Preparation method of nikethamide bulk drug

Abstract

The invention belongs to the field of medicine synthesis, and relates to a preparation method of a raw material medicine, in particular to a preparation method of a nikethamide raw material medicine, which is prepared by four steps of salifying, condensing, neutralizing and washing, and oxidizing and steaming water to decolor. In the production of nikethamide, nikethamide is firstly salified, after the reaction activity of nikethamide is improved, nikethamide is further condensed with diethylamine, the reaction is an exothermic reaction, the reaction temperature is strictly controlled in the reaction process, the reaction rate of condensation is improved, and the yield is also improved; furthermore, through post-treatment such as oxidation, water distillation and decoloration, the produced raw material medicine has good characters and chemical stability, and meets the requirements of Chinese pharmacopoeia 2020 edition on nikethamide. According to the invention, the production process of the nikethamide bulk drug is optimized, the production period is shortened, and the cost is reduced.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, relates to a production process and method of a raw material drug, and particularly relates to a preparation method of a nikethamide raw material drug. Background Art

[0002] The chemical name of nikethamide is N,N-diethylnicotinamide, and its structural formula is shown in Formula I. It is a commonly used respiratory stimulant in clinical practice, mainly used for emergency treatment of central respiratory and circulatory failure and poisoning emergency of anesthetics and other central depressants. A large number of research results have shown that nikethamide can improve the blood gas indexes of patients with chronic obstructive pulmonary disease, reduce hypercapnia, and improve pulmonary ventilation function. Respiratory stimulants combined with non-invasive ventilators have achieved relatively ideal results in the clinical treatment of chronic obstructive pulmonary disease.

[0003]

[0004] Niclosamide API is an important pharmaceutical raw material, mainly used to manufacture Niclosamide injection. At present, the production method of Niclosamide API mainly uses nicotinic acid as raw material, and then reacts with ethylenediamine after chlorination to obtain the product. However, nicotinic acid has a high cost and poor reaction activity, and the yield is low. Therefore, improving the yield by improving the synthesis process route is still a problem that needs to be solved urgently. Summary of the invention

[0005] In view of the problems existing in the background technology, the present invention provides a method for preparing a nikethamide bulk drug, which simplifies the operation, reduces the production cost, and is more conducive to industrial production.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] The raw material of nikethamide includes the following raw materials: toluene, nicotinic acid, diethylamine, phosphorus oxychloride, sodium hydroxide, purified water, sodium carbonate, potassium permanganate and activated carbon.

[0008] Preferably, the sodium hydroxide is a 20% sodium hydroxide solution.

[0009] On the basis of the above technical solution, the present invention also provides the following optional technical solution:

[0010] A nikethamide raw material production process comprises the following steps:

[0011] Step (a): Salt formation: Add nicotinic acid and toluene into a reaction kettle, stir and cool, add diethylamine dropwise after the temperature drops to a certain level, and continue stirring at low temperature for 10 minutes after the reaction is completed;

[0012] Step (b): after condensation into salt, add phosphorus oxychloride dropwise, control the reaction temperature below 95°C, raise the temperature to react for 5 hours after the addition is complete, cool and stand for liquid separation after the reaction is complete, discard the toluene layer, and collect the material layer;

[0013] Step (c): neutralization washing: control the temperature at 50°C, add 20% sodium hydroxide solution to the material layer until it is neutral, let it stand and discard the water layer, continue to add purified water and sodium carbonate to the upper material liquid, stir, let it stand, discard the water layer, and repeat washing twice;

[0014] Step (d): oxidation, water distillation, decolorization: potassium permanganate is added to the washed liquid, heated for reaction for 3 hours, activated carbon is added for decolorization after distillation, insoluble matter is filtered out, and the liquid is dried and concentrated under reduced pressure to obtain the nikethamide bulk drug.

