IE47184B1 - Improvements in or relating to organic compounds - Google Patents

Improvements in or relating to organic compounds

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Publication number
IE47184B1
IE47184B1 IE1780/78A IE178078A IE47184B1 IE 47184 B1 IE47184 B1 IE 47184B1 IE 1780/78 A IE1780/78 A IE 1780/78A IE 178078 A IE178078 A IE 178078A IE 47184 B1 IE47184 B1 IE 47184B1
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IE
Ireland
Prior art keywords
process according
alkyl
signifies
quinazolinone
substituted
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IE1780/78A
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IE781780L (en
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Sandoz Ltd
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Publication of IE781780L publication Critical patent/IE781780L/en
Publication of IE47184B1 publication Critical patent/IE47184B1/en

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    • 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]

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  • 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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

A process for producing 4-aryl- quinazolin-2(1H)-ones comprises dehydrating a corresponding 4-aryl- 5,6,7,8-tetrahydro-2(1H)- quinazolinone with sulphur in an inert organic solvent, in the presence of an inorganic metal oxide, hydroxide or salt (other than of magnesium, aluminium or an alkali metal), which forms a metal sulphide under the reaction conditions. The products are known as anti- inflammatory agents.

Description

This invention relates to a process for the preparation of 4-aryl-quinazoline-2(lH)-ones, in particular a compound of formula I, in which R^ signifies a (C^-Cg) hydrocarbon radical optionally mono-, di or tri-substituted with fluoro, chloro or bromo, Rg signifies monocyclic aryl, and Rg and R^, which may be the same or different, each signifies a hydrogen atom, a (C^-Cg) alkyl or alkoxy radical, or fluorine, chlorine, bromine or trifluoromethyl, or Rg and R^ together signify 6,7methylenedioxy, by dehydrogenating a corresponding 4-aryl-5,6,7,8-tetrahydro-2(lH)-quinazolinone, in particular a compound of . 15 - 2 formula II, in which R^, , Rj and R^ 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, aluminberyllium iuniyor an alkali metal, and which forms a metal sulphide under the reaction conditions.
The process of the invention is suitably effected 10 at temperatures in the range of from 125° to 250°C, preferably 130° to 200°C and more preferably in the range 135° to 170°C.
The reaction is carried out in an organic solvent inert under the reactive conditions. Preferred solvents include ethylene glycol, propylene glycol, ethoxyethoxyethanol, dioxane, toluene, xylene and p-cymene. It is generally preferred to employ a solvent boiling at the desired reaction temperature in order to utilise reflux conditions, e.g. p-cymene under the more preferred temp20 erature conditions.
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 : 1 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. Preferred metals include calcium, titanium, zirconium, chromium, lead, molybdenum, manganese, 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, particularly an oxide. The preferred metal compounds include calcium oxide, zinc oxide and, in particular, ferric oxide. A number of the metal compounds which may be used, e.g. calcium chloride, react vrith 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 4 7184 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 quinazolinone 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 preferably 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 preferably 2 to 3 : 1 The process of the present invention may be effected under sub- or super-atmospheric pressure but is most suitably carried out under atmospheric pressure. A blanket or constant flow of a. gas, inert under the reaction conditions, e.g. nitrogen, over the reaction mixture is preferred.
The reaction may typically be run from about 1 to hours. - 5 The process of the invention results in substantially 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(1H)-one and the corresponding 3,4-dihydro derivative.
The compounds II are either known per se or may be prepared from known materials by methods described in the literature.
In the compounds of the formulae I end II, the 10 (C^-Cg) hydrocarbon radical of may for example be (C^-Cg) alkyl, (Cg-C?) cycloalkyl, (C^-C^) cycloalkylalkyl, having a (Cg-Cg) oycloalkyl and a (C^-Cg) alkyl portion, phenyl, benzyl or phenethyl. Examples of halo-substituted hydrocarbon radicals for R^ include (C^-Cg) alkyl, mono-, di15 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 substituted radicals are preferably substituted by the same halogen atoms.
In the compounds of the formula I and II, Rg is more preferably a radical of formula III or IV, in which Y and Y^ may be the same or different, each signifies a hydrogen, fluorine, chlorine or bromine atom, a (C^-Cg) alkyl,or alkoxy radical, or a trifluoromethyl group, provided that when one of Y and Y^ signifies a trifluoromethyl group, the other signifies a hydrogen atom, and Yj signifies a hydrogen, fluorine, chlorine or bromine atom, or a (C^-Cg) alkyl or alkoxy radical.
The compounds of formula I are known for their anti-inflammatory activity and in this regard is preferably (Cy-C/) alkyl or cyclopropylmethyl, more preferably (C^-Cg) alkyl, especially isopropyl. Rg is preferably a phenyl radical optionally mono- or di-substituted as indicated above, and is more preferably phenyl or £-fluorophenyl. Rg and R^ may each be hydrogen. Preferably, however, at least one is C^g-alkyl, in particular methyl, for example in the 7-position, or C^_g-alkoxy, e.g. methoxy, for example in the 6-position.
Compounds that are most preferably prepared are 7-methyl-l-isopropyl-4-phenyl-2(IH)-quinazolinone and l-isopropyl-4-£-fluorophenyl-7-methyl-2(IH)-quinazolinone.
The following Examples illustrate the process of the invention. - 7 EXAMPLE 1: 7-Methyl-l-lsopropyl-4-phenyl-2(IH)-quinazol' inone A mixture of 200 ml of g-cymene, 40 g of ferric oxide and 7 g of sulphur is heated to reflux (ca. 175°C), and there is then added thereto dropwise over a period of 40 minutes a hot (130°C) solution of 28.2 g of 7-methyll-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(IH)-quinazolinone in 200 ml of g-cymene. The resulting solution is refluxed for 3.5 hours during which time 1.8 ml of water are collected in a Dean Stark separator. The reaction solution is then cooled to 28°C and filtered through a Celite pad which is then washed 4 times each with 25 ml of toluene. The toluene washings are extracted with 50 ml of 4N hydrochloric acid and the g-cymene filtrate is extracted with 350 ml of 4N hydrochloric acid. The acid extracts are combined and extracted with 100 ml of toluene, and such toluene extracts discarded. The acid solution remaining after such toluene 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 from ethyl acetate to obtain 7-methyl-l25 isopropyl-4-phenyl-quinazolin-2(lH)-one, m.p. 139-141°C. - 8 EXAMPLE 2: 1-Isopropyl-4-p-fluorophenyl-7-roethyl-2(IH) 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 atmosphere to reflux and there is then added thereto, over a period of 20 minutes dropwise, a hot (100-110°C) solution of 10 g of 7-methyl-l-isopropyl-4-£-fluoropheny1-5,6,7,8-tetrahydro-2(IH)-quinazolinone in 100 ml of xylene. 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 80°C and filtered through a celite (Trademark) pad.
The filtrate and the filter cake are washed 3 times each with 50 ml of toluene. The filtrates are com15 bined and then extracted successively with 200, 100 and 50 ml of 4N hydrochloric 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,are added 200 ml of toluene and 115 g of 50% aqueous sodium hydroxide solution while stirring and cooling. The phases are separated and the aqueous phase washed twice each with 100 ml of toluene. - 9 The toluene phases are combined, washed twice each with 100 ml of water, followed hy drying over anhydrous magnesium sulphate, filtering through Celite and concentrating to yield 8.8 g (90%) of yellow crystals.
Recrystallisation occurs from ethylacetate to obtain the title compound with m.p. 175-176.5°C.
EXAMPLE 3; 1-Isopropy1-4-pheny1-7-methy1-2 (IH)-quinazolinone A mixture of 28.2 g of 7-methyl-l-isopropyl-4phenyl-5,6,7,8-tetrahydro-2(IH)-quinazolinone, 9.6 g of sulphur, 10 g of sodium hydroxide, 20 g of calcium (Trademark) chloride and 200 ml ofCarbitol y (2-[2-ethoxyethoxy]ethanol) is heated under a nitrogen blanket at 150°C for 2 hours.
The resulting mixture is then cooled to 65°C, 500 ml of benzene added and the mixture cooled with stirring to 15°C and the liquid phase decanted. The organic phase is washed with water and evaporated to obtain an oil which is dissolved in a mixture of 100 ml of benzene and 100 ml of 50% aqueous hydrochloric acid. The resulting mixture is stirred for one hour at room temperature, the phases separated and the acid phase treated with 50 ml of benzene. The acid phase is neutralised with 50% sodium hydroxide solution, extracted with 150 ml of benzene and the benzene extracts washed with water until neutral. After drying over sodium sulphate, the benzene solution is evaporated to obtain the - 10 crude product which is recrystallised from ethyl acetate to obtain l-isopropyl-4-phenyl-7-methyl-2(IH)-quinazolinone, m.p. 141-142°C.
EXAMPLE 4i 7-Methyl-l-isopropyl-4-(p-fluorophenyl)-quin5 azolin-2(IH)-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. 138°C) under a nitrogen blanket is added a pre-heated (100-115°C) solution of 10.0 g of 7-methyl-ΙΙΟ isopropyl-4-(£-fluorophenyl)-5,6,7,8-tetrahydro-2(1H)quinazolinone in 100 ml of a mixture of xylenes. After addition (ca. 20 minutes), the resulting mixture is refluxed overnight, cooled and filtered through Celite. The solids are washed with toluene and the filtrate and washings ex15 tracted four times with 4N hydrochloric acid and the extracts washed with 100 ml of toluene. 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 agueous phase is extracted twice each with 100 ml of toluene and the organic phase water washed and dried. The crude yellcw solid obtained on filtering and concentration in vacuo is dissolved in 100 ml of ethyl acetate, filtered and concentrated to a volume of 50 ml and cooled to 0°C to 4718 - 11 obtain a precipitate which is recrystallised from ethyl acetate to yield 7-methyl-l-isopropy 1-4-(jo-f luorophenyl) quinazolin-2(IH)-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 10 Examples and employing appropriate starting materials in approximately equivalent amounts, the following compounds may be obtained:5,7-dimethyl-l-isopropyl-4-phenyl-quinazolin-2(IH)-one; l-isopropyl-7-methyl-4- (ja-me thy Iphenyl) -quinazolin-2 (IH) 15 one; l-isopropyl-7-methyl-4-(2-thienyl)-quinazolin-2(IH)-one; l-cyclopropylmethyl-6-methoxy-4-phenyl-guinazolin-2(IH)-one

Claims (24)

1. ' j. .-ucons for the· production c r .? 4--.·.·. ·· quinazoJin-2 (]'l)-cne by dehydrogenating a correspond!n 4-ary 1- 5,6,7,f'-: ·' --tr «hydro-2 (111) -quinazolinone wi th sv 1 !h? in an inert organic solvent, characterised in that il-c dehydrogenation is effected in the presence cf an inorganic metal compound which is an oxide, hydroxide or salt of a beryllium metal, other than magnesium, aluminium,or an alkali metal, imd which forms a metal sulphide under the reaction conditions .
2. A process for the production of a compound of formula T, R 3 R ? in which R^ signifies a (C^-Cg) hydrocarbon radical optionally mono-, di- or tri-substituted with fluoro, chloro or bromo .signifies monocyclic aryl, and Rg and R^, which may be the same or different, each signifies a hydrogen atom, a (c -Cg) alkyl or alkoxy radical, or fluorine, chlorine, bromine or trifluoromethyl, or Rg and R^ togollier signify 6,7methylenedioxy, - 13 by dehydrogenating a corresponding 5,6,7,8-tetrahydro2 (IH)-quinazolinone of the formula H, in which R^, Rj, R^ and R^ are as defined above, with sulphur, in an inert organic solvent, characterised 5 by performing the dehydrogenation in the presence of an inorganic metal compound which is an oxide, hydroxide or salt beryllium of a metal, other than magnesium, aluminium,^ or an alkali metal, and which forms a metal sulphide under the reaction conditions.
3. A process according to Claim 1 or 2, in which the dehydrogenation is carried out at a temperature of from 125-250°C, in which the mol ratio of sulphur to tetrahydroquinazolinone starting material is at least 1.7 : 1 and in to which the mol ratio of inorganic metal compound^ tetrahydroquinazolinone starting material is at least 1:1.
4. A process according to Claim 3, in which the temperature is from 130-200°C.
5. A process according to Claim 4, in which the temperature is from 135-170°C. - 14
6. A process according to any one of Claims 3 to 5, in which the mol ratio of sulphur to the tetrahydroquinazolinone starting material is from 1.9 : 1 to 4 : 1.
7. A process according to Claim 6, in which the 5 mol ratio is in the range of 2:1 to 3:1.
8. A process according to any one of Claims 3 to 7, in which the mol ratio of inorganic metal compound to the tetrahydroquinazolinone starting material is from 1.8 : 1 to 6 : 1.
9. 10 9. A process according to Claim 8, in which the ratio is from 2 : 1 to 4 : 1. 10. A process according to Claim 9, in which the ratio is from 2.1 : 1 to 3 : 1.
10. 11. A process according to any one of claims 15 2 to 10, in which the (Cg-Cg) hydrocarbon radical of Rg is (Cg-Cg) alkyl, optionally mono-, di- or tri-substituted by fluorine, chlorine or bromine, (Cg-Cy) eycloalkyl, cycloalkylalkyl, having a (Cg-Cg) eycloalkyl and a (Cg-Cg) alkyl portion, or phenyl, benzyl or phenethyl, optionally 20 mono- or di-substituted by fluorine, chlorine or bromine.
11. 12. A process according to any one of claims 2 to 11, in which Rg signifies a radical of formula III or IV, - 15 in which Y and Y may be the same or different, each signifies a hydrogen, fluorine, chlorine or bromine atom, a (Cg-Cg) alkyl or alkoxy radical, or a trifluoromethyl group, 5 provided that when one of Y and Yg signifies a trifluoromethyl group, the other signifies a hydrogen atom, and Y 2 signifies a hydrogen, fluorine, chlorine or bromine atom, or a (Cg-Cg) alkyl 10 or alkoxy radical.
12. 13. A process according to Claim 11 or 12, in which Rg is (Cg-Cg) alkyl or cyclopropylmethyl.
13. 14. A process according to Claim 13, in which Rg is (Cg-Cg) alkyl.
14. 15 15. A process according to Claim 14, in which Rg is isopropyl.
15. 16. A process according to any one of claims 2 to 15, in which Rg is phenyl, unsubstituted, mono- or di-substituted with fluoro, chloro, bromo, (Cg-Cg) alkyl or 20 alkoxy, or mono-substituted by trifluoromethyl.
16. 17. A process according to Claim 16, in which Rg is phenyl or £-fluorophenyl. - 16 in which at
17. 18. A process according to any one of claims 2 to 17,/ least one of R^ and R^ is (C^-C 3 )alkyl.
18. 19. A process according to Claim 18, in which at least one of R^ and is methyl. 5
19. 20. A process according to Claim 19, in which the 7-position is occupied by methyl.
20. 21. A process according to any one of Claims 1 to 20, for the production of 7-methyl-l-isopropyl~4-phenyl2 (lH)-quinazolinone. 10
21.
22. A process according to any one of Claims 1 to 20 for the production of l-isopropyl-4-g-fluorophenyl7-methyl-2(IH)-quinazolinone.
23. A process for the production of 4-ary1-2(1H)quinazolinone, substantially as herein described with 15 reference to any one of the Examples.
24. A 4-ary1-2(IH)-quinazolinone, whenever produced by a process according to any one of the preceding Claims,
IE1780/78A 1977-09-06 1978-09-04 Improvements in or relating to organic compounds IE47184B1 (en)

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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)

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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.

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BE785937A (en) * 1971-07-08 1973-01-08 Sandoz Sa NEW DERIVATIVES OF QUINAZOLINE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS

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FI66362B (en) 1984-06-29
AR228235A1 (en) 1983-02-15
FI66362C (en) 1984-10-10
FR2401917B1 (en) 1982-12-17
ATA639978A (en) 1984-03-15
GR73605B (en) 1984-03-26
IE781780L (en) 1979-03-06
DK382078A (en) 1979-03-07
SE7809098L (en) 1979-03-07
DK144999B (en) 1982-07-26
HU183018B (en) 1984-04-28
AU523728B2 (en) 1982-08-12
CA1111847A (en) 1981-11-03
PL209423A1 (en) 1979-06-04
GB2003873B (en) 1982-03-10
PL114207B1 (en) 1981-01-31
PT68505A (en) 1978-10-01
AT376211B (en) 1984-10-25
YU211078A (en) 1982-10-31
IL55492A0 (en) 1978-12-17
ZA785061B (en) 1980-04-30
ES473103A1 (en) 1979-04-01
NL7808981A (en) 1979-03-08
FR2401917A1 (en) 1979-03-30
IT1106289B (en) 1985-11-11
NO782945L (en) 1979-03-07
CH642638A5 (en) 1984-04-30
BE870185A (en) 1979-03-05
DE2837403A1 (en) 1979-03-08
JPS5455583A (en) 1979-05-02
FI782619A (en) 1979-03-07
SU900810A3 (en) 1982-01-23
GB2003873A (en) 1979-03-21
IL55492A (en) 1982-08-31
DD138657A5 (en) 1979-11-14
IT7850936A0 (en) 1978-09-01
AU3957178A (en) 1980-03-13
DK144999C (en) 1982-12-13
NZ188329A (en) 1981-05-15

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