CA1111847A - Preparation of quinazoline derivatives - Google Patents
Preparation of quinazoline derivativesInfo
- Publication number
- CA1111847A CA1111847A CA310,645A CA310645A CA1111847A CA 1111847 A CA1111847 A CA 1111847A CA 310645 A CA310645 A CA 310645A CA 1111847 A CA1111847 A CA 1111847A
- Authority
- CA
- Canada
- Prior art keywords
- signifies
- metal
- methyl
- toluene
- quinazolinone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
- C07D239/82—Oxygen atoms with an aryl radical attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Novel process for producing 4-aryl-2(1H)-quinazolinones know as anti-inflammatory agents, by dehydrogenating a corresponding 4-aryl-5,6,7,8-tetrahydro-2(1H)-quinazolinone in the presence of an inorganic metal compound.
Novel process for producing 4-aryl-2(1H)-quinazolinones know as anti-inflammatory agents, by dehydrogenating a corresponding 4-aryl-5,6,7,8-tetrahydro-2(1H)-quinazolinone in the presence of an inorganic metal compound.
Description
~$1~ 7 Preparation of Quinazoline Derivatives This invention relates to a process for the prep-aration of 4-aryl-quinazoline-2(lH)-ones, in particular a compound of formula I, R4 IRl R3 R~ I
in which Rl signifies a (Cl-C8) hydrocarbon radical optionally mono-, di or tri-substituted with fluoro, chloro or bromo, R2 signifies monocyclic aryl, and R3 and R4, which may be the same or different, each signifies a hydrogen atom, a (Cl-C
alkyl or alkoxy radical, or fluorine, chlorine, bromine or trifluoromethyl, or R3 and R4 together signify 6,7-methylenedioxy, by dehydrogenating a corresponding 4-aryl-5,6,7,8-tetra-hydro-2(1H)-quinazolinone, in particular a compound of ~111847 formula II, R
~ N`C = O II
in which Rl, R2, R3 and R4 are as defined above, with sulphur, in an inert organic solvent, characterised in that the dehydrogenation is effected in the presence of an inorganic metal compound which is an oxide, hydroxide or salt of a metal, other than magnesium, aluminium, beryllium or an alkali metal, and which forms a metar-sulphide under the reaction conditions.
The process of the invention is suitably effec-ted at temperatures in the range of from 125 to 250C, preferably 130 to 200C and more preferably in the range 135 to 200C.
The reaction is carried out in an organic solvent inert under the reactive conditions. Preferred solvents include ethylene glycol, propylene glycol, ethoxyethoxy-ethanol, dioxane, toluene, xylene and ~-cymeme. It is generally preferred to employ a solvent boiling at the desired reaction temperature in order to utilise reflux conditions, e.y. ~-cymene under the more preferred temperature conditions.
i The mol ratio of sulphur to the quinazolinone starting material may vary fairly widely but is suitably at least 1.7 : 1. The upper limit is not particularly critical, but it is unnecessary and inefficient to employ the sulphur in an amount exceeding a mol ratio of 6 : 1.
More suitably, the mol ratio will be in the range of from 1.9 : l to 4 : 1, preferably in the range of 2 : 1 to 3 : 1.
The metal compound to be employed is, as indicated, one which forms a sulphide under the reaction conditions. In addition to the alkali metals and magnesium and aluminium, as a practical matter the rare earth metals and metals with an atomic number of 84 or greater are not preferred. Pref-erred metals include calcium, titanium, zirconium, chro~ium, lead, molyb~enum, mangane~e, iron, tin, cobalt, nickel, palladium, copper, silver, zinc, cadmium, mercury, antimony and bismuth, more preferably calcium, iron or zinc. The metal compound may be a salt, for example a salt of a strong acid, such as a halide, e.g. chloride, sulphate or nitrate, but is preferably an oxide or hydroxide, pa:rticularly an oxide. The preferred metal compounds include calcium oxide, ~inc oxide and, in particular,ferric oxide. A number of the metal compounds which may be used, e.g. calcium chloride, react with hydrogen sulphide to form an acidic medium and the resulting metal sulphides tend to be unstable or soluble in such medium. In such cases, it is preferred to include ~ 4 ~ 600-~744/X
in the reaction mixture a hydroxide base, e.g. an alkali metal hydroxide or alkaline earth metal hydroxide, or an excess of the metal compound when this is a hydroxide base.
Preferably, an alkali metal hydroxide, e.g. potassium or sodium hydroxide, is used.
The mol ratio of metal compound to the quinazolin-one starting material is suitably at least 1 : 1, preferably at least 1.5 : 1. The upper limit is not critical but mol ratios in excess of 10 : 1 offer no additional advantage.
