SU417945A3 - METHOD OF OBTAINING QUINAZOLINON-2 DERIVATIVES - Google Patents

Description

one

This invention relates to a new process for the preparation of quinazolinone-2 (1H) derivatives or their salts, which can be used in the pharmaceutical industry.

A known method for producing quinazolinop-2 (1H) derivatives, which consists in melting the 2-aminobenzophenone derivatives in urea at 180-200 ° C. This method has a number of drawbacks both in its implementation (it is difficult to control the reaction temperature during fusion), as well as during the separation of the target product after the fusion is carried out, since the reaction mass hardens and is difficult to process.

This method cannot be used to obtain 1-substituted quinazolinone-2 (111) by direct fusion of 2-amino-substituted bepzofepopa.

A novel method is proposed for the preparation of quinazolinone-2 (111) derivatives, carried out in soft words (e.g., room temperature), by which the target products can be easily separated. In addition, the method can be used both for the synthesis of quinazolone-2 (1H) unsubstituted in position 1, and for 1-substituted derivatives.

The described method relates to the preparation of quinazolinone-2 (1H) of the general formula I where R is hydrogen, C1 4 alkyl, C1 4 alkenyl, aralkyl, (C1 4 alkoxy)) C1-4 alkyl or di (C |,) -alkyl) -amino- (C1 4 -alkyl); 30 Ri, R2 and Ra - each can be hydrogen, halogen, C1 4-al1 yl, C1 4-alkoxy, nitro. Ci-4-alkylthio, C1 4-alkylsulfonyl or trifluoromethyl. The method consists in that the trihaloacetamidobenzophenone derivative of the general formula II where Xy Xg and Xs mean the same or different halogen atoms, and R, Ri, Ha and Rs have the above values, react with ammonia and then release the target compound in a known manner in a free form or in the form of salts. The reaction of compounds of formula II with ammonia takes place in a solvent medium, for example, methanol, ethanol, isonropanol, tertiary butyl alcohol, etc. Ammonia is used in an amount not less than stoichiometric, and it is added to the reaction mixture in a liquid or gaseous state. , as well as in the form of an alcohol solution. Usually, the reaction proceeds at room temperature, but the temperature may be higher or lower (if necessary), which affects the desired degree of reaction. In the case when R is hydrogen, a derivative of quinazolinone, it can also be present in the form of the corresponding derivative of 2-hydroxy-quinazoline due to the presence of keto-enol tautomerization. Accordingly, quinazoline derivatives can form various salts when treated with suitable bases. Examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. According to the proposed method, the following quinazolinone derivatives are obtained: 4-phenylquinazolinone-2 (1H); 4-phenyl-5-chloroquinazolinone-2 (1H); 4-phenyl-6-chloroquinazolinone-2 (1H); 4-phenyl-7-chloroquinazolinone-2 (1H); 4-phenyl-6-bromoquinazolinon-2 (1H); 4-phenyl-6-methylquinazolinon-2 (1H); 4-phenyl-6-methoxy-dipasolinone-2 (1H); 4-phenyl-6-pitroquinazolinon-2 (1H); 4-phenyl-6-methylthioquinazolipon-2 (1H); 4-phenyl-6-methylsulfonylquinazolinone2 (1H); 4 - phenyl - 6 - trifluoromethylhipazolinon2 {1H); 4-phenyl-6-chloro-8-nitroquinazolinone-2 (1H); 4-phenyl-6,8-dichloroquinazolinone-2 (1H); 4-phenyl-6,7-dimethoxyquinazolinone-2 (1H); 4- (o-chlorophenyl) -6-chloroquinazolinone-2 (1H); 4- (o - chlorophenyl) - 6 - nitroquinazolinone2 {1H); 4- (w-chlorophenyl) - 6 - methoxyquinazolinop2 {1H); 4- (o-fluorophenyl) -6-chloroquinazolinone-2 (1H); 4- (o-fluorophenyl) -6-nitroquinazolinone2 (1H); 4- (l-methoxyphenyl) -6-chloroquinazolinone2 (1H); 4- (l-tolyl) -6-chloroquinazolinone-2 (1H); 4- (o-tolyl) -6-chloroquinazolinone-2 (1H); 4 - (". - nitrophenyl) - 6 - nitroquinazolipop2 (1H); 1-methyl-4-phenylquinazolinon-2 (1H); 1-methyl-4-phenyl-5-chloroquinazolinone-2 (1H); 1-methyl-4-phenyl-6-chloroquinazolinone-2 (1H); 1-methyl-4-phenyl-7-chloroquinazolinone-2 (1H); 1-methyl-4-phenyl-6-bromoquinazolinone-2 (1H); 1-methyl-4-phenyl-6-fluoroquinazolinone-2 (1H); 1-methyl-4-phenyl-6-chloro-8 - methylquinazolinop-2 (1H); 1-methyl-4-phenyl - b - methoxyquinazolinone 2 (1H); 1-methyl-4-phenyl-6-methylthioquinazolinone 2 (11-1); 1-methyl-4-phenyl-6 - methylsulfonylquinazolinone-2 (1H); 1-methyl-4-phenyl-6 - trifluoromethyl-quinazolinone-2 (1H); 1-methyl-4-phenyl - 6.8 - dichloroquinazolinone2 (1H); 1-methyl-4- (o-fluorophenpl) -6-nitroquinazolipon-2 (1H); 1-methyl-4- (o-chlorophenyl) -6-nitroquinazolinop-2 (1H); 1-methyl-4 - (. M-chlorophenyl) -6-nitroquinazolinone-2 (1H); 1-methyl-4 - (/ g-chlorophenyl) -6-nitroquinazolinone-2 (1H); 1-methyl-4- (o-tolyl) -6-nitroquinazolinone 2 (1H); 1-ethyl-4-phenyl-6-nitroquinazolipon-2 (1H); 1-lropyl-4-phenyl - 6 - nitroquinazolinone2 (III); 1-methyl-4- (d-methoxyphenyl) -6-chloroquinazolinone-2 (1H); 1-methyl-4- (o-chlorophenyl) -6-chloroquinazolinop-2 (1H); 1-methyl-4- (p-chlorophenyl) -6-chloroquinazolinone-2 (1H); 1-methyl-4- (lg-chlorophenyl) -6-chloroquinazolinone-2 (1H); 1-methyl-4 - (./ and-chlorfepyl) -6 - methoxyquinazolinone-2 (1H); 1-methyl-4- (o-fluorophenyl) -6-chloroquinazolinone-2 (1H); 1-methyl-4 - ((1-fluorophenyl) -6 - chloroquinazolinone-2 (1H); 1-ethyl-4- (o-tolyl) -6-chloroquinazolinone2 (1H); 1-ethyl-4-phenyl-6-chloroquinazolinone-2 (1H); 1-isopropyl-4-phenyl-6-chloroquinazolinone2 (1H); 1-isopropyl-4-phenyl-6-bromoquinazolinone2 (1H);

