CN111253376A - Preparation method of fubitasvir SRSS type isomer - Google Patents
Preparation method of fubitasvir SRSS type isomer Download PDFInfo
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- CN111253376A CN111253376A CN202010172957.XA CN202010172957A CN111253376A CN 111253376 A CN111253376 A CN 111253376A CN 202010172957 A CN202010172957 A CN 202010172957A CN 111253376 A CN111253376 A CN 111253376A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- -1 aryl halogen compounds Chemical class 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000002904 solvent Substances 0.000 claims abstract description 40
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 20
- 239000011230 binding agent Substances 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims abstract description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 235000011056 potassium acetate Nutrition 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000004440 column chromatography Methods 0.000 claims description 21
- 238000000926 separation method Methods 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 239000003480 eluent Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 7
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical group Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 238000005070 sampling Methods 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000035484 reaction time Effects 0.000 abstract description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 3
- 150000001642 boronic acid derivatives Chemical class 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000000243 solution Substances 0.000 description 6
- 239000006004 Quartz sand Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000004886 process control Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000009736 wetting Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 3
- 101800001014 Non-structural protein 5A Proteins 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of forbitasvir SRSS type isomers, wherein S-S type organic borate compounds and R-S type aryl halogen compounds are subjected to SUZUKI reaction under the action of a catalyst, so that the SRSS 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; when the S-S type organic borate compound and the R-S type aryl halogen compound react, sodium carbonate, potassium acetate or N, N-diisopropylethylamine is added to be used as an acid-binding agent, so that the reaction time can be greatly saved, and particularly, the reaction time is greatly reduced by adding the sodium carbonate to be used as the acid-binding agent; the ratio of the volume of the solvent I to the mass of the S-S type organoboronate compound is controlled to be in the range of 8 to 12, particularly about 10 times, whereby the reaction is more sufficient and the reaction residue is less.
Description
Technical Field
The invention relates to research on fubivir isomers, in particular to a preparation method of fubivir SRSS type isomers.
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, because the fubitasvir has 4 chiral centers and theoretically has 15 chiral isomer impurities, wherein the most important isomer impurity is SRSS configuration, the research on SRSS type fubitasvir isomers is related to the quality 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 SRSS type forbivir isomer needs to obtain the SRSS type forbivir isomer in batches, so that the preparation method of the SRSS 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 fubitasvir SRSS type isomer, which has simple process flow and low cost.
In order to solve the technical problems, the preparation method of the fubitasvir SRSS 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 S-S 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 S-S 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 Fosbitavir SRSS 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 S-S type organic borate compound and the R-S type aryl halogen compound in the liquid so as 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 SRSS 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 one of sodium carbonate, potassium acetate and N, N-diisopropylethylamine.
Further, in the step b, the catalyst is PdCl2(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 to the volume V of the solvent I in mL added into the solvent I is 1: 8-12.
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 to the volume V of the solvent I in mL added into the solvent I is 1: 10.
and further, the preparation method of the forbitasvir SRSS type isomer also comprises the steps of column chromatography separation and purification, wherein the crude forbitasvir SRSS 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 forbitasvir SRSS type isomer intermediate sample, the forbitasvir SRSS 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 forbitasvir SRSS type isomer.
The invention has the technical effects that: compared with the prior art, the preparation method of the forbitasvir SRSS type isomer has the advantages that S-S type organic borate compound and R-S type aryl halogen compound are subjected to SUZUKI reaction under the action of a catalyst, the SRSS type isomer of the forbitasvir can be prepared in batches, the process route is simple, the implementation is easy, and the cost is low; when the S-S type organic borate compound and the R-S type aryl halogen compound react, sodium carbonate, potassium acetate or N, N-diisopropylethylamine is added to be used as an acid-binding agent, so that the reaction time can be greatly saved, and particularly, the reaction time is greatly reduced by adding the sodium carbonate to be used as the acid-binding agent; the ratio of the volume of the solvent I to the mass of the S-S type organoboronate compound is controlled to be in the range of 8 to 12, particularly about 10 times, whereby the reaction is more sufficient and the reaction residue is less.
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 SRSS 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 S-S 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 to mix the S-S type organic borate compound and the R-S type aryl halogen compound 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 the forbizivir SRSS 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 S-S 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 SRSS type isomer.
The preparation method of the fubitasvir SRSS isomer also comprises the steps of column chromatography separation and purification, wherein the crude fubitasvir SRSS isomer obtained in the step c is subjected to column chromatography separation by using a chromatographic column, and an eluent obtained by the column chromatography separation is subjected to reduced pressure concentration to obtain a fubitasvir SRSS isomer intermediate sample, and the method specifically comprises the following steps: firstly, mixing 5g of 100-through 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 forbizivir SRSS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbitasvir SRSS 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 5.0g of a finished product of the forbitasvir SRSS type isomer.
Example 2
A preparation method of the forbitasvir SRSS 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 S-S 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 to mix the S-S type organic borate compound and the R-S type aryl halogen compound 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 the forbizivir SRSS 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 S-S 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 SRSS type isomer.
The preparation method of the fubitasvir SRSS isomer also comprises the steps of column chromatography separation and purification, wherein the crude fubitasvir SRSS isomer obtained in the step c is subjected to column chromatography separation by using a chromatographic column, and an eluent obtained by the column chromatography separation is subjected to reduced pressure concentration to obtain a fubitasvir SRSS isomer intermediate sample, and the method specifically comprises the following steps: firstly, mixing 5g of 100-through 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 forbizivir SRSS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbitasvir SRSS 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 4.85g of a finished product of the forbitasvir SRSS type isomer.
