to limit the scope of the inven-tion.
~xample 1 To a solution of 3.13 g of l-cyclopropylmethyl-
The reaction may be usually effected with-out isolation of the intermediate. In this reaction, the compounds of the formula (I) may be substantially prepared as a hydrochloride or hydrobromide, which easily liberates the hydrogen halide by contacting with an alkali.
This invention is further disclosed in the following Examples of more preferred embodiments there-of, which are presented for the purpose of illustrationand it is not intended to limit the scope of the inven-tion.
~xample 1 To a solution of 3.13 g of l-cyclopropylmethyl-
4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone in 60 ml of hot methanol was added dropwise 3 g of bromine at 60 - 65C, and the stirred mixture was gently re-fluxed for 1 hour. The solvent was then removed under - reduced pressure to give the hydrobromide of the ~046~63 1 product as orange residue. To the residue was added 50 ml of ammonia water and the resulting suspension was well stirred. The colorless precipitate was collected by filtration, washed with water and dried to give 3.06 g of 1-cyclopropylmethyl-4-phenyl-6-chloro-2(1H)-quinazolinone, m.p. 174 - 175C.
: Example 2 To a suspension of 3.13 g of l-cyclopropyl-methyl-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone and 3.2 g of sodium methoxide in 60 ml of methanol was added dropwise a solution of 5 g of bromine in 20 ml of methanol, and the mixture was refluxed for 6 hours with stirring. The solvent was then removed undér reduced pressure and the residue was triturated with aqueous sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and - dried to give 3.06 g of 1-cyclopropylmethyl-4-phenyl-6-chloro-2(1H)-quinazolinone, m.p. 172 - 173C.
Example 3 To a solution of 3.13 g of l-cyclopropyl-methyl-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone in 20 ml of ch~oroform was added dropwise 3.8 g of bromine, and the mixture was stirred at room temperature for 10 hours. The solvent was then removed under re-duced pressure and the residual orange crystals was washed with isopropanol-isopropyl ether and dried to give 3.94 g of 1-cyclopropylmethyl-4-phenyl-6-chloro-- 2(1H)-quinazolinone hydrobromide, m.p. 187 - 189C.
1~)4f~Q63 1 Example 4 To a solution of 3.08 g of l-cyclopropyl-methyl-4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quinazoli-none in 15 ml of hot dioxane was added dropwise 2.3 g of bromine, and the mixture was stirred at 75 - 80C
for 6 hours. After cooling, the precipitate was filter-ed, washed with ethanol-n-hexane and dried to give -I 3.8 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-2(lH)-quinazolinone hydrobromide as orange crystals, which were recrystallized from methanol-isopropanol to give -orange needles, m.p. 196.5 - 197C. (decomp.).
~xample 5 . To a solution of 3.08 g of l-cyclopropyl-methyl-4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quina-zolinone in 30 ml of ethanol was added dropwise at 75C a solution of 4.8 g of bromine in 15 ml of ethanol~ -The resulting mixture was stirred at 75C for 2 hours.
To the reaction mixture was then added portionwise ~ g of sodium ethoxide at 60 - 70C with stirring. Then, most of the ethanol was distilled off and 50 ml of water was added to the residue to dissolve the in-organic salt and crystallize the product. The result-ing yellow precipitate was collected by filtration, washed with water and dri~d to give 3.02 g of l-cyclo-propylmethyl-4-phenyl-6-methoxy-2(lH)-quinazolinone, - m.p. 114 - 115C.
, Example 6 To ~ solution of 3.0~ g of l-cyclopropylmcthyl-- ~04~63 .
1 4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quinazolinone and 0.8 g of sodium hydroxide in 30 ml of hot methanol was added gradually at 65 - 70~ 15 g of sodium hypo-chlorite solution (12% available chlorine) prepared from chlorine and aqueous sodium hydroxide according to a known procedure. The stirred mixture was heated at 70C
for additional 1 hour. After cooling, 30 ml of water was added with stirring ~o the react-ion mixture, and the resulting mixture was cooled in ice water. The precipitate was filtered with suction, washed with water, and dried to give 2.9 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-2(lH)-quinazoiinone, m.p. 114 - 115C.
, Example 7 To a solution of 3.41 g of 1-(2,2,2-trifluoro-ethyl)-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone in 20 ml of hot methanol was added dropwise at about 60C a solution of 4.0 g of bromine in 5 ml of methanol.
The mixture was heated at 60C for 2 hour with stirring.
~o the reaction mixture was then added gradually 40 g of lO~o aqueous sodium carbonate solution at 50 - 60C.
After cooling, the colorless precipitate was filtered with suction, washed with water, and dried to give 3.35 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(lH)-quinazolinone, m.p.-183.5 - 184.5C.
Example 8 Using a proccdurc similar to that describcd in Examples 1 - 7, and starting with a corresponding 3,4-dihydro-2(1H)-quin~zolinone derivative, there wcre .
-~04~Q63 1 obtained the follo.~ing compounds in excellent yields.
l-Cyclopropylmethyl-4-phenyl-2(1H)-quinaæoli-none, m.p. 154 - 155C.
l-Cyclopropylmethyl-4-phenyl~6-bromo-2(lH)-quinazolinone, m.p. 163 - 164C.
l-Cyclopropylmethyl-4-phenyl-7-methyl-2(11I)-quinazolinone, m.p. 126 - 127C.
l-Cyclopropylmethyl-4-phenyl-7-methoxy-2(1H)-quinazolinone, m.p. 169 - 170C.
101-Cyclopropylmethyl-4-phenyl-6-methylthio-2(lH)-quinazolinone, m.p. 133 - 134C.
l-Cyclopropylmethyl-4-phenyl-6-nitro-2(lH)-quinazolinone, m.p. 172 - 173C.
l-Cyclopropylmethyl-4-phenyl-6-trifluoromethyl-152(lH)-quinazolinone, m.p. 166 - 167C.
l-Cyclopropylmethyl-4-phenyl-6,8-dichloro-2(lH)-quinazolinone, m.p. 158 - 159C.
l-Cyclopropylmethyl-4-phenyl-7,8-methylene-dioxy-2(1H)-quinazolinone, m.p. 228 - 229C.
201-Cyclopropylmethyl-4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone, m.p. 168 - 169C.
l-Cyclopropylmethyl-4-(p-methoxyphenyl)-6-methoxy-2(1H)-quinazolinone, m.p. 148 - 149C.
l-Cyc-lopropylmethyl-4-(p-nitrophenyl)-6-25methoxy-2(1H)-quinazolinone, m.p. 147 - 149C.
l-Cyclopropylmethyl-4-(o-tolyl)-6-chloro-2(lH)-quinazolinone, m.p. 204 - 205C.
l-Cyclopropylmethyl-4-(p-tolyl)-6-methoxy-2(1H)-quinazolinone, m.p. 136 - 1~8C.
1~)46Q63 1 1-Cyclopropylmethyl-4-(2-pyridyl)-6-chloro-2(lH)-quinazolinone, m.p. 120 - 121C.
l-Cyclohexyl~ethyl-4-phenyl-6-nitro-2(lH)-quinazolinone, m.p. 201 - ~202C.
1-Cyclohexyl-4-phenyl-6-nitro-2(lH)-quinazolinone m.p. 186 - 187C.
l-Methyl-4-phenyl-6-chloro-?(lH)-quinazolinone, ,. m.p. 220 - 221C.
l-Ethyl-4-phenyl-6-chloro-2(lH)-quinazolinone, m.p. 167 - 168C.
l~Isopropyl-4-phenyl-6-methoxy-2(1H)-quinazoli-none, m.p. 140 - 142C.
l-Isopropyl-4-phenyl-7-methoxy-2(lH)-quina-zolinone m.p. 134 - 136C.
1-Isopropyl-4-phenyl-7-methyl-2(lH)-quinazoli-none, m.p. 141 - 142C.
i-Isopropyl-4-phenyl-6-dimethylamlno-2(lH)-quinazolinone, m.p. 167 - 168C.
l-~enzyl-4-phenyl-6-nitro-2(lH)-quinazolinone, m.p. 173 - 174C.
l-(o-Methylbenzyl)-4-phenyl-6-nitro-2(lH)-quinazolinone, m.p. 200 - 201C.
l-Methoxymethyl-4-phenyl-6-chloro-2(lH)-quina-zolinone, m.p. 165 - 166C.
1-(2-Ethoxyethyl)-4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone, m.p. 146 - 147C.
1-(2-Chloroethyl)-4-phenyl-6-nitro-2(lH)-quinazolinone m.p. 190 - 191C.
1-(2,2-Difluorocthyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 197 - 198C.
