CN111205298A - Preparation method of forbitasvir RRRS type isomer - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to a preparation method of forbitasvir RRRS type isomers, wherein an R-R type organic borate compound and an R-S type aryl halogen compound are subjected to SUZUKI reaction under the action of a catalyst, so that the RRRS type isomers of the forbitasvir can be prepared in batches, and the preparation method has the advantages of simple process route, easiness in implementation and low cost; sodium carbonate is added as an acid-binding agent when the R-R type organic borate compound and the R-S type aryl halogen compound react, so that the reaction time can be greatly saved; when the sodium carbonate is used as an acid-binding agent, the molar mass ratio of the dosage of the sodium carbonate to the R-R type organic boric acid ester compound is controlled to be 1.5: 1, the reaction is relatively complete.
Description
Technical Field
The invention relates to research on a forbitasvir isomer, in particular to a preparation method of a forbitasvir RRRS type isomer.
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 preparation of the fubitasvir is prepared by Suzuki coupling reaction of an organic boric acid (ester) compound and an aryl halogen compound, the fubitasvir has 4 chiral centers and theoretically has 15 chiral isomer impurities, wherein the RRRS type isomer has important influence on the medicinal properties of the fubitasvir and plays a key role in the application of the fubitasvir.
The research on the properties, the effects and the like of the RRRS-type forbivir isomer needs to obtain the RRRS-type forbivir isomer in batches, so that the preparation method of the RRRS-type forbivir isomer, which is low in cost and easy to realize, is designed, and the technical problem which needs to be solved by the technical personnel in the field is urgently needed.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of the forbestavir RRRS type isomer, which has simple process flow and low cost.
In order to solve the technical problems, the preparation method of the forbitasvir RRRS type isomer 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 R-R type organic borate compound shown as a formula I and an R-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the R-R type organic borate compound and the R-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 a forbizivir RRRS type isomer 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 R-R type organic borate compound and the R-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 forbizivir RRRS type isomer.
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 PdCl2(dppf)。
Further, in the step b, the ratio of the weight W of the R-R type organic borate compound shown as the formula I in g to the volume V of the solvent I in mL added into the solvent I is 1: 10.
further, in the step b, the molar mass ratio of the acid-binding agent to the R-R type organic borate compound shown in the formula I is 1.5: 1.
and further, the preparation method of the forbestavir RRRS type isomer also comprises the steps of column chromatography separation and purification, wherein the crude forbestavir RRRS type isomer obtained in the step c is subjected to column chromatography separation by adopting a chromatography column, an eluent obtained by the column chromatography separation is subjected to reduced pressure concentration to obtain a forbestavir RRRS type isomer intermediate sample, the forbestavir RRRS type isomer intermediate sample is fully dissolved by methanol and added into a sodium hydroxide solution until solid is separated out, the mixture is stirred at room temperature for at least 30 minutes and then filtered to obtain a filter cake, and the filter cake is dried to obtain a finished product of the forbestavir RRRS type isomer.
The invention has the technical effects that: compared with the prior art, the preparation method of the forbitasvir RRRS type isomer has the advantages that the R-R type organic borate compound and the R-S type aryl halogen compound are subjected to SUZUKI reaction under the action of the catalyst, the forbitasvir RRRS type isomer can be prepared in batches, the process route is simple, the implementation is easy, and the cost is low; sodium carbonate is added as an acid-binding agent when the R-R type organic borate compound and the R-S type aryl halogen compound react, so that the reaction time can be greatly saved; when the ratio of the volume of the solvent I to the mass of the R-R type organoboronate compound is controlled to be about 10 times, the reaction is more sufficient, and the residue after the reaction is less; when the sodium carbonate is used as an acid-binding agent, the molar mass ratio of the dosage of the sodium carbonate to the R-R type organic boric acid ester compound is controlled to be 1.5: 1, the reaction is relatively complete. With increasing amounts of sodium carbonate, the reaction did not continue to run further down, so the feed equivalence ratio of sodium carbonate was determined to be in the range of 1: 1.5, the reaction rate can be effectively accelerated, and the cost is saved.
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
A preparation method of the forbitasvir RRRS type isomer comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 60mL of solvent I, and placing the solvent I in a reaction container with a volume of 100 mL;
step b, adding 6.0g of R-R type organic borate compound shown as a formula I and 5.0g of R-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the R-R type organic borate compound and the R-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, continuously operating for 5 times, heating to 90 ℃ and refluxing, and maintaining the refluxing for 4 hours to generate a forbizivir RRRS type isomer shown as a formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate with the dosage of 2.5g, and the catalyst is PdCl2(dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, confirming the residual contents of the R-R type organic borate compound and the R-S type aryl halogen compound in the liquid, and referring to the measurement result in table 1 to ensure that the temperature is reduced 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 forbizivir RRRS type isomer.