Example 3
A preparation method of the forbitasvir SRSS 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 S-S 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 to mix the S-S type organic borate compound and the R-S type aryl halogen compound 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 the forbizivir SRSS 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 S-S 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 SRSS type isomer.
The preparation method of the fubitasvir SRSS isomer also comprises the steps of column chromatography separation and purification, wherein the crude fubitasvir SRSS isomer obtained in the step c is subjected to column chromatography separation by using a chromatographic column, and an eluent obtained by the column chromatography separation is subjected to reduced pressure concentration to obtain a fubitasvir SRSS isomer intermediate sample, and the method specifically comprises the following steps: firstly, mixing 5g of 100-through 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 forbizivir SRSS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbitasvir SRSS 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 4.95g of a finished product of the forbitasvir SRSS 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
The amount of solvent I used has been increasingly studied, considering that the extent of dissolution of the substrate by the amount of solvent may have an influence on the reaction results.
A preparation method of the forbitasvir SRSS 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 S-S 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 to mix the S-S type organic borate compound and the R-S type aryl halogen compound 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 the forbizivir SRSS 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 S-S type organic borate compound and the R-S type aryl halogen compound in the liquid, and referring to the measurement result in table 2 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 SRSS type isomer.
The preparation method of the fubitasvir SRSS isomer also comprises the steps of column chromatography separation and purification, wherein the crude fubitasvir SRSS isomer obtained in the step c is subjected to column chromatography separation by using a chromatographic column, and an eluent obtained by the column chromatography separation is subjected to reduced pressure concentration to obtain a fubitasvir SRSS isomer intermediate sample, and the method specifically comprises the following steps: firstly, mixing 5g of 100-through 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 forbizivir SRSS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbitasvir SRSS 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 4.95g of a finished product of the forbitasvir SRSS type isomer.
Example 5
The amount of solvent I used has been increasingly studied, considering that the extent of dissolution of the substrate by the amount of solvent may have an influence on the reaction results.
A preparation method of the forbitasvir SRSS type isomer comprises the following steps:
step a, mixing tetrahydrofuran, dimethylformamide and water according to a volume ratio of 5:1:1 to obtain 72mL of solvent I, and placing the solvent I in a reaction container with a volume of 100 mL;
step b, adding 6.0g of S-S 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 to mix the S-S type organic borate compound and the R-S type aryl halogen compound 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 the forbizivir SRSS 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 S-S type organic borate compound and the R-S type aryl halogen compound in the liquid, and referring to the measurement result in table 2 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 SRSS type isomer.
The preparation method of the fubitasvir SRSS isomer also comprises the steps of column chromatography separation and purification, wherein the crude fubitasvir SRSS isomer obtained in the step c is subjected to column chromatography separation by using a chromatographic column, and an eluent obtained by the column chromatography separation is subjected to reduced pressure concentration to obtain a fubitasvir SRSS isomer intermediate sample, and the method specifically comprises the following steps: firstly, mixing 5g of 100-through 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 forbizivir SRSS type isomer intermediate sample; and (3) completely dissolving the intermediate sample of the forbitasvir SRSS 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 4.95g of a finished product of the forbitasvir SRSS type isomer.
TABLE 2 comparative data for different amounts of solvent I
From the comparison of the results of examples 4 and 5 with the results of example 1, it can be seen that the ratio of the weight W of the S-S type organoboronate compound of the formula I as measured in g to the volume V of the solvent I as measured in mL, added to the solvent I, is 1: 10, is a more suitable choice.
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. A preparation method of the fubitasvir SRSS 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 S-S 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 S-S 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 Fosbitavir SRSS 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 S-S type organic borate compound and the R-S type aryl halogen compound in the liquid so as 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 SRSS type isomer.
2. The process for preparing forbitasvir SRSS 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 method for preparing forbitasvir SRSS type isomers according to claim 2, wherein in the step b, the acid-binding agent is one of sodium carbonate, potassium acetate and N, N-diisopropylethylamine.
4. The process for the preparation of the forbitasvir SRSS isomer of claim 2 or 3 wherein in the step b, the catalyst is PdCl2(dppf)。
5. The process for preparing forbitasvir SRSS type isomer according to claim 4, wherein in the step b, the ratio of the weight W of the S-S type organic borate compound represented by formula I added to the solvent I in g to the volume V of the solvent I in mL is 1: 8-12.
6. The process for preparing forbitasvir SRSS type isomer according to claim 5, wherein in the step b, the ratio of the weight W of the S-S type organoboronate compound represented by formula I in g to the volume V of the solvent I in mL added to the solvent I is 1: 10.
7. the preparation method of the forbitasvir SRSS isomer according to claim 6, characterized by further comprising the steps of column chromatography separation and purification, wherein the crude forbitasvir SRSS 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 forbitasvir SRSS isomer intermediate sample, the forbitasvir SRSS isomer intermediate sample is completely dissolved by 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 forbitasvir SRSS isomer.
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| CN112461971A (en) * | 2020-11-20 | 2021-03-09 | 常州寅盛药业有限公司 | Fubitasvir and detection method thereof |
| 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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| 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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| 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 |
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| CN112461971A (en) * | 2020-11-20 | 2021-03-09 | 常州寅盛药业有限公司 | Fubitasvir and detection method thereof |
| 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 |
| CN112461971B (en) * | 2020-11-20 | 2022-10-04 | 常州寅盛药业有限公司 | Forbitasvir and detection 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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