1-isopropyl-4-phenyl-6-methoxy-quinazolinone-2 (1H);

1-isopropyl-4-phenyl-6-nitroquinazolinone2 (1H);

1-isopropyl-4-phenyl-6-trifluoromethylchimazolion-2 (1H);

1-isopropyl-4- (o-fluorophenyl) -6-chloro-nnazolinone-2 (1H);

1-isopropyl-4- (l-chlorophenyl) -6-chloro-hinazolinone-2 (1H);

1-isopropyl-4- (o-tolyl) - 6 - chloroquinazolinone-2 (1H);

1-isopropyl-4- (p-tolyl) -6-chlorchiazolinone-2 (1H);

1-isopropyl-4- (o-chlorophenyl) -6-methoxy-vinyne-2 (1H);

1-isobutyl-4-phenyl-6-chloroquinazolinone2 (1H);

1-n-butyl-4 - phenyl - 6 - chloroquinazolinone2 (1H);

1-allyl-4-phenyl-6-chlorquinazolino-2 (1H);

1-beisyl-4-phenyl-6-chloroquinazolinone2 (1H);

1-ethoxyethyl-4- (o-fluorophenyl) -6-chloro-hinazolinone-2 (1H);

1- (p-diethylaminoethyl) -4- (o-fluorophenyl) -6 chlorochinazolinone-2 (1H);

1- (p-diethylaminoethyl) -4-phenyl-6 - chlorochinazolinone-2 (1H).

The starting trihaloacetamidobenzophenones of the formula II are usually obtained by reacting a 2-aminobenzophenone derivative of the formula

where R, RI, R2 and Ra are as defined above, with trihaloacetic acid of the formula

 X

x -c-soon

at

where Xi, X2 and Xs have the above values,

or with its reactive derivatives, for example, with acid halides, anhydrides, esters, etc. It is usually preferable to use trihaloacetic acid halides, for example, acid chloride and bromide.

Example 1

Stage A. A solution of 5.5 g of trichloroacetic acid chloride in 20 ml of dry benzene is added dropwise to a solution of 13.9 g of 2-amino-5-chlorobenzophenone in 40 ml of dry

benzene with stirring and cooling with ice. The mixture is filtered, the insoluble material is washed with water and dried. 7 g of 2-amino-5-chlorobenzophenone are obtained. The filtrate is concentrated under vacuum to dryness. The oily residue is crystallized from 20 ml of ethanol. Obtain 8.7 g (77%) of 2-trichloroacetamide-5-chlorbepzofenop with t. Pl. 90.5-92.5 ° C. After psekrnnatalizatsni from the mixture

ethanol and benzene give colorless crystals; m.p. 93.0-94.0 ° C.

Step B. To a solution of 5.7 g of 2-trichloroacetamido-5-chlorobenzophenone in 200 ml of thanol, 50 g of a 10% solution are added.

ammonia in the metapol and the mixture left at room temperature. The solution is concentrated in vacuo to dryness and the residue is washed with 30 ml of ether, then with water and dried. Obtain 2.4 g of 4-phenyl-6-.lorochinazolinone-2 (1H): t. Pl. 300 ° C.

To a suspension of 1.0 g of the compound in 30 ml of ethanol is added 10 g of a 10% sodium hydroxide solution in water. The mixture is dissolved by heating and cooled. The sodium salt is obtained as yellow needles; so nl 300 ° C. Example 2

Stage A. A solution of 1.8 g of trichloroacetic acid chloride in 5 ml of benzene is added dropwise to a mixture of 2.1 g of 2-amino5-nitrobenzophenone, 40 ml of benzene, 40 ml of methylene chloride and 2 ml of Pyridine, and the mixture is left at room temperature for 1 hour. The reaction mixture is washed with water and dried over sodium sulfate, the solvent is removed under vacuum. The residue crystallized from 5 ml of ethanol to give 2.5 g (74.2%) of 2-trichloroacetamido-5-nitrobenzophenone. After recrystallization from a mixture of ethanol and chloroform, prisms are obtained; m.p.

119 ° C.

Step B. To a solution of 2.3 g of 2-trichloroacetamido-5-nitrobenzophenone in 200 ml of tertiary butyl alcohol was added 1.7 g of a 10% ammonia-methanol solution and

the mixture is allowed to stand at room temperature for two dpi. The solvent is removed in vacuo and the residue is washed with 30 ml of methylene chloride. Obtain 0.8 g of 4-phenyl-6-nitroquinazolinone-2 (1P) in the form of colorless crystals; m.p. 300 ° C. Example 3

Stage A. To a mixture of 12.1 g of 2-amino-5-nitrobenzophenone, 120 ml of methylene chloride and 10 ml of pyridine are added dropwise 10.9 g

trichloroacetic acid chloride at room temperature. The mixture is then stirred for 2 hours, 50 ml of water are added with stirring. The organic layer is separated, dried over sodium sulfate.

and evaporated under vacuum. The red oily residue is crystallized by treatment with 20 ml of ethanol under cooling. 15.1 g (77.9%) of 2-trichloroacetamido-5-nitrobenzophepon are obtained; m.p. 116-117.5 ° C. After recrystallization from a mixture of ethanol and chloroform, light brown crystals are obtained; m.p. 118.0-119.0 ° C.

Stage B. A solution of 3.9 g of 2-trichloroacetamido-5-nitrobenzophenone in 100 ml of tertiary butyl alcohol is heated with 3.4 g of a 10% solution of ammonia in ethanol at a temperature of approximately 120 ° C for 3 hours. test tube. The mixture is then concentrated in vacuo to dryness. The residue is washed with methylene chloride and dried, which gives 1.8 g (67.4%) of 4-phenyl-6-nitroquinazolinone-2 (1H).

Example 4

Step A. To a solution of 8.6 g of 2-methylamino-5-chlorobenzophenone in 100 ml of ether is added dropwise 7.6 g of trichloroacetic acid chloride at room temperature. The mixture is stirred under reflux for 4 hours. After cooling, the reaction mixture is washed with water. The ether layer is separated, dried over sodium sulfate and evaporated in vacuo. 30 ml of ethanol and 10 ml of petroleum ether are added to the oily residue. The precipitate is separated by filtration and dried. 10.8 g (78.5%) of 2- (L-methyltrichloroacetamido) -5-chlorobenzophenone are obtained; m.p. 116-117 ° C. After recrystallization from ethanol, 10.3 g of colorless crystals are obtained with a m.p. 117-118 ° C.

Stage B. A solution of 2.0 g of 2- (L-methyltrichloroacetamido) -5-chlorobenzophenone in 100 ml of ethanol is saturated, cooled with ammonia under cooling and the mixture is allowed to stand at room temperature. The mixture is concentrated under vacuum to dryness. The residue is washed with 20 ml of ether and dried. 0.7 g of 1-methyl-4-phenyl-6-chloroquinazolinone-2 (1H) are obtained; m.p. 220.5-221.0 ° C.

After recrystallization from a mixture of chloroform and methanol, light yellow crystals are obtained; m.p. 221-222 ° C.

Example 5. Analogously to Example 1, but replacing the 2-amino-5-chlorobenzophenone used in Step A with 2-amino-6-chlorobenzophenone, 4-phenyl-5-chloroquinazolinone2 (1H) is obtained; m.p. 284 ° C.

Example 6. Analogously to example 1, but replacing the 2-amino-5-chlorobenzophenone used in stage A with 2-amino-5-methoxybenzophenone, 4-fepyl-6-methoxy-nexinazolinone-2 (1H) is obtained; m.p. 28GS.

Example 7. In accordance with the procedure described in Example 1, but using 2-amino-5-methylbenzophenone, 2-amino-5-methylsulfonylbenzophenone or 2-amino-2,5-dichlorobenzophenone instead of 2-amino acid as starting materials. 5-chlorobenzophenone, 4-methyl-6-methylquinazolinone-2 (1P), 4-phenyl-6-methylsulfonylquinazolinone-2 (1H) and 4-o-chlorophenyl-6-chloroquinazolinone-2 (1H), respectively, are obtained.

Example 8. Analogously to Example 4, but replacing 2-methylamino-5-chlorobenzophenone used in stage A with 2-methylamino-3-chloro-5-methoxybenzophenone, 1-methyl- (l1-chlorophenyl) -6-methoxy-quinazolinon2 is obtained ( 1H); m.p. 199-200 ° C.

Similarly, following a similar procedure, but replacing 2-methylamino-5-chlorobenzophenone, used in step A, with 2-ethylamino-2methyl-5-chlorobenzophenone, 1-ethyl-4- (otolyl) -6-chloroquinazolinone-2 ( 1H) t PL 174-175 ° C.

Compounds are prepared analogously.

1-methyl-4-phenyl - 6 - methoxyquinazolinone 2 (1H); m.p. 167-168 ° C;

1-benzyl-4-phenyl-6-chloroquinazolinone2 (1H); m.p. 183-184 ° C;

1-methyl-4-phenyl-6 - trifluoromethyl-quinazolinone-2 (1H); m.p. 199-20GS;

1-ethyl-4-phenyl-6-chloroquinazolinone -2 (1H); m.p. 167-168 ° C;

1-methyl-4 - (/ g-chlorophenyl) -6-chloroquinazolinone-2 (III); m.p. 221-222 ° C.

Example 9. Analogously to Example 4, but replacing 2-methylamino-5-chlorobenzophenone with 2 isopropylamino-5-chlorobenzophenone, 1-isopropyl-4-phenyl-6-chlorochinazolinone2 (1P) is obtained; m.p. 119-120 ° C.

Example 10

Stage A. A solution of 4.0 g of trichloroacetic acid chloride in 10 ml of isopropyl ether is added dropwise to a solution of 4.9 g of 2-allylamino-5-chlorobenzophenone in 50 ml of isopropyl ether at room temperature. The mixture is stirred using a reflux condenser for 4 hours. After cooling, the reaction mixture is washed with water. The ether layer is separated, dried over sodium sulfate and evaporated in vacuo. The yellow residue is crystallized from 80 ml of methanol. 3.5 g of 2- (M-allyl-trichloroacetamido) -5-chlorobenzophenone are obtained in the form of light yellow crystals; m.p. 131.5-132.5 ° C.

Step B. To a solution of 2.1 g of 2- (M-allyl-trichloroacetamido) -5-chlorobenzophenone in a mixture of 20 ml of chloroform and 50 ml of ethanol was added 5.2 g of a 5% ammonia-ethanol solution and the mixture was settled at room temperature in for four days. The solvent is removed in vacuo. The residue is washed with 20 ml of ether and dried. 0.71 g of 1-allyl-4-phenyl-6-chloroquinazolinone is obtained; m.p. 185.0-186 ,.

Example 11

Step A. To a mixture of 5.0 g of 2-ethoxyethylamino-5-chloro-2-fluorobenzophenone, 40 ml of methylene chloride and 3 ml of pyridine a solution of 7.2 g of trichloroacetic acid chloride in 10 ml of methylene chloride is added dropwise at room temperature . The mixture is stirred using a reflux condenser for 6 hours. After cooling, the reaction mixture is washed with water. The organic layer is separated, dried over sodium sulfate and concentrated in vacuo. The oily residue is subjected to chromatography on a column filled with Si.