1046a~63 1 1-(2,2,2-Trifluoroethyl)-4-phenyl-6-methoxy-2(lH)-quinazolinone, m.p. 157 - 158C.
1-(2,2,2-Trifluoroethyl)-4-phenyl-6-methyl-2(1H)-quinazolinone, m.p. 178 - 179C.
1-(2,2,3,3,3-Pentafluoropropyl)-4-phenyl-6-methyl-2(lH)-quinazolinone, m.p. 175 - 176C.
.. . .
_ ~
: Example 2 To a suspension of 3.13 g of l-cyclopropyl-methyl-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone and 3.2 g of sodium methoxide in 60 ml of methanol was added dropwise a solution of 5 g of bromine in 20 ml of methanol, and the mixture was refluxed for 6 hours with stirring. The solvent was then removed undér reduced pressure and the residue was triturated with aqueous sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and - dried to give 3.06 g of 1-cyclopropylmethyl-4-phenyl-6-chloro-2(1H)-quinazolinone, m.p. 172 - 173C.
Example 3 To a solution of 3.13 g of l-cyclopropyl-methyl-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone in 20 ml of ch~oroform was added dropwise 3.8 g of bromine, and the mixture was stirred at room temperature for 10 hours. The solvent was then removed under re-duced pressure and the residual orange crystals was washed with isopropanol-isopropyl ether and dried to give 3.94 g of 1-cyclopropylmethyl-4-phenyl-6-chloro-- 2(1H)-quinazolinone hydrobromide, m.p. 187 - 189C.
1~)4f~Q63 1 Example 4 To a solution of 3.08 g of l-cyclopropyl-methyl-4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quinazoli-none in 15 ml of hot dioxane was added dropwise 2.3 g of bromine, and the mixture was stirred at 75 - 80C
for 6 hours. After cooling, the precipitate was filter-ed, washed with ethanol-n-hexane and dried to give -I 3.8 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-2(lH)-quinazolinone hydrobromide as orange crystals, which were recrystallized from methanol-isopropanol to give -orange needles, m.p. 196.5 - 197C. (decomp.).
~xample 5 . To a solution of 3.08 g of l-cyclopropyl-methyl-4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quina-zolinone in 30 ml of ethanol was added dropwise at 75C a solution of 4.8 g of bromine in 15 ml of ethanol~ -The resulting mixture was stirred at 75C for 2 hours.
To the reaction mixture was then added portionwise ~ g of sodium ethoxide at 60 - 70C with stirring. Then, most of the ethanol was distilled off and 50 ml of water was added to the residue to dissolve the in-organic salt and crystallize the product. The result-ing yellow precipitate was collected by filtration, washed with water and dri~d to give 3.02 g of l-cyclo-propylmethyl-4-phenyl-6-methoxy-2(lH)-quinazolinone, - m.p. 114 - 115C.
, Example 6 To ~ solution of 3.0~ g of l-cyclopropylmcthyl-- ~04~63 .
1 4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quinazolinone and 0.8 g of sodium hydroxide in 30 ml of hot methanol was added gradually at 65 - 70~ 15 g of sodium hypo-chlorite solution (12% available chlorine) prepared from chlorine and aqueous sodium hydroxide according to a known procedure. The stirred mixture was heated at 70C
for additional 1 hour. After cooling, 30 ml of water was added with stirring ~o the react-ion mixture, and the resulting mixture was cooled in ice water. The precipitate was filtered with suction, washed with water, and dried to give 2.9 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-2(lH)-quinazoiinone, m.p. 114 - 115C.
, Example 7 To a solution of 3.41 g of 1-(2,2,2-trifluoro-ethyl)-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone in 20 ml of hot methanol was added dropwise at about 60C a solution of 4.0 g of bromine in 5 ml of methanol.
The mixture was heated at 60C for 2 hour with stirring.
~o the reaction mixture was then added gradually 40 g of lO~o aqueous sodium carbonate solution at 50 - 60C.
After cooling, the colorless precipitate was filtered with suction, washed with water, and dried to give 3.35 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(lH)-quinazolinone, m.p.-183.5 - 184.5C.
Example 8 Using a proccdurc similar to that describcd in Examples 1 - 7, and starting with a corresponding 3,4-dihydro-2(1H)-quin~zolinone derivative, there wcre .
