FI66362B - PROCEDURE FOR FRAMSTATION OF AV 4-ARYL-QUINAZOLIN-2 (1H) -ON - Google Patents

Description

R3 ^ 7I fBl Advertisement, announcement ,,, .- jjäSTgk W () UTLÄGGNI NGSSKMFT 6 6362 (S1) K ».lk ^ a.3 c 07 D 239/82, 409/04 ENGLISH I —Fl N LAN D (21 ) PK «nuih * k« nu * —P «« nt * n * eki> lnj 782619 (22) HakamlaplM — AMBknbif ^ ic 28.08.78 (Fl) (23) AlkupUvi — Glttl (k «c * daf 28.08.78 (41) TnHut (ulklMkit —BlhrH offaMNf 07.03.79

Patent and Registration Office / 4 «ΝίΜΜΜρΜοη | aka« t | «lkaiMa» date— 29.06.84

Patani-OCh is described by AmOkan vtb ^ d odt vctskrtftan piMIcifil (32) (33) (31) Pjrrdenr «uelknit-B ^ lrt prior ** 06.09.77 USA (US) 830411 (71) Sandoz AG, CH-4002 Basel , Switzerland-Switzerland (CH) (72) Joseph Antonio Smith, Fanwood, New Jersey, USA (74) Oy Kolster Ab (54) Process for the preparation of 4-aryl-quinazolin-2 (1H) -one -Förfarande för The present invention relates to a process for the preparation of 4-aryl-quinazoline of formula 1 R 1 \ 1H-1N-1N-quinazolin-2 (1H) -one. - »o II i

Kv J N

Y 'Y

R3 li-

Where ^.

R 1 represents C 1-8 alkyl or. C4-8-cycloa1kyl, K1 'R_ denotes a -phenyl group which, optionally, is substituent, C1-3-alkyl or halogen, or a thienyl group FU and R-, which may be the same or different. each a hydrogen atom or a β-alkyl or a-1 coke group, ···

Removal of hydrogen from the corresponding 4-aryl-5,6,7,8-tetrahydro 2 (1H).

66362

quinazolinone of formula II

4 f

R I

X '' C = G

Il I II

Ύ'Χ.

R 1, R 2, R 3, R 3 and R 2 are as defined above, in sulfur in an inert organic solvent.

A process for the removal of hydrogen from 1-alkyl-4-phenyl-5,6,7,2-tetrahydro-2 (1H) -quinazolinones by sulfur is known, for example, from GB Patent Publication No. 1,335,255.

However, the process according to the invention generally gives higher yields than the corresponding known processes which do not use a metal compound and which usually give a mixture of the desired quinazolin-2 (1H) -one and the corresponding 3,4-dihydro derivative.

This is evident, for example, from the experiments performed by the applicant, in which the yield of 7-methyl-1-isopropanyl-4-phenyl-2 (1H) -quinazolinone was obtained by the method of GB Patent Publication 1 3Θ3 255 only 35%, while the yield of the same compound was obtained by the method of the present invention. 72%.

The process according to the invention is characterized in that the dehydrogenation is carried out in the presence of an inorganic metal compound which is an oxide, hydroxide or salt of a metal other than magnesium, aluminum, beryllium or an early metal and which forms a metal sulphide under the reaction conditions.

The process according to the invention is preferably carried out at a temperature of 130-200 ° C and most preferably in the range 135-170 ° C.

The reaction is carried out in an organic, reaction-neutral solvent. Preferred solvents are ethylene glycol, propylene glycol, ethoxyethoxyethanol, dioxane, toluene, xylene and p-cymene. In general, it is preferable to use a solvent boiling at the desired reaction temperature in order to take advantage of boiling conditions, e.g., β-simunone under the preferred temperature conditions.

The molar ratio of sulfur to the starting quinazolinone 3 66362 can vary over a relatively wide range, but a suitable ratio is at least 1: 7: 1. The upper limit is not particularly critical, but it is unnecessary and inefficient to use sulfur to an extent where the molar ratio is greater than 6: 1. Preferably, the molar ratio is in the range of 2: 1 to 3: 1.

The metal compound used is a compound which forms a sulfide under the reaction conditions. In addition to alkali metals and magnesium, beryllium and aluminum, for practical reasons rare earth metals and metals with an atomic number greater than 84 are not recommended. Preferred metals are calcium, titanium, zirconium, chromium, lead, molybdenum, manganese, iron, tin, cobalt, nickel, palladium, copper, silver, zinc, cadmium, mercury, antimony and bismuth, most preferably calcium, iron or zinc. The metal compound may be a salt, e.g. a salt of a strong acid, such as a halide, e.g. chloride, sulphate or nitrate, but it is mainly an oxide or hydroxide, especially an oxide. Preferred metal compounds are calcium oxide, zinc oxide and especially ferric oxide. Several useful metal compounds, e.g., lithium chloride, react with hydrogen sulfide to form an acidic medium, and the metal sulfides formed tend to be unstable or soluble in such a medium. In such cases, it is recommended to include in the reaction mixture a hydroxide base, e.g., an alkali metal hydroxide or an alkaline earth metal hydroxide, or an excess of a metal compound when it is a hydroxide base. Alkali metal hydroxide, e.g. potassium or sodium hydroxide, is mainly used.