More suitably, the mol ratio will be in the range of from 1.8 : 1 to 6 : 1, preferably 2 : 1 to 4 : 1 and more pref-erably in the range of from 2.1 : 1 to 3 : 1.
Where employed, the hydroxide base is conveniently present in a mol ratio relative to the quinazolinone starting material, of at least 1 : 1, suitably at least 1.5 : 1, preferably 1.8 to 6 : 1, more pre~erably 2 to 3 : 1.
The process of the present invention may be effec-ted under sub- or super-atmospheric pressure but is most suitably carried out under atmospheric pressure. A blanket or constant flow of a yas, inert under the reaction con-ditions, e.g. nitrogen, over the reaction mixture is pref-er~ed.
The reaction may typically be run from about 1 to 15 hours.
The process of the invention results in substanti-ally higher yields than the corresponding known process, which does not employ a metal compound, and which usually results in a mixture of the desired quinazolin-2(1~)-or.e and the corresponding 3,4-dihydro derivative.
The compounds II are either known ~ se or may be prepared from kno~m materials by methods described in the literature.
In the compounds of the formulae I and I~ the (Cl-C8) hydrocarbon radical of Rl may for example be (Cl-C6) alkyl, (C3-C7) cycloalkyl, (C4-C7~ cycloalkylalkyl, having a (C3-C6) cycloalkyl and a (Cl-C2) alkyl portion, phenyl, benzyl or phenethyl. Examples of halo-substituted hydro-carbon radicais for Rl include (Cl-C6) alkyl, mono~, di-or tri-substituted by fluorine, chlorine or bromine and phenyl, benzyl or phenethyl, mono- or di-substituted by fluorine, chlorine or bromine. Di- or tri-halogen substit-uted radicals are preferably substituted by the same halo~en atoms.
In the compounds of the formula I ~ d II, R2 is more preferably a rad~cal of formula III or IV, ~ lll or ~ y IV
l84'7 in which Y and Yl may be the same or different, each signifies a hydrogen, fluorine, chlorine or bromine atom, a (Cl-C3) alkyl or alkoxy radical, or a trifluoromethyl group, provided that when one of Y and Yl signi-fies a trifluoromethyl group, the other signifies a hydrogen atom, and Y2 signifies a hydrogen, fluorine, chlorine or bromine atom, or a (Cl-C3) alkyl or alkoxy radical.
The compounds of formula I are known for their anti-inflammatory activity and in this regard R1 is prefer-ably (Cl-C6) alkyl or cyclopropylmethyl, more preferably (Cl-C6) alkyl, especially isopropyl. R2 is preferably a phenyl radical optionally mono- or di-substituted as indic-ated above, and is more preferably phenyl or ~-fluorophenyl.
R3 and ~4 may each be hydrogen. Preferably, however, at least one is Cl 3-alkyl, in particular methyl, for example in the 7-position, or Cl 3-alkoxy, e.g. methoxy, for example in the 6-position.
Compounds that are most preferably prepared are 7-methyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone and l-isopropyl-4-~-fluorophenyl-7-methyl-2(lH)-quinazolinone.
The following Examples llustrate the process of ~he invention.
'7 ~ 7 ~ 600-6744/X
EX~IPLE 1: 7-Methyl-l-isopropyl-4-~henvl-2(~ g~uina .
inone A mixture of 200 ml of ~-cymene, 40 g of ferric oxide and 7 g of sulphur is heated to reflu~ (ca. 175C), and there is then added thereto dropwise over a period of 40 minutes a hot (130C) solution of 28.2 g of 7-methyl-l-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1Il)-quinazolin-one in 200 ml of ~-cymene. The resulting solution is refluxed for 3.5 hours duriny which time 1.8 ml of water are collected in a Dean Stark separator. The reaction solution is then cooled to 28C and filtered through a Celite pad which is then ~7ashed 4 times each with 25 ml of toluene. Th~ toluene washings are extracted with 50 ml of 4N hydrochloric acid and the ~-cymene filtrate is extracted with 350 ml of 4N hydrochloric acid. T~e ac~d extracts are combined and extracted with 100 ml of toluene~ and such toluene extracts discar~ed. The acid solution remaining after such tolue~e extraction is treated by addition of 350 ml of toluene and 110 g of 50~ aqueous sodium hydroxide solution. The phases are separated and the toluene phase washed twice each with 100 ml of water, followed by drying over sodium sulphate, filtering and evaporation in vacuo. The solid residue is crystallised ~rom ethyl acetate to obtain 7 methyl-l-isopropyl-4-pher.yl-quinazolin-2(1H~-one, m.p. 139-141C.
. ,~.
r ~ '~ .