[0015] Synthesis route of Nikethamide:

[0016]

[0017] Preferably, the specific preparation method of the salt in step (a) is: weigh nicotinic acid and add it into a reaction kettle, stir, cool to below 50°C, and after the liquid temperature is below 50°C, start to drop diethylamine, the reaction is exothermic, control the drop rate, keep the temperature below 55°C, and after the drop addition is completed, stir for another 10 minutes at below 55°C.

[0018] Preferably, the specific preparation method of the condensation in step (b) is as follows: after the salt formation is completed, phosphorus oxychloride is added dropwise to the feed liquid, the reaction is exothermic, the temperature is controlled below 95°C, after the addition is completed, the temperature is raised to 105-115°C and kept for reaction for 5 hours, after the reaction is completed, the internal temperature is reduced to 60-70°C; purified water is added, stirred for 30 minutes after the water is added, allowed to stand for more than 30 minutes, the liquid is separated, the lower layer of the material layer is placed in a turnover barrel for collection, the upper toluene layer is treated as waste liquid, and the material layer is pumped into the reactor after separation.

[0019] Preferably, the specific preparation method of neutralization and washing in step (c) is: sodium hydroxide and purified water are configured into a 20% sodium hydroxide solution, which is configured in advance and cooled to room temperature; the feed liquid temperature is controlled below 50°C, sodium hydroxide solution is added dropwise, the temperature is controlled below 50°C, and the pH is stopped at 7; after neutralization, the internal temperature is raised to 55-65°C, stirred for 30 minutes, allowed to stand for 30 minutes, the lower water layer is discarded, and the upper feed liquid remains in the reactor; purified water and sodium carbonate are added, 55-65°C, stirred for 30 minutes, allowed to stand for 30 minutes, the lower water layer is discarded, and the upper feed liquid remains in the reactor, purified water and sodium carbonate are added, and the washing operation is repeated twice.

[0020] Preferably, the specific steps of oxidation, water distillation and decolorization in step (d) are: the feed liquid is pumped into the reactor, potassium permanganate is added, stirred at 40-50° C. for 3 hours, the vacuum of the receiving tank is opened to make the vacuum degree in the reactor ≤-0.09 MPa, the temperature is increased, the feed liquid temperature does not exceed 140° C., until anhydrous water is distilled out, distilled at 130-140° C. for another hour, cooled to 75-85° C., activated carbon is added, stirred at 75-85° C. for 30 minutes, the insoluble matter is filtered out, dried, concentrated under reduced pressure and weighed to obtain the nikethamide raw material.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The present invention optimizes the production process of the raw material drug. The nikethamide prepared by the method has a short cycle, low cost, high mechanization and automation of production, greatly improving production efficiency and yield, and is suitable for industrial production. In the production of the nikethamide raw material described in the present invention, nicotinic acid is first salified, and its reaction activity is increased and then further condensed with diethylamine. The reaction is an exothermic reaction. The reaction temperature is strictly controlled during the reaction, the reaction rate of the condensation is increased, and the yield is also improved. At the same time, the raw material drug produced by oxidation, water distillation, decolorization and other post-treatments has good properties and chemical stability, meeting the requirements of the 2020 edition of the Chinese Pharmacopoeia for nikethamide. DETAILED DESCRIPTION

[0023] The following embodiments of the technical solution of the present invention are described in detail in conjunction with the embodiments. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and are therefore only used as examples, and cannot be used to limit the protection scope of the present invention.

[0024] It should be noted that the experimental methods used in the implementation examples are all conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial channels.

[0025] In the present invention, unless otherwise specified, all "parts" and percentages (%) refer to percentages by weight.

[0026] In the present invention, unless otherwise specified, the sum of all percentages in all compositions is 100%.

[0027] In the present invention, unless otherwise specified, the numerical range "a-b" represents an abbreviation of any real number combination between a-b, where a and b are real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations.

[0028] In the present invention, unless otherwise specified, all embodiments and preferred embodiments mentioned herein can be combined with each other to form a new technical solution.