A suitable molar ratio of the Meta 11 compound to the quinazolinone starting material is at least 1: 1, most preferably at least 1.5: 1. The upper limit is not critical, but molar ratios above 10: 1 do not offer any additional advantages. A more suitable molar ratio is in the range of 1.8: 1 to 6: 1, mainly in the range of 2: 1 to 4: 1, and more preferably in the range of 2.1: 1 to 3: 1.

When a hydroxide base is used, a suitable molar ratio of quinazolinone to the starting material is at least 1: 1, suitably at least 1.5: 1, preferably 1.8-6: 1, most preferably 2-3: 1.

The process of the present invention may be carried out at a pressure lower or higher than atmospheric pressure, but is most preferably carried out at atmospheric pressure. It is recommended that the reaction mixture be protected by a continuously flowing gas inert to the reaction, e.g. nitrogen.

The typical reaction time is about 1 to 15 hours.

Compounds II are either known or can be prepared from known substances by methods described in the literature.

The compounds of the formula I are known for their anti-inflammatory activity.

In the compounds of formula I, R 1 is preferably isopropyl and is preferably phenyl or E-fluorophenyl, R 3 and R 2 may each be hydrogen. Preferably, however, at least one is C 1-6 alkyl, in particular methyl, for example in the / position, or C 1-2 alkoxy, e.g. methoxy, for example in the 6-position.

The most preferred compounds are 7-methyl-1-isopropyl-4-phenyl-2 (1H) -quinazolinone and 1-isopropyl-4H-fluorophenyl-7-methyl-2 (1H) -quinazolinone.

The following examples illustrate the method of the invention.

Example 1 7-Methyl-1-isopropyl-4-phenyl-2 (1H) -quinazolinone

A mixture of 200 ml of E-cymene, 40 g of ferric oxide and 7 g of sulfur is heated to boiling point (about 175 ° C) and then a hot solution (130 ° C) of 28.2 g of 7 ° C is added dropwise over 40 minutes. -methyl-1-isopropyl-4-phenyl-5,6,7,0-tetrahydro-2 (1H) -quinazolinone in 200 ml of E-cymene. The resulting solution is boiled (r) 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 pad of Celite®, which is then washed four times with 25 ml of toluene. The toluene washes are extracted with 50 ml of 4N hydrochloric acid and the ε-cymene filtrate is extracted with 350 ml of 4N hydrochloric acid. The acidic extracts are combined and extracted with 100 ml of toluene, and these toluene extracts are discarded. After extraction with toluene in this way, the remaining acidic solution is treated by adding 350 ml of toluene and 110 g of 50% aqueous sodium hydroxide solution. The phases are separated and the toluene phase is washed twice with 1-0 ml of visor, then dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The solid residue is crystallized from ethyl acetate to give 7-methyl-1-isopropyl-4-phenyl-quinazolin-2 (1H) -one, m.p.

139-141 ° C, yield 72%.

5 66362

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

A mixture of 67 ml of xylene, 13.3 g of ferric oxide and 2.5 g of sulfur is heated to reflux under nitrogen and then a hot (100-110 ° C) solution of 10 g of 7-methyl- 1-Isopropyl-4-p-fluorophenyl-5,6,7,8-tetrahydro-2 (1H) -quinazolinone in 100 ml of xylene. The resulting solution is boiled for 10 hours, during which time water is collected by Dean Stark separation. The reaction mixture is then cooled to 80 ° C and filtered through a pad of Celitew.

The filtrate and filter cake are washed three times with 50 ml portions of toluene. The filtrates are combined and then extracted successively with 200, 100 and 50 ml of 4N hydrochloric acid. The acidic extracts are combined and washed with 100 ml of toluene, which are discarded. After extraction with toluene, 200 ml of toluene are added to the remaining acidic solution and 115 g of 50% aqueous sodium hydroxide solution are added with stirring and cooling. The phases are separated and the aqueous phase is washed twice with 100 ml portions of toluene.

The toluene phases are combined, washed twice with 100 ml portions of water, then dried over anhydrous magnesium sulfate, filtered through Celite and concentrated to give 0.8 g (90%) of yellow crystals. Recrystallization is performed from ethyl acetate to give the title compound, m.p. is 175-176.5 ° C, yield 67%.

