CN111718297A - Eltrombopag diethanolamine salt and preparation method thereof - Google Patents
Eltrombopag diethanolamine salt and preparation method thereof Download PDFInfo
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- CN111718297A CN111718297A CN201910203536.6A CN201910203536A CN111718297A CN 111718297 A CN111718297 A CN 111718297A CN 201910203536 A CN201910203536 A CN 201910203536A CN 111718297 A CN111718297 A CN 111718297A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
Abstract
The invention relates to the technical field of medicine preparation, and discloses eltrombopag diethanolamine salt and a preparation method thereof, wherein the preparation method comprises the following steps: dissolving ethanolamine in an organic solvent, heating to 60-75 ℃, stirring for dissolving, dropwise adding a tetrahydrofuran solution of eltrombopag free acid into the ethanolamine solution, keeping the temperature, stirring, cooling after dropwise adding, and filtering, wherein the volume of the tetrahydrofuran is as follows: the mass of the eltrombopag free acid is as follows: the volume ratio of the organic solvent is 6-11: 1: 12-24. The method ensures full salification in a homogeneous reaction system, the prepared eltrombopag diethanolamine salt has low impurity content, the reaction operation is simple, and the method is suitable for amplification and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicine preparation, and in particular relates to eltrombopag diethanolamine salt and a preparation method thereof.
Background
Eltrombopag was developed by the uk pharmaceutical macroprokitin smig, a once daily oral Thrombopoietin (TPO) receptor agonist that elevates platelet levels in the blood by inducing stimulation of bone marrow stem cell proliferation and differentiation. Currently, eltrombopag has been approved by over 100 countries worldwide for the treatment of thrombocytopenia (thrombocytopatholinia) in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP), while 43 countries have been approved for the treatment of thrombocytopenia in patients with Chronic Hepatitis C (CHC), in order to initiate and maintain standard interferon-based therapies for liver disease. In 8 months 2014, the FDA further approved eltrombopag for the treatment of cytopenia (cytopenia) in patients with Severe Aplastic Anemia (SAA) who are inadequately responsive to immunosuppressive therapy (IST). The drug is marketed under the name Promacta in the united states, is favorable for refolding in hong kong, and is resolde in europe and other countries and regions.
The chemical name of the eltrombopag diethanolamine salt is as follows: 3 '- { (2Z) -2- [1- (3, 4-xylyl) -3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4-ylidene ] hydrazino } -2' -hydroxy-3-biphenylcarboxylic acid diethanolamine of the formula:
the solubility of the free acid of the eltrombopag in water is 5 mug/mL, and the bioavailability is low; original research company Kulansu Schk in patent CN100542530C reports that the solubility of eltrombopag in water can be improved to 14.2mg/mL by preparing eltrombopag into diethanolamine salt, thereby improving the bioavailability of eltrombopag in vivo.
Patent CN100542530C reports two preparation methods of the API at the same time, one is that ethanol, tetrahydrofuran or a mixed solvent of the two is used for dissolving the eltromopap free acid, and then ethanolamine is dropwise added into the solution for salt formation at room temperature, but the obtained eltromopap diethanolamine solvent residue is seriously over-limited and is far greater than 0.5 percent of ethanol limit and 0.072 percent of tetrahydrofuran limit in ICH-Q3C; secondly, ethanol is used as a solvent to dissolve ethanolamine, the temperature is raised to reflux, and solution of eltrombopag dissolved in tetrahydrofuran is dripped while ethanol is distilled out, the eltrombopag diethanolamine salt solvent obtained by the method is qualified in residue, the tetrahydrofuran residue is 0.05 percent (limit is 0.072 percent), but the tetrahydrofuran which has great harm to human bodies is excessive in dosage, the mass ratio of the volume to the eltrombopag reaches 20, the operation is complicated, the eltrombopag needs to be filtered after being dissolved in the tetrahydrofuran, the eltrombopag needs to be dripped while being distilled when being added into the ethanolamine, the distillation speed is controlled to be more than or equal to the dripping speed, and the industrial production is difficult.
Patent CN106966984A reports a similar method, i.e. adding eltrombopag free acid to a suitable solvent and stirring, adding a certain amount of ethanolamine and stirring to form salt. The method avoids the problem of unqualified solvent residue caused by using tetrahydrofuran, but introduces a new problem that the salt formation of the eltrombopag is probably insufficient. The free acid of the Eltrombopag is insoluble in organic solvents (such as ethyl acetate, acetone and the like) of the Eltrombopag, the system is always in a suspension heterogeneous system, and the Eltrombopag diethanolamine salt obtained by adding ethanolamine is also insoluble, so that the surface of solid particles of the Eltrombopag and the ethanolamine can be fully contacted to form salt, but the inside of the particles is wrapped and cannot form salt, and the bioavailability is influenced finally.
It can be seen that, during the production process, eltrombopag diethanolamine is easy to form a solvent compound, excessive residual solvent affects the bioavailability of the medicine, especially, solvents such as tetrahydrofuran which are harmful to human bodies, and excessive residual solvent affects the quality of the medicine, and in addition, the residual solvent in the solvent compound formed by eltrombopag diethanolamine is basically not removed by drying, so how to reduce the solvent residue from the process itself is the key point of the API preparation research.
Disclosure of Invention
The invention aims to provide eltrombopag diethanolamine salt and a preparation method thereof, and solves the problems that the solvent residue in eltrombopag diethanolamine salt does not conform to the ICH guiding principle and the regulations of Chinese pharmacopoeia, and the preparation process is complicated to operate and difficult to realize industrial production due to excessive tetrahydrofuran consumption.
The technical problem to be solved by the invention is realized by adopting the following technical scheme.
The invention provides a preparation method of eltrombopag diethanolamine salt, which comprises the following steps:
dissolving ethanolamine in organic solvent, heating, stirring for dissolving, dripping tetrahydrofuran solution of eltromopap free acid into the obtained ethanolamine solution, keeping the temperature, stirring, cooling after dripping, filtering to obtain wet product, and drying the wet product to obtain eltromopap diethanolamine salt.
Further, in the preparation method, the temperature rise refers to the temperature rise to 60-75 ℃, preferably 65-70 ℃.
Further, in the preparation method, the volume of tetrahydrofuran: mass of free acid of eltrombopag: the volume ratio of the organic solvent is 6-11: 1: 12-24.
In the volume-mass ratio, the volume unit is ml, and the mass unit is g.
The invention also provides eltrombopag diethanolamine salt, wherein the ethanol residue in eltrombopag diethanolamine salt is less than 0.08%, and the tetrahydrofuran residue is less than 0.03%.
The ethanol residue is less than 0.08 percent, and the tetrahydrofuran residue is less than 0.03 percent, namely the mass of the residual ethanol accounts for less than 0.08 percent of the mass of the eltrombopag diethanolamine salt, and the mass of the residual tetrahydrofuran accounts for less than 0.03 percent of the mass of the eltrombopag diethanolamine salt.
The invention has the beneficial effects that:
the invention provides eltrombopag diethanolamine salt and a preparation method thereof, the method respectively prepares eltrombopag free acid solution and diethanolamine salt solution, ensures full salt formation in a homogeneous reaction system, controls the dosage of a reaction solvent, ensures simple reaction operation, is suitable for amplification, does not need reflux, strictly controls the addition rate of the reaction solution, does not have the risk of insufficient salt formation, reduces the dosage of the solvent, reduces the reaction temperature, is energy-saving and environment-friendly, has low requirements on equipment, is suitable for industrial production, and further reduces the solvent residual quantity of tetrahydrofuran and ethanol on the premise that the solvent residual accords with Chinese pharmacopoeia.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The following is a specific description of the method for preparing eltrombopag diethanolamine salt according to the embodiment of the present invention.
The embodiment of the invention provides a preparation method of eltrombopag diethanolamine salt, which comprises the following steps: dissolving ethanolamine in organic solvent, heating, stirring for dissolving, dripping tetrahydrofuran solution of free acid of eltrombopag into ethanolamine solution, keeping the temperature, stirring, cooling after dripping, filtering to obtain wet product, and drying to obtain eltrombopag diethanolamine salt. Wherein, preferably, the volume of the tetrahydrofuran: mass of free acid of eltrombopag: the volume ratio of the organic solvent is 6-11: 1: 12-24. The method comprises the following steps: dissolving ethanolamine in an organic solvent, heating to 60-75 ℃, stirring for dissolving to obtain a dissolved ethanolamine solution, slowly dropwise adding the prepared eltrombopag free acid solution into the ethanolamine solution, wherein the eltrombopag free acid solution and the ethanolamine solution can be fully salified in a homogeneous reaction system because both the eltrombopag free acid solution and the ethanolamine solution are clear solutions.
Therefore, according to the preparation method of eltrombopag diethanolamine salt provided by the invention, by controlling the reaction process, especially the temperature and the dosage of the reaction solvent, reflux is not needed and the addition rate of the reaction solution is strictly controlled, so that the risk of insufficient salt formation is avoided, the dosage of the solvent is reduced, the reaction temperature is reduced, the solvent residue of the prepared eltrombopag diethanolamine salt is further reduced on the premise that the solvent residue conforms to Chinese pharmacopoeia, the reaction operation is simple and suitable for amplification, and the preparation method is suitable for industrial production.
In some embodiments, the reaction equation during the preparation of eltrombopag diethanolamine salt is as follows:
in some embodiments, the volume of tetrahydrofuran: mass of free acid of eltrombopag: the volume ratio of the organic solvent is 8-10: 1: 15-24.
In some embodiments, the preparation of the tetrahydrofuran solution of eltrombopag free acid comprises: dissolving eltrombopag free acid in tetrahydrofuran, heating to 40-50 deg.C, and stirring to dissolve.
In some embodiments, the preparation of the ethanolamine solution comprises: dissolving ethanolamine in organic solvent, heating to 60-75 deg.C, preferably 65-70 deg.C, and stirring to dissolve.
In some embodiments, the organic solvent is selected from one or any of ethanolamine, ethanol, methanol, isopropanol, and butanol.
The embodiment of the invention provides a preparation method of eltrombopag diethanolamine salt, which comprises the steps of preparing a free acid solution of eltrombopag and an ethanolamine solution with good solubility in order to ensure full salt formation.
In the preparation process of the eltrombopag free acid solution, because the eltrombopag free acid has poor solubility in various solvents, solvents with too high boiling points such as DMSO can be dissolved but are difficult to dry, the solvents with the boiling points lower than 100 ℃ have higher solubility only including tetrahydrofuran and dioxane, the latter has half of the limit value of tetrahydrofuran, the toxicity is higher, and simultaneously, the salt formation can be ensured only by forming salt in a homogeneous reaction system, so the proper low boiling point solvent only includes tetrahydrofuran, the eltrombopag free acid is dissolved in the tetrahydrofuran, heated to 40-50 ℃, stirred and dissolved, and the eltrombopag free acid solution is obtained. In the preparation process of the ethanolamine, the ethanolamine is dissolved in one or more of ethanolamine, ethanol, methanol, isopropanol and butanol, heated to 60-75 ℃, and stirred to be dissolved to obtain an ethanolamine solution.
Therefore, the dissolved eltrombopag free acid solution is slowly dripped into the ethanolamine solution, so that the full salification of the eltrombopag free acid solution and the ethanolamine solution can be ensured, and a solvent compound is not easy to form, namely, the content of the solvent in the product is controlled from the source, so that the solvent residue of the obtained eltrombopag diethanolamine salt further reduces the solvent residue of tetrahydrofuran and ethanol on the premise of meeting the Chinese pharmacopoeia.
In some embodiments, the temperature of the incubation agitation is 60-75 deg.C, preferably 65-70 deg.C.
In some embodiments, the temperature is reduced to 20-30 ℃ after the addition is complete.
The preparation method of eltrombopag diethanolamine salt provided by the embodiment of the invention comprises the steps of heating a tetrahydrofuran solution of eltrombopag free acid to 40-50 ℃, dissolving glycolic acid in an organic solvent, heating to 60-75 ℃, then slowly dripping the eltrombopag free acid solution into the ethanolamine solution, keeping the temperature and stirring at 60-75 ℃, controlling the dosage of a reaction solvent, fully salifying the eltrombopag free acid and the ethanolamine, and strictly controlling the addition rate of the reaction solution without refluxing in the process, so that the risk of salt formation is avoided, the dosage of the solvent is reduced, and the reaction temperature is reduced.
In some embodiments, the wet product is dried by vacuum drying or hot air drying at 40-100 deg.C, preferably 40-60 deg.C for 4-48 hr.
The embodiment of the invention also provides the eltrombopag diethanolamine salt prepared by the preparation method, wherein the residual ethanol in the eltrombopag diethanolamine salt is less than 0.08%, and the residual tetrahydrofuran is less than 0.03%.
In some embodiments, the residual amount of ethanol in eltrombopag diethanolamine salt is < 0.05%, and tetrahydrofuran < 0.01%.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
13.7g (0.22mol) of ethanolamine (analytical grade, the same below) and 235mL of ethanol (industrial grade, the same below) are added into a 500mL three-neck flask, magnetic stirring is carried out, and the temperature of an oil bath is increased to 65 ℃; adding 10g (0.023mol) of eltrombopag free acid (I) into 90mL of tetrahydrofuran (industrial grade, the same below) to be dissolved in moderate heat (40 ℃) to obtain a solution of the eltrombopag free acid (I), slowly dripping the solution into the ethanol solution, preserving heat and stirring; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 12.0g of the eltromopa diethanolamine (II), wherein the yield is 93.6%, the residual ethanol of the solvent is less than 0.07% by GC detection, the tetrahydrofuran is less than 0.02%, and the residual solvent is qualified.
Example 2
13.7g (0.22mol) of ethanolamine and 235mL of ethanol are added into a 500mL three-neck flask, magnetic stirring is carried out, and the temperature of an oil bath is increased to 67 ℃; adding 10g (0.023mol) of eltromopa free acid (I) into 90mL of tetrahydrofuran to be dissolved in moderate heat (50 ℃), slowly dripping the obtained solution of eltromopa free acid (I) into the ethanol solution, keeping the temperature and stirring; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 12.1g of the eltromopa diethanolamine (II), wherein the yield is 94.3%, the residual ethanol of the solvent is less than 0.05% by GC detection, the tetrahydrofuran is less than 0.01%, and the residual solvent is qualified.
Example 3
13.7g (0.22mol) of ethanolamine and 235mL of ethanol are added into a 500mL three-neck flask, magnetic stirring is carried out, and the temperature of oil bath is raised to 70 ℃; adding 10g (0.023mol) of eltromopa free acid (I) into 90mL of tetrahydrofuran to be dissolved in moderate heat (45 ℃), slowly dripping the obtained solution of eltromopa free acid (I) into the ethanol solution, and stirring at a constant temperature; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 12.2g of the eltromopa diethanolamine (II), wherein the yield is 95.2%, the residual ethanol of the solvent is less than 0.07% by GC detection, the tetrahydrofuran is less than 0.02%, and the residual solvent is qualified.
Example 4
Adding 52g (0.85mol) of ethanolamine and 456mL of ethanol into a 1L three-neck flask, mechanically stirring, and heating in oil bath to 65 ℃; adding 38g (0.086mol) of eltrombopag free acid (I) into 260mL of tetrahydrofuran, dissolving and clearing with moderate heat (45 ℃), slowly dripping the obtained solution of eltrombopag free acid (I) into the ethanol solution, preserving heat and stirring; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting 47.14g of the eltromopa diethanolamine (II), obtaining 96.7% of yield, detecting by GC that the residual ethanol of the solvent is less than 0.05%, the tetrahydrofuran is less than 0.01%, and obtaining qualified residual solvent.
Example 5
Adding 260g (4.26mol) of ethanolamine and 2.9L of ethanol into a 5L three-neck flask, mechanically stirring, and heating in oil bath to 67 ℃; 190g (0.43mol) of eltrombopag free acid (I) is added into 1.5L of tetrahydrofuran to be dissolved and cleared by moderate heat (40 ℃), and the obtained solution of eltrombopag free acid (I) is slowly dripped into the ethanol solution to be stirred under heat preservation; dropping for 2 hours, cooling to 20-30 ℃ in water bath, filtering, putting the filter cake into a vacuum drying oven for 8 hours at 45 ℃, collecting to obtain 235.7g of the eltromopa diethanolamine (II), wherein the yield is 96.7%, the residual ethanol of the solvent is less than 0.08% by GC detection, the tetrahydrofuran is less than 0.02%, and the residual solvent is qualified.
Example 6
5200g (85.2mol) of ethanolamine and 91.2L of ethanol are added into a 100L three-neck flask, mechanically stirred and heated to 65 ℃ in oil bath; adding 3800g (8.6mol) of eltromopa free acid (I) into 38.0L of tetrahydrofuran, dissolving at 40 deg.C, slowly dripping the obtained solution of eltromopa free acid (I) into the above ethanol solution, keeping the temperature, and stirring; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 4704.3g of eltromopa diethanolamine (II), wherein the yield is 96.5%, the residual ethanol of the solvent is less than 0.07% by GC detection, the tetrahydrofuran is less than 0.03%, and the residual solvent is qualified.
Example 7
5200g (85.2mol) of ethanolamine and 57.0L of ethanol are added into a 100L three-neck flask, mechanically stirred and heated to 65 ℃ in oil bath; adding 3800g (8.6mol) of eltromopa free acid (I) into 30.4L of tetrahydrofuran, dissolving at 40 deg.C, slowly dripping the obtained solution of eltromopa free acid (I) into the above ethanol solution, keeping the temperature, and stirring; dripping for 2 hours, cooling to 20-30 ℃ in water bath, filtering, putting the filter cake into a vacuum drying oven for 8 hours at 45 ℃, collecting to obtain 4689.7g of eltromopa diethanolamine (II), wherein the yield is 96.2%, the residual ethanol of the solvent is less than 0.05% by GC detection, the tetrahydrofuran is less than 0.01%, and the residual solvent is qualified.
Example 8
5200g (85.2mol) of ethanolamine and 91.2L of ethanol are added into a 100L three-neck flask, mechanically stirred and heated to 65 ℃ in oil bath; adding 3800g (8.6mol) of eltromopa free acid (I) into 38.0L of tetrahydrofuran, dissolving at 40 deg.C, slowly dripping the obtained solution of eltromopa free acid (I) into the above ethanol solution, keeping the temperature, and stirring; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 4704.3g of eltromopa diethanolamine (II), wherein the yield is 96.5%, the residual ethanol of the solvent is less than 0.07% by GC detection, the tetrahydrofuran is less than 0.03%, and the residual solvent is qualified.
Example 9
10400g (170.4mol) of ethanolamine and 114.0L of ethanol are added into a 200L three-neck flask, mechanical stirring is carried out, and the temperature is raised to 65 ℃ in oil bath; 7600g (17.2mol) of eltromopa free acid (I) is added into 60.8L of tetrahydrofuran to be dissolved and cleared by moderate heat (50 ℃), and the obtained solution of eltromopa free acid (I) is slowly dripped into the ethanol solution to be stirred under heat preservation; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 9369.6g of eltromopa diethanolamine (II), wherein the yield is 96.1%, the residual ethanol of the solvent is less than 0.05% by GC detection, the tetrahydrofuran is less than 0.01%, and the residual solvent is qualified.
Example 10
10400g (170.4mol) of ethanolamine and 182.4L of ethanol are added into a 200L three-neck flask, mechanical stirring is carried out, and the temperature is raised to 65 ℃ in oil bath; 7600g (17.2mol) of eltromopa free acid (I) is added into 76.0L of tetrahydrofuran to be dissolved and cleared by moderate heat (40 ℃), and the obtained solution of eltromopa free acid (I) is slowly dripped into the ethanol solution to be stirred under heat preservation; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 9398.9g of eltromopa diethanolamine (II), wherein the yield is 96.4%, the residual ethanol of the solvent is less than 0.08% by GC detection, the tetrahydrofuran is less than 0.03%, and the residual solvent is qualified.
Comparative example 1
Adding 140g of ethanolamine and 1.5L of ethanol into a 5L three-neck flask, mechanically stirring, and heating to 50-55 ℃ in an oil bath; adding 100g (0.23mol) of eltrombopag free acid (I) into 2L of tetrahydrofuran at room temperature, stirring and dissolving to obtain solution of eltrombopag free acid (I), slowly dripping into the ethanol solution, and stirring at constant temperature; after dripping for about 2 hours, cooling to 20-30 ℃ in a water bath, carrying out suction filtration, putting a filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting 119.6g of the eltromopa diethanolamine (II), obtaining 93.7% of yield, qualified product with 0.27% < 0.5% of residual ethanol in a GC detection solvent, 0.22% > 0.072% of tetrahydrofuran, serious overrun and unqualified dissolved residue.
Comparative example 2
Adding 140g of ethanolamine and 1.5L of ethanol into a 5L three-neck flask, mechanically stirring, and heating to 50-55 ℃ in an oil bath; adding 100g (0.23mol) of eltrombopag free acid (I) into 2L of tetrahydrofuran, slightly heating (40-50 ℃) to dissolve, slowly dripping the obtained solution of eltrombopag free acid (I) into the ethanol solution, preserving heat and stirring; dropping for about 2 hours, cooling to 20-30 ℃ in water bath, filtering, putting the filter cake into a vacuum drying oven for 8 hours at 45 ℃, collecting to obtain 122.8g of the eltromopa diethanolamine (II), wherein the yield is 96.2%, the content of the residual ethanol in the solvent is qualified when 0.20% < 0.5% by GC detection, the content of tetrahydrofuran is 0.37% > 0.072%, the overrun is serious, and the dissolution residue is unqualified.
Comparative example 3
Adding 140g of ethanolamine and 1.5L of ethanol into a 5L three-neck flask, mechanically stirring, adding 100g (0.23mol) of eltromopa free acid (I) into 2L of tetrahydrofuran at room temperature to dissolve, slowly dropwise adding the obtained solution of eltromopa free acid (I) into the ethanol solution, stirring to form salt, cooling to 20-30 ℃ in a water bath after dropwise adding, stirring and crystallizing, performing suction filtration, putting a filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃ to obtain 120.2g of eltromopa diethanolamine (II), obtaining the yield of 94.2%, detecting 0.88% of residual ethanol in a solvent by GC and more than 0.5%, and 1.231% of tetrahydrofuran and more than 0.072%, and having serious overrun and unqualified dissolved residue.
Comparative example 4
In a 100mL three-necked flask, 1g (2.3mmol) of eltrombopag free acid (I) and 16.75mL of tetrahydrofuran were added, dissolved with stirring at 20-30 ℃, and water (2.0mL) was slowly added while controlling the temperature to be higher than 28 ℃. After the addition of water, the temperature was returned to 30 ℃ and the solution was filtered through a microfiltration membrane to remove insoluble impurities. The filtrate was cooled to room temperature. Ethanolamine (0.324g, 5.2mmol) was dissolved in ethanol (26ml) and stirred at room temperature under nitrogen. Adding the filtrate containing the free acid into the ethanolamine solution for 20-30 minutes. The resulting dark red suspension was stirred for 3 hours, the solid was separated by filtration and dried in a vacuum oven at 50 ℃ for 8 hours to give 1.22g (96%) of eltromopa diethanolamine (II), GC detected residual solvent ethanol 1.30% > 0.5%, tetrahydrofuran 1.05% > 0.072%, not qualified in dissolution.
Comparative example 5
8g (18.4mmol) of Eltrombopag free acid (I) was dissolved in a 500ml round-bottomed three-necked flask containing tetrahydrofuran (240ml) at room temperature under a nitrogen atmosphere, and ethanolamine (2.59g, 41.6mmol) was slowly added dropwise over a period of 5 minutes using a syringe. The resulting dark red suspension was stirred at room temperature for 1.5 hours, the filter cake was filtered and washed with tetrahydrofuran (16 ml. times.2), the filter cake was dried in a vacuum oven at 50 ℃ for 8 hours to give 10.37g of eltrombopamidrolamine (II), 2.40% of tetrahydrofuran remaining in the solvent was detected by GC, which was 0.072%, had severe overrun, and failed to dissolve.
Comparative example 6
8g (18.4mmol) of Eltepopa free acid (I) was suspended at room temperature in a 2L three-necked flask containing ethanol (800ml), and ethanolamine (2.59g, 41.6mmol) was slowly added dropwise over a period of 5 minutes using a syringe. Stirring the obtained dark red suspension at room temperature for 1.5 hours, carrying out suction filtration, washing the filter cake with ethanol (10ml multiplied by 2), putting the filter cake into a vacuum oven at 50 ℃ for drying for 8 hours to obtain 9.83g (96%) of eltromopa diethanolamine (II), detecting 1.30% of ethanol residual by GC and more than 0.5%, and having serious overrun and unqualified dissolved residual.
Comparative example 7
To a 10L four-necked flask, 259g of eltrombopag free acid (I) was added, tetrahydrofuran (4660ml) was added thereto, and the mixture was stirred at room temperature until completely dissolved, and the solution was filtered, washed with tetrahydrofuran (520ml) on a Buchner funnel, and the filtrates were combined. Meanwhile, another 10L four-necked flask was prepared, a distillation apparatus was set up, ethanol (7770ml) and ethanolamine (354ml) were added, and the solution was stirred vigorously while heating until the solvent started to boil (BP.76-77C). Transferring the tetrahydrofuran solution of the aforementioned free acid of Elatriporpa into a dropping funnel, and when the solvent is distilled off at a constant rate (about 50ml of distillate is collected), starting to drop Elatriporpa solution, keeping the dropping rate equal to or slightly lower than the distillation rate. After the completion of the addition, the dropping funnel was washed with ethanol (260 ml. times.2) to ensure that all the free acid was washed into the reaction system, and then the distillation apparatus was replaced with a reflux apparatus and stirred under reflux under a nitrogen atmosphere for 30 minutes. It was allowed to cool slowly (overnight) to room temperature (about 20 ℃) with stirring under nitrogen. The suspension was filtered by suction, and the resulting dark purple filter cake was washed with ethanol (520 ml. times.2), and the filter cake was dried in a vacuum oven at 50 ℃ for 8 hours to give 323.9g of eltrombopamidrolamine (II) with a yield of 98%, with 0.12% < 0.5% of residual ethanol in the solvent and 0.05% < 0.072% by GC assay, and the residue was acceptable.
Comparative example 8
Adding 13.7g (0.22mol) of ethanolamine and 235mL of ethanol into a 500mL three-neck flask, magnetically stirring, and heating to 60-65 ℃ in an oil bath; adding 10g (0.023mol) of eltromopa free acid (I) into 120mL of tetrahydrofuran, slightly heating (40-50 ℃) to dissolve and clear, slowly dripping the obtained solution of eltromopa free acid (I) into the ethanol solution, and stirring at a constant temperature; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 11.9g of the eltromopa diethanolamine (II), wherein the yield is 93.1%, the residual ethanol of the solvent is 0.14% < 0.5%, the tetrahydrofuran is 0.09% > 0.072% by GC detection, and the dissolved residue is unqualified.
Comparative example 9
Adding 13.7g (0.22mol) of ethanolamine and 235mL of ethanol into a 500mL three-neck flask, magnetically stirring, and heating to 65-70 ℃ in an oil bath; adding 10g (0.023mol) of eltromopa free acid (I) into 210mL of tetrahydrofuran, slightly heating (40-50 ℃) to dissolve and clear, slowly dripping the obtained solution of eltromopa free acid (I) into the ethanol solution, and stirring at a constant temperature; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 11.8g of the eltromopa diethanolamine (II), wherein the yield is 92.8%, the residual ethanol of the solvent is 0.15% < 0.5%, the tetrahydrofuran is 1.17% > 0.072% by GC detection, and the dissolved residue is unqualified.
Comparative example 10
Adding 13.7g (0.22mol) of ethanolamine and 120mL of ethanol into a 500mL three-neck flask, magnetically stirring, and heating in oil bath to 60-65 ℃; adding 10g (0.023mol) of eltromopa free acid (I) into 90mL of tetrahydrofuran, slightly heating (40-50 ℃) to dissolve and clear, slowly dripping the obtained solution of eltromopa free acid (I) into the ethanol solution, and stirring at a constant temperature; after dripping for about 2 hours, cooling to 20-30 ℃ in a water bath, carrying out suction filtration, putting a filter cake into a vacuum drying oven for drying for 8 hours at 45 ℃, collecting to obtain 12.0g of the eltromopa diethanolamine (II), wherein the yield is 93.6%, the content of the residual ethanol in the solvent is 0.2% < 0.5% by GC detection, the dissolved residue is qualified, the content of the tetrahydrofuran is 0.088% > 0.072%, and the dissolved residue is unqualified.
Comparative example 11
Adding 13.7g (0.22mol) of ethanolamine and 150mL of ethanol into a 500mL three-neck flask, magnetically stirring, and heating in oil bath to 60-65 ℃; adding 10g (0.023mol) of eltromopa free acid (I) into 90mL of tetrahydrofuran, slightly heating (40-50 ℃) to dissolve and clear, slowly dripping the obtained solution of eltromopa free acid (I) into the ethanol solution, and stirring at a constant temperature; after dripping for about 2 hours, cooling to 20-30 ℃ in water bath, carrying out suction filtration, putting the filter cake into a vacuum drying oven for 8 hours at 45 ℃, collecting to obtain 11.9g of the eltromopa diethanolamine (II), wherein the yield is 93.1%, the solvent residual ethanol is 0.67% < 0.5%, the tetrahydrofuran is 0.02% < 0.072%, and the residual solvent is qualified.
The following are the structural characterization data of eltrombopagolamine prepared by the invention:
1H NMR(400MHz,DMSO-d6):14.687(brs,1H),8.209(brs,1H),7.838-7.776(m,3H),7.634(d,J＝8Hz,1H),7.384(t,J＝7.9Hz,2H),7.091-7.040(m,2H),6.873(brs,1H),6.344(m,8H),3.604(t,J＝5.2Hz,4H),2.867(t,J＝5.2Hz,4H),2.373(brs,3H),2.237(s,3H),2.194(s,3H)；
13C NMR(100MHz,DMSO-d6):170.77,-162,149.52,139.59，138.63，137.84,137.53,135.89,130.51,130.11,129.33,128.94,127.18,126.60,119.80,118.63,114.98,58.06,41.54,19.81,18.83，17.17
HRESI-MS: [ M-H ] -theoretical 441.1563, found 441.1566.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (10)
1. The eltrombopag diethanolamine salt is characterized in that the ethanol residue in the eltrombopag diethanolamine salt is less than 0.08%, and the tetrahydrofuran residue is less than 0.03%.
2. The eltrombopag diethanolamine salt of claim 1, wherein the eltrombopag diethanolamine salt has < 0.05% ethanol residue and < 0.01% tetrahydrofuran residue.
3. The preparation method of eltrombopag diethanolamine salt is characterized by comprising the following steps:
dissolving ethanolamine in an organic solvent, heating, stirring for dissolving, dropwise adding a tetrahydrofuran solution of free acid of eltromopap into the ethanolamine solution, keeping the temperature and stirring, cooling after dropwise adding, filtering to obtain a wet product, and drying the wet product to obtain eltromopap diethanolamine salt.
4. The method according to claim 3, wherein the temperature is raised to 60-75 ℃, preferably 65-70 ℃.
5. The method according to claim 3, wherein the volume of the tetrahydrofuran is: the mass of the eltrombopag free acid is as follows: the volume ratio of the organic solvent is 6-11: 1: 12-24, such as 8-10: 1: 15-24.
6. The method according to claim 3, wherein the preparation of the solution of eltrombopag free acid in tetrahydrofuran comprises: dissolving the eltrombopag free acid in tetrahydrofuran, heating to 40-50 ℃, and stirring to dissolve.
7. The preparation method according to claim 3, wherein the organic solvent is selected from one or more of ethanolamine, ethanol, methanol, isopropanol and butanol, such as ethanol.
8. The method according to claim 3, wherein the temperature of the heat-insulating stirring is 60 to 75 ℃, preferably 65 to 70 ℃.
9. The preparation method according to claim 3, wherein the temperature is reduced to 20-30 ℃ after the dropwise addition is completed.
10. The method according to claim 3, wherein the wet product is dried by vacuum drying or hot air drying at 40-100 deg.C, preferably 40-60 deg.C for 4-48 hr.
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| CN108191763A (en) * | 2018-02-10 | 2018-06-22 | 扬子江药业集团四川海蓉药业有限公司 | A kind of synthetic method of Ai Qu pools pa ethanol amine |
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| CN108191763A (en) * | 2018-02-10 | 2018-06-22 | 扬子江药业集团四川海蓉药业有限公司 | A kind of synthetic method of Ai Qu pools pa ethanol amine |
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