CN115850056B - Preparation method of ibuprofen L-lysine salt - Google Patents
Preparation method of ibuprofen L-lysine salt Download PDFInfo
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- CN115850056B CN115850056B CN202211631022.9A CN202211631022A CN115850056B CN 115850056 B CN115850056 B CN 115850056B CN 202211631022 A CN202211631022 A CN 202211631022A CN 115850056 B CN115850056 B CN 115850056B
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- IHHXIUAEPKVVII-ZSCHJXSPSA-N [(1s)-5-amino-1-carboxypentyl]azanium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical class OC(=O)[C@@H](N)CCCC[NH3+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 IHHXIUAEPKVVII-ZSCHJXSPSA-N 0.000 title claims abstract description 46
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- 238000000034 method Methods 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
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- 229910052799 carbon Inorganic materials 0.000 claims description 7
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- 238000009835 boiling Methods 0.000 claims description 3
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Abstract
The invention provides a preparation method of ibuprofen L-lysine salt, which comprises the following steps: 1) Feeding ibuprofen and L-lysine serving as raw materials, heating and dissolving the ibuprofen and the L-lysine in a lower alcohol or aqueous lower alcohol solution, filtering while the solution is hot, and concentrating and drying filtrate to obtain ibuprofen-L-lysine salt-containing viscous liquid; 2) Adding pure water into the ibuprofen-containing L-lysine salt viscous liquid for dissolution, then adding a low-polarity solvent for reflux azeotropic water diversion, and separating residual alcohol and water to obtain a dispersed solid; 3) And cooling, filtering and decompressing the dispersed solid, and drying to obtain the ibuprofen L-lysine salt with dispersed particles. The invention adopts low-polarity solvent to reflux and azeotropy split water, utilizes the advantages of low solubility of ibuprofen L-lysine salt in low-polarity solvent, high salt forming yield and no higher optical rotation, and the obtained product is powdery dispersed solid, does not need to be crushed, is easy to dry, has small residue, low water content and difficult moisture absorption, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of ibuprofen L-lysine salt.
Background
Ibuprofen (Ibuprofen) is a nonsteroidal antipyretic analgesic anti-inflammatory and antirheumatic drug which is produced in the beginning of 80 s in China, and the ibuprofen can reduce the synthesis of prostaglandin by inhibiting cyclooxygenase, and has analgesic and anti-inflammatory effects; has antipyretic effect by regulating the central nervous system by hypothalamic body temperature. The conventional dosage forms include tablets, capsules, injections, suppositories, syrups, oral liquids, boxes, sustained-release pellets and the like.
Ibuprofen is almost insoluble in water, most of clinical medicines in China are oral preparations, and the ibuprofen has relatively slow onset of action like other oral non-steroidal anti-inflammatory analgesics, so that the ibuprofen is limited in application in clinical pain. The ibuprofen L-lysine salt is a salt compound formed by combining ibuprofen and L-lysine, has the characteristics of easily available raw materials and good water solubility, changes the solubility of the ibuprofen, increases the absorption rate in vivo, shortens the analgesic onset time due to the increase of the absorption rate, has the characteristic of vivid quick-acting analgesic, and also provides assistance for preparing the ibuprofen into various liquid dosage forms.
In the preparation process of ibuprofen L-lysine salt, the conventional crystallization process is found that the ibuprofen L-lysine salt and alcohols easily form solvent compounds, or the ibuprofen L-lysine salt has extremely fine particle size and is difficult to filter; or swelling occurs and filtration is hardly possible; the drying process is easy to agglomerate, and the dissolution residue exceeds the standard. Document Organic Process Research & Development 2003, 7, 717-722 reports that L-lysine preferentially combines with dexibuprofen to form salts during the formation of salts with ibuprofen, which results in higher optical rotation and lower melting points of the L-lysine salt of ibuprofen than ibuprofen.
Currently, literature/patents on processes for the preparation of ibuprofen L-lysine salts are mainly as follows:
new medicine of shanxi 1986, 15 (8): 54, the salt formation mode of ethanol and water is adopted to prepare the ibuprofen L-lysine salt, the yield is 60 percent, and the melting point is 152-156 ℃.
The salt formation mode of the ibuprofen L-lysine salt disclosed in the patent US04279926 is similar to that of the ethanol and water, the optical rotation [ a ] D 20 =13.1 DEG of the prepared ibuprofen L-lysine salt is similar to that of the ethanol and water, and the melting point is 150-158 ℃, and the yield is not given.
Pharmaceutical progress 2006, 30 (10): 460 also discloses salification with ethanol + water followed by concentration to remove the solvent to give a pale yellow product.
Journal of Chinese Hospital pharmacy 1995, 15 (12): 532 discloses that the ibuprofen L-lysine salt is directly salified in pure water to prepare an aqueous solution of ibuprofen L-lysine salt, and the aqueous solution is used as an injection.
However, the above disclosed ibuprofen L-lysine salt preparation process has the following problems: new medicine of shanxi 1986, 15 (8): 54 and patent US04279926 are both prepared by salifying and crystallizing in ethanol and water, but the yield is low, the optical rotation is difficult to be qualified, the literature value [ a ] D 20 = +13.1 DEG, and the melting point is relatively low; pharmaceutical progress 2006, 30 (10): 460 improves the process, after salifying in ethanol and water, concentrating to remove the solvent, improving the yield, but the process requires decompression and water removal at room temperature, has strict operation requirements, and the product concentration process is a viscous liquid, so industrialization is difficult to realize, and the product with qualified water content is obtained; journal of Chinese Hospital pharmacy 1995, 15 (12): 532, the preparation of an aqueous solution of ibuprofen L-lysine salt does not give a solid product, which is disadvantageous in terms of production and transport.
Disclosure of Invention
The invention aims to provide a preparation method of ibuprofen L-lysine salt, which can at least solve part of defects in the prior art.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a method for preparing ibuprofen L-lysine salt, comprising the following steps:
1) Feeding ibuprofen and L-lysine serving as raw materials, heating and dissolving the ibuprofen and the L-lysine in lower alcohol or aqueous lower alcohol solution, filtering while the solution is hot, removing insoluble impurities, and concentrating and drying filtrate to obtain ibuprofen-L-lysine salt-containing viscous liquid;
2) Adding pure water into the ibuprofen-containing L-lysine salt viscous liquid in the step 1) for dissolution, then adding a low-polarity solvent for reflux azeotropic water diversion, and separating residual alcohol and water to obtain a dispersed solid;
3) And (3) cooling, filtering and decompressing the dispersed solid obtained in the step (2), and drying to obtain the ibuprofen L-lysine salt with dispersed particles.
Furthermore, the purities of the ibuprofen and the L-lysine are both more than 98.5%, and the molar ratio of the ibuprofen to the L-lysine is 1:1.0-1.05.
Further, the lower alcohol adopts lower aliphatic alcohol with carbon of C1-C4, and the mass volume ratio of the ibuprofen to the lower alcohol or the aqueous solution of the lower alcohol is 1:1-20.
Further, the heating and dissolving temperature in the step 1) is 30-100 ℃.
Further, adding activated carbon into the solution heated and dissolved in the step 1).
Further, the adding amount of the pure water in the step 2) is that the mass-volume ratio of the ibuprofen to the pure water is 1:0.1-5.
Further, the low-polarity solvent in the step 2) is any one of n-hexane, n-heptane, petroleum ether, methylcyclohexane and toluene.
Furthermore, the addition amount of the low-polarity solvent is 1:4-50 of the mass-volume ratio of the ibuprofen to the low-polarity solvent.
Further, the reflux azeotropic water diversion temperature in the step 2) is the boiling point of the low-polarity solvent.
Further, the step 3) is carried out at a reduced pressure drying temperature of 60-65 ℃ and a reduced pressure drying time of 3 hours, so that the water content of the ibuprofen L-lysine salt is less than 1%.
Compared with the prior art, the invention has the beneficial effects that:
(1) The preparation method of the ibuprofen L-lysine salt provided by the invention adopts the low-polarity solvent to reflux and azeotropy separate water from the ibuprofen L-lysine salt liquid, and the ibuprofen L-lysine salt has the advantages of poor solubility in the low-polarity solvent, high salt forming yield, no higher optical rotation, no need of crushing, easiness in drying, small residue dissolution, low water content and difficulty in moisture absorption, and is suitable for industrial production.
(2) The yield of the ibuprofen L-lysine salt prepared by the method can reach 96%, the water content is less than 1%, the solvent residue is less than 500ppm, the optical rotation (a) D 20=5.2～6.5°（C=1,H2 O) of the product is 160-166 ℃, the melting point is 57.0-60.0% of the ibuprofen, and the L-lysine content is 40.0-43.0%.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a preparation method of ibuprofen L-lysine salt, which comprises the following steps:
(1) Feeding ibuprofen and L-lysine serving as raw materials, heating and dissolving the ibuprofen and the L-lysine in a lower alcohol or aqueous lower alcohol solution, filtering while the solution is hot, and filtering mechanical impurities in a system and insoluble impurities in the L-lysine to ensure that the turbidity of a finished product is qualified; concentrating the filtrate to dryness, and recovering the organic solvent to obtain viscous liquid containing ibuprofen L-lysine salt.