, - 1$11847 .;
EX~PLE 2~ sopro~yl-4-p-fluoro~henyl-7-methyl-2(lH) quinazolinone A mixture of 67 ml of xylene, 13.3 g of ferric oxide and 2.5 g of sulphur is heated under a nitrogen 5 atmosphere to reflux and there is then added thereto, ;
over a period of 20 minutes drop~Jise, a hot ~100-110C) solution of 10 g of 7-methyl-1-isopropyl-4-~-fluoro-phenyl-5,6,7,8-tetrahydro-2(lH)-quinazolinone in 100 ml of Yylene. The resulting solution is refluxed for 10 hours, during which time water is collected in a Dean Stark separator. The reaction mixture is then cooled to 80C and filtered through a Cellte~iad.
The filtrate and the filter cake are washed 3 times each with 50 ml of toluene. The filtrates are com-bined and then extracted successively with 200, 100 and50 ml of 4N hydrochlorlc acid. The acid extracts are combined and washed with 100 ml of toluene, the toluene extracts being discarded. To the acid solution, remaining after such toluene extraction,aré added 200 ml of toluene and 115 g of 50% aqueous sodium hydroxide solution ~;hilc stirring and cooling. TAe phases are separated and the aqueou~ phase washed twice each with 100 ml of toluene.
~''~' ' .
;
: -.., - . - .
~ '- '" ' ~ ~
84'7 The toluene phases are combined, wached twice each with 100 ml of water, followed by drying over anhydrous magnesium sulphate, filtering through Celite ~
and concentrating to yield 8.8 g (90%) of yellow crystals.
. 5 Recrystallisation occurs from ethylacetate to obtain the title compound with m.p. 175-176.5C.
EX~MPLE 3: 1-Iso~ro~vl-4-Dhenvl-7-methvl-2(1~)-auinazolinone A mixture of 28.2 g of 7-~.ethyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(lH)-quinazolinone, 9.6 g of 10 sulphur, 10 g of sodium hydroxide, 20 g of calcium chloride and 200 ml of carbitol (2-[2-ethoxyethoxy]ethanol~
~s heated under a nitrogen blanket at 150C for 2 hours.
The resulting miY.ture is then cooled to 65C, 500 ml of benzene added and the mixture cooled with stirring to 15C
15 and the liquid phase decanted. The organic phase is washed with ~ater and evaporated to obtain an oil which is dissol-ved in a mixture of 100 ml of benzene and 100 ml of 50~
aqueous hydrochloric acid. The xesultiny mixture is stirred for one hour at room temperature, tr.e phases separated and 20 the acid phase treated with 50 ml of benzene~ The acid phase is neutralised with 50~ sodium hydroxide solution, extracted with 150 ml o~ benzene and the benzene extracts washed with water until neu~ral. ~fter drying over sodium sulphate, the benzene sclution is evapcra~ed to obtain the B
crude product which is recrystallised from ethyl acetate to obtaln l-isopropyl-4-phenyl-7-methyl-2(lH)-quinazolinone, m.p. 141-142C.
EXAMPL~ 4: 7-Methyl-l-isopro~yl-4-(p-fluorophenvl)-quin azolin-2-(lH)-one To a stirred mixture of 4.3 g of sulphur, 6.8 g of zinc oxide and 67 ml of a mixture of xylenes heated to reflux (ca. 138C) under a nitrogen blanket is added a pre-heated (100-115C) solution of 10.0 g of 7-methyl-1-isopropyl-4-(~-fluorophenyl)-5,6,7,8-tetrahydro-2(1~)-quinazolinone in 100 ml of a mixture of xylenes. After addition'(ca. 20 m-nutes), the resulting ~ixture is refluxed overnight, cooled and filtered through Cellte. The solids ~
are washed with toluene and the filtrate and washin~s ex-tracted four times with 4N hydrochloric acid and the extractswashed with 100 ml of toluéne. The aqueous phase is treated with 200 ml of toluene and treated portionwise with 115 g of 50~ sodium hydroxide solution in an ice-bath. The aqueous phase is extracted twice each with 100 ml of toluene and the organic phase water washed and dried. The crude yellow solid obtained on filtering and concentration in vacuo is dissolved in 100 ml of ethyl acetate, filtered and concentrated to a volume o, 50 ml and cooled to 0C to ~ '.
- 11 - 6oo-G744/x obtain a precipitate which is recrystallised from ethyl acetate to yield 7-methyl-1-isopropyl-4~ fluorophenyl)-quinazolin-2(lH)-one.
EXAMPLE 5:
The procedure of Example 4 is repeated employing an equivalent molar amount of lead dioxide in place of zinc oxide to yield the same product.