Example 3 1-Isopropyl-4-phenyl-7-methyl-2 (1H) -quinazolinone

A mixture of 28.2 g of 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2 (1H) -quinazolinone, 9.6 g of sulfur, 10 g of sodium hydroxide and , 20 g of calcium chloride and 200 ml of carbitol (2- / 2-ethoxyethoxy7ethanol) are heated under nitrogen at 150 ° C for two hours. The resulting mixture is then cooled to 65 ° C, 500 ml of benzene are added and the mixture is cooled to 15 ° C with stirring and the liquid phase is decanted off. The organic phase is washed with water and evaporated to dryness to give 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 1 hour at room temperature, the phases are separated and the acid phase is treated with 50 ml of benzene. The acid phase is neutralized with 50% aqueous sodium hydroxide solution, extracted with 150 ml of benzene and the benzene extracts are washed with water until neutral. After drying over sodium sulfate, the benzene solution is evaporated to dryness to give a crude product which is recrystallized from ethyl acetate to give 1-isopropyl-4-phenyl-7-methyl-2 (1H) -quinazolinone, m.p. 141-142 ° C, yield 56%.

Example 4 7-Methyl-1-isopropyl-4- (p-fluorophenyl) -quinazolin-2- (1H) -one

To a stirred mixture of 4.3 g of sulfur, 6.6 g of zinc oxide and 67 ml of a mixture of xylenes heated to boiling (approx. 138 ° C) under nitrogen is added a preheated (100-115 ° C) solution of 10.0 g 7-methyl-1-isopropyl-4- (p-fluorophenyl) -5,6,7,8-tetrahydro-2 (1H) -quinazolinone in 100 ml of a mixture of xylenes. After the addition (after about 20 minutes), the resulting mixture is boiled.

cooled overnight, cooled and filtered through Celite. The solids are washed with toluene and the filtrate and washings are extracted four times with 4N hydrochloric acid and the extracts are washed with 100 ml of toluene. The aqueous phase is treated with 200 ml of toluene and then with 115 g of 50% sodium hydroxide solution added portionwise in an ice bath. The aqueous phase is extracted twice with 100 ml portions of toluene and the organic phase is washed with water and dried. The crude yellow solid obtained by filtration and evaporation to dryness 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 give a precipitate which is recrystallized from ethyl acetate to give 7 -methyl-1-isopropyl-4- (E-fluorophenyl) -quinazol-Solin-2 (1H) -one, yield 71%.

Example 5

The procedure of Example 4 is repeated using equivalent molar amounts of lead oxide instead of zinc oxide to give • '' • amuu l.i j n ti> 1. ia, Surin tn RO <, {potty.i).

66362

Example B

In the same manner as in any of the above examples, and using approximately equivalent amounts of suitable starting materials, the following compounds are obtained; 5,7-dimethyl-1-isopropyl-4-phenyl-quinazolin-2 (1H) -one, 68% yield; 1-isopropyl-7-methyl-4- (E-methylphenyl) quinazolin-2 (1H) -one, 64% yield; 1-Isopropyl-7-methyl-4- (2-thienyl) -quinazolin-2 (1H) -one, 45% yield 1-cyclopropylmethyl-6-methoxy-4-phenyl-quinazolin-2 (1H) -one onia, yield 60%.

Claims (4)

66362 a A process for the preparation of 4-aryl-quinazolin-2 (1H) -one of formula I R 1 represents a phenyl group optionally substituted by C 1-6 alkyl or halogen, or a thienyl group, and R 3 and R 4, which may be the same or different, each represent a hydrogen atom or a C 1-6 alkyl or alkoxy group by removing hydrogen from the corresponding 4-aryl-5-aryl group. , 6,7, β-tetrahydro-2 (1H) -quinazolinone of formula IX I1 R4v 1 Λ c = O in an inert organic solvent, characterized in that the hydrogen removal is carried out in the presence of an inorganic metal compound which is an oxide, hydroxide or salt of a metal other than magnesium, aluminum, beryllium or an alkali metal and which forms a metal sulphide under the reaction conditions. 9 66362 Process according to Claim 1, characterized in that the dehydrogenation is carried out at a temperature of 130 to 200 ° C, the molar ratio of sulfur to tetrahydroquinazolinone starting material being 2: 1 to 3: 1 and wherein the molar ratio of inorganic metal compound to tetrahydroquinazolinone starting material is at least 1: 1. Process according to Claim 1 or 2, characterized in that 7-methyl-1-isopropyl-4-phenyl-2 (1H] -quinazolinone is prepared. Process according to Claim 1 or 2, characterized in that 1-isopropyl-4-p-fluorophenyl-7-methyl-2 (1H) -quinazolinone is prepared. 10 66362