CN111303169B - Preparation method of fubitavir - Google Patents
Preparation method of fubitavir Download PDFInfo
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- CN111303169B CN111303169B CN202010172934.9A CN202010172934A CN111303169B CN 111303169 B CN111303169 B CN 111303169B CN 202010172934 A CN202010172934 A CN 202010172934A CN 111303169 B CN111303169 B CN 111303169B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
The invention relates to a preparation method of fubivir, wherein S-S type organic borate compound and S-S type aryl halogen compound are subjected to SUZUKI reaction under the action of a catalyst to prepare fubivir in batches, and the preparation method is simple in process route, easy to implement and completeThe cost is low; by controlling the catalyst PdCl 2 (dppf) can effectively control the content of heavy metal Pd in the final finished product; the purification is carried out by adopting a liquid chromatographic column, and ethyl acetate is used as a mobile phase, so that the yield is not lower than 70%, the purity is more than 99.5%, and the content of single impurities in a finished product is detected to be within 0.10%.
Description
Technical Field
The invention relates to the research of fubivir, in particular to a preparation method of fubivir.
Background
The fubitasvir is a novel HCV NS5A inhibitor, and the main action mechanism of the fubitasvir is to prevent HCV replication by inhibiting NS5A protein so as to achieve the effect of treating chronic hepatitis C. The fubitasvir is prepared by Suzuki coupling reaction of an organic boric acid (ester) compound and an aryl halogen compound.
The design of a preparation method of the fubitasvir, which is low in cost and easy to implement, is a technical problem which needs to be solved urgently by a person skilled in the art.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of the fubizivir, which has the advantages of simple process flow and low cost.
In order to solve the technical problems, the preparation method of the fubitasvir provided by the invention comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water to obtain a solvent I and placing the solvent I in a reaction container;
step b, adding an S-S type organic borate compound shown as a formula I and an S-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the S-S type organic borate compound and the S-S type aryl halogen compound are mixed with the solvent I obtained in the step a, adding an acid binding agent and a catalyst, decompressing and vacuumizing the reaction vessel, performing nitrogen replacement, heating to 90 ℃ and refluxing, and maintaining the refluxing for at least 4 hours to generate the fubizivir shown as a formula III, wherein the reaction formula is as follows:
and c, sampling and detecting the refluxed liquid, confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, cooling to room temperature after the reaction is finished, filtering, collecting filtrate, and filtering and concentrating the collected filtrate to obtain the crude product of the fubitasvir.
Further, in the step a, the volume ratio of tetrahydrofuran, dimethylformamide and water in the solvent I is 5:1: 1.
Further, in the step b, the acid-binding agent is sodium carbonate.
Further, in the step b, the catalyst is PdCl 2 (dppf)。
Further, in the step b, the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g as a unit to the volume V of the solvent I in mL as a unit added to the solvent I is 1: 10.
further, in the step b, PdCl is added 2 The mass ratio of the (dppf) to the S-S type organic borate compound is 0.007 to 0.017: 1.
and further, the preparation method of the fubitasvir further comprises the steps of liquid chromatography separation and purification, wherein the fubitasvir crude product obtained in the step c is added into a liquid chromatography column for separation, the filler in the liquid chromatography column is 300-400-mesh silica gel, the mobile phase is ethyl acetate, and the effluent liquid of the main product peak is subjected to reduced pressure concentration to obtain the fubitasvir finished product.
The invention has the technical effects that: compared with the prior art, the preparation method of the forbitasvir has the advantages that the S-S type organic borate compound and the S-S type aryl halogen compound are subjected to SUZUKI reaction under the action of the catalyst, and the forbitasvir can be prepared in batchesThe method has the advantages of simple process route, easy realization and low cost; when the S-S type organic borate ester compound and the S-S type aryl halogen compound react, sodium carbonate is added as an acid-binding agent, so that the reaction time can be greatly saved; when the ratio of the volume of the solvent I to the mass of the S-S type organoboronate compound needs to be controlled to be about 10 times, the reaction is more sufficient, and the residue after the reaction is less; by controlling the catalyst PdCl 2 (dppf) can effectively control the content of heavy metal Pd in the final finished product; the purification is carried out by adopting a liquid chromatographic column, and ethyl acetate is used as a mobile phase, so that the yield is not lower than 70%, the purity is more than 99.5%, and the content of single impurities in a finished product is detected to be within 0.10%.
Detailed Description
To further illustrate the present invention, some specific embodiments are described below, and some implementation methods of the present invention are described in conjunction with specific operation procedures.
Example 1
Firstly, a solvent is researched, and reagents such as tetrahydrofuran, dimethylformamide, 1, 4-dioxane, water and the like are selected for carrying out a plurality of tests, and the method specifically comprises the following steps:
a preparation method of fubitasvir comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 120mL of solvent I, and placing the solvent I in a reaction container with a volume of 250 mL;
and b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing a reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 4 hours, and generating the forbizivir shown in the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in the table 1.
