KR790001080B1 - Process for preparing 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide - Google Patents

Abstract

Chloroacetylation of 2-amino-5-chlorobenzophen-one with chloroacetyl chloride gave 2-chloro-ace-tamido-5-chlorobenzophenone followed by iminochlorination to give 2-(1'-chloro-mino-2'-chloromethyl)-5- chlorobenzophenone, which underwent cyclization to give the tite compd. I.

Description

Method for preparing 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide

The present invention relates to a method for preparing 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide and its derivatives. 1, 4-benzodiazepine 4-oxide, i.e., 7-chloro-2-methylamino-5-phenyl-3H-1, 4-benzodiazepine 4-oxide (chloro diazeoxide) and 7-chloro-1, 3-dihydro -1-Methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one (diazepam) is widely used in the treatment of tension, anxiety, nervousness, fatigue, depression, confusion and mental neurosis caused by acute alcoholism It is well known that it works.

The present invention relates to a process for preparing 6-chloro-2-chloro-methyl-4-phenylquinazolin, which is an extremely important intermediate for the synthesis of well-known psychotherapeutic chloro diazepoxide and diazepam. This intermediate is prepared by cyclization of 2- (1'-chloroimino-2'-chloromethyl) -5-chloro benzophenone.

In reduction, 2-amino-5-chlorobenzophenone is prepared by chloroacetylation to 2-chloroacetamido-5-chloro benzophenone, followed by the production of iminochloride.

7-chloro-2-methylamino-5-phenyl-3H-1, 4-benzodiazepine 4-oxide (chlorodiazepoxide) and 7-chloro-1, 3-dihydro-1-methyl-5-phenyl-2H -1,4-benzodiazepin-2-one) diazepam) is well known to use the important intermediate 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide. This compound is prepared by converting 2-amino-5-chlorobenzo-phenone into an oxime (α and β-oxime mixture) and then treating with a mixture of hydrochloric acid and vinegar acid. It is contacted with methylamine to obtain chlorodiazepoxide or diazepam in several steps.

The novel preparation of the present invention is characterized by the use of novel intermediates 2-chloroacetamido-5-chloro benzophenone and 2-1'-chloroimino-2'-chloromethyl-5-chlorobenzophenone. A method for preparing chloro-2-chloromethyl-4-phenylquinazolin-3-oxide is provided. According to this reforming method, the oxime mixture of 2-amino-5-chlorobenzophenone which is electrically harmful is prevented, so that the required intermediate compound can be obtained in high yield.

2-Chloroacetamido-5-chlorobenzophenone is obtained by chloroacetylation of 2-amino-5-chlorophenone to prepare a starting material in the novel production process of the present invention. Next, 2- (1'-chloroimino-2'-chloromethyl) -5-chlorobenzophenone is produced by iminochloride production. In the present invention, 2- (1'-chloroimino-2'-chloromethyl) -5-chlorobenzophenone compound is cyclized to give 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide. Make

An overview of the overall synthesis is as follows.

The starting material in the production method of the present invention is made as follows.

A solution of 2-amino-5-chlorobenzophenone dissolved in an organic solvent such as benzene, methyl chloride or chloroform is added slightly in a molar ratio in an aqueous solution of 3N NaOH at a molar ratio while maintaining a temperature of about 5 to 25 ° C., especially about 15 ° C., under a nitrogen atmosphere. One ethyl acetate solution is added and mixed. Then, a slight excess of chloroacetyl chloride was added dropwise in a molar ratio for about 15 minutes while maintaining the reaction temperature at 15-25 ° C. Practically, the reaction is completed in about 1.5 hours, but the reaction time is 1 to 4 hours. Chloroacetyl chloride gives good results, but it is clear that the corresponding bromine compounds can also be used under the same conditions.

As a better alternative, 2-chloroacetamido-5-chlorobenzophenone is dissolved in methylene chloride and contacted with about 1.5 to 2 molar equivalents of thionylchloride and about 3 molar equivalents of pyridine at room temperature under nitrogen atmosphere. The mixed mixture is heated to reflux at 40-42 ° C. for about 18-20 hours. When chloroform is used instead of methylene chloride, the reaction temperature is about 60 ° C and benzene is about 80 ° C. Phosgene or phosphorus pentachloride may be used instead of thionyl chloride.

To the methylene chloride crude solution of 2- (1'-chloroimino-2-chloromethyl) -5-chlorobenzophenone obtained as described above, a slight excess of hydroxylamine hydrochloride in molar ratio is added followed by 2-3 molar equivalents. Pyridine is added. The same base may also be added to pyridine. The solution is stirred at 25-40 ° C. until the reaction is substantially complete (20-48 hours).

Instead of methylene chloride, chloroform may be used at a reaction temperature of about 60 ° C, or benzene at a reaction temperature of about 80 ° C. If necessary, the hydroxylamine system itself can be used. In this case, pyridine or the same basic material does not need to be used. If necessary, the above-mentioned mixture may be poured into an aqueous solution of soda carbonate to concentrate the separated methylene chloride layer, thereby releasing 6-chloro-2-chloromethyl-4-quinazolin-3-oxide from the resulting mixture. The compound can also be liberated with hydrochloride, which is accomplished by pouring the reaction mixture into ice water and manipulating the separated methylene chloride layer.

