CN113045605B - Preparation method and purification method of fosaprepitant dimeglumine - Google Patents

Preparation method and purification method of fosaprepitant dimeglumine Download PDF

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CN113045605B
CN113045605B CN202110343430.3A CN202110343430A CN113045605B CN 113045605 B CN113045605 B CN 113045605B CN 202110343430 A CN202110343430 A CN 202110343430A CN 113045605 B CN113045605 B CN 113045605B
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刘世领
刘洪斌
景林涛
孙应
兰宇涛
闵梦成
刘秋娜
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Zhejiang Arthur Pharmaceutical Co ltd
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Abstract

The invention discloses a preparation method and a purification method of fosaprepitant dimeglumine, which take aprepitant in a formula I as a raw material, adjust the pH value by saturated sodium bicarbonate in the presence of a proper organic solvent and purified water, and perform condensation reaction with a phosphorus reagent under the action of phosphinothricin to obtain a product solution; filtering the product solution by an ultrafiltration membrane to remove the phosphase, removing excessive phosphorus reagent by column chromatography, acidifying, eluting, concentrating at low temperature to dryness, adding methanol to precipitate a solid, performing suction filtration, washing with methanol, and collecting the solid, wherein the solid is a crude product; adding a proper amount of methanol into the crude product, adding 2 equivalents of meglumine, stirring for dissolving, concentrating at low temperature again, dissolving a small amount of methanol, dripping into a solvent of an ethanol/acetonitrile system, stirring at low temperature for crystallizing, and performing suction filtration to obtain the fosaprepitant dimeglumine shown in the formula II. The preparation method and the purification method provided by the invention have the advantages of mild reaction conditions, low equipment requirement and high safety.

Description

Preparation method and purification method of fosaprepitant dimeglumine
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a preparation and purification method of fosaprepitant dimeglumine.
Background
Because platinum, adriamycin and other anti-tumor drugs can generate serious vomiting reaction in the using process, acute nausea and vomiting can cause dehydration, electrolyte disorder and malnutrition of patients, severe patients can bleed, infect and even die due to digestive tract mucosa injury, so that the patients have fear of chemotherapy heart, the compliance is obviously reduced, chemotherapy decrement or discontinuation treatment is caused, and the treatment effect is seriously influenced. Thus, antiemetic drugs are an area of adjuvant therapy against tumors; meanwhile, antiemetics are also used for the prevention and treatment of surgical emesis. With the increasing incidence of tumor in modern society, the market capacity of antiemetic drugs is also rising and rising, and is always in an increasing state. The dosage of antiemetic drugs in 2005 is 2.5 billion yuan, and it has reached 5.7 billion yuan by 2009.
The NK-1 receptor antagonist is an antiemetic drug with a brand-new action mechanism, and plays an antiemetic role by inhibiting substance P from sending a signal for generating nausea and vomiting to cranial nerves. Aprepitant was first marketed in the united states as the first NK-1 receptor antagonist in 2003, opening new research directions in this field. It can effectively prevent acute nausea and emesis caused by chemotherapy, and has the outstanding advantage of preventing emesis and delayed emesis caused by chemotherapy at the same time. In 2009, the merck company aprepitant sold in $ 3.13 billion, and its amount of medication has been well on the rise since its introduction to the market. And fosaprepitant is a prodrug of aprepitant, is equivalent in drug effect and is an injection preparation. During the treatment process, oral administration of the aprepitant to vomit patients is difficult to realize, and rectal or intravenous administration is required, so fosaprepitant is a good supplement for oral aprepitant.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method and a purification method of fosaprepitant dimeglumine.
The technical scheme adopted by the invention for solving the technical problem is as follows: a preparation method and a purification method of fosaprepitant dimeglumine mainly comprise the following steps: taking aprepitant as a raw material, adjusting the pH value of the aprepitant by using saturated sodium bicarbonate in the presence of a proper organic solvent and purified water, and carrying out condensation reaction on the aprepitant and a phosphorus reagent under the action of a phosphinothricin to obtain a product solution; filtering the product solution by an ultrafiltration membrane to remove the phosphase, removing excessive phosphorus reagent by column chromatography, acidifying, eluting, concentrating at low temperature to dryness, adding methanol to precipitate a solid, performing suction filtration, washing with methanol, and collecting the solid, wherein the solid is a crude product;
the purification method of the crude product comprises the following steps: adding a proper amount of methanol into the crude product, adding 2 equivalents of meglumine, stirring for dissolving, concentrating at low temperature again, dissolving a small amount of methanol, dripping into a solvent of an ethanol/acetonitrile system, stirring at low temperature for crystallization, and performing suction filtration to obtain a product fosaprepitant dimeglumine shown in a formula II;
Figure BDA0003000186240000021
further, the organic solvent is any one or a combination of ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate and ethyl propionate. Preferably the organic solvent is butyl acetate.
Further, the phosphorus reagent is any one or a combination of several of phosphoric acid, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate and sodium dihydrogen phosphate. Preferably the phosphorus reagent is sodium hydrogen phosphate.
Further, in the preparation method, the mass ratio of aprepitant to the organic solvent to the purified water to the phosphorus reagent to the phosphinase is as follows: 4.0-6.0: 45-48: 90-95: 60-70: 1.
further, the temperature of the condensation reaction is 15-25 ℃, and preferably the temperature is 20-25 ℃; the time of the condensation reaction is 8-12 hours.
Furthermore, the column chromatography is macroporous adsorption resin chromatography, and the eluent is purified water.
Further, the phosphinothricin is ppdk (pyruvate phosphate dikinase).
Further, in the ethanol/acetonitrile system, the volume ratio of ethanol to acetonitrile is 1: 2 to 5. Preferably in a ratio of 1: 1.