[0029] In the present invention, unless otherwise specified, all the steps mentioned herein may be performed sequentially or randomly, but are preferably performed sequentially; for example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially; for example, the method may further include step (c), which means that step (c) may be added to the method in any order, for example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0030] In the present invention, unless otherwise specified, the specific numerical values ​​and specific substances in the embodiments of the present invention may be combined with other features of the description part of the present invention; for example, if the specification mentions that the reaction temperature is 10-100°C, and the embodiment mentions that the reaction temperature is 20°C, then it can be considered that the present invention has specifically disclosed the range of 10-20°C, or the range of 20-100°C, and this range can be combined with other features of the description part to form a new technical solution.

[0031] Example

[0032] Preparation of Nikethamide API

[0033] The specific raw materials are shown in Table 1.

[0034] Table 1

[0035]

[0036]

[0037] Nicotinic acid, diethylamine and phosphorus oxychloride are raw materials, toluene and purified water are synthesis reagents, sodium hydroxide and sodium carbonate are neutralization reagents, potassium permanganate is an oxidation reagent, and activated carbon is used for decolorization.

[0038] The synthesis process of nikethamide raw material is as follows:

[0039] Add 1kg nicotinic acid and 2.1L toluene into the reactor, stir, and cool to below 50°C. After the liquid temperature is below 50°C, start to drop 1.2L diethylamine. The reaction is exothermic. Control the drop rate to keep the temperature below 55°C. After the drop addition is completed, stir for another 10 minutes at below 55°C.

[0040] After the salt formation is completed, 0.53L of phosphorus oxychloride is added to the feed liquid, the reaction is exothermic, and the temperature is controlled below 95°C. After the addition is completed, the temperature is raised to 105-115°C and kept for 5 hours. After the reaction is completed, the internal temperature is reduced to 60-70°C. Add purified water, stir for 30 minutes after adding water, let it stand for more than 30 minutes, separate the liquid, put the lower layer of the material into the turnover barrel for collection, and treat the upper toluene layer as waste liquid. After separation, the material layer is pumped into the reactor.

[0041] Add 0.8kg of sodium hydroxide to purified water to make a 20% sodium hydroxide solution. Prepare in advance and cool to room temperature. The temperature of the feed liquid is controlled below 50°C. Add sodium hydroxide solution dropwise and control the temperature below 50°C. Stop when pH=7. After neutralization, the internal temperature rises to 55-65°C, stir for 30 minutes, let stand for 30 minutes, discard the lower water layer, and leave the upper feed liquid in the reactor. Add purified water and 0.8kg of sodium carbonate, stir for 30 minutes at 55-65°C, let stand for 30 minutes, discard the lower water layer, and leave the upper feed liquid in the reactor. Add purified water and sodium carbonate again, and repeat the washing operation twice.

[0042] The feed liquid is pumped to the reactor. Add 0.0085kg potassium permanganate and stir at 40-50℃ for 3 hours. Open the vacuum of the receiving tank to make the vacuum degree in the reactor ≤-0.09MPa, increase the temperature, and the feed liquid temperature does not exceed 140℃ until no water is evaporated, and distill for another hour at 130-140℃. Cool down to 75-85℃, add 0.085kg activated carbon, and stir at 75-85℃ for 30 minutes. Filter out the insoluble matter, dry, concentrate under reduced pressure, and weigh to obtain 1kg of nikethamide raw material.

[0043] The prepared nikethamide raw material was tested according to the 2020 edition of the Chinese Pharmacopoeia, and the results are shown in Table 2.

[0044] Table 2

[0045]

[0046]

[0047] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. These modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and specification of the present invention.

Claims

1. A nikethamide bulk drug, characterized in that: The invention comprises the following raw materials: toluene, nicotinic acid, diethylamine, phosphorus oxychloride, sodium hydroxide, purified water, sodium carbonate, potassium permanganate and activated carbon.

2. The nikethamide bulk drug according to claim 1, characterized in that The sodium hydroxide is a 20% sodium hydroxide solution.