Example 2
A preparation method of fubitasvir comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 140mL of solvent I, and placing the solvent I in a reaction container with a volume of 250 mL;
and b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 12, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 4 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in the table 1.
Example 3
A preparation method of fubitasvir comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 480mL of solvent I, and placing the solvent I into a reaction container with a volume of 1000 mL;
step b, adding 48.0g of S-S type organic borate compound shown as the formula I and 40.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 3 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 20.0g, and the catalyst is PdCl 2 (dppf), in an amount of 1.2g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in the table 1.
Example 4
A preparation method of fubitasvir comprises the following steps:
step a, taking 120mL of 1, 4-dioxane as a solvent I and placing the solvent I into a reaction vessel with the volume of 250 mL;
and b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 16 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in the table 1.
Example 5
Step a, mixing tetrahydrofuran and water according to a volume ratio of 5:1 to obtain 120mL of solvent I, and placing the solvent I in a reaction container with a volume of 250 mL;
and b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 3 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agentIs sodium carbonate in 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in the table 1.
Example 6
Step a, mixing tetrahydrofuran and water according to a volume ratio of 5:1 to obtain 480mL of solvent I, and placing the solvent I into a reaction container with a volume of 1000 mL;
step b, adding 48.0g of S-S type organic borate compound shown as the formula I and 40.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 20 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 20.0g, and the catalyst is PdCl 2 (dppf), in an amount of 1.2g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in the table 1.
Example 7
A preparation method of fubitasvir comprises the following steps:
step a, taking 120mL of tetrahydrofuran as a solvent I and placing the solvent I into a reaction vessel with the volume of 250 mL;
and b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 16 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in the table 1.
TABLE 1 comparison of solvent test data for different types and amounts
As can be unambiguously derived from table 1, only tetrahydrofuran: water is added according to the weight ratio of 5:1 as a solvent I, a small experiment can be carried out on a scale of 10g, but the reaction cannot be completed when the scale is enlarged to 48g, and the temperature is raised after the sodium carbonate is added, so that the reaction liquid is obviously divided into two phases, the water layer is clarified, and the acid-binding agent sodium carbonate is influenced to enter a tetrahydrofuran reaction solution; the reaction solution is not obviously layered after the DMF is added, and solid is adsorbed on the wall of the reaction bottle along with the reaction, so the use of the DMF is favorable for mutual solubility between the two phases. And the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g as a metering unit to the volume V of the solvent I in mL as a metering unit added into the solvent I is 1: 10 is the best choice.
Example 8
Due to PdCl 2 (dppf) is a homogeneous catalyst and is difficult to remove after completion of the reaction by dissolving in a solution, and therefore the amount of the catalyst used was examined.
A preparation method of fubitasvir comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 120mL of solvent I, and placing the solvent I into a reaction vessel with a volume of 250 mL;
and b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing a reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 4 hours, and generating the forbizivir shown in the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.20g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in a table 2.
Example 9
Due to PdCl 2 (dppf) is a homogeneous catalyst and is difficult to remove after the reaction is complete because it dissolves in solutionThis was considered for the amount of catalyst used.
A preparation method of fubitasvir comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 120mL of solvent I, and placing the solvent I in a reaction container with a volume of 250 mL;
step b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 4 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.37g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in a table 2.
Example 10
Due to PdCl 2 (dppf) is a homogeneous catalyst and is difficult to remove after completion of the reaction by dissolving in a solution, and therefore the amount of the catalyst used was examined.
A preparation method of fubitasvir comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 120mL of solvent I, and placing the solvent I in a reaction container with a volume of 250 mL;
and b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 4 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.08g,
and c, sampling and detecting the refluxed liquid, and confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, wherein the measurement results are shown in a table 2.
TABLE 2 catalyst PdCl 2 (dppf) comparison of different amounts
From the comparison of the results of examples 8, 9 and 10, although the complete reaction can still be obtained when the equivalent number of the catalyst is 0.031, the content of Pd heavy metal ions in the final product exceeds the standard, since Fribetovir is used for medicine, the content of heavy metal ions must be controlled within ten parts per million (10ppm), and when the equivalent number of the catalyst is 0.007, the reaction speed is very slow and the reaction is incomplete; in summary, the catalyst PdCl 2 The mass ratio of (dppf) to the S-S type organic borate compound participating in the reaction is controlled to be 0.007-0.017: 1.
Example 11
A preparation method of fubitasvir comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 120mL of solvent I, and placing the solvent I in a reaction container with a volume of 250 mL;
and b, adding 12.0g of S-S type organic borate compound shown as the formula I and 10.0g of S-S type aryl halogen compound shown as the formula II into a reaction vessel so as to mix the S-S type organic borate compound and the S-S type aryl halogen compound with the solvent I obtained in the step a, wherein the ratio of the weight W of the S-S type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL in the solvent I added into the solvent I is 1: 10, adding an acid-binding agent and a catalyst, decompressing and vacuumizing the reaction container, performing nitrogen replacement, continuously operating for 5 times, heating to 90 ℃, refluxing for 4 hours, and generating the fubitasvir shown as the formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 5.0g, and the catalyst is PdCl 2 (dppf), in an amount of 0.20g,
and c, sampling and detecting the refluxed liquid, confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, cooling to room temperature after the reaction is finished, filtering, collecting filtrate, and filtering and concentrating the collected filtrate to obtain the crude product of the fubitasvir.
And c, adding the crude fubitasvir obtained in the step c into a liquid chromatographic column for separation, wherein the size of the liquid chromatographic column is 100 x 400mm (D x H), adding 1Kg of 300-400 mesh silica gel as a filler, the model of a detector is NU3000, the detection wavelength is 220nm, ethyl acetate is used as a mobile phase, the flow rate is set to 100mL/min, collecting effluent liquid of a main product peak, and carrying out reduced pressure concentration to obtain the finished fubitasvir, wherein the main peak purity is 99.51% and the maximum unknown single impurity content is 0.09%.
For comparison, the finished product of the fubitasvir obtained by the step c is separated by a manual column chromatography method, the purity of the main peak is 98.48%, and the maximum unknown single impurity content is 0.28%.
The original process adopts manual column chromatography for separation and purification, and if the purity is unqualified, the column chromatography is required for purification for multiple times. Considering that the industrial preparation-grade liquid chromatography separation and purification technology is mature in many large pharmaceutical factories and is used in a process difficult to separate and purify, a proper filler is selected through experiments, and a hectogram-grade finished product is successfully produced by using a liquid chromatography preparation system, so that reliable data support is provided for subsequent ordering of large production equipment.
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious variations or modifications which fall within the spirit of the invention are intended to be covered by the scope of the present invention.
Claims (1)
1. The preparation method of the fubitasvir is characterized by comprising the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water to obtain a solvent I and placing the solvent I in a reaction container;
step b, adding an S-S type organic borate compound shown as a formula I and an S-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the S-S type organic borate compound and the S-S type aryl halogen compound are mixed with the solvent I obtained in the step a, adding an acid binding agent and a catalyst, decompressing and vacuumizing the reaction vessel, performing nitrogen replacement, heating to 90 ℃ and refluxing, and maintaining the refluxing for at least 4 hours to generate the fubizivir shown as a formula III, wherein the reaction formula is as follows:
c, sampling and detecting the refluxed liquid, confirming the residual contents of the S-S type organic borate compound and the S-S type aryl halogen compound in the liquid, cooling to room temperature after the reaction is finished, filtering, collecting filtrate, and filtering and concentrating the collected filtrate to obtain a crude product of the fubitasvir;
the preparation method of the fubitasvir further comprises the steps of liquid chromatography separation and purification, wherein the fubitasvir crude product obtained in the step c is added into a liquid chromatography column for separation, the filler in the liquid chromatography column is 300-400-mesh silica gel, the mobile phase is ethyl acetate, and the effluent liquid of the main product peak is subjected to reduced pressure concentration to obtain a fubitasvir finished product;
in the step a, the volume ratio of tetrahydrofuran, dimethylformamide and water in the solvent I is 5:1: 1;
in the step b, the acid-binding agent is sodium carbonate;
in the step b, the catalyst is PdCl 2 （dppf）；
In the step b, the ratio of the weight W of the S-S type organic borate compound shown as the formula I in the solvent I in g as a metering unit to the volume V of the solvent I in mL as a metering unit is 1: 10;
in the step b, PdCl is added 2 The mass ratio of (dppf) to the S-S type organic borate compound is 0.007 to 0.017: 1.
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| CN115286639B (en) * | 2020-11-20 | 2023-09-22 | 常州寅盛药业有限公司 | Fubi-tavir and verification method thereof |
| CN112461972B (en) * | 2020-11-20 | 2022-10-28 | 常州寅盛药业有限公司 | Fribobita Wei Duizhao product and verification method thereof |
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| CN104860931A (en) * | 2014-02-21 | 2015-08-26 | 常州寅盛药业有限公司 | Hepatitis C virus inhibitors and pharmaceutical uses thereof |
| CN109846878A (en) * | 2017-11-30 | 2019-06-07 | 常州寅盛药业有限公司 | HCV-Ab IgG combination medicine |
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| CN108947875A (en) * | 2018-07-05 | 2018-12-07 | 南通沃兰化工有限公司 | A kind of synthetic method of 2,4- diphenyl sulfone phenol |
| CN110872244A (en) * | 2018-09-03 | 2020-03-10 | 湖北江田精密化学有限公司 | Method for synthesizing 2, 4-diphenylsulfonyl phenol |
| CN111303169B (en) * | 2019-12-30 | 2022-09-16 | 常州寅盛药业有限公司 | Preparation method of fubitavir |
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| CN104860931A (en) * | 2014-02-21 | 2015-08-26 | 常州寅盛药业有限公司 | Hepatitis C virus inhibitors and pharmaceutical uses thereof |
| CN109846878A (en) * | 2017-11-30 | 2019-06-07 | 常州寅盛药业有限公司 | HCV-Ab IgG combination medicine |
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