CN110862345A - Preparation method of salazosulfapyridine intermediate - Google Patents
Preparation method of salazosulfapyridine intermediate Download PDFInfo
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- CN110862345A CN110862345A CN201911248705.4A CN201911248705A CN110862345A CN 110862345 A CN110862345 A CN 110862345A CN 201911248705 A CN201911248705 A CN 201911248705A CN 110862345 A CN110862345 A CN 110862345A
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- sulfasalazine
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- sulfate
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- hydroxychloroquinoline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
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.
Description
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.
Example 1
Adding 10g of 4-amino-7-chloroquinoline into a mixing container filled with 150g of dichloromethane, introducing nitrogen into the mixing container, and heating to 65 ℃; stirring for 50min, adding 5- (N-ethyl-N-hydroxyethyl) -2-aminopentane and catalyst DMPA, heating to 85 deg.C, and stirring for 20 min; cooling to 70 ℃, reacting for 2.5h, further cooling to 10 +/-2 ℃, standing and separating a water phase and an organic phase in the mixture to obtain a hydroxychloroquinoline matrix; adding copper sulfate into a hydroxychloroquinoline matrix, stirring for 2.5h, separating solids in the mixed solution, and further drying to obtain a hydroxychloroquine sulfate material; the yield of the hydroxychloroquine sulfate material is 89%, and HPLC is more than or equal to 92%.
Example 2
Adding 20g of 4-amino-7-chloroquinoline into a mixing container filled with 300g of trichloroethane, introducing nitrogen into the mixing container, and heating to 70-75 ℃; stirring for 55min, adding 5- (N-ethyl-N-hydroxyethyl) -2-aminopentane and catalyst DMA into the mixing container, continuously heating to 87 ℃, and continuously stirring for 15 min; cooling to 65 ℃, reacting for 3h, further cooling to 10 +/-2 ℃, standing and separating a water phase and an organic phase in the mixture to obtain a hydroxychloroquinoline matrix; adding ferrous sulfate into a hydroxychloroquinoline matrix, stirring for 2.5h, separating solids in the mixed solution, and further drying to obtain a hydroxychloroquine sulfate material; the yield of the hydroxychloroquine sulfate material is 94 percent, and HPLC is more than or equal to 95 percent.
Example 3
Adding 15g of 4-amino-7-chloroquinoline into a mixing container filled with 225g of dichloroethane, introducing argon into the mixing container, and heating to 65-70 ℃; stirring for 60min, adding 5- (N-ethyl-N-hydroxyethyl) -2-aminopentane and catalyst DMPA into the mixing container, continuously heating to 83 deg.C, and continuously stirring for 35 min; cooling to 50 ℃, reacting for 3h, further cooling to 10 +/-2 ℃, standing and separating a water phase and an organic phase in the mixture to obtain a hydroxychloroquinoline matrix; adding ferrous sulfate into a hydroxychloroquinoline matrix, stirring for 3h, separating solids in the mixed solution, and further drying to obtain a hydroxychloroquine sulfate material; the yield of the hydroxychloroquine sulfate material is 94 percent, and HPLC is more than or equal to 95 percent.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (7)
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.
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| CN201911248705.4A CN110862345B (en) | 2019-12-09 | 2019-12-09 | Preparation method of salazosulfapyridine intermediate |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107266323A (en) * | 2017-07-18 | 2017-10-20 | 宜宾莱特医药化工有限公司 | A kind of side chain and its synthetic method, and using the method for side chain synthesis hydroxychloroquine sulfate |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107266323A (en) * | 2017-07-18 | 2017-10-20 | 宜宾莱特医药化工有限公司 | A kind of side chain and its synthetic method, and using the method for side chain synthesis hydroxychloroquine sulfate |
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