3. The nikethamide bulk drug according to claim 1, characterized in that The preparation method of the drug comprises the following steps: Step (a): Salt formation: Add nicotinic acid and toluene into a reaction kettle, stir and cool, add diethylamine dropwise after the temperature drops to a certain level, and continue stirring at low temperature for 10 minutes after the reaction is completed; Step (b): after condensation into salt, add phosphorus oxychloride dropwise, control the reaction temperature below 95°C, raise the temperature to react for 5 hours after the addition is complete, cool and stand for liquid separation after the reaction is complete, discard the toluene layer, and collect the material layer; Step (c): neutralization washing: control the temperature at 50°C, add 20% sodium hydroxide solution to the material layer until it is neutral, let it stand and discard the water layer, continue to add purified water and sodium carbonate to the upper material liquid, stir, let it stand, discard the water layer, and repeat washing twice; Step (d): oxidation, water distillation, decolorization: potassium permanganate is added to the washed liquid, heated for reaction for 3 hours, activated carbon is added for decolorization after distillation, insoluble matter is filtered out, and the liquid is dried and concentrated under reduced pressure to obtain the nikethamide bulk drug. Synthesis route of Nikethamide:

4. The method for preparing the nikethamide bulk drug according to claim 3, characterized in that: The specific preparation method of the salt in step (a) is as follows: weigh toluene and nicotinic acid, add them into a reaction kettle, stir, and cool to below 50°C; after the feed liquid temperature is below 50°C, start to drop diethylamine, the reaction is exothermic, control the drop rate, and keep the temperature below 55°C; after the drop addition is completed, stir for another 10 minutes at below 55°C.

5. The method for preparing the nikethamide bulk drug according to claim 3, characterized in that: The specific preparation method of the condensation of step (b) is as follows: after the salt is formed, phosphorus oxychloride is added dropwise to the feed liquid, the reaction is exothermic, and the temperature is controlled below 95°C; after the addition is completed, the temperature is raised to 105-115°C and kept for reaction for 5 hours; after the reaction is completed, the internal temperature is reduced to 60-70°C; purified water is added, and after the water is added, it is stirred for 30 minutes, allowed to stand for more than 30 minutes, and the liquid is separated, and the lower layer of the material layer is placed in a turnover barrel for collection, and the upper toluene layer is treated as waste liquid. After separation, the material layer is pumped into the reactor.

6. The method for preparing the nikethamide bulk drug according to claim 3, characterized in that: The specific preparation method of step (c) neutralization and washing is as follows: sodium hydroxide and purified water are configured into a 20% sodium hydroxide solution, which is configured in advance and cooled to room temperature; the feed liquid temperature is controlled below 50°C, sodium hydroxide solution is added dropwise, the temperature is controlled below 50°C, and the pH is stopped at 7; after neutralization, the internal temperature is raised to 55-65°C, stirred for 30 minutes, allowed to stand for 30 minutes, the lower water layer is discarded, the upper feed liquid is left in the reactor, purified water and sodium carbonate are added, 55-65°C, stirred for 30 minutes, allowed to stand for 30 minutes, the lower water layer is discarded, the upper feed liquid is left in the reactor, purified water and sodium carbonate are added, 55-65°C, stirred for 30 minutes, allowed to stand for 30 minutes, the lower water layer is discarded, the upper feed liquid is left in the reactor, purified water and sodium carbonate are added, and the washing operation is repeated twice.

7. The method for preparing the nikethamide bulk drug according to claim 3, characterized in that: The specific steps of oxidation, water distillation and decolorization in step (d) are as follows: the feed liquid is pumped into the reaction kettle. Potassium permanganate is added and stirred at 40-50°C for 3 hours; the vacuum of the receiving tank is turned on to make the vacuum degree in the kettle ≤-0.09MPa. Raise the temperature of the liquid to no more than 140°C until no water is distilled out, distill for another hour at 130-140°C, cool to 75-85°C, add activated carbon, The mixture was stirred at 75-85°C for 30 minutes, the insoluble matter was filtered off, and the mixture was dried, concentrated under reduced pressure, and weighed to obtain the nikethamide bulk drug.

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