The invention has the beneficial effects that: in the preparation method adopted in the prior art, strong bases such as butyl lithium, sodium hexamethyldisilazide or potassium hexamethyldisilazide and the like are generally used as condensation reagents; and hydrogenating to obtain the target product. Strong alkali and hydrogenation have strict requirements on equipment and reaction conditions, and the safety is lower. The preparation method and the purification method provided by the invention have the advantages of mild reaction conditions, low equipment requirement and high safety.
Drawings
FIG. 1 shows the preparation of the objective Compound according to example 41H NMR chart.
FIG. 2 is an HPLC chart of the objective compound obtained according to the preparation method of example 4.
Detailed Description
The invention is further illustrated by the following specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
Example 1
A500 mL three-necked flask was charged with 10.68g of the intermediate (compound of formula I), 100mL of ethyl formate was added to dissolve the solid, stirring was turned on, purified water (50mL) was added, the temperature was controlled to 15-20 deg.C, and 2.15 g of the phosphorizing enzyme PPDK was added by slowly adding an aqueous solution of sodium hydrogen phosphate (14.2 g in 150mL of water). And simultaneously dropwise adding a saturated sodium bicarbonate solution through a point-to-point titrator to control the pH value in the system to be 8.3-8.6. TLC (n-hexane/EtOA ═ 1/2) showed disappearance of starting material, about 8 hours after which the reaction was stopped and allowed to stand for phase separation. The water phase is filtered by an ultrafiltration membrane to remove the phosphorizing enzyme. The filtrate was collected and the excess sodium hydrogen phosphate was filtered off through macroporous resin. Eluting the product with 0.05mol/L dilute hydrochloric acid, collecting filtrate, concentrating under reduced pressure at 25 deg.C, evaporating to dryness, dissolving the obtained residue in methanol, stirring for 2 hr, precipitating white solid, vacuum filtering, washing with methanol, and draining to obtain white solid (8.0g, 13.03 mmol). The solid was added to 24mL of methanol and meglumine (5.09 g, 26.05mmol) was added and the system was clear after stirring at room temperature for 1 hour. The methanol solution was dropped into ethanol/acetonitrile (240.0mL,1:1), crystallized at low temperature and then filtered under suction. Collecting the solid to obtain a solid: 10.3 g, total yield: 51.3% and 95.2% HPLC purity. Calculated value C, 44.23; h, 5.62; o,25.48, and the detection value is C, 44.21; h, 5.62; and O, 25.47.
Example 2
A500 mL three-necked flask was charged with 10.68g of the intermediate (compound of formula I), 100mL of ethyl acetate was added to dissolve the solid, stirring was turned on, purified water (50mL) was added, the temperature was controlled to 15-20 deg.C, and 2.15 g of the phosphorizing enzyme PPDK was added by slowly adding an aqueous solution of sodium hydrogen phosphate (14.2 g in 150mL of water). And simultaneously dropwise adding a saturated sodium bicarbonate solution by using a point titration apparatus to control the pH value in the system to be between 8.3 and 8.6 by TLC (n-hexane/EtOA: 1/2), wherein the raw material disappears, stopping the reaction for about 8 hours, and standing for phase separation. The water phase is filtered by an ultrafiltration membrane to remove the phosphorizing enzyme. The filtrate was collected and the excess sodium hydrogen phosphate was filtered off through macroporous resin. Eluting the product with 0.05mol/L dilute hydrochloric acid, collecting filtrate, concentrating under reduced pressure at 25 deg.C, evaporating to dryness, dissolving the obtained residue in methanol, stirring for 2 hr, precipitating white solid, vacuum filtering, washing with methanol, and draining to obtain white solid (9.38g, 15.27 mmol). The solid was added to 28mL of methanol and meglumine (5.96 g, 30.53mmol) was added and the system was clear after stirring at room temperature for 1 hour. The methanol solution was dropped into ethanol/acetonitrile (281.4mL,1:1), crystallized at low temperature and then filtered under suction. Collecting the solid to obtain a solid: 9.2 g, total yield: 45.8% and HPLC purity 94.3%. Calculated value C, 44.23; h, 5.62; o,25.48, and the detection value is C, 44.21; h, 5.63; o, 25.43.
Example 3
