CN114478404A - Purification method of faviravir intermediate hydroxyl - Google Patents
Purification method of faviravir intermediate hydroxyl Download PDFInfo
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Abstract
The invention provides a purification method of a faviravir intermediate hydroxyl compound (formula II), which comprises the following steps: adding an organic solvent A and an inorganic base aqueous solution into a hydroxyl substance (formula II) solution, separating liquid, and retaining an aqueous phase; adjusting the pH value of the water phase to acidity, adding an organic solvent B, separating liquid, and collecting an organic phase; adding water into the collected organic phase, concentrating under reduced pressure, cooling, crystallizing, and filtering to obtain hydroxyl compound (formula II). The purification method can obtain high-purity crystalline hydroxy substance (formula II) free alkali (non-salifying form) solid, solves the problem that the hydroxy substance (formula II) is oily and is difficult to obtain solid, and has the purity of 99.6 percent and high yield (all over 70 percent). Meanwhile, the purification process is simple to operate, is convenient for industrial amplification, and has very good industrial prospect.
Description
Technical Field
The invention relates to the field of medicament purification, in particular to a purification method of a medicament intermediate, and particularly relates to a purification method of a faviravir intermediate hydroxyl compound (formula II).
Background
Faviravir (formula i), chemically named 6-fluoro-3-hydroxypyrazine-2-carboxamide, is a novel broad-spectrum antiviral drug developed by fushan chemical pharmaceuticals, japan to target RNA-dependent RNA polymerase (RdRp), approved for marketing in 3 months 2014 in japan for the treatment of new and recurrent influenza. The action mechanism of the Faviravir (formula I) is mainly that after entering the body, the Faviravir generates a nucleoside analogue triphosphate form under the action of a series of cellular phosphokinases, so that the replication and transcription of the virus are interfered. Researches find that the Vilarvir (formula I) has good inhibitory activity to various RNA viruses in vitro or in vivo, is expected to be developed and applied to treatment of various virus infections, and has good market prospect.
6-fluoro-3-hydroxy-2-cyanopyrazine (hydroxyl substance for short, formula II) is a high-grade intermediate for synthesizing bulk drug Vilarvir (formula I), and can be converted into Vilarvir (formula I) through one-step hydrolysis reaction, and the chemical reaction equation is as follows:
if the purity of the hydroxyl compound (formula II) is low, the difficulty of impurity removal of the finished product of the Lavir (formula I) is increased undoubtedly; meanwhile, the hydroxyl compound (formula II) is not easy to solidify and is easy to become oily, and the coating of the solvent can cause inaccurate feeding, thereby causing instability of the chemical reaction process. Therefore, it is difficult to obtain high purity solid hydroxy compound (formula II).
The Fuji film Fushan chemical company, published patent CN201510024656.1, identified in the art as a well-recognized problem, namely, "6-fluoro-3-hydroxy-2-cyanopyrazine (formula II) is soluble in water and various organic solvents and thus is not easily separated from the reaction mixture in high yield by simple operations", and thus it was selected to obtain the hydroxy organic amine salt (formula III) by salifying the hydroxy compound (formula II) with an organic amine. The treatment process can obtain hydroxyl organic ammonium salt (formula III) (the patent does not describe specific purity data), but the hydrolysis process related to the subsequent preparation method Vilarvir (formula I) needs to try to remove the added organic amine to obtain free hydroxyl (formula II), so that the unnecessary production cost of the Favilavir (formula I) is increased, the organic amine is expensive due to the use of the organic amine in a molar equivalent, and the cost of wastewater treatment is increased due to the use of the organic amine.
Fushan chemical industry Co., Ltd discloses patent CN201180053816.5, which adopts a new chemical reaction to prepare hydroxyl compound (formula II), but the precursor compound (formula IV) has a complex structure and needs a plurality of chemical reactions to prepare the hydroxyl compound, and the preparation method needs to use ion exchange resin DOWEX to pass through a column for purification treatment, thereby limiting the industrialization amplification of the technology.
Disclosure of Invention
The invention provides a purification method of faviravir intermediate hydroxyl compound (formula II). The purification method can obtain high-purity crystalline hydroxy substance (formula II) free alkali (non-salifying form) solid, solves the problem that the hydroxy substance (formula II) is oily and is difficult to obtain solid, and has the purity of 99.6 percent and high yield (all over 70 percent). The purification process is simple to operate, is convenient for industrial amplification, and has very good industrial prospect.
