CN108976240B - Refining method of methylnaltrexone bromide - Google Patents
Refining method of methylnaltrexone bromide Download PDFInfo
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- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
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Abstract
The invention discloses a refining method of methylnaltrexone bromide, which comprises the following steps: (1) adding a stabilizer into a mixed solvent of lower alkanol and water, stirring for dissolving, and uniformly mixing; (2) adding a crude methylnaltrexone bromide product into the mixture obtained in the step (1), uniformly mixing, heating until the solid is completely dissolved, stirring and preserving heat; (3) hot filtering, transferring the filtrate into a reaction kettle, stirring, cooling and crystallizing; (4) filtering, recovering the precipitate, and drying to obtain refined methyhaaltrexone bromide. The method does not need particularly harsh nitrogen protection, is very simple and convenient to operate, and can still achieve the same sample quality as a laboratory when the batch amplification is carried out to 1-5 kg. On the basis, the yield is equivalent to that reported in the literature, and the purity of the methyhaaltrexone bromide sample refined by the process can reach more than 99.5 percent, even more than 99.8 percent.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a refining method of methylnaltrexone bromide.
Background
Methylnaltrexone bromide (methylnaltrexone, MNTX) is a selective mu opioid receptor antagonist, acts on gastrointestinal opioid receptors, and can completely block or partially block intestinal smooth muscle relaxation reaction caused by morphine analgesic drugs, so that constipation side effect caused by opioid drugs can be reduced or limited. Meanwhile, the methylnaltrexone bromide is a quaternary ammonium salt and cannot penetrate through a blood brain barrier, so that the methylnaltrexone bromide serving as an opioid receptor antagonist with peripheral action can improve the constipation effect of opioid on the premise of not influencing the analgesic effect of the opioid on a central nervous system due to the characteristics.
The preparation process route and the refining scheme of the methylnaltrexone bromide are subjected to document retrieval and investigation, so that the methylnaltrexone bromide is found to be prepared by taking naltrexone hydrochloride as a raw material, two strategies are mainly adopted, firstly, hydroxyl at the 3-position is dissociated and protected, N-methylation is carried out on a protected intermediate, a protecting group is removed after the methylation is finished, whether anion exchange is needed or not is determined according to the situation to obtain a crude methylnaltrexone bromide, and then refining is carried out to obtain a high-purity sample; and secondly, directly adopting a methylating reagent to methylate after dissociating, and then refining to obtain the high-purity methylnaltrexone bromide. The commonly used methylating agents are methyl bromide, methyl iodide, dimethyl sulfate, dimethyl carbonate and the like, and no matter which methylating agent is adopted, the problems of incomplete reaction of raw materials, more impurities, high impurity content and the like exist, so that the refining and purifying process is very important for obtaining the high-purity methylnaltrexone bromide which can be used as the medicine.
US4176186 reports the purification by ion exchange resin and multiple column chromatography, but the obtained sample still has high single impurity content and is difficult to meet the requirement of medicinal standard.
International patent application WO2004043964 a2 improves the preparation and purification method, but the process adopts naltrexone direct methylation to cause the content of 3-alkoxy impurities in the obtained sample to be very high, then strong alkali treatment is carried out in aqueous solution, under the protection of nitrogen, the 3-hydroxyl group of the methylnaltrexone bromide is converted into sodium salt, then alcohol is used to precipitate the sodium salt, the 3-alkylation by-product is left in the solution to achieve the purpose of removing, and then the acid of the filter cake is adjusted to obtain the methylnaltrexone bromide, the method mainly has two problems, firstly, the operation steps are extremely complicated; secondly, methylnaltrexone bromide has poor stability under alkaline conditions and very high requirements for nitrogen protection, otherwise, a series of side reactions such as free radical degradation and the like are easily caused under the condition of 3-phenol anions, so that the risk of overproof genotoxic impurities is caused, and the nitrogen protection effect with the high requirements is difficult to achieve in the subsequent large-scale production process.
International patent application WO2006127899 a2 further improves by protecting the 3-hydroxyl group and methylating with methyl iodide to reduce the content of 3-alkoxy impurities, and then performing anion exchange with ion exchange resin to obtain crude methylnaltrexone bromide. The crude product is recrystallized in methanol under nitrogen protection, the main purpose is to remove S isomer impurities, and the removal of other impurities is not mentioned (especially for high-risk genotoxic impurities).
In summary, the existing refining method of methyhaaltrexone bromide mainly adopts a system of alcohol or alcohol and water for refining under the protection of nitrogen, firstly dissolving, decoloring with activated carbon, then carrying out thermal filtration, and then cooling and crystallizing to obtain methyhaaltrexone bromide with higher purity. Through the systematic research of the inventor, the purification according to the purification process disclosed above can not obtain the product with expected quality, the purification process has very high requirement for nitrogen protection, and the residual small amount of air can have relatively large influence on the product quality, especially coupling impurity (impurity 1) and genotoxic impurity (impurity 3). The problem is more obvious along with the enlargement of the batch, when the batch reaches 1-2 kg, even if nitrogen protection and solvent degassing treatment are adopted, according to the refining method, the content of the impurity 1 can reach 1 percent, and the content of the impurity 3 can reach hundreds or even thousands of ppm, which far exceeds the acceptable limit. Meanwhile, the nitrogen protection device and the solvent degassing device are complex to operate in industrial production, and the equipment cost is high, so that a good refining process is very necessary to replace a refining method in the literature, and particularly the problem of high requirement on nitrogen protection is solved.
Disclosure of Invention
The inventor finds a refining process capable of solving the problems by means of long-term research experience and experimental exploration, the process does not need particularly harsh nitrogen protection, and meanwhile, the operation is very simple and convenient, and when the batch is enlarged to 1-5 kg, the sample quality can still be equivalent to that of a laboratory. On the basis, the yield is equivalent to that reported in the literature, and the purity of the methyhaaltrexone bromide sample refined by the process can reach more than 99.5 percent, even more than 99.8 percent.
The invention aims to provide a refining method of methylnaltrexone bromide, which is suitable for industrialization.
In one embodiment of the present invention, the present invention provides a novel refining process of methylnaltrexone bromide, comprising the steps of:
(1) adding a stabilizer into a mixed solvent of lower alkanol and water, stirring for dissolving, and uniformly mixing;
(2) adding a crude methylnaltrexone bromide product into the mixture obtained in the step (1), uniformly mixing, heating until the solid is completely dissolved, stirring and preserving heat;
(3) hot filtering, transferring the filtrate into a reaction kettle, stirring, cooling and crystallizing;
(4) filtering, recovering the precipitate, and drying to obtain refined methyhaaltrexone bromide.
In a preferred embodiment of the present invention, the present invention provides a novel refining process of methylnaltrexone bromide, wherein the crude methylnaltrexone bromide in step (2) can be prepared by the method described in example 6 of patent CN101646675, and the crude methylnaltrexone bromide mentioned below is prepared by this method.
In a preferred embodiment of the invention, the invention provides a novel refining process of methylnaltrexone bromide, wherein the lower alkanol used in the step (1) is one or a mixture of methanol, ethanol and isopropanol, and preferably methanol or ethanol.
In a preferred embodiment of the present invention, the present invention provides a novel refining process of methylnaltrexone bromide, wherein the stabilizing agent used in step (1) is one of sodium thiosulfate, sodium sulfite, ascorbic acid, tocopherol and glycine, preferably sodium thiosulfate.
In a preferred embodiment of the invention, the invention provides a novel refining process of methylnaltrexone bromide, wherein the mass ratio of the lower alkanol in the step (1) to the crude methylnaltrexone bromide in the step (2) is 4: 1-8: 1, and preferably 6: 1.
In a preferred embodiment of the invention, the invention provides a novel refining process of methylnaltrexone bromide, wherein the mass ratio of the water in the step (1) to the crude methylnaltrexone bromide in the step (2) is 0.5: 1-2: 1, and preferably 1: 1.
In a preferred embodiment of the invention, the invention provides a novel refining process of methylnaltrexone bromide, wherein the mass ratio of the stabilizer in the step (1) to the crude methylnaltrexone bromide in the step (2) is 1: 1000-1: 100, and preferably 5: 1000.
In a preferred embodiment of the invention, the invention provides a novel refining process of methylnaltrexone bromide, wherein the temperature of the heat preservation in the step (2) is 50-80 ℃, and preferably 65-75 ℃.
In a preferred embodiment of the invention, the invention provides a novel refining process of methylnaltrexone bromide, wherein the heat preservation time in the step (2) is 0-1 h, preferably 0.5 h.
In a preferred embodiment of the present invention, the present invention provides a novel refining process of methylnaltrexone bromide, wherein the temperature reduction in step (3) means that the temperature is reduced to 0 to 25 ℃, preferably 0 to 5 ℃.
In a preferred embodiment of the invention, the invention provides a novel refining process of methylnaltrexone bromide, wherein the time for crystallization in the step (3) is 5-24 hours, and preferably 8-12 hours.
In a preferred embodiment of the present invention, the present invention provides a novel refining process of methylnaltrexone bromide, wherein the drying manner in step (4) is vacuum drying or forced air drying, preferably vacuum drying.
In a preferred embodiment of the present invention, the present invention provides a novel refining process of methylnaltrexone bromide, wherein the drying manner in step (4) is vacuum drying, and the vacuum degree (negative pressure) is 0.05 to 0.09MPa, preferably 0.06 to 0.09 MPa.
In a preferred embodiment of the invention, the invention provides a novel refining process of methylnaltrexone bromide, wherein the drying temperature in the step (4) is 30-50 ℃, and preferably 40-45 ℃.
Compared with the prior art, the method does not need nitrogen protection in the production process, does not need operations such as degassing on a used solvent system, and the like, avoids installation of a nitrogen protection device in the industrialization process, does not need additional solvent degassing equipment, and achieves the batch volume of 1-5 kg after amplified production, and the purity of the prepared refined methyhaaltrexone bromide product is up to more than 99.5 percent, even more than 99.8 percent, the content of the impurity 1 is less than 0.05 percent, the content of the genotoxic impurity 3 is less than 20ppm, and the sample stability is good, thereby meeting the medicinal requirements.
Therefore, the invention provides a novel refining process of methylnaltrexone bromide, namely, the refining process is convenient for industrial production operation, and the obtained sample has high purity and good stability.
Detailed Description
The present invention will be specifically described below with reference to examples. It should be properly understood that: the method in the embodiment of the present invention is given for illustration only and not for limitation of the present invention, so that the simple modification of the present invention on the premise of the method of the present invention falls within the scope of the claimed invention.
Example 1a
Adding 120ml of anhydrous methanol, 20ml of purified water and 100mg of sodium thiosulfate into a 250ml dry three-necked bottle, stirring and dissolving, uniformly mixing, adding 20g of crude methylnaltrexone bromide, heating to 70 ℃, stirring and dissolving, keeping the temperature and stirring for 30min after dissolving, thermally filtering, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, drying in vacuum at 40-45 ℃, weighing at a vacuum degree (negative pressure) of 0.07-0.08 MPa, obtaining 17.6g of refined methylnaltrexone bromide, wherein the purity is 99.8% by HPLC detection.
Example 1b
Adding 120ml of absolute ethyl alcohol, 20ml of purified water and 100mg of sodium thiosulfate into a 250ml dry three-necked bottle, stirring, dissolving and mixing uniformly, adding 20g of crude methylnaltrexone bromide, heating to 70 ℃, stirring and dissolving, keeping the temperature and stirring for 30min after dissolving, carrying out hot filtration, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, carrying out vacuum drying at 40-45 ℃, and weighing at a vacuum degree (negative pressure) of 0.07-0.08 MPa to obtain 18.2g of refined methylnaltrexone bromide, wherein the HPLC detection purity is 99.9%.
Example 1c
Adding 120ml of isopropanol, 20ml of purified water and 100mg of sodium thiosulfate into a 250ml dry three-necked bottle, stirring, dissolving and mixing uniformly, adding 20g of crude methylnaltrexone bromide, heating to 70 ℃, stirring and dissolving, keeping the temperature and stirring for 30min after dissolving, performing hot filtration, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, performing vacuum drying at 40-45 ℃, and weighing to obtain 18.3g of refined methylnaltrexone bromide, wherein the HPLC detection purity is 99.9%.
Example 2a
Adding 120ml of absolute ethyl alcohol, 20ml of purified water and 100mg of sodium sulfite into a 250ml dry three-necked bottle, stirring, dissolving and mixing uniformly, adding 20g of crude methylnaltrexone bromide, heating to 70 ℃, stirring and dissolving, keeping the temperature and stirring for 30min after dissolving, performing hot filtration, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, performing vacuum drying at 40-45 ℃, and weighing to obtain 18.0g of refined methylnaltrexone bromide, wherein the HPLC detection purity is 99.5%.
Example 2b
Adding 120ml of absolute ethyl alcohol, 20ml of purified water and 100mg of ascorbic acid into a 250ml dry three-necked bottle, stirring, dissolving and mixing uniformly, adding 20g of crude methylnaltrexone bromide, heating to 70 ℃, stirring and dissolving, keeping the temperature and stirring for 30min after dissolving, carrying out hot filtration, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, carrying out vacuum drying at 40-45 ℃, and weighing at a vacuum degree (negative pressure) of 0.07-0.08 MPa to obtain 17.8g of refined methylnaltrexone bromide, wherein the purity is 99.7% by HPLC (high performance liquid chromatography).
Example 2c
Adding 120ml of absolute ethyl alcohol, 20ml of purified water and 100mg of tocopherol into a 250ml dry three-necked bottle, stirring, dissolving and mixing uniformly, adding 20g of crude methylnaltrexone bromide, heating to 70 ℃, stirring and dissolving, keeping the temperature and stirring for 30min after dissolving, performing hot filtration, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, performing vacuum drying at 40-45 ℃, and weighing to obtain 17.2g of refined methylnaltrexone bromide, wherein the HPLC detection purity is 99.5%.
Example 3
Adding 12L of absolute ethyl alcohol, 2L of purified water and 10g of sodium thiosulfate into a 30L dry and clean double-layer glass reaction kettle, stirring, dissolving and mixing uniformly, adding 2kg of crude methylnaltrexone bromide, heating to 70 ℃, stirring and dissolving, keeping the temperature and stirring for 30min after dissolving, performing heat filtration, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, performing vacuum drying at 40-45 ℃, weighing at a vacuum degree (negative pressure) of 0.07-0.08 MPa, and obtaining 1.86kg of refined methylnaltrexone bromide, wherein the purity is 99.8% by HPLC detection.
Comparative example 1a
Adding 120ml of absolute ethyl alcohol, 20ml of purified water and 20g of crude methylnaltrexone bromide into a 250ml dry three-necked bottle, introducing nitrogen for protection, stirring and mixing uniformly, heating to 70 ℃, stirring and dissolving, keeping the temperature and stirring for 30min after dissolution, performing hot filtration, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, performing vacuum drying at 40-45 ℃, and weighing to obtain 17.2g of refined methylnaltrexone bromide, wherein the purity is 99.4% by HPLC (high performance liquid chromatography) detection.
Comparative example 1b
Adding 12L of absolute ethyl alcohol, 2L of purified water and 2kg of crude methylnaltrexone bromide into a 30L dry and clean double-layer glass reaction kettle, introducing nitrogen for protection, stirring and mixing uniformly, heating to 70 ℃, stirring and dissolving, preserving heat and stirring for 30min after dissolving, performing thermal filtration, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 8-12 h, filtering, collecting a filter cake, performing vacuum drying at 40-45 ℃, and weighing at a vacuum degree (negative pressure) of 0.07-0.08 MPa to obtain 1.78kg of refined methylnaltrexone bromide, wherein the HPLC detection purity is 98.1%.
Comparative example 2
Adding 120ml of absolute ethyl alcohol, 20ml of purified water and 100mg of sodium thiosulfate into a 250ml dry three-necked bottle, stirring, dissolving and mixing uniformly, adding 20g of crude methylnaltrexone bromide, heating to 70 ℃, stirring, dissolving, blowing compressed air into a system after dissolving, keeping the temperature, stirring for 30min, performing heat filtration, cooling the filtrate to 0-5 ℃, stirring, crystallizing for 8-12 h, filtering, collecting a filter cake, performing vacuum drying at 40-45 ℃, and weighing at a vacuum degree (negative pressure) of 0.07-0.08 MPa to obtain 17.8g of refined methylnaltrexone bromide, wherein the purity is 99.6% by HPLC (high performance liquid chromatography).
TABLE 1 comparison of product quality of methylnaltrexone bromide with the literature methods (comparative examples)
Claims (17)
1. A refining method of methylnaltrexone bromide is characterized by comprising the following steps:
(1) adding a stabilizer into a mixed solvent of lower alkanol and water, stirring for dissolving, and uniformly mixing;
(2) adding a crude methylnaltrexone bromide product into the mixture obtained in the step (1), uniformly mixing, heating until the solid is completely dissolved, stirring and preserving heat;
(3) hot filtering, transferring the filtrate into a reaction kettle, stirring, cooling and crystallizing;
(4) filtering, recovering the precipitate, and drying to obtain refined methyhaaltrexone bromide;
wherein, the stabilizing agent in the step (1) is sodium thiosulfate, sodium sulfite, ascorbic acid or tocopherol;
the lower alkanol in the step (1) is one or a mixed solvent of methanol, ethanol or isopropanol.
2. The method according to claim 1, wherein the lower alkanol in step (1) is methanol or ethanol.
3. The method of claim 1, wherein the stabilizer of step (1) is sodium thiosulfate.
4. The method according to claim 1, wherein the mass ratio of the lower alkanol in the step (1) to the crude methylnaltrexone bromide in the step (2) is 4: 1-8: 1.
5. The method according to claim 4, wherein the mass ratio of the lower alkanol in the step (1) to the crude methylnaltrexone bromide in the step (2) is 6: 1.
6. The method according to claim 1, wherein the mass ratio of the water in the step (1) to the crude methylnaltrexone bromide in the step (2) is 0.5: 1-2: 1.
7. The method of claim 6, wherein the mass ratio of the water in the step (1) to the crude methylnaltrexone bromide in the step (2) is 1: 1.
8. The method according to claim 1, wherein the temperature of the heat preservation in the step (2) is 50-80 ℃.
9. The method according to claim 8, wherein the temperature of the heat preservation in the step (2) is 65-75 ℃;
and (3) keeping the temperature for 0-1 h.
10. The method according to claim 1, wherein the temperature reduction in step (3) is carried out to a temperature of 0-25 ℃.
11. The method according to claim 10, wherein the temperature reduction in step (3) is carried out to a temperature of 0-5 ℃.
12. The method according to claim 1, wherein the time for crystallization in step (3) is 5-24 h.
13. The method according to claim 12, wherein the time for crystallization in step (3) is 8-12 h.
14. The method according to claim 1, wherein the temperature of the drying in the step (4) is 30-50 ℃.
15. The method according to claim 14, wherein the temperature of the drying in the step (4) is 40-45 ℃.
16. The method according to any one of claims 1 to 15, wherein the mass ratio of the stabilizer in the step (1) to the crude methylnaltrexone bromide in the step (2) is 1:1000 to 1: 100.
17. The method of claim 16, wherein the mass ratio of the stabilizer in step (1) to the crude methylnaltrexone bromide in step (2) is 5: 1000.
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