Specifically, the purities of the ibuprofen and the L-lysine are both greater than 98.5%, the molar ratio of the ibuprofen to the L-lysine is 1:1.0-1.05, wherein the L-lysine is easy to absorb moisture, the molar ratio of the ibuprofen to the L-lysine is calculated by folding the material into a dry product, and the molar ratio of the ibuprofen to the L-lysine is preferably 1:1.02.
The lower alcohol adopts lower aliphatic alcohols with carbon of C1-C4, such as methanol, ethanol, isopropanol, n-butanol and the like, and the lower alcohol or aqueous solution of the lower alcohol is preferably anhydrous methanol or 95-100% ethanol; the mass volume ratio of the ibuprofen to the lower alcohol or the aqueous solution of the lower alcohol is 1:1-20, preferably 1:3-8. The heating and dissolving temperature is 30-100 ℃, and the reflux temperature is preferable.
Optimally, a small amount of activated carbon is added into the solution after heating and dissolving for decoloring, and as alcohol insoluble substances are formed in the process of preparing L-lysine and storing for a long time, the turbidity of the finished product in a lower alcohol solution is unqualified, and impurities can be filtered out in the process of decoloring the activated carbon.
(2) Adding pure water into the ibuprofen-containing L-lysine salt viscous liquid in the step (1) for dissolution, then adding a low-polarity solvent for reflux azeotropic water diversion, and separating residual alcohol and water to obtain a dispersed solid.
Specifically, the mass-volume ratio of ibuprofen to pure water is 1:0.1-5, preferably 1:0.5-2; the low polarity solvent can be any one of n-hexane, n-heptane, petroleum ether, methylcyclohexane and toluene, and is preferably n-heptane and methylcyclohexane; the mass-volume ratio of ibuprofen to the low-polarity solvent is 1:4-50, preferably 1:8-15; the reflux azeotropic water diversion temperature adopts the boiling point of a low-polarity solvent, in the reflux water diversion process, residual alcohol is firstly removed, water is then removed, no water drop is removed, and water diversion is continued until ibuprofen L-lysine salt is in a dispersed powdery solid, and no water is removed from a water separator.
(3) Cooling, filtering and decompressing the dispersed solid obtained in the step (2), and drying to obtain the ibuprofen L-lysine salt with dispersed particles; wherein the decompression drying temperature is 60-65 ℃, and the decompression drying time is 3 hours, so that the water content of the ibuprofen L-lysine salt is less than 1%.
The yield of the ibuprofen L-lysine salt product prepared by the method can reach 96%, the water content is less than 1%, the solvent residue is less than 500ppm, the optical rotation of the product [ a ] D 20=5.2～6.5°（C=1,H2 O), and the melting point is 160-166 ℃; the ibuprofen content is 57.0-60.0%, and the L-lysine content is 40.0-43.0%. The prepared product is powdery dispersed solid, does not need to be crushed, is easy to dry, has small dissolved residue and low water content, is not easy to absorb moisture, and is suitable for industrial production.
The specific procedures and effects of the method for producing ibuprofen L-lysine salt according to the present invention are described below by way of specific examples.
Example 1:
41.3g (0.200 mol) of ibuprofen, 29.8g (0.204 mol) of L-lysine (dry product) and 2.0g of active carbon are put into 180ml of methanol, the mixture is heated to reflux, filtered while the mixture is hot, a small amount of methanol is used for washing, the filtrate is concentrated to dryness under reduced pressure, 40.0g of water is added, and the mixture is heated for dissolution; adding 480ml of n-heptane, heating, refluxing and water diversion until no water is separated, and continuing refluxing and water diversion for 1h; then cooling to room temperature, filtering, and washing a filter cake with a small amount of n-heptane; finally, the mixture was dried under reduced pressure at 60 to 65℃for 3 hours to give 67.4g (0.191 mol) of an off-white solid.
The detection shows that the product yield is 95.6%, the optical rotation [ a ] D 20=5.8°（C=1,H2 O) and the melting point is 161.2-165.8 ℃.
Example 2:
41.3g (0.200 mol) of ibuprofen, 29.8g (0.204 mol) of L-lysine (dry product) and 2.0g of active carbon are put into 150ml of ethanol with water content of 2%, the mixture is heated to reflux, filtered while the mixture is hot, a small amount of ethanol is used for washing, the filtrate is concentrated to dryness under reduced pressure, 50.0g of water is added, and the mixture is heated for dissolving; adding 500ml of n-heptane, heating, refluxing and water diversion until no water is separated, and continuing refluxing and water diversion for 1h; then cooling to room temperature, filtering, and washing a filter cake with a small amount of n-heptane; finally, the mixture was dried under reduced pressure at 60 to 65℃for 3 hours to give 67.7g (0.192 mol) of an off-white solid.
The detection shows that the product yield is 96.0%, the optical rotation [ a ] D 20=5.6°（C=1,H2 O) and the melting point is 160.8-165.7 ℃.
Example 3:
41.3g (0.200 mol) of ibuprofen, 29.8g (0.204 mol) of L-lysine (dry product) and 2.0g of active carbon are put into 250ml of ethanol containing 1% of water, the mixture is heated to reflux, filtered while the mixture is hot, a small amount of ethanol is used for washing, the filtrate is concentrated to dryness under reduced pressure, 50.0g of water is added, and the mixture is heated for dissolving; 600ml of methylcyclohexane is added, the temperature is raised, water is separated by reflux, and the water is continuously separated by reflux for 1h after the water is separated from the water; then cooling to room temperature, filtering, and washing a filter cake with a small amount of methylcyclohexane; finally, drying under reduced pressure at 60-65 ℃ for 3h to obtain 66.3g (0.188 mol) of off-white solid.
The product yield is 94.1% through detection, the optical rotation [ a ] D 20=6.0°（C=1,H2 O) and the melting point is 160.5-164.3 ℃.
The foregoing examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention, and all designs that are the same or similar to the present invention are within the scope of the present invention.
Claims (8)
1. A method for preparing ibuprofen L-lysine salt, which is characterized by comprising the following steps:
1) Feeding ibuprofen and L-lysine serving as raw materials, heating and dissolving the ibuprofen and the L-lysine in lower alcohol or aqueous lower alcohol solution, filtering while the solution is hot, removing insoluble impurities, and concentrating and drying filtrate to obtain ibuprofen-L-lysine salt-containing viscous liquid; wherein, the lower alcohol adopts lower aliphatic alcohol with C1-C4 carbon;
2) Adding pure water into the ibuprofen-containing L-lysine salt viscous liquid in the step 1) for dissolution, then adding a low-polarity solvent for reflux azeotropic water diversion, and separating residual alcohol and water to obtain a dispersed solid; wherein the reflux azeotropic water diversion temperature is the boiling point of the low-polarity solvent; wherein the low polarity solvent is n-heptane or methylcyclohexane;
3) And (3) cooling, filtering and decompressing the dispersed solid obtained in the step (2), and drying to obtain the ibuprofen L-lysine salt with dispersed particles.
2. A process for the preparation of ibuprofen L-lysine salt according to claim 1, characterized in that: the purities of the ibuprofen and the L-lysine are both more than 98.5%, and the molar ratio of the ibuprofen to the L-lysine is 1:1.0-1.05.
3. A process for the preparation of ibuprofen L-lysine salt according to claim 1, characterized in that: the mass volume ratio of the ibuprofen to the lower alcohol or the aqueous solution of the lower alcohol is 1:1-20.
4. A process for the preparation of ibuprofen L-lysine salt according to claim 1, characterized in that: the heating and dissolving temperature in the step 1) is 30-100 ℃.
5. A process for the preparation of ibuprofen L-lysine salt according to claim 1, characterized in that: and adding active carbon into the solution heated and dissolved in the step 1).
6. A process for the preparation of ibuprofen L-lysine salt according to claim 1, characterized in that: the adding amount of the pure water in the step 2) is 1:0.1-5 of the mass volume ratio of the ibuprofen to the pure water.
7. A process for the preparation of ibuprofen L-lysine salt according to claim 1, characterized in that: the addition amount of the low-polarity solvent is 1:4-50 of the mass-volume ratio of the ibuprofen to the low-polarity solvent.
8. A process for the preparation of ibuprofen L-lysine salt according to claim 1, characterized in that: the step 3) is carried out at a reduced pressure drying temperature of 60-65 ℃ and a reduced pressure drying time of 3 hours, so that the water content of the ibuprofen L-lysine salt is less than 1%.
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| CN202211631022.9A CN115850056B (en) | 2022-12-19 | Preparation method of ibuprofen L-lysine salt |
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| CN202211631022.9A CN115850056B (en) | 2022-12-19 | Preparation method of ibuprofen L-lysine salt |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5380867A (en) * | 1992-12-02 | 1995-01-10 | Hoechst Celanese Corporation | Selective precipitation of α-aryl carboxylic acid salts |
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5380867A (en) * | 1992-12-02 | 1995-01-10 | Hoechst Celanese Corporation | Selective precipitation of α-aryl carboxylic acid salts |
Non-Patent Citations (1)
| Title |
|---|
| 布洛芬赖氨酸盐及其注射剂的研制;栾立标，张钧寿，朱家壁;中国药科大学学报;19940430(第02期);80-82 * |
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