Preparation process and method of nikethamide injection

Abstract

The invention belongs to the technical field of medicinal preparations, and particularly relates to a nikethamide injection preparation process and method, and the nikethamide injection is prepared by the six steps of salifying, condensing, neutralizing and washing, oxidizing and steaming water to decolor, refining and packaging. The prepared nikethamide injection can be used for treating respiratory and circulatory failure caused by diseases or central inhibition drug poisoning. The composition especially has a remarkable curative effect on respiratory failure caused by pulmonary heart disease and respiratory suppression caused by excessive morphine. Meanwhile, the nikethamide injection prepared by the invention has good solubility and stability, is simple in preparation process and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a preparation process and method of nikethamide injection. Background Art

[0002] Nicothamide, also known as coramine, has a chemical name of N,N-diethylnicotinamide and a structural formula as shown in Formula I. It is one of the first-aid drugs commonly used in clinical practice. In addition, nikethamide can also be used for central respiratory depression and circulatory failure. It can not only directly stimulate the medullary respiratory center, increase the sensitivity of the respiratory center to carbon dioxide, promote respiratory rate and increase tidal volume, but also act on the carotid body chemoreceptors to jointly promote the increase of respiratory rate and amplitude.

[0003]

[0004] The preparation of nikethamide reported in the literature now is to use nicotinic acid as a raw material and diethylamine to form a salt, then react with phosphorus oxychloride, dehydrate to generate nikethamide hydrochloride, then neutralize with sodium hydroxide, extract with an organic solvent, and distill under reduced pressure to obtain the finished product. The nikethamide injection prepared by the existing technology also has the problems of unstable chemical properties, easy discoloration of the solution, and easy change of content, which brings difficulties to the production, storage and clinical application of nikethamide injection. Summary of the invention

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

[0006] This is achieved through the following technical solutions:

[0007] (1) Salt formation: weigh toluene and nicotinic acid in portions, cool and add diethylamine dropwise;

[0008] (2) Condensation: After salt formation, add phosphorus oxychloride dropwise and heat to react for 5 hours. After the reaction is complete, cool and allow to stand for separation;

[0009] (3) Neutralization washing: add sodium hydroxide solution to the feed liquid until the pH is 7, discard the water layer after neutralization, wash the upper layer of the feed liquid with purified water and sodium carbonate, and repeat the washing twice;

[0010] (4) Oxidation, water distillation, and decolorization: The feed liquid is pumped into a reaction kettle, potassium permanganate is added, heated for reaction for 3 hours, vacuumed, distilled, activated carbon is added after cooling, stirred for 30 minutes, and filtered;

[0011] (5) Refining: Vacuuming, distilling off the low-boiling products and discarding them, collecting the positive boiling products until the total weight reaches 80%, stopping the distillation, and when the refining is completed, the remaining materials in the kettle are discharged and discarded;

[0012] (6) Packaging: Weigh the fine material and add it into a medicinal screw-mouth aluminum bottle. After passing QA, it is transferred to the outer packaging room and packaged and placed in the finished product warehouse.

[0013] The synthetic route of Nikethamide injection is as follows:

[0014]

[0015] Preferably, the raw materials are as follows: 18 parts of toluene, 9 parts of nicotinic acid, 7 parts of diethylamine, 8 parts of phosphorus oxychloride, 7 parts of sodium hydroxide, 43 parts of purified water, 7 parts of sodium carbonate, 0.2 parts of potassium permanganate, and 0.8 parts of activated carbon.

[0016] Preferably, the specific preparation method of the salt in step (1) is: 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, and the drop rate is controlled to keep the temperature below 55° C. After the dropwise addition is completed, stir for another 10 minutes at below 55° C.

[0017] Preferably, the specific preparation method of the condensation in step (2) is as follows: after the salt formation is completed, phosphorus oxychloride is added dropwise to the feed liquid, the reaction is exothermic, and the temperature is controlled below 95°C. After the dropwise addition is completed, the temperature is raised to 105-115°C for insulation 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, and allowed to stand for more than 30 minutes, and the liquid is separated, 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.

[0018] Preferably, the specific preparation method of neutralization and washing in step (3) 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, and the temperature is controlled below 50°C. Stop when pH=7. After neutralization, the internal temperature rises 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 again, and the washing operation is repeated twice.

[0019] Preferably, the specific steps of oxidation, water distillation and decolorization in step (4) are as follows: the feed liquid is pumped into a reactor. 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 reactor ≤-0.09MPa, the temperature is raised, and the feed liquid temperature does not exceed 140°C until no water is distilled out, and distilled at 130-140°C for another hour. The temperature is lowered to 75-85°C, activated carbon is added, and stirred at 75-85°C for 30 minutes. The feed liquid is filtered through a filter using nitrogen to a refining reactor.

[0020] Preferably, the specific operation steps of the refining in step (5) are: open the vacuum of the receiving tank to make the vacuum degree in the reactor ≤ 0.095MPa, open the reactor to heat, and as the temperature rises, the low boiling is evaporated, and the low boiling is collected into the receiving tank until the total weight is 10%, and the low boiling is released and discarded. The positive boiling is collected until the total weight is 80%, and the positive boiling is collected into a turnover barrel. Stop distillation, refining is completed, and the remaining liquid in the kettle is released and discarded.

[0021] Preferably, the specific operation steps of step (6) packaging are: add the qualified fine material to the weighed medicinal screw-mouth aluminum bottle according to the standard of 25.00±0.10g per bottle, and seal the medicinal screw-mouth aluminum bottle after weighing. After QA confirms that it is qualified, put the fine material into the transfer cabin and pass it to the outer packaging room. Open the transfer cabin door, take out the inner packaged fine material bottle, put it into the cardboard barrel, put in the product certificate and buffer, cover the barrel cover, insert the seal, and stick the filled barrel outer label to the side of the cardboard barrel. Repeat the operation to complete the packaging of all the fine materials transferred from the transfer cabin. After QA confirms that it is qualified, the packaged finished product is put into the finished product warehouse.

[0022] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0023] The present invention discloses a preparation process and method of nikethamide injection, specifically including the synthesis of nikethamide and the preparation of injection. The synthesized nikethamide injection can be used for respiratory and circulatory failure caused by diseases or central nervous system depressant poisoning. It has a significant therapeutic effect on respiratory failure caused by cor pulmonale and respiratory depression caused by morphine overdose. At the same time, the nikethamide injection prepared by the present invention has good solubility and stability, a simple preparation process, and is suitable for industrial production. DETAILED DESCRIPTION

[0024] 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.

[0025] 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.

[0026] In the present invention, unless otherwise specified, all "parts" and percentages (%) refer to percentages by weight.

[0027] In the present invention, unless otherwise specified, the sum of all percentages in all compositions is 100%.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] Example

[0033] 1. Salt formation: Weigh 1.85 kg toluene and 1 kg nicotinic acid into the reactor, stir, and cool to below 50°C. After the liquid temperature is below 50°C, start to drop 0.83 kg 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.

[0034] 2. Condensation: After the salt formation is completed, add 0.88 kg of phosphorus oxychloride to the 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.

[0035] 3. Neutralization washing: Prepare 20% sodium hydroxide solution with 0.8kg sodium hydroxide and 4.8kg purified water, 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 sodium carbonate, 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 sodium carbonate again, and repeat the washing operation twice.

[0036] 4. Oxidation, water distillation, decolorization: Pump the feed liquid into 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, raise the temperature, and the feed liquid temperature does not exceed 140℃ until no water is distilled out, 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. Use nitrogen to filter the feed liquid through the filter to the refining reactor.

[0037] 5. Refining: Open the vacuum of the receiving tank to make the vacuum degree in the reactor ≤0.095MPa, turn on the reactor to heat, as the temperature rises, the low boiling point evaporates, collect the low boiling point into the receiving tank, collect until the total weight is 10%, release the low boiling point and discard it. Collect the positive boiling point to 80% of the total weight, collect the positive boiling point into the turnover barrel. Stop distillation, refining is completed, and the remaining liquid in the kettle is released and discarded.

[0038] 6. Packaging: Add the qualified fine materials into the weighed medicinal screw-mouth aluminum bottles according to the standard of 25.00±0.10kg per bottle. After weighing, seal the medicinal screw-mouth aluminum bottles. After QA confirms that it is qualified, put the fine materials into the transfer cabin and pass them to the outer packaging room. Open the transfer cabin door, take out the inner-packed fine material bottles, put them into the cardboard barrel, put in the product certificate and buffer, cover the barrel cover, insert the seal, and stick the filled-in barrel label on the side of the cardboard barrel. Repeat the operation to complete the packaging of all the fine materials transferred from the transfer cabin. After QA confirms that it is qualified, the packaged finished products are put into the finished product warehouse.

[0039] Performance Testing

[0040] Determination of the content of nikethamide injection by HPLC

[0041] Methanol-water (30:70) was selected as the mobile phase, the detection wavelength was 263 nm, and the flow rate was 1.0 ml min -1 , the injection volume was 10 μl; nikethamide bulk drug was used as the reference substance, and nikethamide injection was used as the test substance.

[0042] Accurately pipette 10 μl of each reference substance and test substance solution, inject into the chromatograph, inject three times continuously, record the chromatogram, and calculate the content of nikethamide in the sample by the external standard method.

[0043] The results showed that the contents of the three batches of samples were 105.4%, 100.2% and 102.7% of the labeled amount respectively.

[0044] 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. The preparation process and method of nikethamide injection comprises the following steps: (1) Salt formation: weigh toluene and nicotinic acid in portions, cool and add diethylamine dropwise; (2) Condensation: After salt formation, add phosphorus oxychloride dropwise and heat to react for 5 hours. After the reaction is complete, cool and allow to stand for separation; (3) Neutralization washing: add sodium hydroxide solution to the feed liquid until the pH is 7, discard the water layer after neutralization, wash the upper layer of the feed liquid with purified water and sodium carbonate, and repeat the washing twice; (4) Oxidation, water distillation, and decolorization: The feed liquid is pumped into a reaction kettle, potassium permanganate is added, heated for reaction for 3 hours, vacuumed, distilled, activated carbon is added after cooling, stirred for 30 minutes, and filtered; (5) Refining: Vacuuming, distilling off the low-boiling products and discarding them, collecting the positive boiling products until the total weight reaches 80%, stopping the distillation, and when the refining is completed, the remaining materials in the kettle are discharged and discarded; (6) Packaging: Weigh the fine material and add it into a medicinal screw-mouth aluminum bottle. After passing QA, it is transferred to the outer packaging room and packaged and placed in the finished product warehouse. The synthetic route of Nikethamide injection is as follows: 。 2. The process and method for preparing nikethamide injection according to claim 1, characterized in that: The raw materials are as follows: 18 parts of toluene, 9 parts of nicotinic acid, 7 parts of diethylamine, 8 parts of phosphorus oxychloride, 7 parts of sodium hydroxide, 43 parts of purified water, 7 parts of sodium carbonate, 0.2 parts of potassium permanganate, and 0.8 parts of activated carbon.

3. The process and method for preparing nikethamide injection according to claim 1, characterized in that: The specific preparation method of the salt in step (1) is as follows: weigh toluene and nicotinic acid, add them into a reaction kettle, stir, and cool to below 50°C. After the liquid temperature is below 50°C, start to drop diethylamine, the reaction is exothermic, and the drop rate is controlled to keep the temperature below 55°C. After the drop addition is completed, stir for another 10 minutes at below 55°C.

4. The process and method for preparing nikethamide injection according to claim 1, characterized in that: The specific preparation method of step (2) condensation is as follows: after the salt formation is completed, 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, stirred for 30 minutes after the water is added, and allowed to stand for more than 30 minutes, and the liquid is separated. The lower layer of the material is collected in a turnover barrel, and the upper toluene layer is treated as waste liquid. After separation, the material layer is pumped into the reactor.

5. The process and method for preparing nikethamide injection according to claim 1, characterized in that: The specific preparation method of step (3) neutralization washing is as follows: sodium hydroxide and purified water are prepared into a 20% sodium hydroxide solution, which is prepared in advance and cooled to room temperature. The feed liquid temperature is controlled below 50°C. Sodium hydroxide solution is added dropwise, and the temperature is controlled below 50°C. Stop when pH=7. After neutralization, the internal temperature rises 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 again, and the washing operation is repeated twice.

6. The process and method for preparing nikethamide injection according to claim 1, characterized in that: The specific steps of oxidation, water distillation and decolorization in step (4) are as follows: the feed liquid is pumped into the reactor. 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 reactor ≤-0.09MPa, the temperature is raised, and the feed liquid temperature does not exceed 140°C until no water is distilled out, and distilled at 130-140°C for another hour. The temperature is lowered to 75-85°C, activated carbon is added, and stirred at 75-85°C for 30 minutes. The feed liquid is filtered through a filter using nitrogen to the refining reactor.

7. The process and method for preparing nikethamide injection according to claim 1, characterized in that: The specific operation steps of the refining in step (5) are as follows: open the vacuum of the receiving tank to make the vacuum degree in the reactor ≤ 0.095 MPa, open the reactor to heat, and as the temperature rises, the low boiling point evaporates, and the low boiling point is collected in the receiving tank until the total weight is 10%, and the low boiling point is released and discarded. The positive boiling point is collected until the total weight is 80%, and the positive boiling point is collected in a turnover barrel. Stop distillation, refining is completed, and the remaining liquid in the kettle is released and discarded.

8. The process and method for preparing nikethamide injection according to claim 1, characterized in that: The specific operation steps of step (6) packaging are as follows: add the qualified fine materials into the weighed medicinal screw-mouth aluminum bottles according to the standard of 25.00±0.10g per bottle, and seal the medicinal screw-mouth aluminum bottles after weighing. After QA confirms that it is qualified, put the fine materials into the transfer cabin and pass them to the outer packaging room. Open the transfer cabin door, take out the inner packed fine material bottles, put them into the cardboard barrel, put in the product certificate and buffer, cover the barrel cover, insert the seal, and stick the filled-in barrel label on the side of the cardboard barrel. Repeat the operation to complete the packaging of all the fine materials transferred from the transfer cabin. After QA confirms that it is qualified, the packaged finished products are put into the finished product warehouse.

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