The technical scheme adopted by the invention is as follows:
a method for purifying a faviravir intermediate hydroxyl compound (formula ii), the method comprising:
adding an organic solvent A and an inorganic alkaline aqueous solution into a hydroxyl substance (formula II) solution, separating liquid, and keeping a water phase;
adjusting the pH value of the water phase to be acidic, adding an organic solvent B, separating liquid, and collecting an organic phase;
thirdly, adding water into the collected organic phase, concentrating under reduced pressure, cooling and crystallizing, and filtering to obtain a hydroxyl substance (formula II);
the organic solvent A and the organic solvent B are selected from organic solvents C which are not mutually soluble with water.
In the step (I), the hydroxyl substance (formula II) solution passes through
The method comprises the following steps: dissolving a hydroxyl compound (formula II) in a solvent 1 to provide a hydroxyl compound; or
The method 2 comprises the following steps: provided by subjecting 3, 6-difluoro-2-cyanopyrazine (formula V) to a hydrolysis reaction in solvent 2, the formula:
preferably using method 2.
The solvent 1 and the solvent 2 are optionally selected from one or a mixture of more of nitriles, aromatic hydrocarbons, ethers, ketones, alcohols, amides, sulfoxides and halogenated alkanes, preferably one or a mixture of more of aromatic hydrocarbons, ethers, amides or sulfoxides, more preferably one or a mixture of more of amides or sulfoxides, and further preferably N, N-dimethylformamide.
The method for hydrolyzing 3, 6-difluoro-2-cyanopyrazine (formula V) may be any method capable of hydrolyzing 3, 6-difluoro-2-cyanopyrazine (formula V) in a solvent to obtain a hydroxyl compound (formula II), for example, the method described in Chinese patent application CN201510024656.1 (example, first process [0024] paragraph- [0033] and first two lines of examples 1-1/1-2), etc., the method disclosed in research papers, or a modification or the like thereof.
Preferably, the organic solvent C is one or a mixture of toluene, ethyl acetate, dichloromethane and chloroform.
Preferably, the inorganic base in step (i) is selected from sodium bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide.
Preferably, the mass concentration of the inorganic alkali aqueous solution in the step I is 1-30%, preferably 5-10%; the volume-mass ratio of the inorganic alkali aqueous solution to the hydroxyl substance (formula II) is 4-10: 1, the unit is mL/g.
Preferably, the acid used for adjusting the pH of the aqueous phase in step (c) is an inorganic acid, preferably hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.
Preferably, the pH value of the water phase is adjusted to be less than or equal to 3 in the second step.
Preferably, the volume ratio of the water added in the third step to the collected organic phase is 0.1-2.0: 1, preferably 0.5-1.0: 1.
Preferably, the temperature of the reduced pressure concentration in the third step is 50-100 ℃.
Preferably, the obtained hydroxyl compound (formula II) is a crystalline solid, and has an X-ray powder diffraction pattern with characteristic peaks expressed in degrees 2 theta at 8.1 +/-0.2 degrees, 8.8 +/-0.2 degrees, 16.1 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.5 +/-0.2 degrees, 23.0 +/-0.2 degrees and 29.0 +/-0.2 degrees.
Preferably, the present invention does not use column chromatography for purification.
Preferably, the volume mass ratio of the organic solvent A to the organic solvent B to the 3, 6-difluoro-2-cyanopyrazine (formula V) is 4-20/4-20: 1, preferably 8/12: 1 in mL/g.
In the invention, the purification principle of the finished product of the hydroxyl substance (formula II) is that (1) the hydroxyl substance (formula II) reacts with inorganic base to generate salt (formula VI), and (VI) the salt (formula VI) reacts with inorganic acid to generate the hydroxyl substance (formula II), and the reaction formula is as follows:
compared with the prior art, the invention has the following beneficial effects:
the hydroxyl compound (formula II) prepared by the invention is a crystalline solid, has high yield (more than 70 percent) and high purity (up to 99.6 percent), and can be directly used for preparing the Vilarvir (formula I); meanwhile, the purification process of the invention has the following main advantages: (1) organic amine is not needed for salt forming operation, so that the cost of the process is reduced; (2) organic impurities and jelly can be removed through acid-base extraction operation, the operation is simple and convenient, the solidification of hydroxyl (formula II) is facilitated, the liquid phase purity is improved, and the impurity removal pressure of subsequent finished products is reduced; (3) the hydroxyl compound (formula II) is obtained in solid form in a dosing operation which is advantageous for the next hydrolysis reaction.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of the hydroxy compound (formula II) prepared in example 1.
