Preparation method and application of 6-chloro-7-bromo-4(3H)-quinazolinone

Abstract

The present invention relates to the technical field of chemicals, and in particular to a preparation method and application of 6-chloro-7-bromo-4 (3H)-quinazolinone. The preparation method heats 2-amino-4-bromo-5-chlorobenzoic acid in DMF or formamide for dissolution, slowly adds thionyl chloride or phosphorus oxychloride and controls the feed liquid temperature to be 60-100 DEG C, continues to react for a certain time at 60-100 DEG C after adding, then cools and crystallizes, and solid-liquid separation is performed after crystallization to obtain 6-chloro-7-bromo-4 (3H)-quinazolinone crude product. The preparation method reaction temperature is relatively low, and reaction conditions are mild, easy to control, and product is easy to separate and purify, so that the reaction yield of synthesizing 6-chloro-7-bromo-4 (3H)-quinazolinone is greatly improved. The preparation method can be used for the preparation of halofuginone.

Description

Technical Field

[0001] The invention belongs to the technical field of chemicals, and particularly relates to a preparation method and application of 6-chloro-7-bromo-4(3H)-quinazolinone. Background Art

[0002] Coccidiosis is one of the most common and serious diseases in poultry and livestock. It is a protozoal disease caused by various coccidia of the genus Eimeria, which parasitize the intestinal epithelial cells of poultry and livestock and rapidly multiply, causing intestinal tissue damage and leading to various pathological changes. Poultry and livestock infected with coccidiosis typically experience decreased food intake and reduced intestinal absorption of nutrients from feed, resulting in slow growth and increased susceptibility to other diseases. Studies have shown that even farms with the strictest epidemic prevention measures and the most advanced equipment cannot avoid the occurrence of coccidiosis. Consequently, coccidiosis causes significant economic losses to the global livestock industry. Currently, coccidiosis is primarily prevented and treated with dietary medications. For example, adding a premix of halofuginone hydrobromide at a dose of 3 mg / kg to chicken feed can effectively prevent and kill various Eimeria species. Halofuginone is a febrifugine analogue synthesized as a potential antimalarial drug. Studies have found that it has strong anticoccidial activity and has been used as an anticoccidial drug to prevent and treat broiler chickens and coccidiosis. As research deepens, people have found that it not only has antiprotozoal activity, but also has mammalian biological characteristics.

[0003] However, there are few reports on the total synthesis of halofuginone in the prior art. The difficulty and key to its synthesis lies in the synthesis of the intermediate 6-chloro-7-bromo-4(3H)-quinazolinone. Current methods for synthesizing 6-chloro-7-bromo-4(3H)-quinazolinone suffer from high reaction temperatures, the carbonization and blackening of the reactants, and the difficulty in separating and purifying the products. Consequently, the product yield is low, making industrialization difficult. Summary of the Invention

[0004] Aiming at the problems of high reaction temperature and low product yield in the current method for synthesizing 6-chloro-7-bromo-4(3H)-quinazolinone, the present invention provides a preparation method and application of 6-chloro-7-bromo-4(3H)-quinazolinone.

[0005] To achieve the above-mentioned purpose, the embodiment of the present invention adopts the following technical solutions:

[0006] A preparation method of 6-chloro-7-bromo-4(3H)-quinazolinone comprises: heating and dissolving 2-amino-4-bromo-5-chlorobenzoic acid in a reaction solvent, slowly adding a chlorinating agent and controlling the feed liquid temperature to be 60-100°C, continuing the reaction at 60-100°C for 1-5 hours after the addition, then cooling and crystallizing, and separating the solid and liquid after crystallization to obtain a crude 6-chloro-7-bromo-4(3H)-quinazolinone. The reaction solvent is DMF or formamide, and the chlorinating agent is thionyl chloride or phosphorus oxychloride.

[0007] The preparation method can achieve the preparation of 6-chloro-7-bromo-4(3H)-quinazolinone at a relatively low reaction temperature by adding a chlorinating agent, thionyl chloride or phosphorus oxychloride. The reaction conditions are mild and easy to control, and the product is easy to separate and purify. The reaction yield of the synthesized 6-chloro-7-bromo-4(3H)-quinazolinone is greatly improved. The preparation method is easy to industrialize, laying a foundation for the further chemical synthesis of hawthorne.

[0008] The synthetic route of the preparation method is as follows:

[0009]

[0010] Through experiments and theoretical analysis, it is speculated that the mechanism of action in this reaction is: thionyl chloride and phosphorus oxychloride activate the carbonyl group of the intermediate 2-formamide group, increasing the electropositivity of the carbonyl carbon atom, thereby promoting the reaction and lowering the reaction temperature. The speculated reaction process is shown below:

[0011]

[0012]

[0013] Preferably, the reaction solvent is DMF. Using DMF as a solvent can obtain a higher yield.

[0014] Preferably, the heating temperature is 85-950°C.

[0015] Preferably, the cooling method is to mix the feed liquid with crushed ice. This method can quickly cool the feed liquid, which is conducive to accelerating the precipitation of crystals.

[0016] Preferably, the chlorinating agent is thionyl chloride. Thionyl chloride can achieve a higher yield than phosphorus oxychloride. The chlorinating agent should be added slowly to ensure that the feed solution temperature remains at 60-100°C.

[0017] Preferably, the molar ratio of the thionyl chloride to the 2-amino-4-bromo-5-chlorobenzoic acid is (0.6-1.2):1.

[0018] Preferably, the molar ratio of the thionyl chloride to the 2-amino-4-bromo-5-chlorobenzoic acid is 1:1.

[0019] Preferably, the molar ratio of the 2-amino-4-bromo-5-chlorobenzoic acid to the formamide is 1:(1-5).

[0020] Preferably, the molar ratio of the 2-amino-4-bromo-5-chlorobenzoic acid to the formamide is 1:3 to 4, and a more preferred molar ratio is 1:3.

[0021] Preferably, the feed liquid temperature is 80-90°C, and more preferably 80°C.

[0022] Preferably, the reaction is continued for 3 hours.

[0023] Preferably, the preparation method further comprises recrystallizing the crude 6-chloro-7-bromo-4(3H)-quinazolinone.

[0024] In addition, an embodiment of the present invention also provides the use of the above-mentioned preparation method of 6-chloro-7-bromo-4(3H)-quinazolinone in the preparation of halofuginone. 6-chloro-7-bromo-4(3H)-quinazolinone is prepared using the above-mentioned preparation method of 6-chloro-7-bromo-4(3H)-quinazolinone, and the obtained product is used to prepare halofuginone.

[0025] In addition, an embodiment of the present invention further provides a method for preparing halofuginone, wherein 6-chloro-7-bromo-4(3H)-quinazolinone is prepared using the above-mentioned method for preparing 6-chloro-7-bromo-4(3H)-quinazolinone, and the obtained product is used to prepare halofuginone. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 HPLC chromatogram of 6-chloro-7-bromo-4(3H)-quinazolinone in the embodiment of the present invention. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0028] The main instruments and reagents used in the following examples are:

[0029] High performance liquid chromatograph FSPD-20A, Shimadzu, Japan;

[0030] 2-Amino-4-bromo-5-chlorobenzoic acid: purchased from Beijing Bailingwei Technology Co., Ltd.; the rest are chemical reagents.

[0031] Example 1

[0032] This embodiment provides a method for preparing 6-chloro-7-bromo-4(3H)-quinazolinone, which specifically comprises the following steps:

[0033] To a 100mL four-necked flask equipped with a thermometer, reflux condenser, mechanical stirrer, and dropping funnel, add 30mL of DMF, followed by 2.50g (0.01mol) of 2-amino-4-bromo-5-chlorobenzoic acid and 1.2mL (0.03mol) of formamide. Heat to 90°C with an electric heating mantle and stir until the solid is completely dissolved. Slowly add 0.70mL (0.01mol) of thionyl chloride dropwise, controlling the temperature between 80±2°C. After the addition is complete, continue the reaction at this temperature for 3 hours. After the reaction is complete, pour the reactants into 60g of crushed ice and stir with a glass rod to obtain a light yellow solid. Filter to obtain a light yellow filter cake, which is then dried in an 80°C oven for 5 hours to yield crude 6-chloro-7-bromo-4(3H)-quinazolinone.

[0034] Place the dried 6-chloro-7-bromo-4(3H)-quinazolinone in a 100ml round-bottom flask, add 20ml of ethanol, heat to dissolve, filter, and refrigerate the filtrate overnight at 4°C to obtain a large amount of solid. Filter the solid to obtain 2.30g of light yellow granules (final product), with a yield of 88.9%. mp 290.3-293.3°C (literature melting point 291.3°C).

[0035] The obtained product was subjected to high performance liquid chromatography (HPLC) analysis, 1H NMR nuclear magnetic resonance (NMR) analysis and mass spectrometry analysis. The obtained HPLC chromatogram is shown in FIG. Figure 1 shown.

[0036] Examples 2 and 3

[0037] On the basis of Example 1, the reaction solvent and chlorinating agent were changed respectively. The preparation process and other parameters were the same as those in Example 1. The specific reaction solvent and chlorinating agent types, as well as the color and yield of the reaction product are shown in Table 1.

[0038] Table 1

[0039] Example Reaction solvent Chlorinating agents Color of the product after recrystallization Final product mass (g) Yield (%) Example 2 DMF Phosphorus oxychloride brownish yellow 2.12 81.84 Example 3 Formamide Thionyl chloride brownish yellow 2.09 80.63

[0040] Examples 4 to 7

[0041] The reaction temperature was changed on the basis of Example 1. The preparation process and other parameters were the same as those in Example 1. The specific reaction temperature and the color and yield of the product obtained by the reaction are shown in Table 2.

[0042] Table 2

[0043] Example Reaction temperature (℃) Color of the product after recrystallization Final product mass (g) Yield (%) Example 4 60 light yellow 2.04 78.87 Example 5 70 light yellow 2.14 82.43 Example 6 90 light yellow 2.31 89.05 Example 7 100 brownish yellow 2.16 83.52

[0044] Examples 8 to 11

[0045] Based on Example 1, the feeding amounts of 2-amino-4-bromo-5-chlorobenzoic acid and formamide were changed respectively. The preparation process and other parameters were the same as those in Example 1. The specific feeding amounts, color, and yield of the reaction product are shown in Table 3.

[0046] Table 3

[0047]

[0048]

[0049] Examples 12 to 14

[0050] On the basis of Example 1, the feeding amounts of 2-amino-4-bromo-5-chlorobenzoic acid and thionyl chloride were changed respectively. The preparation process and other parameters were the same as those in Example 1. The specific feeding amounts, the color and yield of the reaction product are shown in Table 4.

[0051] Table 4

[0052]

[0053] Examples 15 to 18

[0054] On the basis of Example 1, the reaction time after adding thionyl chloride was changed respectively. The preparation process and other parameters were the same as those in Example 1. The specific reaction time and the color and yield of the product obtained by the reaction are shown in Table 5.

[0055] Table 5

[0056] Example Reaction time (h) Color of the product after recrystallization Final product mass (g) Yield (%) Example 15 1 light yellow 2.15 82.83 Example 16 2 light yellow 2.16 83.40 Example 17 4 light yellow 2.32 89.42 Example 18 5 light yellow 2.21 85.34

[0057] Comparative Example 1

[0058] The reaction solvent was changed on the basis of Example 1. The preparation process and other parameters were the same as those in Example 1. The specific reaction solvent type and the color and yield of the reaction product are shown in Table 6.

[0059] Table 6

[0060]

[0061]

[0062] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing 6-chloro-7-bromo-4(3H)-quinazolinone, characterized in that: 2-Amino-4-bromo-5-chlorobenzoic acid and formamide are heated and dissolved in a reaction solvent, a chlorinating agent is slowly added and the feed liquid temperature is controlled at 60-100°C. After the addition is complete, the reaction is continued at 60-100°C for 1-5 hours, and then the temperature is lowered for crystallization. After crystallization, solid-liquid separation is performed to obtain a crude 6-chloro-7-bromo-4(3H)-quinazolinone; the reaction solvent is DMF or formamide, the chlorinating agent is thionyl chloride; the molar ratio of thionyl chloride to 2-amino-4-bromo-5-chlorobenzoic acid is (0.6-1.2):

1.

2. The method for preparing 6-chloro-7-bromo-4(3H)-quinazolinone according to claim 1, wherein The reaction solvent is DMF; and / or The heating temperature is 85-95°C; and / or The cooling method is to mix the feed liquid with crushed ice.

3. The method for preparing 6-chloro-7-bromo-4(3H)-quinazolinone according to claim 1, wherein The molar ratio of the thionyl chloride to the 2-amino-4-bromo-5-chlorobenzoic acid is 1:

1.

4. The method for preparing 6-chloro-7-bromo-4(3H)-quinazolinone according to claim 1, wherein The molar ratio of the 2-amino-4-bromo-5-chlorobenzoic acid to the formamide is 1:(1-5); and / or The feed liquid temperature is 80-90°C; and / or The reaction time is 3 hours.

5. The method for preparing 6-chloro-7-bromo-4(3H)-quinazolinone according to claim 4, wherein The molar ratio of the 2-amino-4-bromo-5-chlorobenzoic acid to the formamide is 1:3-4.

6. The method for preparing 6-chloro-7-bromo-4(3H)-quinazolinone according to any one of claims 1 to 5, characterized in that: The preparation method further comprises recrystallizing the crude 6-chloro-7-bromo-4(3H)-quinazolinone.

7. Use of the preparation method of 6-chloro-7-bromo-4(3H)-quinazolinone according to any one of claims 1 to 6 in the preparation of halofuginone, characterized in that: 6-chloro-7-bromo-4(3H)-quinazolinone was prepared by the preparation method of 6-chloro-7-bromo-4(3H)-quinazolinone, and the obtained product was used to prepare halofuginone.

8. A method for preparing halofuginone, characterized in that: 6-chloro-7-bromo-4(3H)-quinazolinone is prepared by the preparation method of 6-chloro-7-bromo-4(3H)-quinazolinone according to any one of claims 1 to 6, and the obtained product is used to prepare halofuginone.

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