The intermediate 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide can be converted to the well-known neurological agents chlorodiazepoxide and diazepam, which can be done by the methods described in the synthesis schemes described above. .

Example 1

[Preparation of 2-chloroacetamido-5-chlorobenzophenone]

In a nitrogen atmosphere, a solution of 24.17 g (0.1 mol) of 2-amino-5-chlorobenzophenone in 200 ml of ethyl acetate was cooled to 15 ° C while stirring. After cooling in an ice-water bath, 36.7 ml (0.11 mol) of 3N NaOH solution was added while maintaining the temperature at 15 ° C. to 20 ° C., and then 8.76 ml (0.11 mole) for 15 minutes while maintaining the reaction temperature at 15-25 ° C. Chloroacetyl chloride was added dropwise. At the end of the addition of chloroacetylchloride a solid mass was produced. The slurry was stirred at 20-23 ° C. for about 1.5 hours.

체적이 되도록 농축한후 초산에틸을 n-헵탄과 치환하였다. 이렇게하여 얻은 백색 결정물질을 여과한후 n-헵탄으로 세척하여 건조한 결과 일정 중량 29.5g의 2-클로로아세트아미도-5-클로로벤조페논(이론치의 96%)을 얻었는데, 융점은 119-120℃였다.The solid was separated through filtration and washed with 100 ml of ethyl acetate. Combined ethyl acetate blue liquid

After concentration to volume, ethyl acetate was substituted with n-heptane. The white crystalline material thus obtained was filtered, washed with n-heptane and dried to obtain 29.5 g of 2-chloroacetamido-5-chlorobenzophenone (96% of theory) having a fixed weight of 119-120. ° C.

analysis

Percent of C ₁₅ H ₁₁ NO ₂ Cl ₂ ; C, 58.46; H, 3. 60;

N, 4.54; Cl, 23.01

Found (%); C, 58.62; H, 3.59; N, 4.45;

Cl, 23.80

Example 2

[Preparation of 2- (1'-Chlorominono-2'-chloromethyl) -5-chlorobenzophenone]

5 g (16.2 mmol) of 2-chloro acetamino-5-chlorobenzophenone were dissolved in 100 ml of methylene chloride under a nitrogen atmosphere. To this solution, 1.77 ml (24.3 mmol) thionylchloride was added at room temperature followed by 3.92 ml (48.6 mmol) pyridine. The mixture was heated to reflux at 40 ° ± 2 ° for 18 hours with stirring. The iminochloride production was clearly confirmed by nmr. In other words, the chemical group of CH ₂ Cl ranged from 4.11 ppm (δ) to 5.17 ppm (δ), while the NH showed a medium phase of 8.6ppm, while the 8.8 ppm (δ) maximal value did not appear.

The methylene chloride solution of the crude iminochloride was passed directly to the next reaction without liberation.

Example 3

[Preparation of 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide]

체적이 되도록 농축한 뒤에 메틸렌클로라이드를 n-헵탄과 치환 시켰다. 생성된 결정물질을 헥산 중에서 분쇄한 다음 여과한후 헥산으로 세척한뒤 건조하여 3g(60.6%)의 6-클로로-2-클로로메틸-4-페닐퀴나졸린-3-옥사이드를 얻었다. 융점 : 132-134℃1.237 g (1.1 equivalent, 17.8 mmol) of hydroxylamine hydrochloride was added to a methylene chloride crude solution of iminochloride (assuming 100% iminochloride of 16.2 mmol) obtained in Example 2 at room temperature (24 ° C). 2.88 ml (2.2 equiv) of pyridine was added. The reaction mixture was stirred at rt for 48 h. The reaction mixture was then poured into ice water containing 5.15 g of sodium carbonate (3 equiv, 48.6 mmol). The separated methylene chloride layer was washed with water, dried over anhydrous magnesium sulfate and filtered. Solution

After concentration to volume, methylene chloride was substituted with n-heptane. The resulting crystals were triturated in hexane, filtered, washed with hexane and dried to give 3 g (60.6%) of 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide. Melting Point: 132-134 ℃

analysis

% Calculated for C ₁₅ H ₁₀ NO ₂ Cl ₂ : C, 59.03; H, 3. 30;

N, 9.18; Cl, 23.24

Found (%); C, 59.23; H, 3. 64;

N, 9.37; Cl, 23.26 (reference)

If necessary, 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide may be liberated with hydrochloride having a melting point of 112-122 ° C. (decomposition), which does not add ice water (sodium carbonate) to the reaction mixture described above. The methylene chloride solution is separated.

Claims (1)

Chloroacetylation of 2-amino-5-chlorobenzophenone to give 2-chloro-acetamido-5-chlorobenzophenone followed by iminochloride to 2- (1'-chloroimino-2'-chloromethyl ) -5-chlorobenzophenone is produced and cyclized to prepare 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide.