阅读说明：本技术 一种柳氮磺吡啶中间体的制备方法 (Preparation method of salazosulfapyridine intermediate ) 是由 肖祖华 江尔胜 于 2019-12-09 设计创作，主要内容包括：本发明提供了一种柳氮磺吡啶中间体的制备方法,其制备方法包括以下步骤：步骤一：将4-氨基-7-氯喹啉加入装有有机溶剂的混合容器中,向所述混合容器中通入惰性气体,并升温至65～75℃；步骤二：搅拌一定时间后,向所述混合容器中加入侧链及催化剂,继续升温至85±3℃,继续搅拌；步骤三：待反应结束后,降温至10±2℃并静置分离,获取羟基氯喹啉基体；步骤四：向所述羟基氯喹啉基体中加入硫酸盐溶液,搅拌3.5～5h,并分离溶液中的固体,进一步烘干获取羟基氯喹硫酸盐材料。本发明的柳氮磺吡啶中间体的制备方法,制备流程简单,适于推广及使用。(The invention provides a preparation method of a salazosulfapyridine intermediate, which comprises the following steps: the method comprises the following steps: adding 4-amino-7-chloroquinoline into a mixing container filled with an organic solvent, introducing inert gas into the mixing container, and heating to 65-75 ℃; step two: after stirring for a certain time, adding a side chain and a catalyst into the mixing container, continuously heating to 85 +/-3 ℃, and continuously stirring; step three: after the reaction is finished, cooling to 10 +/-2 ℃, standing and separating to obtain a hydroxychloroquinoline matrix; step four: and adding a sulfate solution into the hydroxychloroquinoline matrix, stirring for 3.5-5 h, separating solids in the solution, and further drying to obtain the hydroxychloroquine sulfate material. The preparation method of the sulfasalazine intermediate has simple preparation process and is suitable for popularization and use.)

1. The preparation method of the sulfasalazine intermediate is characterized by comprising the following steps of:

the method comprises the following steps: adding 4-amino-7-chloroquinoline into a mixing container filled with an organic solvent, introducing inert gas into the mixing container, and heating to 65-75 ℃;

step two: after stirring for a certain time, adding a side chain and a catalyst into the mixing container, continuously heating to 85 +/-3 ℃, and continuously stirring;

step three: after the reaction is finished, cooling to 10 +/-2 ℃, standing and separating to obtain a hydroxychloroquinoline matrix;

step four: and adding a sulfate solution into the hydroxychloroquinoline matrix, stirring for 3.5-5 h, separating solids in the solution, and further drying to obtain the hydroxychloroquine sulfate material.

2. The method of preparing a sulfasalazine intermediate as claimed in claim 1, wherein; the inert gas in the first step is one or more of nitrogen, helium, argon and carbon dioxide.

3. The method of preparing a sulfasalazine intermediate as claimed in claim 1, wherein: the mass ratio of the 4-amino-7-chloroquinoline to the organic solvent is 1: 15.

4. The method of preparing a sulfasalazine intermediate as claimed in claim 1, wherein: and in the second step, the stirring time is 45-65 min, and the side chain is 5- (N-ethyl-N-hydroxyethyl) -2-aminopentane.

5. The method of preparing a sulfasalazine intermediate as claimed in claim 1, wherein: the catalyst in the second step is DMPA and/or DMA.

6. The method of preparing a sulfasalazine intermediate as claimed in claim 1, wherein: the reaction time in the third step is 2.5-3 h, and the reaction environment temperature is 65-75 ℃.

7. The method of preparing a sulfasalazine intermediate as claimed in claim 1, wherein: the sulfate in the fourth step is a strong acid weak base salt with sulfate, and the molar ratio of the sulfate to the hydroxychloroquinoline matrix is 2.5: 1.

Technical Field

The invention provides a preparation method of a sulfasalazine intermediate, and belongs to the technical field of chemical industry.

Background

Sulfasalazine (SASP), also known as 5- [ p- (2-pyridinamidosulfonyl) benzene ] azosalicylic acid. Molecular formula is C18H14N4O5S, molecular weight: 398.39.

sulfasalazine is an azo compound of salicylic acid and sulfapyridine, and has antibacterial, antirheumatic and immunosuppressive effects. In the intestinal tract, the bacteria are decomposed into Sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA).

The prior method for producing the salazosulfapyridine requires mixing and manufacturing of various intermediates, wherein catalysts or solvents with chronic toxicity need to be added, so that the method is not environment-friendly and increases the production cost; in addition, the production process is complicated, the production time is long, and the industrialization is not facilitated.