FIG. 2 is an electron micrograph of the hydroxyl compound (formula II) prepared in example 1.
Detailed Description
The following examples are intended to further illustrate the present invention, but it should be understood that the following examples are only illustrative of the present invention and are not to be construed as limiting the scope of the present invention, which is defined by the appended claims.
In the following examples, all temperatures are in degrees celsius unless otherwise indicated; unless otherwise indicated, various starting materials and reagents were obtained commercially and were used without further purification; unless otherwise indicated, each solvent is a technical grade solvent and is used without further treatment.
Example 1
4.1mL of acetic acid was added to 17.5mL of a N, N-dimethylformamide solution containing 3, 6-difluoro-2-cyanopyrazine (formula V) (5.0g, 35mmol) at 5 to 15 ℃, 10mL of triethylamine was added dropwise thereto, and the mixture was stirred for 2 hours, after which the reaction was completed (HPLC-monitored content of 3, 6-difluoro-2-cyanopyrazine (formula V) was less than 0.3%). 40mL of 5% sodium hydroxide solution and 20mL of toluene were added, and the aqueous phase was collected by liquid separation. Toluene 20mL was added to the aqueous phase and the mixture was washed 1 time, leaving the aqueous phase. Regulating the pH value to be less than or equal to 3 by using a hydrochloric acid solution, adding 20mL of toluene, separating liquid and retaining an organic phase; the aqueous phase was extracted 2 times with 40mL of toluene and the organic phases were combined. Adding 30mL of water into the organic phase, concentrating under reduced pressure at 50-70 ℃, ending concentration after more solids are separated out, cooling to room temperature, stirring for 0.5-1.0 h, and filtering to obtain a yellow solid (formula II), wherein an X-ray powder diffraction pattern of the yellow solid is shown in figure 1, the HPLC purity is 99.5%, and the yield is 71%.
Example 2
4.1mL of acetic acid was added to 17.5mL of a N, N-dimethylformamide solution containing 3, 6-difluoro-2-cyanopyrazine (formula V) (5.0g, 35mmol) at 5 to 15 ℃, 10mL of triethylamine was added dropwise thereto, and the mixture was stirred for 2 hours, after which the reaction was completed (HPLC-monitored content of 3, 6-difluoro-2-cyanopyrazine (formula V) was less than 0.3%). 20mL of 10% sodium hydroxide solution and 20mL of toluene were added, and the aqueous phase was collected by liquid separation. Toluene 20mL was added to the aqueous phase and the mixture was washed 1 time, leaving the aqueous phase. Regulating the pH value to be less than or equal to 3 by using a hydrochloric acid solution, adding 20mL of toluene, separating liquid and retaining an organic phase; the aqueous phase was extracted 2 times with 40mL of toluene and the organic phases were combined. Adding 60mL of water into the organic phase, concentrating under reduced pressure at 80-100 ℃, ending concentration after more solids are separated out, cooling to room temperature, stirring for 0.5-1.0 h, and filtering to obtain a yellow solid (formula II), wherein the HPLC purity is 99.6%, and the yield is 73%.
Example 3
4.1mL of acetic acid was added to 17.5mL of a N, N-dimethylformamide solution containing 3, 6-difluoro-2-cyanopyrazine (formula V) (5.0g, 35mmol) at 5 to 15 ℃, 10mL of triethylamine was added dropwise thereto, and the mixture was stirred for 2 hours, after which the reaction was completed (HPLC-monitored content of 3, 6-difluoro-2-cyanopyrazine (formula V) was less than 0.3%). 20mL of 10% sodium hydroxide solution and 20mL of methylene chloride were added, and the aqueous phase was collected by separation. The aqueous phase was washed 1 time with 20mL of dichloromethane and the aqueous phase was retained. Regulating the pH value to be less than or equal to 3 by using a hydrochloric acid solution, adding 20mL of dichloromethane, separating liquid and keeping an organic phase; the aqueous phase was extracted 2 times with 40mL of dichloromethane and the organic phases were combined. Adding 60mL of water into the organic phase, concentrating under reduced pressure at 50-70 ℃, ending concentration after more solids are separated out, cooling to room temperature, stirring for 0.5-1.0 h, and filtering to obtain a yellow solid (formula II), wherein the HPLC purity is 99.3%, and the yield is 70%.
Example 4
4.1mL of acetic acid was added to 17.5mL of a N, N-dimethylformamide solution containing 3, 6-difluoro-2-cyanopyrazine (formula V) (5.0g, 35mmol) at 5 to 15 ℃, 10mL of triethylamine was added dropwise thereto, and the mixture was stirred for 2 hours, after which the reaction was completed (HPLC-monitored content of 3, 6-difluoro-2-cyanopyrazine (formula V) was less than 0.3%). 40mL of 5% sodium hydroxide solution and 20mL of chloroform were added, and the aqueous phase was collected by liquid separation. Chloroform 20mL is added into the water phase to wash for 1 time, and the water phase is reserved. Regulating the pH value to be less than or equal to 3 by using a hydrochloric acid solution, adding 20mL of trichloromethane, separating liquid and keeping an organic phase; the aqueous phase was extracted 2 times with 40mL of chloroform and the organic phases were combined. Adding 40mL of water into the organic phase, concentrating under reduced pressure at 50-70 ℃, finishing concentrating after more solids are separated out, cooling to room temperature, stirring for 0.5-1.0 h, and filtering to obtain a yellow solid (formula II), wherein the HPLC purity is 99.4%, and the yield is 76%.
Example 5
5.0g of the hydroxy compound (formula II) was dissolved in 15mL of N, N-dimethylformamide. 20mL of 10% sodium hydroxide solution and 20mL of toluene were added to the solution system, and the aqueous phase was collected by liquid separation. Toluene 20mL was added to the aqueous phase and the mixture was washed 1 time, leaving the aqueous phase. Regulating the pH value to be less than or equal to 3 by using a hydrochloric acid solution, adding 20mL of toluene, separating liquid and retaining an organic phase; the aqueous phase was extracted 2 times with 40mL of toluene and the organic phases were combined. Adding 60mL of water into the organic phase, concentrating under reduced pressure at 80-100 ℃, ending concentration after more solids are separated out, cooling to room temperature, stirring for 0.5-1.0 h, and filtering to obtain a yellow solid (formula II), wherein the HPLC purity is 99.4%, and the yield is 72%.
Example 6
5.0g of the hydroxy compound (formula II) was dissolved in 15mL of acetonitrile. 20mL of 10% sodium hydroxide solution and 20mL of chloroform were added to the solution system, and the aqueous phase was collected by liquid separation. Chloroform 20mL is added into the water phase to wash for 1 time, and the water phase is reserved. Regulating the pH value to be less than or equal to 3 by using a hydrochloric acid solution, adding 20mL of trichloromethane, separating liquid and keeping an organic phase; the aqueous phase was extracted 2 times with 40mL of chloroform and the organic phases were combined. Adding 60mL of water into the organic phase, concentrating under reduced pressure at 80-100 ℃, ending concentration after more solids are separated out, cooling to room temperature, stirring for 0.5-1.0 h, and filtering to obtain a yellow solid (formula II), wherein the HPLC purity is 99.3%, and the yield is 71%.
The X-ray powder diffraction patterns of the yellow solid (formula II) prepared in the embodiments 2-6 are consistent with those in the figure 1.
Claims (10)
1. A method for purifying a faviravir intermediate hydroxyl compound (formula II), which is characterized by comprising the following steps:
adding an organic solvent A and an inorganic alkaline aqueous solution into a hydroxyl substance (formula II) solution, separating liquid, and keeping a water phase;
adjusting the pH value of the water phase to be acidic, adding an organic solvent B, separating liquid, and collecting an organic phase;
thirdly, adding water into the collected organic phase, concentrating under reduced pressure, cooling and crystallizing, and filtering to obtain a hydroxyl substance (formula II);
the organic solvent A and the organic solvent B are selected from organic solvents C which are not mutually soluble with water.
2. The purification process according to claim 1, wherein in step (I), the solution of the hydroxyl compound (formula II) is passed through
The method comprises the following steps: dissolving a hydroxyl compound (formula II) in a solvent 1 to provide a hydroxyl compound; or
The method 2 comprises the following steps: provided by subjecting 3, 6-difluoro-2-cyanopyrazine (formula V) to a hydrolysis reaction in solvent 2, the formula:
preferably using method 2.
3. The purification method according to claim 2, wherein the solvent 1 and the solvent 2 are selected from one or more of nitriles, aromatic hydrocarbons, ethers, ketones, alcohols, amides, sulfoxides and halogenated alkanes, preferably from one or more of aromatic hydrocarbons, ethers, amides and sulfoxides, more preferably from one or more of amides and sulfoxides, and even more preferably from N, N-dimethylformamide.
4. The purification method according to any one of claims 1 to 3, wherein the organic solvent C is selected from one or more of toluene, ethyl acetate, dichloromethane and chloroform.
5. Purification process according to any one of claims 1 to 4, characterized in that the inorganic base in step (i) is chosen from sodium bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide.
6. The purification method according to any one of claims 1 to 5, wherein the mass concentration of the aqueous solution of inorganic base in the first step is 1 to 30%, preferably 5 to 10%; the volume-mass ratio of the inorganic alkali aqueous solution to the hydroxyl substance (formula II) is 4-10: 1, the unit is mL/g.
7. The purification process according to any one of claims 1 to 6, wherein the acid used to adjust the pH of the aqueous phase in step (ii) is an inorganic acid, preferably hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid; adjusting the pH value of the water phase to be less than or equal to 3.
8. The purification method according to any one of claims 1 to 7, wherein the volume ratio of the water added in step (c) to the collected organic phase is 0.1 to 2.0:1, preferably 0.5 to 1.0: 1.
9. the purification method according to any one of claims 1 to 8, wherein the temperature for the concentration under reduced pressure in step (c) is 50 to 100 ℃.
10. The purification process according to any one of claims 1 to 9, wherein the obtained hydroxy compound (formula II) is a crystalline solid having an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 θ at 8.1 ± 0.2 °, 8.8 ± 0.2 °, 16.1 ± 0.2 °, 18.8 ± 0.2 °, 19.5 ± 0.2 °, 23.0 ± 0.2 °, 29.0 ± 0.2 °.
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| CN112645889A (en) * | 2020-12-24 | 2021-04-13 | 杭州煌森生物科技有限公司 | Refining method of Favipiravir |
| WO2021240295A1 (en) * | 2020-05-26 | 2021-12-02 | Glenmark Life Sciences Limited | Process for preparation of favipiravir |
| CN113735785A (en) * | 2020-05-28 | 2021-12-03 | 南京桦冠生物技术有限公司 | Preparation method of 3, 6-dichloropyrazine-2-carbonitrile |
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2022
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Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
| CN101809003A (en) * | 2007-09-27 | 2010-08-18 | 富山化学工业株式会社 | Organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same |
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| CN103347884A (en) * | 2010-11-12 | 2013-10-09 | 富士胶片株式会社 | Pyrazino[2,3-d]isooxazole derivative |
| WO2021240295A1 (en) * | 2020-05-26 | 2021-12-02 | Glenmark Life Sciences Limited | Process for preparation of favipiravir |
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Inventor after: Cai Jianguang Inventor after: Du Jiaqiu Inventor after: Wang Linghui Inventor after: Lin Tanghuan Inventor after: Cai Chenxin Inventor after: Yang Kai Inventor after: Sun Peng Inventor after: Chen Liru Inventor after: Wu Zhongwei Inventor after: Yang Zhiqing Inventor before: Cai Jianguang Inventor before: Du Jiaqiu Inventor before: Wang Linghui Inventor before: Lin Tanghuan Inventor before: Cai Chenxin Inventor before: Yang Kai Inventor before: Sun Peng Inventor before: Chen Liru Inventor before: Wu Zhongwei Inventor before: Yang Zhiqing |