-~04~Q63 1 obtained the follo.~ing compounds in excellent yields.
l-Cyclopropylmethyl-4-phenyl-2(1H)-quinaæoli-none, m.p. 154 - 155C.
l-Cyclopropylmethyl-4-phenyl~6-bromo-2(lH)-quinazolinone, m.p. 163 - 164C.
l-Cyclopropylmethyl-4-phenyl-7-methyl-2(11I)-quinazolinone, m.p. 126 - 127C.
l-Cyclopropylmethyl-4-phenyl-7-methoxy-2(1H)-quinazolinone, m.p. 169 - 170C.
101-Cyclopropylmethyl-4-phenyl-6-methylthio-2(lH)-quinazolinone, m.p. 133 - 134C.
l-Cyclopropylmethyl-4-phenyl-6-nitro-2(lH)-quinazolinone, m.p. 172 - 173C.
l-Cyclopropylmethyl-4-phenyl-6-trifluoromethyl-152(lH)-quinazolinone, m.p. 166 - 167C.
l-Cyclopropylmethyl-4-phenyl-6,8-dichloro-2(lH)-quinazolinone, m.p. 158 - 159C.
l-Cyclopropylmethyl-4-phenyl-7,8-methylene-dioxy-2(1H)-quinazolinone, m.p. 228 - 229C.
201-Cyclopropylmethyl-4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone, m.p. 168 - 169C.
l-Cyclopropylmethyl-4-(p-methoxyphenyl)-6-methoxy-2(1H)-quinazolinone, m.p. 148 - 149C.
l-Cyc-lopropylmethyl-4-(p-nitrophenyl)-6-25methoxy-2(1H)-quinazolinone, m.p. 147 - 149C.
l-Cyclopropylmethyl-4-(o-tolyl)-6-chloro-2(lH)-quinazolinone, m.p. 204 - 205C.
l-Cyclopropylmethyl-4-(p-tolyl)-6-methoxy-2(1H)-quinazolinone, m.p. 136 - 1~8C.
1~)46Q63 1 1-Cyclopropylmethyl-4-(2-pyridyl)-6-chloro-2(lH)-quinazolinone, m.p. 120 - 121C.
l-Cyclohexyl~ethyl-4-phenyl-6-nitro-2(lH)-quinazolinone, m.p. 201 - ~202C.
1-Cyclohexyl-4-phenyl-6-nitro-2(lH)-quinazolinone m.p. 186 - 187C.
l-Methyl-4-phenyl-6-chloro-?(lH)-quinazolinone, ,. m.p. 220 - 221C.
l-Ethyl-4-phenyl-6-chloro-2(lH)-quinazolinone, m.p. 167 - 168C.
l~Isopropyl-4-phenyl-6-methoxy-2(1H)-quinazoli-none, m.p. 140 - 142C.
l-Isopropyl-4-phenyl-7-methoxy-2(lH)-quina-zolinone m.p. 134 - 136C.
1-Isopropyl-4-phenyl-7-methyl-2(lH)-quinazoli-none, m.p. 141 - 142C.
i-Isopropyl-4-phenyl-6-dimethylamlno-2(lH)-quinazolinone, m.p. 167 - 168C.
l-~enzyl-4-phenyl-6-nitro-2(lH)-quinazolinone, m.p. 173 - 174C.
l-(o-Methylbenzyl)-4-phenyl-6-nitro-2(lH)-quinazolinone, m.p. 200 - 201C.
l-Methoxymethyl-4-phenyl-6-chloro-2(lH)-quina-zolinone, m.p. 165 - 166C.
1-(2-Ethoxyethyl)-4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone, m.p. 146 - 147C.
1-(2-Chloroethyl)-4-phenyl-6-nitro-2(lH)-quinazolinone m.p. 190 - 191C.
1-(2,2-Difluorocthyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 197 - 198C.
1046a~63 1 1-(2,2,2-Trifluoroethyl)-4-phenyl-6-methoxy-2(lH)-quinazolinone, m.p. 157 - 158C.
1-(2,2,2-Trifluoroethyl)-4-phenyl-6-methyl-2(1H)-quinazolinone, m.p. 178 - 179C.
1-(2,2,3,3,3-Pentafluoropropyl)-4-phenyl-6-methyl-2(lH)-quinazolinone, m.p. 175 - 176C.
.. . .