EXAMPLE 6:
In a manner analogous to any one of the preceding Exampies and employing appropriate starting materials in approximately equivalent amounts, the following compounds may be obtained:-5,7-dimethyl-1-isopropyl-4-phenyl-quinazolin-2~lH)-one;
l-isopropyl-7-methyl-4-(~-methylphenyl)-quinazolin-2(lH)-one;l-isopropyl~7-methyl-4-(2-thienyl)-quinazolin-2(1H)-one;
l-cyciopropylme~hyl-6-methoxy-4-phenyl-quinazolin-2(lH)-one.
in which Rl signifies a (Cl-C8) hydrocarbon radical optionally mono-, di or tri-substituted with fluoro, chloro or bromo, R2 signifies monocyclic aryl, and R3 and R4, which may be the same or different, each signifies a hydrogen atom, a (Cl-C
alkyl or alkoxy radical, or fluorine, chlorine, bromine or trifluoromethyl, or R3 and R4 together signify 6,7-methylenedioxy, by dehydrogenating a corresponding 4-aryl-5,6,7,8-tetra-hydro-2(1H)-quinazolinone, in particular a compound of ~111847 formula II, R
~ N`C = O II
in which Rl, R2, R3 and R4 are as defined above, with sulphur, in an inert organic solvent, characterised in that the dehydrogenation is effected in the presence of an inorganic metal compound which is an oxide, hydroxide or salt of a metal, other than magnesium, aluminium, beryllium or an alkali metal, and which forms a metar-sulphide under the reaction conditions.
The process of the invention is suitably effec-ted at temperatures in the range of from 125 to 250C, preferably 130 to 200C and more preferably in the range 135 to 200C.
The reaction is carried out in an organic solvent inert under the reactive conditions. Preferred solvents include ethylene glycol, propylene glycol, ethoxyethoxy-ethanol, dioxane, toluene, xylene and ~-cymeme. It is generally preferred to employ a solvent boiling at the desired reaction temperature in order to utilise reflux conditions, e.y. ~-cymene under the more preferred temperature conditions.
i The mol ratio of sulphur to the quinazolinone starting material may vary fairly widely but is suitably at least 1.7 : 1. The upper limit is not particularly critical, but it is unnecessary and inefficient to employ the sulphur in an amount exceeding a mol ratio of 6 : 1.
More suitably, the mol ratio will be in the range of from 1.9 : l to 4 : 1, preferably in the range of 2 : 1 to 3 : 1.
The metal compound to be employed is, as indicated, one which forms a sulphide under the reaction conditions. In addition to the alkali metals and magnesium and aluminium, as a practical matter the rare earth metals and metals with an atomic number of 84 or greater are not preferred. Pref-erred metals include calcium, titanium, zirconium, chro~ium, lead, molyb~enum, mangane~e, iron, tin, cobalt, nickel, palladium, copper, silver, zinc, cadmium, mercury, antimony and bismuth, more preferably calcium, iron or zinc. The metal compound may be a salt, for example a salt of a strong acid, such as a halide, e.g. chloride, sulphate or nitrate, but is preferably an oxide or hydroxide, pa:rticularly an oxide. The preferred metal compounds include calcium oxide, ~inc oxide and, in particular,ferric oxide. A number of the metal compounds which may be used, e.g. calcium chloride, react with hydrogen sulphide to form an acidic medium and the resulting metal sulphides tend to be unstable or soluble in such medium. In such cases, it is preferred to include ~ 4 ~ 600-~744/X
in the reaction mixture a hydroxide base, e.g. an alkali metal hydroxide or alkaline earth metal hydroxide, or an excess of the metal compound when this is a hydroxide base.
Preferably, an alkali metal hydroxide, e.g. potassium or sodium hydroxide, is used.
The mol ratio of metal compound to the quinazolin-one starting material is suitably at least 1 : 1, preferably at least 1.5 : 1. The upper limit is not critical but mol ratios in excess of 10 : 1 offer no additional advantage.
More suitably, the mol ratio will be in the range of from 1.8 : 1 to 6 : 1, preferably 2 : 1 to 4 : 1 and more pref-erably in the range of from 2.1 : 1 to 3 : 1.
Where employed, the hydroxide base is conveniently present in a mol ratio relative to the quinazolinone starting material, of at least 1 : 1, suitably at least 1.5 : 1, preferably 1.8 to 6 : 1, more pre~erably 2 to 3 : 1.
The process of the present invention may be effec-ted under sub- or super-atmospheric pressure but is most suitably carried out under atmospheric pressure. A blanket or constant flow of a yas, inert under the reaction con-ditions, e.g. nitrogen, over the reaction mixture is pref-er~ed.
The reaction may typically be run from about 1 to 15 hours.