The preparation method of the forbesartan RRRS type isomer further comprises the steps of separating and purifying by column chromatography, carrying out column chromatography separation on the forbesartan RRRS type isomer crude product obtained in the step c by adopting a chromatographic column, and carrying out reduced pressure concentration on eluent obtained by the column chromatography separation to obtain a forbesartan RRRS type isomer intermediate sample, and specifically comprises the following steps: firstly, mixing 5g of 100-mesh 200-mesh silica gel, then adding 40g of 300-400-mesh silica gel into a chromatographic column, fully wetting by using petroleum ether, adding 10g of quartz sand into the chromatographic column, then using a mixed solution of the petroleum ether and ethyl acetate as an elution machine to wash the chromatographic column, performing process control by using TLC, collecting eluent, and concentrating under reduced pressure to obtain a fubivir RRRS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbtavivir RRRS type isomer by using 100mL of methanol, adding the fully dissolved intermediate sample into 300mL of 1mol/L sodium hydroxide solution until solid is separated out, stirring at room temperature for at least 30 minutes, filtering to obtain a filter cake, and drying the filter cake to obtain 5.0g of a finished product of the forbtavivir RRRS type isomer.
Example 2
A preparation method of the forbitasvir RRRS type isomer comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 60mL of solvent I, and placing the solvent I in a reaction container with a volume of 100 mL;
step b, adding 6.0g of R-R type organic borate compound shown as a formula I and 5.0g of R-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the R-R type organic borate compound and the R-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, continuously operating for 5 times, heating to 90 ℃ and refluxing, and maintaining the refluxing for 16 hours to generate a forbizivir RRRS type isomer shown as a formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is potassium acetate with the dosage of 2.3g, and the catalyst is PdCl2(dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, confirming the residual contents of the R-R type organic borate compound and the R-S type aryl halogen compound in the liquid, and referring to the measurement result in table 1 to ensure that the temperature is reduced 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 forbizivir RRRS type isomer.
The preparation method of the forbesartan RRRS type isomer further comprises the steps of separating and purifying by column chromatography, carrying out column chromatography separation on the forbesartan RRRS type isomer crude product obtained in the step c by adopting a chromatographic column, and carrying out reduced pressure concentration on eluent obtained by the column chromatography separation to obtain a forbesartan RRRS type isomer intermediate sample, and specifically comprises the following steps: firstly, mixing 5g of 100-mesh 200-mesh silica gel, then adding 40g of 300-400-mesh silica gel into a chromatographic column, fully wetting by using petroleum ether, adding 10g of quartz sand into the chromatographic column, then using a mixed solution of the petroleum ether and ethyl acetate as an elution machine to wash the chromatographic column, performing process control by using TLC, collecting eluent, and concentrating under reduced pressure to obtain a fubivir RRRS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbestavir RRRS type isomer by using 100mL of methanol, adding the intermediate sample into 300mL of 1mol/L sodium hydroxide solution until solid is separated out, stirring at room temperature for at least 30 minutes, filtering to obtain a filter cake, and drying the filter cake to obtain 4.8g of a finished product of the forbestavir RRRS type isomer.
Example 3
A preparation method of the forbitasvir RRRS type isomer comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 60mL of solvent I, and placing the solvent I in a reaction container with a volume of 100 mL;
step b, adding 6.0g of R-R type organic borate compound shown as a formula I and 5.0g of R-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the R-R type organic borate compound and the R-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, continuously operating for 5 times, heating to 90 ℃ and refluxing, and maintaining the refluxing for 8 hours to generate a forbizivir RRRS type isomer shown as a formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is N, N-diisopropylethylamine with the dosage of 3.05g, and the catalyst is PdCl2(dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, confirming the residual contents of the R-R type organic borate compound and the R-S type aryl halogen compound in the liquid, and referring to the measurement result in table 1 to ensure that the temperature is reduced 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 forbizivir RRRS type isomer.
The preparation method of the forbesartan RRRS type isomer further comprises the steps of separating and purifying by column chromatography, carrying out column chromatography separation on the forbesartan RRRS type isomer crude product obtained in the step c by adopting a chromatographic column, and carrying out reduced pressure concentration on eluent obtained by the column chromatography separation to obtain a forbesartan RRRS type isomer intermediate sample, and specifically comprises the following steps: firstly, mixing 5g of 100-mesh 200-mesh silica gel, then adding 40g of 300-400-mesh silica gel into a chromatographic column, fully wetting by using petroleum ether, adding 10g of quartz sand into the chromatographic column, then using a mixed solution of the petroleum ether and ethyl acetate as an elution machine to wash the chromatographic column, performing process control by using TLC, collecting eluent, and concentrating under reduced pressure to obtain a fubivir RRRS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbestavir RRRS type isomer by using 100mL of methanol, adding the intermediate sample into 300mL of 1mol/L sodium hydroxide solution until solid is separated out, stirring at room temperature for at least 30 minutes, filtering to obtain a filter cake, and drying the filter cake to obtain 4.9g of a finished product of the forbestavir RRRS type isomer.
TABLE 1 comparative data for different acid scavengers
As can be clearly seen from table 1, sodium carbonate is the most ideal acid-binding agent, which can greatly reduce the reaction time and make the reaction more complete.
Example 4
On the premise of determining that the type of the acid-binding agent is sodium carbonate, the feeding amount of the sodium carbonate is optimized, so that the research on the dosage of the sodium carbonate is increased.
A preparation method of the forbitasvir RRRS type isomer comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 48mL of solvent I, and placing the solvent I in a reaction container with a volume of 100 mL;
step b, adding 6.0g of R-R type organic borate compound shown as a formula I and 5.0g of R-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the R-R type organic borate compound and the R-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, continuously operating for 5 times, heating to 90 ℃ and refluxing, and maintaining the refluxing for 4 hours to generate a forbizivir RRRS type isomer shown as a formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate, the dosage is 1.28g, namely the molar mass ratio of the sodium carbonate to the R-R type organic boric acid ester compound shown in the formula I is 1:1, the catalyst is PdCl2(dppf) in an amount of 0.3g, step c, sampling and inspecting the refluxed liquid, and visually observing to confirm that the R-R type organoboronate compound and the R-S type aryl halogen compound in the liquid are not completely reacted and are apparently remained.
Example 5
A preparation method of the forbitasvir RRRS type isomer comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 48mL of solvent I, and placing the solvent I in a reaction container with a volume of 100 mL;
step b, adding 6.0g of R-R type organic borate compound shown as a formula I and 5.0g of R-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the R-R type organic borate compound and the R-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, continuously operating for 5 times, heating to 90 ℃ and refluxing, and maintaining the refluxing for 4 hours to generate a forbizivir RRRS type isomer shown as a formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate, the dosage is 1.92g, namely the molar mass ratio of the sodium carbonate to the R-R type organic borate compound shown in the formula I is 1.5: 1, the catalyst is PdCl2(dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, and visually observing to confirm that the R-R type organic borate compound and the R-S type aryl halogen compound in the liquid are completely reacted and no obvious residue exists. And after the reaction is observed, cooling to room temperature, filtering, collecting filtrate, and filtering and concentrating the collected filtrate to obtain a crude product of the forbizivir RRRS type isomer.
The preparation method of the forbesartan RRRS type isomer further comprises the steps of separating and purifying by column chromatography, carrying out column chromatography separation on the forbesartan RRRS type isomer crude product obtained in the step c by adopting a chromatographic column, and carrying out reduced pressure concentration on eluent obtained by the column chromatography separation to obtain a forbesartan RRRS type isomer intermediate sample, and specifically comprises the following steps: firstly, mixing 5g of 100-mesh 200-mesh silica gel, then adding 40g of 300-400-mesh silica gel into a chromatographic column, fully wetting by using petroleum ether, adding 10g of quartz sand into the chromatographic column, then using a mixed solution of the petroleum ether and ethyl acetate as an elution machine to wash the chromatographic column, performing process control by using TLC, collecting eluent, and concentrating under reduced pressure to obtain a fubivir RRRS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbtavivir RRRS type isomer by using 100mL of methanol, adding the fully dissolved intermediate sample into 300mL of 1mol/L sodium hydroxide solution until solid is separated out, stirring at room temperature for at least 30 minutes, filtering to obtain a filter cake, and drying the filter cake to obtain 5.0g of a finished product of the forbtavivir RRRS type isomer.
Example 6
A preparation method of the forbitasvir RRRS type isomer comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 48mL of solvent I, and placing the solvent I in a reaction container with a volume of 100 mL;
step b, adding 6.0g of R-R type organic borate compound shown as a formula I and 5.0g of R-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the R-R type organic borate compound and the R-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, continuously operating for 5 times, heating to 90 ℃ and refluxing, and maintaining the refluxing for 4 hours to generate a forbizivir RRRS type isomer shown as a formula III, wherein the reaction formula is as follows:
wherein the acid-binding agent is sodium carbonate, the dosage is 2.56g, namely the molar mass ratio of the sodium carbonate to the R-R type organic boric acid ester compound shown in the formula I is 2: 1, the catalyst is PdCl2(dppf), in an amount of 0.3g,
and c, sampling and detecting the refluxed liquid, and visually observing to confirm that the R-R type organic borate compound and the R-S type aryl halogen compound in the liquid are completely reacted and no obvious residue exists. And after the reaction is observed, cooling to room temperature, filtering, collecting filtrate, and filtering and concentrating the collected filtrate to obtain a crude product of the forbizivir RRRS type isomer.
The preparation method of the forbesartan RRRS type isomer further comprises the steps of separating and purifying by column chromatography, carrying out column chromatography separation on the forbesartan RRRS type isomer crude product obtained in the step c by adopting a chromatographic column, and carrying out reduced pressure concentration on eluent obtained by the column chromatography separation to obtain a forbesartan RRRS type isomer intermediate sample, and specifically comprises the following steps: firstly, mixing 5g of 100-mesh 200-mesh silica gel, then adding 40g of 300-400-mesh silica gel into a chromatographic column, fully wetting by using petroleum ether, adding 10g of quartz sand into the chromatographic column, then using a mixed solution of the petroleum ether and ethyl acetate as an elution machine to wash the chromatographic column, performing process control by using TLC, collecting eluent, and concentrating under reduced pressure to obtain a fubivir RRRS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbtavivir RRRS type isomer by using 100mL of methanol, adding the fully dissolved intermediate sample into 300mL of 1mol/L sodium hydroxide solution until solid is separated out, stirring at room temperature for at least 30 minutes, filtering to obtain a filter cake, and drying the filter cake to obtain 5.0g of a finished product of the forbtavivir RRRS type isomer.
TABLE 2 comparative data for different dosages of acid-binding agent
From the results of example 4, example 5 and example 6, it is clear that the molar mass ratio of sodium carbonate to the weight of the R-R type organoboronate compound/R-S type arylhalogen compound is 1.5: 1, the reaction proceeds relatively completely. The reaction does not tend to continue further with increasing amounts of sodium carbonate. The feed equivalence ratio of sodium carbonate was determined to be in the range of 1: 1.5, the reaction rate can be effectively accelerated, and the cost is saved.
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 (7)
1. The preparation method of the forbitasvir RRRS type isomer 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 R-R type organic borate compound shown as a formula I and an R-S type aryl halogen compound shown as a formula II into a reaction vessel, so that the R-R type organic borate compound and the R-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 a forbizivir RRRS type isomer 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 R-R type organic borate compound and the R-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 forbizivir RRRS type isomer.
2. The process for preparing forbitasvir RRRS type isomer according to claim 1, wherein the volume ratio of tetrahydrofuran, dimethylformamide and water in the solvent I in the step a is 5:1: 1.
3. The process for preparing forbitasvir RRRS type isomer of claim 2, wherein in the step b, the acid-binding agent is sodium carbonate.
4. The process for preparing the forbitasvir RRRS type isomer of claim 2 or 3, wherein in the step b, the catalyst is PdCl2(dppf)。
5. The process for preparing the forbitasvir RRRS type isomer of claim 4, wherein in the step b, the ratio of the weight W of the R-R type organic borate compound represented by the formula I in g to the volume V of the solvent I in mL added to the solvent I is 1: 10.
6. the preparation method of the forbitasvir RRRS type isomer according to claim 5, wherein in the step b, the molar mass ratio of the acid-binding agent to the R-R type organic borate compound shown in the formula I is 1.5: 1.
7. the preparation method of the forbivir RRRS type isomer according to claim 6, characterized by further comprising the steps of column chromatography separation and purification, wherein the crude forbivir RRRS type isomer obtained in the step c is subjected to column chromatography separation by using a chromatography column, an eluent obtained by the column chromatography separation is subjected to reduced pressure concentration to obtain a forbivir RRRS type isomer intermediate sample, the forbivir RRRS type isomer intermediate sample is fully dissolved by using methanol and added into a sodium hydroxide solution until a solid is separated out, the mixture is stirred at room temperature for at least 30 minutes and then filtered to obtain a filter cake, and the filter cake is dried to obtain a finished product of the forbivir RRRS type isomer.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112461972A (en) * | 2020-11-20 | 2021-03-09 | 常州寅盛药业有限公司 | Fubitavir reference substance and detection method thereof |
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Application publication date: 20200529 |