_ ~
Claims (4)
EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED
AS FOLLOWS:
1. A process for preparing a compound of the formula, wherein R1 and R2 are individually hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, nitro, trifluoromethyl, di-lower alkylamino, or R1 and R2 together may form methylene-dioxy; R3 is phenyl, halophenyl, nitrophenyl, lower alkylphenyl, lower alkoxyphenyl or pyridyl; and R is lower alkyl, lower cycloalkyl, lower cycloalkyl-lower-alkyl, aralkyl, lower alkoxy-lower alkyl or lower haloalkyl; or a pharmaceutically acceptable acid addi-tion salt thereof, which comprises reacting a compound of the formula, wherein R, R1, R2 and R3 are as defined above, with chlorine or bromine in the presence or absence of an alkali in an inert solvent.
2. A process according to Claim 1, wherein the reaction is carried out at a temperature within a range of from room temperature to a boiling point of the solvent employed.
3. A process according to Claim 1, wherein the inert solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, methoxyethanol, ethoxyethanol, tetrahydrofuran, dioxane, water, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, benzene, toluene and a mixture thereof.
4. A process according to Claim 1, wherein the amount of chlorine or bromine is at least equimolar to the 3,4-dihydro-2(1H)-quinazolinone.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP49080506A JPS518287A (en) | 1974-07-13 | 1974-07-13 | Kinazorinonjudotaioyobi sonoenno seizoho |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1046063A true CA1046063A (en) | 1979-01-09 |
Family
ID=13720187
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA231,296A Expired CA1046063A (en) | 1974-07-13 | 1975-07-11 | Process for preparing 2(1h)-quinazolinone derivatives |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS518287A (en) |
| AT (1) | AT342600B (en) |
| CA (1) | CA1046063A (en) |
| CH (1) | CH612186A5 (en) |
| DK (1) | DK137083B (en) |
| HU (1) | HU170223B (en) |
| NL (1) | NL7507921A (en) |
| SE (1) | SE414404B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7696216B2 (en) | 2002-12-23 | 2010-04-13 | Novartis Ag | Aryl-quinazoline/aryl-2-amino-phenyl methanone derivatives |
| US8476286B2 (en) | 2001-06-15 | 2013-07-02 | Novartis Ag | Quinazoline derivatives which promote the release of parathyroid hormone |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1066039A4 (en) | 1998-03-02 | 2003-02-26 | Cocensys Inc | Substituted quinazolines and analogs and the use thereof |
| US9834525B2 (en) * | 2014-02-04 | 2017-12-05 | University Of Tennessee Research Foundation | Inhibitors of paxillin function and related compositions and methods |
-
1974
- 1974-07-13 JP JP49080506A patent/JPS518287A/en active Granted
-
1975
- 1975-07-03 NL NL7507921A patent/NL7507921A/en not_active Application Discontinuation
- 1975-07-08 AT AT525775A patent/AT342600B/en not_active IP Right Cessation
- 1975-07-10 HU HUSU895A patent/HU170223B/hu unknown
- 1975-07-10 SE SE7507922A patent/SE414404B/en unknown
- 1975-07-10 CH CH902875A patent/CH612186A5/en not_active IP Right Cessation
- 1975-07-11 DK DK318075AA patent/DK137083B/en unknown
- 1975-07-11 CA CA231,296A patent/CA1046063A/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8476286B2 (en) | 2001-06-15 | 2013-07-02 | Novartis Ag | Quinazoline derivatives which promote the release of parathyroid hormone |
| US7696216B2 (en) | 2002-12-23 | 2010-04-13 | Novartis Ag | Aryl-quinazoline/aryl-2-amino-phenyl methanone derivatives |
| US8569317B2 (en) | 2002-12-23 | 2013-10-29 | Novartis Ag | Aryl-quinazoline/aryl-2amino-phenyl methanone derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| DK318075A (en) | 1976-01-14 |
| JPS518287A (en) | 1976-01-23 |
| NL7507921A (en) | 1976-01-15 |
| HU170223B (en) | 1977-04-28 |
| DK137083B (en) | 1978-01-16 |
| ATA525775A (en) | 1977-08-15 |
| AT342600B (en) | 1978-04-10 |
| DK137083C (en) | 1978-07-17 |
| CH612186A5 (en) | 1979-07-13 |
| SE7507922L (en) | 1976-01-14 |
| SE414404B (en) | 1980-07-28 |
| JPS5416506B2 (en) | 1979-06-22 |
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