Method for synthesizing 7-bromo-6-chloro-4-quinazolinone

A synthesis method and quinolone technology are applied in the field of synthesis of pharmaceutical intermediates, and can solve the problems of long reaction time, occurrence of side reactions, complicated steps, etc., and achieve the effects of feasible process conditions, prevention of amino groups from being oxidized, and simplification of reaction steps.

Active Publication Date: 2012-02-15
JIANGXI WANLI PHARMA CO LTD
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0004] 1. EmanuelM et al. used 6-bromoisatin as a raw material to obtain 7-bromo-6-chloro-4(3H)-quinolone through a three-step reaction, but the raw material 6-bromoisatin has not yet been industrialized in China, so the raw material was prepared The steps are cumbersome, currently only imported or small-scale production in the laboratory, so the price is higher
[0005] 2. Mao Zhongxing, Mao Guanxing, Jin Junting, and Huang Wenbin disclosed a synthetic method. The second step in the synthesis uses a single solvent water, and the raw materials are not soluble in water, so the reaction yield is low, or even not. carry out; the fourth step reaction yield is also lower, only 67%
[0006] 3.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 Preparation of 2,4-dibromo-5-chlorotoluene.

[0022] Under stirring at 0°C, add 25.3g of m-chlorotoluene, 2g of anhydrous ferric chloride and 70ml of brominated n-butane into a 500ml three-neck flask to form a suspension, then add 64g of bromine dropwise for about 4 hours. Continue the reaction for 1 hour under ice bath conditions, then wash twice with 200ml of water, and wash the organic layer twice with 100ml of saturated sodium bicarbonate solution; Crystallization gave 41.54 g of white crystals, with a yield of 73%.

[0023] The technical indicators of gained 2,4-dibromo-5-chlorotoluene are as follows:

[0024] White crystal, melting point 92~95℃;

[0025] 1 H NMR (CDCl 3 ): δ: 2.331(3H); 7.261(1H); 7.770(1H);

[0026] ESI-MS m / z (%): 126.5([M+H] - , 100).

Embodiment 2

[0027] Example 2 Preparation of 2,4-dibromo-5-chlorobenzoic acid.

[0028] Weigh 28.45g of 2,4-dibromo-5-chlorotoluene and 20g of potassium permanganate into a three-neck flask with a reflux device and a stirrer, then add 110ml of pyridine and 220ml of water, start stirring, and heat to reflux for 6 hours , Then, add potassium permanganate 25g again, repeat 4 times, continue to reflux, and track with thin-layer chromatography, until the end of reaction. Filter while hot and wash with boiling water to remove manganese dioxide, acidify the filtrate with hydrochloric acid to pH = 1, cool, filter, and dry to obtain pure 2,4-dibromo-5-chlorobenzoic acid, weighing 27.36g, The yield was 87%.

[0029] The technical index of gained 2,4-dibromo-5-chlorobenzoic acid is:

[0030] White solid, melting point 173~176℃;

[0031] 1 H NMR (CDCl 3 ), δ: 7.993(1H), 8.074(1H);

[0032] ESI-MS m / z (%): 314.5([M-H] - , 100).

Embodiment 3

[0033] Example 3 Preparation of 2-amino-4-bromo-5-chlorobenzoic acid

[0034] At room temperature and under nitrogen protection, weigh 0.75g of cuprous oxide and 50ml of concentrated ammonia water into a three-necked flask with a stirrer, then add dropwise 16g of 2,4-dibromo-5-chlorobenzoic acid and 40ml of concentrated ammonia water A mixed solution formed with 12ml of ethyl acetate, during which the reaction temperature was maintained at 35°C, dropped over 40 minutes, then continued to stir at 30°C for 5 hours, then added 0.81g of EDTA and adjusted pH = 3.1 to 3.5 with hydrochloric acid, stirred, and suction filtered , remove the insoluble matter, the mother liquor was extracted 3 times with ethyl acetate, the organic phases were combined, and then the ethyl acetate was distilled off to obtain 11.72 g of a brownish yellow solid with a yield of 92%.

[0035] The technical index of gained 2-amino-4-bromo-5-chlorobenzoic acid is:

[0036] Brown-yellow solid, melting point 250-...

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Abstract

The invention discloses a method for synthesizing 7-bromo-6-chloro-4-quinazolinone. The method comprises the following steps of: (1) dripping liquid bromine into suspension of m-chlorotoluene, n-butyl bromide and anhydrous ferric trichloride, washing with water and a saturated sodium bicarbonate solution, distilling, and recrystallizing; (2) mixing water, pyridine, tertiary butanol and the like, dissolving a product in the step (1) and potassium permanganate in a mixed solution, heating and refluxing, continuously adding potassium permanganate, filtering, washing with boiling water, regulating the pH value, cooling and filtering; (3) dissolving a product in the step (2) in a mixed solution of stronger ammonia water and ethyl acetate at room temperature under the protection of nitrogen, dripping into suspension of cuprous oxide and stronger ammonia water, adding ethylene diamine tetraacetic acid (EDTA), regulating the pH value, evaporating the ethyl acetate, cooling, and performing suction filtration; and (4) mixing a product in the step (3) and formamide, dissolving in dimethyl formamide (DMF), heating and refluxing, cooling, precipitating, filtering, washing with absolute ethanol, and recrystallizing by using ethylene glycol monomethyl ether. The method has the advantages of cheap raw materials, simplified steps and practicable process, avoids 6-bromoisatin, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] 7-Bromo-6-chloro-4(3H)-quinolone is an important intermediate for the synthesis of Stenorol, an effective drug against poultry coccidiosis, which is commonly used in the market and related compounds. The main component of Sudan is hemosanone hydrobromide. It was first extracted from Changshan, a traditional Chinese medicine, by Cyanamid Company of the United States, and then the company completed the research on the artificial synthesis of Changshanone. The medicine is mainly used for preventing and treating coccidiosis of domestic animals and poultry. The advantages of the phloxanthone are small dosage, good clinical effect and no drug resistance or little drug resistance. According to the latest research, this type of compound can also inhibit the excessive production of collagen and the production of cell activity. At the same time,...

Claims

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Application Information

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IPC IPC(8): C07D215/233
Inventor 陆豫王严非余勃唐楚颖
Owner JIANGXI WANLI PHARMA CO LTD
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