The process of the invention results in substanti-ally higher yields than the corresponding known process, which does not employ a metal compound, and which usually results in a mixture of the desired quinazolin-2(1~)-or.e and the corresponding 3,4-dihydro derivative.
The compounds II are either known ~ se or may be prepared from kno~m materials by methods described in the literature.
In the compounds of the formulae I and I~ the (Cl-C8) hydrocarbon radical of Rl may for example be (Cl-C6) alkyl, (C3-C7) cycloalkyl, (C4-C7~ cycloalkylalkyl, having a (C3-C6) cycloalkyl and a (Cl-C2) alkyl portion, phenyl, benzyl or phenethyl. Examples of halo-substituted hydro-carbon radicais for Rl include (Cl-C6) alkyl, mono~, di-or tri-substituted by fluorine, chlorine or bromine and phenyl, benzyl or phenethyl, mono- or di-substituted by fluorine, chlorine or bromine. Di- or tri-halogen substit-uted radicals are preferably substituted by the same halo~en atoms.
In the compounds of the formula I ~ d II, R2 is more preferably a rad~cal of formula III or IV, ~ lll or ~ y IV
l84'7 in which Y and Yl may be the same or different, each signifies a hydrogen, fluorine, chlorine or bromine atom, a (Cl-C3) alkyl or alkoxy radical, or a trifluoromethyl group, provided that when one of Y and Yl signi-fies a trifluoromethyl group, the other signifies a hydrogen atom, and Y2 signifies a hydrogen, fluorine, chlorine or bromine atom, or a (Cl-C3) alkyl or alkoxy radical.
The compounds of formula I are known for their anti-inflammatory activity and in this regard R1 is prefer-ably (Cl-C6) alkyl or cyclopropylmethyl, more preferably (Cl-C6) alkyl, especially isopropyl. R2 is preferably a phenyl radical optionally mono- or di-substituted as indic-ated above, and is more preferably phenyl or ~-fluorophenyl.
R3 and ~4 may each be hydrogen. Preferably, however, at least one is Cl 3-alkyl, in particular methyl, for example in the 7-position, or Cl 3-alkoxy, e.g. methoxy, for example in the 6-position.
Compounds that are most preferably prepared are 7-methyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone and l-isopropyl-4-~-fluorophenyl-7-methyl-2(lH)-quinazolinone.
The following Examples llustrate the process of ~he invention.
'7 ~ 7 ~ 600-6744/X
EX~IPLE 1: 7-Methyl-l-isopropyl-4-~henvl-2(~ g~uina .
inone A mixture of 200 ml of ~-cymene, 40 g of ferric oxide and 7 g of sulphur is heated to reflu~ (ca. 175C), and there is then added thereto dropwise over a period of 40 minutes a hot (130C) solution of 28.2 g of 7-methyl-l-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1Il)-quinazolin-one in 200 ml of ~-cymene. The resulting solution is refluxed for 3.5 hours duriny which time 1.8 ml of water are collected in a Dean Stark separator. The reaction solution is then cooled to 28C and filtered through a Celite pad which is then ~7ashed 4 times each with 25 ml of toluene. Th~ toluene washings are extracted with 50 ml of 4N hydrochloric acid and the ~-cymene filtrate is extracted with 350 ml of 4N hydrochloric acid. T~e ac~d extracts are combined and extracted with 100 ml of toluene~ and such toluene extracts discar~ed. The acid solution remaining after such tolue~e extraction is treated by addition of 350 ml of toluene and 110 g of 50~ aqueous sodium hydroxide solution. The phases are separated and the toluene phase washed twice each with 100 ml of water, followed by drying over sodium sulphate, filtering and evaporation in vacuo. The solid residue is crystallised ~rom ethyl acetate to obtain 7 methyl-l-isopropyl-4-pher.yl-quinazolin-2(1H~-one, m.p. 139-141C.
. ,~.
r ~ '~ .
, - 1$11847 .;
EX~PLE 2~ sopro~yl-4-p-fluoro~henyl-7-methyl-2(lH) quinazolinone A mixture of 67 ml of xylene, 13.3 g of ferric oxide and 2.5 g of sulphur is heated under a nitrogen 5 atmosphere to reflux and there is then added thereto, ;
over a period of 20 minutes drop~Jise, a hot ~100-110C) solution of 10 g of 7-methyl-1-isopropyl-4-~-fluoro-phenyl-5,6,7,8-tetrahydro-2(lH)-quinazolinone in 100 ml of Yylene. The resulting solution is refluxed for 10 hours, during which time water is collected in a Dean Stark separator. The reaction mixture is then cooled to 80C and filtered through a Cellte~iad.
The filtrate and the filter cake are washed 3 times each with 50 ml of toluene. The filtrates are com-bined and then extracted successively with 200, 100 and50 ml of 4N hydrochlorlc acid. The acid extracts are combined and washed with 100 ml of toluene, the toluene extracts being discarded. To the acid solution, remaining after such toluene extraction,aré added 200 ml of toluene and 115 g of 50% aqueous sodium hydroxide solution ~;hilc stirring and cooling. TAe phases are separated and the aqueou~ phase washed twice each with 100 ml of toluene.
~''~' ' .
;
: -.., - . - .
~ '- '" ' ~ ~
84'7 The toluene phases are combined, wached twice each with 100 ml of water, followed by drying over anhydrous magnesium sulphate, filtering through Celite ~
and concentrating to yield 8.8 g (90%) of yellow crystals.
. 5 Recrystallisation occurs from ethylacetate to obtain the title compound with m.p. 175-176.5C.
EX~MPLE 3: 1-Iso~ro~vl-4-Dhenvl-7-methvl-2(1~)-auinazolinone A mixture of 28.2 g of 7-~.ethyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(lH)-quinazolinone, 9.6 g of 10 sulphur, 10 g of sodium hydroxide, 20 g of calcium chloride and 200 ml of carbitol (2-[2-ethoxyethoxy]ethanol~
~s heated under a nitrogen blanket at 150C for 2 hours.
The resulting miY.ture is then cooled to 65C, 500 ml of benzene added and the mixture cooled with stirring to 15C
15 and the liquid phase decanted. The organic phase is washed with ~ater and evaporated to obtain an oil which is dissol-ved in a mixture of 100 ml of benzene and 100 ml of 50~
aqueous hydrochloric acid. The xesultiny mixture is stirred for one hour at room temperature, tr.e phases separated and 20 the acid phase treated with 50 ml of benzene~ The acid phase is neutralised with 50~ sodium hydroxide solution, extracted with 150 ml o~ benzene and the benzene extracts washed with water until neu~ral. ~fter drying over sodium sulphate, the benzene sclution is evapcra~ed to obtain the B
crude product which is recrystallised from ethyl acetate to obtaln l-isopropyl-4-phenyl-7-methyl-2(lH)-quinazolinone, m.p. 141-142C.
EXAMPL~ 4: 7-Methyl-l-isopro~yl-4-(p-fluorophenvl)-quin azolin-2-(lH)-one To a stirred mixture of 4.3 g of sulphur, 6.8 g of zinc oxide and 67 ml of a mixture of xylenes heated to reflux (ca. 138C) under a nitrogen blanket is added a pre-heated (100-115C) solution of 10.0 g of 7-methyl-1-isopropyl-4-(~-fluorophenyl)-5,6,7,8-tetrahydro-2(1~)-quinazolinone in 100 ml of a mixture of xylenes. After addition'(ca. 20 m-nutes), the resulting ~ixture is refluxed overnight, cooled and filtered through Cellte. The solids ~
are washed with toluene and the filtrate and washin~s ex-tracted four times with 4N hydrochloric acid and the extractswashed with 100 ml of toluéne. The aqueous phase is treated with 200 ml of toluene and treated portionwise with 115 g of 50~ sodium hydroxide solution in an ice-bath. The aqueous phase is extracted twice each with 100 ml of toluene and the organic phase water washed and dried. The crude yellow solid obtained on filtering and concentration in vacuo is dissolved in 100 ml of ethyl acetate, filtered and concentrated to a volume o, 50 ml and cooled to 0C to ~ '.
- 11 - 6oo-G744/x obtain a precipitate which is recrystallised from ethyl acetate to yield 7-methyl-1-isopropyl-4~ fluorophenyl)-quinazolin-2(lH)-one.
EXAMPLE 5:
The procedure of Example 4 is repeated employing an equivalent molar amount of lead dioxide in place of zinc oxide to yield the same product.
EXAMPLE 6:
In a manner analogous to any one of the preceding Exampies and employing appropriate starting materials in approximately equivalent amounts, the following compounds may be obtained:-5,7-dimethyl-1-isopropyl-4-phenyl-quinazolin-2~lH)-one;
l-isopropyl-7-methyl-4-(~-methylphenyl)-quinazolin-2(lH)-one;l-isopropyl~7-methyl-4-(2-thienyl)-quinazolin-2(1H)-one;
l-cyciopropylme~hyl-6-methoxy-4-phenyl-quinazolin-2(lH)-one.
Claims (2)
1. A process for the production of a compound of formula I, I
in which R1 signifies a (C1-C8) hydrocarbon radical optionally mono-, di- or tri-substituted with fluoro, chloro or bromo R2 signifies monocyclic aryl, and R3 and R4, which may be the same or different, each signifies a hydrogen atom, a (C1-C3) alkyl or alkoxy radical, or fluorine, chlorine, bromine or trifluoro-methyl, or R3 and R4 together signify 6,7-methylenedioxy, by dehydrogenating a corresponding 5,6,7,8-tetrahydro-
in which R1 signifies a (C1-C8) hydrocarbon radical optionally mono-, di- or tri-substituted with fluoro, chloro or bromo R2 signifies monocyclic aryl, and R3 and R4, which may be the same or different, each signifies a hydrogen atom, a (C1-C3) alkyl or alkoxy radical, or fluorine, chlorine, bromine or trifluoro-methyl, or R3 and R4 together signify 6,7-methylenedioxy, by dehydrogenating a corresponding 5,6,7,8-tetrahydro-
2(1H)-quinazolinone of the formula II, II
in which R1, R2, R3 and R4 are as defined above, with sulphur, in an inert organic solvent, characterised by performing the dehydrogenation in the presence of an inorganic metal compound which is an oxide, hydroxide or salt of a metal, other than magnesium, aluminium, beryllium or an alkali metal, and which forms a metal sulphide under the reaction conditions.
in which R1, R2, R3 and R4 are as defined above, with sulphur, in an inert organic solvent, characterised by performing the dehydrogenation in the presence of an inorganic metal compound which is an oxide, hydroxide or salt of a metal, other than magnesium, aluminium, beryllium or an alkali metal, and which forms a metal sulphide under the reaction conditions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83041177A | 1977-09-06 | 1977-09-06 | |
| US830,411 | 1977-09-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1111847A true CA1111847A (en) | 1981-11-03 |
Family
ID=25256956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA310,645A Expired CA1111847A (en) | 1977-09-06 | 1978-09-05 | Preparation of quinazoline derivatives |
Country Status (28)
| Country | Link |
|---|---|
| JP (1) | JPS5455583A (en) |
| AR (1) | AR228235A1 (en) |
| AT (1) | AT376211B (en) |
| AU (1) | AU523728B2 (en) |
| BE (1) | BE870185A (en) |
| CA (1) | CA1111847A (en) |
| CH (1) | CH642638A5 (en) |
| DD (1) | DD138657A5 (en) |
| DE (1) | DE2837403A1 (en) |
| DK (1) | DK144999C (en) |
| ES (1) | ES473103A1 (en) |
| FI (1) | FI66362C (en) |
| FR (1) | FR2401917A1 (en) |
| GB (1) | GB2003873B (en) |
| GR (1) | GR73605B (en) |
| HU (1) | HU183018B (en) |
| IE (1) | IE47184B1 (en) |
| IL (1) | IL55492A (en) |
| IT (1) | IT1106289B (en) |
| NL (1) | NL7808981A (en) |
| NO (1) | NO782945L (en) |
| NZ (1) | NZ188329A (en) |
| PL (1) | PL114207B1 (en) |
| PT (1) | PT68505A (en) |
| SE (1) | SE7809098L (en) |
| SU (1) | SU900810A3 (en) |
| YU (1) | YU211078A (en) |
| ZA (1) | ZA785061B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH637114A5 (en) * | 1978-08-16 | 1983-07-15 | Sandoz Ag | 2- (N-CARBOALKOXYAMINO) -BENZOPHENONE, THEIR PRODUCTION AND USE. |
| CH645362A5 (en) * | 1979-07-05 | 1984-09-28 | Sandoz Ag | METHOD FOR PRODUCING 4-PHENYL-2 (1H) -QUINAZOLINONES. |
| GB0230015D0 (en) * | 2002-12-23 | 2003-01-29 | Novartis Ag | Organic compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE785937A (en) * | 1971-07-08 | 1973-01-08 | Sandoz Sa | NEW DERIVATIVES OF QUINAZOLINE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
-
1978
- 1978-08-25 CH CH904578A patent/CH642638A5/en not_active IP Right Cessation
- 1978-08-28 DE DE19782837403 patent/DE2837403A1/en not_active Withdrawn
- 1978-08-28 FI FI782619A patent/FI66362C/en not_active IP Right Cessation
- 1978-08-29 DK DK382078A patent/DK144999C/en not_active IP Right Cessation
- 1978-08-29 NO NO782945A patent/NO782945L/en unknown
- 1978-08-29 SE SE7809098A patent/SE7809098L/en unknown
- 1978-08-31 FR FR7825162A patent/FR2401917A1/en active Granted
- 1978-08-31 GB GB7835143A patent/GB2003873B/en not_active Expired
- 1978-09-01 IT IT50936/78A patent/IT1106289B/en active
- 1978-09-01 NL NL7808981A patent/NL7808981A/en not_active Application Discontinuation
- 1978-09-04 IL IL55492A patent/IL55492A/en unknown
- 1978-09-04 JP JP10769178A patent/JPS5455583A/en active Pending
- 1978-09-04 NZ NZ188329A patent/NZ188329A/en unknown
- 1978-09-04 PT PT68505A patent/PT68505A/en unknown
- 1978-09-04 IE IE1780/78A patent/IE47184B1/en unknown
- 1978-09-04 BE BE190237A patent/BE870185A/en not_active IP Right Cessation
- 1978-09-05 HU HU78SA3133A patent/HU183018B/en unknown
- 1978-09-05 YU YU02110/78A patent/YU211078A/en unknown
- 1978-09-05 ES ES473103A patent/ES473103A1/en not_active Expired
- 1978-09-05 SU SU782658400A patent/SU900810A3/en active
- 1978-09-05 CA CA310,645A patent/CA1111847A/en not_active Expired
- 1978-09-05 PL PL1978209423A patent/PL114207B1/en unknown
- 1978-09-05 AU AU39571/78A patent/AU523728B2/en not_active Expired
- 1978-09-05 AR AR273577A patent/AR228235A1/en active
- 1978-09-05 AT AT0639978A patent/AT376211B/en not_active IP Right Cessation
- 1978-09-05 DD DD78207656A patent/DD138657A5/en unknown
- 1978-09-06 ZA ZA785061A patent/ZA785061B/en unknown
-
1980
- 1980-01-04 GR GR57147A patent/GR73605B/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3723432A (en) | 1-substituted-4-aryl-2(1h)-quinazolinones and their preparation | |
| US3700673A (en) | 3-4-dihydrobenzo(b) (1,7)naphthyridin-1(2h)-ones | |
| CA1215712A (en) | Ortho substituted dihydroxy-2(1h) quinazolinone-1- alkanoic acids | |
| CA1151652A (en) | 3-(alkylthio, alkylsulphinyl or alkylsulphonyl)-4- quinolones | |
| CA1049521A (en) | Process for preparing 3,4-dihydro-2(1h)-quinazolinone derivatives | |
| CA1111847A (en) | Preparation of quinazoline derivatives | |
| HU183048B (en) | Process for producing bracket-2s,3r-bracket closed-, bracket-2s,3s-bracket closed-, bracket-2rs,3r-bracket closed- or bracket-2rs,3rs-bracket closed-3-amino-2-hydroxy-propionyl-glycine derivatives | |
| US4556739A (en) | 3,4-Dialkoxy-2-alkylcarbonyl analino compounds | |
| US4171441A (en) | Preparation of quinazolin-2(1H)-ones | |
| US4639518A (en) | Substituted quinazolinediones | |
| US3960856A (en) | Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide | |
| SU591149A3 (en) | Method of preparing derivatives of triazoloisoquinoline | |
| US2948726A (en) | New phenazine derivatives | |
| US3926993A (en) | Process for production of quinazoline derivatives | |
| Abdel-Rahman et al. | SYNTHESIS OF SOME NEW THIENO [2, 3-b] PYRIDINES, PYRIDO [3′, 2′: 4, 5]-THIENO [3, 2-d] PYRIMIDINES AND PYRIDO [3′, 2′: 4, 5] THIENO [3, 2-d][1, 2, 3]-TRIAZINES | |
| CA1287051C (en) | Phenylpiperazine derivatives and their acid addition salts | |
| KR820001716B1 (en) | Process for preparing 4-aryl-quinazoline-2(1h)-ones | |
| CA1095914A (en) | 4-hydroxy-2-quinolinone-3-carboxylic acid compounds | |
| PL119712B1 (en) | Process for preparing 6-piperidin-2,4-diaminopyrimidine 3-oxideina | |
| US4617392A (en) | 4-alkyl-5,6-methylenedioxy-2-1[H]-quinazolinones useful as cardiotonic agents | |
| EP0270201B1 (en) | A method for the preparation of a 2,4-diamino-3-oxy-pyrimidine derivative | |
| RU1838309C (en) | Method of synthesis of quinazoline derivatives or their pharmaceutically acceptable acid-additive salts | |
| SU474985A3 (en) | The method of obtaining 1-alkyl-4-phenyl-2 (1H) quinazolinone | |
| CA1224468A (en) | Ortho substituted dihydroxy-2(1h)quinazolinone-1- alkanoic acids | |
| Agui et al. | Studies on quinoline derivatives and related compounds. IV. Synthesis of 4‐substituted 1‐alkyl‐1, 4‐dihydro‐3‐quinolinecarboxylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |