SU900810A3 - Process for producing 4-arylquinazoline-2-/1h/-ons - Google Patents

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

soba they did not exceed the specified value.

The purpose of the invention is to increase the yield of target products.

This goal is achieved by the fact that according to the method for producing 4-arylquinazolin-2 (1H) -ones of general formula I, the fact that 4-aryl-4,6,7,8-tetrahydro-2 (1H) -heena zolinone of the above General formula II, where R, Rj, Rj and RI have the above values, is subjected to dehydrogenation by the action of sulfur in an inert organic solvent medium when heated to 125250 ° C, in the presence of an oxide or iron (III) salt of zinc, lead or calcium.

The molar ratio of sulfur to the starting tetrahydroquinazolinone is preferably 1.9: 1-4: 1. The molar ratio of the oxide or salt of iron (III), zinc, lead, or calcium and the initial tetrahydroquinazolinone is 1.8: 1-6: 1.

A distinctive feature of the process is to conduct dehydrogenation in the presence of an oxide or salt of iron (III), zinc, lead, or calcium at 125-250 ° C.

Example 1. 7-Methyl-1-1-isopropip-4-h}) E1-1-2 (III) -quinazolinone.

A mixture of 200 MP of p-cumope, 40 g of iron (III) oxide and 7 g of sulfur is heated to reflux (about) and then a hot () solution of 28.2 g of 7-metric acid is added dropwise over 40 min. -1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2 (IH) -quinazolinone in 200 Kp p-cumene. The resulting solution was boiled for 3.5 hours, during which time 1.8 ml of water was collected in a Dean-Stark trap. Then the reaction solution is cooled to and filtered through a plate of celite, which is then washed with toluene (4 X 25 mp). The toluene washings were extracted with 50 ml of 4N hydrochloric acid, and the n-cumene filtrate was extracted with 350 ml of 4N hydrochloric acid. The acidic extracts are collected and extracted with toluene and the toluene extract is discarded. The acidic solution remaining after extraction is treated by adding 350 mp of toluene and PO g of a 50% aqueous solution of sodium hydroxide. Phases are harvested and. The luol phase is washed with water (2 X 100 mp) and then dried.

over sodium sulfate, filter, and evaporate in vacuo to 1-1e. The solid residue is crystallized from ethipacetate to give 7-nethyl-1-isopropyl-4-fe1-hl-quinazolin-2 (H) -one. . T.gsh. ng-ul C. Yield 72%.

Example 2. 1-Isopropip-4- (p-fluorophenyl) -7-methyl-2 (1H) -quinazolinone.

A mixture of 67 ml of xylene, 13.3 g of iron oxide and 2.5 g of sulfur is heated to reflux under a nitrogen atmosphere and then a hot (100-110 °) solution is added dropwise over 20 minutes

5 10 g 7-metsh1-1-isopropsh1-4- (p-fluorophenyl) -5,6, 7, .8-tetrahydro-2 (1H) -quinazolinone in 100 ml of xylene. The resulting solution was boiled for 10 hours during which water was collected in a Dean-Stark trap. The reaction mixture is then cooled to 80 ° and filtered through a filter.

The filtrate and the filter residue were washed with toluene (3 x 50 mp), the filtrate was collected and then extracted successively with 200, 100 and 50 ml of 4N hydrochloric acid. Acid extracts are collected and washed with 100 ml of toluene, the toluene layers are discarded.

To the acidic solution remaining after extraction, add 200 ml of toluene and 115 g of a 50% aqueous solution of caustic soda with stirring and cooling. The phases are separated and the aqueous phase is washed with toluene (2 "100 ml).

The toluene layers were collected, washed with water (2 S 100 ml), then dried over anhydrous magnesium sulphate, filtered through celite and concentrated to obtain 8.8 g (90%) of yellow crystals. Crystallization from ztiratelt get the specified connection with so pl. 175-176,5 ° C. Yield 67%.

Example 3. 1-Isopropyl-4-phenyl-7-me. Tm1-2 (1H) -quinazolinone.