A500 mL three-necked flask was charged with 10.68g of the intermediate (compound of formula I), 100mL of isopropyl acetate was added to dissolve the solid, stirring was turned on, purified water (50mL) was added, the temperature was controlled to 15-20 deg.C, and 2.15 g of the phosphorinase PPDK was added by slowly adding an aqueous solution of sodium hydrogen phosphate (14.2 g in 150mL of water). And simultaneously dropwise adding a saturated sodium bicarbonate solution through a point-to-point titrator to control the pH value in the system to be 8.3-8.6. TLC (n-hexane/EtOA ═ 1/2) showed disappearance of starting material, about 8 hours after which the reaction was stopped and allowed to stand for phase separation. The water phase is filtered by an ultrafiltration membrane to remove the phosphorizing enzyme. The filtrate was collected and the excess sodium hydrogen phosphate was filtered off through macroporous resin. Eluting the product with 0.05mol/L dilute hydrochloric acid, collecting filtrate, concentrating under reduced pressure at 25 deg.C, evaporating to dryness, dissolving the obtained residue in methanol, stirring for 2 hr to separate out white solid, vacuum filtering, washing with methanol, and draining to obtain white solid (10.72g, 17.45 mmol). The solid was added to 32mL of methanol and meglumine (6.82 g, 34.90mmol) was added and the system was clear after stirring at room temperature for 1 hour. The methanol solution was dropped into ethanol/acetonitrile (321.6mL,1:1), crystallized at low temperature and then filtered under suction. Collecting the solid to obtain a solid: 13.7 g, total yield: 68.2% and HPLC purity 98.6%. Calculated value C, 44.23; h, 5.62; o,25.48, and the detection value is C, 44.22; h, 5.65; and O, 25.49.
Example 4
Adding 10.68g of intermediate (compound shown in formula I) into a 500mL three-neck flask, adding 100mL of isopropyl acetate to dissolve the solid, stirring, adding purified water (100mL), controlling the temperature to 15-20 ℃, adding 2.15 g of phosphorizing enzyme PPDK (phosphate dihydrate), slowly adding an aqueous solution of sodium hydrogen phosphate (14.2 g of sodium hydrogen phosphate is dissolved in 150mL of water), and simultaneously dropwise adding a saturated sodium bicarbonate solution through a point-to-point titrator to control the pH value in the system to be 8.3-8.6. TLC (n-hexane/EtOA ═ 1/2) showed disappearance of starting material, about 8 hours after which the reaction was stopped and allowed to stand for phase separation. The water phase is filtered by an ultrafiltration membrane to remove the phosphorizing enzyme. The filtrate was collected and the excess sodium hydrogen phosphate was filtered off through macroporous resin. Eluting the product with 0.05mol/L dilute hydrochloric acid, collecting filtrate, concentrating under reduced pressure at 25 deg.C, evaporating to dryness, dissolving the obtained residue in methanol, stirring for 2 hr, precipitating white solid, vacuum filtering, washing with methanol, and draining to obtain white solid (10.78g, 17.55 mmol). The solid was added to 32mL of methanol and meglumine (6.86 g, 35.10mmol) was added and the system was clear after stirring at room temperature for 1 hour. The methanol solution was dropped into ethanol/acetonitrile (323.4mL,1:1), crystallized at low temperature and then filtered under suction. Collecting the solid to obtain a solid: 15.9 g, yield: 79.1%, HPLC purity 99.29%, calculated as C, 44.23; h, 5.62; o,25.48, and the detection value is C, 44.26; h, 5.61; and O, 25.46.
Example 5
Adding 10.68g of an intermediate (a compound shown as a formula I) into a 500mL three-neck flask, adding 100mL of isopropyl acetate to dissolve a solid, starting stirring, adding purified water (50mL), controlling the temperature to 15-20 ℃, adding 2.15 g of phosphorizing enzyme PPDK (phosphate dehydrogenase), slowly adding an aqueous solution of sodium hydrogen phosphate (14.2 g of the intermediate is dissolved in 150mL of water), and simultaneously dropwise adding a saturated sodium bicarbonate solution through a point-of-site titrator to control the pH value in the system to be 8.3-8.6. TLC (n-hexane/EtOA ═ 1/2) showed disappearance of starting material, about 8 hours after which the reaction was stopped and allowed to stand for phase separation. The water phase is filtered by an ultrafiltration membrane to remove the phosphorizing enzyme. The filtrate was collected and the excess sodium hydrogen phosphate was filtered off through macroporous resin. Eluting the product with 0.05mol/L dilute hydrochloric acid, collecting filtrate, concentrating under reduced pressure at 25 deg.C, evaporating to dryness, dissolving the obtained residue in methanol, stirring for 2 hr, precipitating white solid, vacuum filtering, washing with methanol, and draining to obtain white solid (7.73g, 12.58 mmol). The solid was added to 23.2mL of methanol and meglumine (6.86 g, 35.10mmol) was added and the system was clear after stirring at room temperature for 1 hour. The methanol solution was dropped into ethanol/acetonitrile (232mL,1:1), crystallized at low temperature and then filtered under suction. Collecting the solid to obtain a solid: 6.2 g, yield: 30.86% and 97.7% HPLC purity. Calculated value C, 44.23; h, 5.62; o,25.48, and the detection value is C, 44.22; h, 5.63; and O, 25.49.
The above embodiments are only for illustrating the invention and are not to be construed as limiting the invention, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention, therefore, all equivalent technical solutions also belong to the scope of the invention, and the scope of the invention is defined by the claims.

Claims (8)

1. A preparation method and a purification method of fosaprepitant dimeglumine are characterized in that the preparation method mainly comprises the following steps: taking aprepitant as a raw material, regulating the pH value of the aprepitant by using saturated sodium bicarbonate in the presence of a proper organic solvent and purified water, and performing condensation reaction on the aprepitant and a phosphorus reagent under the action of a phosphase to obtain a product solution; filtering the product solution by an ultrafiltration membrane to remove the phosphase, removing excessive phosphorus reagent by column chromatography, acidifying, eluting, concentrating at low temperature to dryness, adding methanol to precipitate a solid, performing suction filtration, washing with methanol, and collecting the solid, wherein the solid is a crude product;
the purification method of the crude product comprises the following steps: adding a proper amount of methanol into the crude product, adding 2 equivalents of meglumine, stirring for dissolving, concentrating at low temperature again, dissolving a small amount of methanol, dripping into a solvent of an ethanol/acetonitrile system, stirring at low temperature for crystallization, and performing suction filtration to obtain a product fosaprepitant dimeglumine shown in a formula II;
Figure FDA0003000186230000011
2. the process for the preparation and purification of fosaprepitant dimeglumine as claimed in claim 1, wherein: the organic solvent is any one or a combination of ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate and ethyl propionate.
3. The process for the preparation and purification of fosaprepitant dimeglumine as claimed in claim 1, wherein: the phosphorus reagent is any one or combination of several of phosphoric acid, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate and sodium dihydrogen phosphate.
4. The process for the preparation and purification of fosaprepitant dimeglumine as claimed in claim 1, wherein: in the preparation method, the mass ratio of aprepitant, the organic solvent, the purified water, the phosphorus reagent and the phosphinothricin is as follows: 4.0-6.0: 45-48: 90-95: 60-70: 1.
5. the process for the preparation and purification of fosaprepitant dimeglumine as claimed in claim 1, wherein: the temperature of the condensation reaction is 15-25 ℃; the time of the condensation reaction is 8-12 hours.
6. The process for the preparation and purification of fosaprepitant dimeglumine as claimed in claim 1, wherein: the column chromatography is carried out by macroporous adsorption resin chromatography, and eluent is purified water.
7. The process for the preparation and purification of fosaprepitant dimeglumine as claimed in claim 1, wherein: the phosphinothricin is PPDK.
8. The process for the preparation and purification of fosaprepitant dimeglumine as claimed in claim 1, wherein: in the ethanol/acetonitrile system, the volume ratio of ethanol to acetonitrile is 1: 2 to 5.
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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2017093899A1 (en) * 2015-12-01 2017-06-08 Piramal Enterprises Limited A process for preparation of fosaprepitant dimeglumine and an intermediate thereof
CN107353303A (en) * 2016-05-09 2017-11-17 上海奥博生物医药技术有限公司 A kind of preparation method of Fosaprepitant phosphate intermediate
WO2018211410A1 (en) * 2017-05-17 2018-11-22 Glenmark Pharmaceuticals Limited Improved process for preparation of fosaprepitant or salt thereof
CN112300212A (en) * 2020-11-30 2021-02-02 商河探荣新技术开发中心 Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists

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US11654154B2 (en) * 2019-01-29 2023-05-23 Navinta Iii Inc Process for preparing injectable Fosaprepitant Dimeglumine compositions having improved storage stability
US20200316097A1 (en) * 2019-02-28 2020-10-08 Ravishanker Kovi Storage-stable ready-to-use injectable formulations of fosaprepitant dimeglumine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093899A1 (en) * 2015-12-01 2017-06-08 Piramal Enterprises Limited A process for preparation of fosaprepitant dimeglumine and an intermediate thereof
CN107353303A (en) * 2016-05-09 2017-11-17 上海奥博生物医药技术有限公司 A kind of preparation method of Fosaprepitant phosphate intermediate
WO2018211410A1 (en) * 2017-05-17 2018-11-22 Glenmark Pharmaceuticals Limited Improved process for preparation of fosaprepitant or salt thereof
CN112300212A (en) * 2020-11-30 2021-02-02 商河探荣新技术开发中心 Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists

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