Therefore, there is a need for further improvement of the production process for preparing sulfasalazine intermediates in order to obtain a more efficient, simpler, more selective, more environmentally friendly, and less costly process for preparing hydroxychloroquinolines sulfate with high purity.

Disclosure of Invention

The invention aims to provide a preparation method of a sulfasalazine intermediate, which is simple in preparation process and suitable for popularization and use.

In order to realize the aim, the invention provides a preparation method of a sulfasalazine intermediate, which comprises the following steps:

the method comprises the following steps: adding 4-amino-7-chloroquinoline into a mixing container filled with an organic solvent, introducing inert gas into the mixing container, and heating to 65-75 ℃;

step two: after stirring for a certain time, adding a side chain and a catalyst into the mixing container, continuously heating to 85 +/-3 ℃, and continuously stirring;

step three: after the reaction is finished, cooling to 10 +/-2 ℃, standing and separating to obtain a hydroxychloroquinoline matrix;

step four: and adding a sulfate solution into the hydroxychloroquinoline matrix, stirring for 3.5-5 h, separating solids in the solution, and further drying to obtain the hydroxychloroquine sulfate material.

As a further improvement of the invention, the inert gas in the first step is one or more of nitrogen, helium, argon and carbon dioxide.

As a further improvement of the invention, the mass ratio of the 4-amino-7-chloroquinoline to the organic solvent is 1: 15.

As a further improvement of the invention, the stirring time in the second step is 45-65 min, and the side chain is 5- (N-ethyl-N-hydroxyethyl) -2-aminopentane.

As a further improvement of the invention, the catalyst in step two is DMPA and/or DMA.

As a further improvement of the method, the reaction time in the third step is 2.5-3 h, and the reaction ambient temperature is 65-75 ℃.

As a further improvement of the present invention, the sulfate in the fourth step is a strong acid weak base salt with sulfate, and the molar ratio of the sulfate to the hydroxychloroquinoline matrix is 2.5: 1.

The invention has the beneficial effects that: the preparation method of the salazosulfapyridine intermediate is safe and environment-friendly, the prepared intermediate can replace a catalyst or a solvent with chronic toxicity, the process temperature is low, the time is short, the energy consumption is reduced, and the equipment utilization rate is improved; meanwhile, the method has the advantages of simple synthetic route, mild reaction conditions, safety, environmental protection, high yield and quality, low manufacturing cost and suitability for industrial production of hydroxychloroquine sulfate.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in detail below with reference to specific embodiments.

It should be noted that, in order to avoid obscuring the present invention with unnecessary details, only the structures and/or processing steps closely related to the scheme of the present invention are shown, and other details not closely related to the present invention are omitted.

In addition, it is also to be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

The invention provides a preparation method of a salazosulfapyridine intermediate, which comprises the following steps:

the method comprises the following steps: adding 4-amino-7-chloroquinoline into a mixing container filled with an organic solvent, introducing inert gas into the mixing container, and heating to 65-75 ℃;

step two: after stirring for a certain time, adding a side chain and a catalyst into the mixing container, continuously heating to 85 +/-3 ℃, and continuously stirring;

step three: after the reaction is finished, cooling to 10 +/-2 ℃, standing and separating to obtain a hydroxychloroquinoline matrix;

step four: and adding a sulfate solution into the hydroxychloroquinoline matrix, stirring for 3.5-5 h, separating solids in the solution, and further drying to obtain the hydroxychloroquine sulfate material.

The hydroxychloroquine sulfate can be used as a sulfasalazine intermediate, and can replace a chronic toxic catalyst or a solvent.

In the invention, the inert gas in the first step is one or more of nitrogen, helium, argon and carbon dioxide, the mass ratio of the 4-amino-7-chloroquinoline to the organic solvent is 1:15, and the preferable organic solvent is an alkane organic solvent.

And in the second step, the stirring time is 45-65 min, the further side chain is 5- (N-ethyl-N-hydroxyethyl) -2-aminopentane, and the catalyst is DMPA and/or DMA.

Furthermore, the reaction time in the third step is 2.5-3 hours, the ambient temperature of the reaction is 65-75 ℃, and the cooling time should be controlled within 2 hours in the cooling process to prevent the agglomeration of the hydroxychloroquinoline matrix.

The sulfate in the fourth step is strong acid weak base salt with sulfate, such as copper sulfate, ferrous sulfate and the like, and the molar ratio of the sulfate to the hydroxychloroquinoline matrix is 2.5: 1.

The following examples are intended to further illustrate the invention, but not to limit the scope of the invention.