A mixture of 28.2 g of 7-methyl-1-isopropyl-4-phenyl-5, 8-tetrahydro-2 (1H) -quinazolinone, .9.6 g of sulfur, 10 g of sodium hydroxide, 20 g of calcium chloride

Claims (3)

and 200 ml of carbitol (2- (2-ethoxyethoxy, si) ethanol) are heated under a layer of nitrogen at 150 for 2 hours. The mixture is cooled to 65, 500 ml of benzene is added and the mixture is cooled with stirring to 15 ° and the water is cooled layer. The organic layer was poured with water and evaporated, a semi-finished oil which was dissolved in a mixture of 100 ml of benzene and 100 ml of 50% aqueous hydrochloric acid. The resulting mixture is stirred for I h at a temperature of about 20 °, the layers are separated and the acid layer is treated with 50 ml of benzene. The acidic layer is neutralized with 50% sodium hydroxide solution, extracted with 150 ml of benzene, and the benzene extracts are washed with water until neutral wash water. After drying over sodium sulfate, the benzene solution is evaporated with KIT to obtain a crude product, which is crystallized from ethyl acetate. 1-isopropyl-4-phenyl-7-methyl-2 (1H) -quinazolinone is obtained. M.p. 141142 S. Yield 56%. . Example 4. 7-Methyl-1-isopropyl-4- (p-fluorophenyl) -quinazolin-2 (1H) -one. A pre-heated (100-115) solution of 10.0 g is added to a stirred mixture of 4.32 g of sulfur, 6.8 g of zinc oxide and 67 ml of a mixture of xylenes heated to boiling under reflux (about 135 °) under nitrogen atmosphere. -metsh1-I-isopropyl-4- (p-fluorophenyl) -5, 6,7,8-tetrahydro-2 (1H) -quinazolino in 100 ml of a mixture of xylenes. The resulting after addition (for about 20 minutes) the mixture is boiled overnight, cooled and filtered through celite. The filter residue is washed with toluene and ptrat and the washings are extracted four times with 4N hydrochloric acid and the extract is washed with 100 ml of toluene. The aqueous layer is treated with 200 ml of toluene and 115 g of 50% sodium hydroxide solution are added in portions in an ice bath in portions. The aqueous layer was extracted with toluene (2 X 100 ml) and the organic layer was washed with water and dried. The crude solid obtained after filtration and concentration under vacuum is dissolved in 100 ml of ethyl acetate, filtered, concentrated to a volume of 50 ml, cooled to a CP. The resulting precipitate was crystallized from ethyl acetate to give 7-methyl-1-isopropyl-4- (p-fluorophenyl) quinazolin-2 (1H) -one. Yield 71% m.p. 175-176,54. Example 5. Analogous to Example 4, except that an equivalent molar amount of lead dioxide was used instead of zinc oxide, the same product 6 was obtained in 80% yield, which contained 50% of the compound. The final yield is 40%. Example 6. A method similar to that described in any of the previous examples, using the corresponding starting materials in equivalent amounts, gives the following compounds: 5,7-dimethyl-1-isopropyl-4-phenyl-quinazolin-2 (1H) -one. Yield 68%. M.p. 145-147 C, 1-isopropyl-7-metip-4- (p-topyl) -quinazolin-2 (1H) -QH. Yield 64%. M.p. 156-157 ° C; 1-isopropyl-7-methyl-4- (2-thienyl) quinazolin-2 (b-on. Yield 45%. M.P. 154-156 ° C; 1-cyclopropylmethyl-6-methoxy-4 phenyl-quinazoline- 2 (1H) -one. Yield 68%. M.P.I5-116 ° C. The proposed method of producing 4-arylquinazolin-2 (1H) -omes allows to obtain celeas products with yields of 40-72%. For example, yield 7- Methyl-1-isopropyl-4-phenyl-2 (lH) -xinazo-linone according to the proposed method is 72%, which is 2 times higher than the yield of this compound obtained by a known method. (1H) -ones of the general formula where RR, is C {-alkyl; Cii-alkyl, Cj. (, Is cycloalknl, xj is f nyl or phenyl substituted at the para position with C;, alkyl, a fluorine atom, or oC-thienyl Rj is a hydrogen atom or Ci-j-alkyl, R is C, .j-alkyl or C, .5-alkoxy, dehydrogenating 4-aryl-4,6,7,8-tetrahydro-2 (1H) -quinazolinone with the general formula P 79 where R, R, R j and R have the above values, the effect of sulfur in an inert organic solvent medium, when heated, is different that, in order to increase the yield of the target products, the reaction is carried out in the presence of an oxide or salt of iron (III), zinc, lead calcium, at 125-250 C. 2. The POP.1 method, distinguished by the fact that the molar ratio of sulfur and initial tetrahydroquinazolinone is 1.9: 1-4: 1. 0 3. The method according to paragraphs. 1 and 2, which is based on the fact that the molar ratio of the oxide or salt of iron (III), zinc, lead, or calcium and the initial tetrahydroquinazolinone is 1.8: 1-6: 1. Sources of information taken into account in the examination 1. Austrian patent number 338279, cl. C 07 D 239/80, published 1977 (prototype).