CN110981879A - Method for preparing NS5A inhibitor-wipatasvir - Google Patents
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Abstract
The invention discloses a method for preparing NS5A inhibitor-wiepatasvir, which mainly comprises five steps, 1) carrying out butt reaction on reaction starting raw materials VPM1, VPM2 and VPM3 under the action of alkali catalysis to prepare an intermediate VP 1; 2) removing amino protecting groups from the intermediate VP1 by a deprotection reagent to obtain an intermediate VP 2; 3) intermediate VP2 and amine compound are cyclized to prepare intermediate VP 3; 4) reacting the intermediate VP3 with VPM4 under the action of a condensing agent to prepare an amide compound intermediate VP 4; 5) and carrying out oxidation reaction on the intermediate VP4 under the action of an oxidant to prepare Velpatasvir. The preparation process of the vipetavir has the characteristics of simplified route, simple reaction conditions, operable enhancement and higher product yield, and is more suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a method for preparing NS5A inhibitor-wipatasvir.
Background
HCV viruses have 6 genotypes in total. The standard treatment regimen is combination of polyethylene glycol interferon (Peg-IFN) and Ribavirin (RBV), the total cure rate is less than 50%, and sufficient dose needs to be adhered to for continuous treatment for more than one year. Peg-IFN which needs to be injected for 1 time in 1 week has the defects of more adverse reactions, poor drug interaction, poor patient compliance and the like, and has limitation on clinical use. Thus, direct antiviral Drugs (DAAs) for treating hepatitis C, which can improve the cure rate, shorten the treatment time, and be used in a full oral form instead of Peg-IFN, are continuously emerging.
Epclusa is a novel pan-genotypic hepatitis C drug developed by Gilidard scientific, and is a compound tablet consisting of NS5B inhibitor sofosbuvir and NS5A inhibitor vepatavir (velpatasvir, VEL), which is orally taken once a day. Epclusa is approved by the FDA and the European Union respectively for treating adult patients infected with gene 1-6 type hepatitis C virus in 2016, can be used for patients without liver cirrhosis or compensated liver cirrhosis alone, and can also be used for treating patients with uncompensated liver cirrhosis by combining with ribavirin. Epclusa obtains better curative effect in each genotype patient, is expected to avoid genotyping test and improves the cure rate of hepatitis C patients.
However, the synthesis process of the vipitavir in the prior art has the defects of complex route, poor operability, low yield and the like, and is not suitable for large-scale production and preparation, which limits the application of the medicine to a certain extent. Therefore, it is necessary to design and develop a new preparation process of wipatavir, which can simplify the preparation process, has higher yield and is suitable for large-scale production.
Disclosure of Invention
Aiming at the problems in the prior art, the invention discloses a method for preparing NS5A inhibitor-wipatasvir, which has the advantages of short route, simple preparation conditions, enhanced operability and suitability for large-scale production.
The technical scheme of the invention is as follows: a method for preparing NS5A inhibitor-wipatasvir comprises the following specific synthetic route:
wherein X ═ Cl or Br;
r is tert-butyloxycarbonyl, benzyloxycarbonyl or benzoyl.
The specific synthesis steps are as follows:
1) preparation of intermediate VP 1: carrying out butt reaction on reaction starting raw materials VPM1, VPM2 and VPM3 under the catalysis of alkali to prepare an intermediate VP 1;
2) preparation of intermediate VP 2: removing amino protecting groups from the intermediate VP1 by a deprotection reagent to obtain an intermediate VP 2;
3) preparation of intermediate VP 3: intermediate VP2 and amine compound are cyclized to prepare intermediate VP 3;
4) preparation of intermediate VP 4: reacting the intermediate VP3 with (R) -2- (methoxycarbonylamino) -2-phenyl acetic acid (VPM4) under the action of a condensing agent to prepare an amide compound intermediate VP 4;
5) and carrying out oxidation reaction on the intermediate VP4 under the action of an oxidant to prepare Velpatasvir.
In step 1, VPM1 is selected from the group consisting of 9-bromo-3- (2-bromoacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one, 9-bromo-3- (2-chloroacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one; the selection range of VPM2 includes (2S,4S) -1- (tert-butoxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid, (2S,4S) -1- (benzyloxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid and (2S,4S) -1- (benzoyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid.
In step 1, the charging molar ratio of VPM1, VPM2 and VPM3 is as follows: 1:1.02: 1.02-1: 1.05: 1.05.
In the step 1, the selection range of the alkali reagent comprises sodium carbonate, cesium carbonate, potassium carbonate and sodium hydroxide; preferably, the alkali reagent is selected from potassium carbonate or cesium carbonate; the feeding molar ratio of the alkali reagent to the VPM1 is as follows: 2:1 to 3: 1.
In the step 2, the selection range of the deprotection reagent comprises hydrochloric acid, sulfuric acid, acetic acid, sodium methoxide, sodium ethoxide, ammonia methanol and palladium carbon/hydrogen; preferably, the amine compound is hydrochloric acid, sodium methoxide, ammonia methanol, or palladium on carbon/hydrogen.
Further, when the deprotecting reagent is other than palladium on carbon, the molar ratio of the deprotecting reagent to VP1 fed is: 1.05: 1-10.0: 1; when the deprotection reagent is palladium carbon, the mass of the palladium carbon is 10% of the mass of the substrate.
In step 3, the amine compound is selected from ammonium carbonate, ammonium formate, ammonium acetate and ammonium propionate; preferably, the amine compound is ammonium formate or ammonium acetate; the feeding molar ratio of the amine compound to the VP2 is as follows: 3.0:1 to 5.0: 1.
In step 4, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), N '-Carbonyldiimidazole (CDI) or a combination of N, N' -Dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt); the charging molar ratio of VP3, VPM4 and the condensing agent is as follows: 1.0:1.1: 1.5-1.0: 1.5: 1.8.
In step 5, the selection range of the oxidant comprises dichloro dicyano benzoquinone (DDQ) and tetrachlorobenzoquinone; the feeding molar ratio of the intermediate VP4 to the oxidant is as follows: 1.0: 1.5-1.0: 2.5.
The invention has the beneficial effects that:
1. the invention discloses a method for preparing NS5A inhibitor-wipatasvir, which comprises the steps of carrying out butt coupling on three main fragments by a one-pot method to construct a wipatasvir nuclear structure, and then carrying out deprotection, cyclization, substitution and oxidation reactions to prepare the wipatasvir and derivatives thereof, wherein the whole preparation route is greatly simplified, the reaction condition is simple, the operation is enhanced, the product yield is high, the method is more suitable for large-scale industrial production, and the enlarged application of the medicament is facilitated;
2. in the preparation route disclosed by the invention, nitrogen atoms on a tetrahydropyrrole ring are protected by amino protecting groups, so that the generation of side reactions and the production of impurities are effectively reduced, and an intermediate product is easy to treat and purify.
Detailed Description
The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications and substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit of the invention.
Example 1:
the synthetic route is as follows:
step one, preparation of VP 1:
9-bromo-3- (2-bromoacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one (VPM1) (20g, 45mmol, 1.0eq), (2S,4S) -1- (tert-butoxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid (VPM2) (11.6g, 46mmol, 1.02eq), cesium carbonate (29.3g, 90mmol, 2.0eq), and 300mL tetrahydrofuran were added to a 1000mL reaction flask at room temperature, stirred, warmed to 50-55 ℃ for reaction, and monitored by TLC for reaction. TLC showed that the starting material VPM2 remained below 2%, cooled to 30-35 deg.C, and then 100mL of VPM3 in tetrahydrofuran (13.2g, 46mmol, 1.02eq) was added dropwise. After the dripping is finished, the temperature is raised to 50-55 ℃ for reaction, and the reaction is monitored by TLC. After the reaction, the mixture was cooled to room temperature, 500mL of water and 500mL of ethyl acetate were added, the mixture was stirred, and the mixture was allowed to stand for liquid separation, the aqueous layer was extracted with ethyl acetate (200 mL. times.3), the organic phases were combined, washed with saturated brine (200 mL. times.1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, 400mL of n-heptane was added to the residue, and the mixture was slurried, filtered, and dried to obtain 31.9g of VP1 as a solid product with a yield of 86%.
Step two, preparation of VP 2:
the intermediate VP1(31.9g, 38mmol, 1.0eq) and 200mL of ethanol were added to a 500mL reaction flask, stirred to dissolve, cooled to 0-5 deg.C, and then the prepared 8mL of 5N hydrochloric acid solution (38mmol, 1.05eq) was slowly added dropwise. After the dripping is finished, the temperature is raised to 75-80 ℃ for reaction, and the reaction is monitored by TLC. After the reaction is finished, 500mL of water is added, stirring is carried out, 20% sodium hydroxide solution is dropwise added until the solution is nearly neutral, isopropyl ether (200mL multiplied by 3) is used for extraction, organic phases are combined, saturated saline solution (150mL multiplied by 1) is used for washing, anhydrous sodium sulfate is used for drying, suction filtration is carried out, filtrate is decompressed and concentrated to be dry, 300mL of ether is added into residual liquid for pulping, suction filtration is carried out, and 25.8g of solid product VP2 is obtained after drying, and the yield is 92%.
Step three, preparation of VP 3:
a500 mL reaction flask was charged with intermediate VP2(25.8g, 35mmol, 1.0eq), ammonium formate (6.7g, 105mmol, 3.0eq) and 200mL ethylene glycol methyl ether, stirred, warmed to 100 ℃ and 105 ℃ for reaction, and monitored by TLC. After the reaction is finished, cooling to 30-35 ℃, adding 150mL of water for quenching, stirring, separating an organic phase, extracting a water layer by using toluene (100mL multiplied by 3), combining the organic phases, washing by using saturated saline (150mL multiplied by 1), drying by using anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate under reduced pressure until the filtrate is dry, adding 200mL of n-hexane into a residual solution for pulping, performing suction filtration, and drying to obtain 21.2g of a solid product VP3 with the yield of 87%.
Step four, preparation of VP 4:
a500 mL reaction flask was charged with intermediate VP3(21.2g, 31mmol, 1.0eq), intermediate VPM4(7.1g, 34mmol, 1.1eq) and 200mL dichloromethane, stirred to dissolve, EDCI (8.9g, 47mmol, 1.5eq) and HOBt (6.3g, 47mmol, 1.5eq) were added, the temperature was raised to 30-35 ℃ for reaction, and the reaction was monitored by TLC. After the reaction, 100mL of 10% acetic acid aqueous solution and 200mL of dichloromethane are added, stirring is carried out for 30min, layers are separated, an organic phase is taken out, the organic phase is respectively washed by saturated sodium bicarbonate aqueous solution (100mL multiplied by 1) and saturated sodium chloride aqueous solution (100mL multiplied by 1), anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is decompressed and concentrated to obtain a solid crude product. The crude product was recrystallized from 200mL of ethyl acetate and n-hexane (2:1) to give 23.3g of VP4 as a solid product. Yield: 86 percent.
Step five, preparing Velpatasvir:
under the protection of nitrogen, intermediate VP4(23.3g, 26mmol, 1.0eq) and 200mL tetrahydrofuran were added to a 500mL reaction flask, stirred to dissolve, cooled to 0-5 deg.C, glacial acetic acid was added, and 50mL of tetrahydrofuran solution (8.9g, 39mmol, 1.5eq) of LDDQ was added dropwise. After the addition, the reaction was carried out at 0-5 ℃ and monitored by TLC. After the reaction is finished, dropwise adding 10% sodium hydroxide solution to adjust the pH to be nearly neutral, adding 150mL of water and 300mL of dichloromethane, stirring, standing and layering; the aqueous layer was extracted with dichloromethane (200 mL. times.3), the organic phases were combined, washed with saturated aqueous sodium chloride (200 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude solid. The crude product was recrystallized from 200mL of isopropanol and water (2:1) to give 20.7g of Velpatasvir as a solid product. Yield: 89 percent.
Example 2:
the synthetic route is as follows:
step one, preparation of VP 1:
9-bromo-3- (2-chloroacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one (VPM1) (30g, 74mmol, 1.0eq), (2S,4S) -1- (benzyloxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid (VPM2) (22.9g, 78mmol, 1.05eq), potassium carbonate (30.6g, 222mmol, 3.0eq), and 400mL acetonitrile were added to a 1000mL reaction flask at room temperature, stirred, warmed to 50-55 deg.C for reaction, and monitored by TLC for reaction. TLC showed that the starting material VPM2 remained below 2%, cooled to 30-35 deg.C, and then 100mL of VPM3 in acetonitrile (22.3g, 78mmol, 1.05eq) was added dropwise. After the dripping is finished, the temperature is raised to 50-55 ℃ for reaction, and the reaction is monitored by TLC. After the reaction, the mixture is cooled to room temperature, 500mL of water and 600mL of ethyl acetate are added, stirring and standing are carried out for liquid separation, the water layer is extracted by ethyl acetate (300mL multiplied by 3), organic phases are combined, the mixture is washed by saturated saline (300mL multiplied by 1), anhydrous sodium sulfate is dried and filtered, the filtrate is concentrated to be dry under reduced pressure, 500mL of n-hexane is added into the residual liquid for pulping, filtering and drying are carried out, 51.1g of a solid product VP1 is obtained, and the yield is 88%.
Step two, preparation of VP 2:
a500 mL reaction flask was charged with intermediate VP1(51.1g, 59mmol, 1.0eq)5.1g palladium on charcoal and 300mL methanol, stirred, replaced with nitrogen, then reacted with hydrogen, warmed to 35-40 deg.C, and monitored by TLC. After the reaction is finished, cooling to room temperature, carrying out suction filtration, recovering a filter cake, sealing with water, storing, concentrating the filtrate under reduced pressure until the filtrate is dried, and drying to obtain 41g of a solid product VP2 with the yield of 95%.
Step three, preparation of VP 3:
a1000 mL reaction flask was charged with intermediate VP2(41g, 56mmol, 1.0eq), ammonium acetate (21.5g, 280mmol, 5.0eq) and 400mL ethylene glycol ethyl ether, stirred, warmed to 100 ℃ and 105 ℃ for reaction, and monitored by TLC. After the reaction is finished, cooling to 30-35 ℃, adding 300mL of water for quenching, stirring, separating an organic phase, extracting a water layer by using toluene (200mL multiplied by 3), combining the organic phases, washing by using saturated saline (200mL multiplied by 1), drying by using anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate under reduced pressure to dryness, adding 500mL of n-hexane into a residual solution, pulping, performing suction filtration, and drying to obtain 33.3g of a solid product VP3 with the yield of 86%.
Step four, preparation of VP 4:
a1000 mL reaction flask was charged with intermediate VP3(33.3g, 48mmol, 1.0eq), intermediate VPM4(13g, 63mmol, 1.3eq) and 300mL dichloromethane, stirred to dissolve, and then added with CDI (13.9g, 86mmol, 1.8eq) and HOBt (11.6g, 86mmol, 1.8eq), heated to 30-35 deg.C for reaction, and monitored by TLC for reaction. After the reaction, 200mL of 10% acetic acid aqueous solution and 300mL of dichloromethane are added, stirring is carried out for 30min, layers are separated, an organic phase is taken out, the organic phase is respectively washed by saturated sodium bicarbonate aqueous solution (200mL multiplied by 1) and saturated sodium chloride aqueous solution (200mL multiplied by 1), anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is decompressed and concentrated to obtain a solid crude product. The crude product was recrystallized from 300mL of ethyl acetate and n-hexane (2:1) to yield 36.2g of VP4 as a solid product. Yield: 85 percent.
Step five, preparing Velpatasvir:
under the protection of nitrogen, intermediate VP4(36.2g, 40mmol, 1.0eq) and 300mL of tetrahydrofuran were added to a 1000mL reaction flask, stirred to dissolve, cooled to 0-5 ℃, glacial acetic acid was added, and 150mL of tetrachlorobenzoquinone tetrahydrofuran solution (24.6g, 100mmol, 2.5eq) was added dropwise. After the addition, the reaction was carried out at 0-5 ℃ and monitored by TLC. After the reaction is finished, dropwise adding 10% sodium hydroxide solution to adjust the pH to be nearly neutral, adding 200mL of water and 400mL of dichloromethane, stirring, standing and layering; the aqueous layer was extracted with dichloromethane (200 mL. times.3), the organic phases were combined, washed with saturated aqueous sodium chloride (300 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude solid. The crude product was recrystallized from 300mL of isopropanol and water (2:1) to yield 32.5g of Velpatasvir as a solid product. Yield: 90 percent.
Example 3:
the synthetic route is as follows:
step one, preparation of VP 1:
9-bromo-3- (2-bromoacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one (VPM1) (15g, 33mmol, 1.0eq), (2S,4S) -1- (benzoyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid (VPM2) (9.2g, 35mmol, 1.05eq), cesium carbonate (23.3g, 66mmol, 2.0eq), and 200mL tetrahydrofuran were stirred at room temperature, warmed to 50-55 deg.C for reaction, and monitored by TLC. TLC showed that the starting material VPM2 remained below 2%, cooled to 30-35 deg.C, and then 80mL of VPM3 in tetrahydrofuran (10g, 35mmol, 1.05eq) was added dropwise. After the dripping is finished, the temperature is raised to 50-55 ℃ for reaction, and the reaction is monitored by TLC. After the reaction, the mixture was cooled to room temperature, 300mL of water and 400mL of ethyl acetate were added, the mixture was stirred, and the mixture was allowed to stand for liquid separation, the aqueous layer was extracted with ethyl acetate (150 mL. times.3), the organic phases were combined, washed with saturated brine (200 mL. times.1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, 300mL of n-heptane was added to the residue, and the mixture was slurried, filtered, and dried to obtain 24.2g of VP1 as a solid product with a yield of 86%.
Step two, preparation of VP 2:
intermediate VP1(24.2g, 29mmol, 1.0eq) and 200mL of methanol were added to a 500mL reaction flask, dissolved with stirring, cooled to 0-5 deg.C, and 145mL of a 2N hydrochloric acid solution (290mmol, 10.0eq) was added slowly. After the addition, the temperature is raised to 20-25 ℃ for reaction, and the reaction is monitored by TLC. After the reaction is finished, the solvent is evaporated under reduced pressure, 200mL of methyl tert-ether is added into the residue for pulping, suction filtration and drying to obtain 19.1g of a solid product VP2 with the yield of 90%.
Step three, preparation of VP 3:
a500 mL reaction flask was charged with intermediate VP2(19.1g, 26mmol, 1.0eq), ammonium formate (6.6g, 104mmol, 4.0eq) and 200mL ethylene glycol methyl ether, stirred, warmed to 100 ℃ and 105 ℃ for reaction, and monitored by TLC. After the reaction is finished, cooling to 30-35 ℃, adding 150mL of water for quenching, stirring, separating an organic phase, extracting a water layer by using toluene (100mL multiplied by 3), combining the organic phases, washing by using saturated saline (150mL multiplied by 1), drying by using anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate to be dry under reduced pressure, adding 150mL of n-heptane into a residual solution for pulping, performing suction filtration, and drying to obtain 15.3g of a solid product VP3 with the yield of 85%.
Step four, preparation of VP 4:
a500 mL reaction flask was charged with intermediate VP3(15.3g, 22mmol, 1.0eq), intermediate VPM4(6.9g, 33mmol, 1.5eq) and 200mL dichloromethane, stirred to dissolve, DCC (8.2g, 40mmol, 1.8eq) and HOBt (5.4g, 40mmol, 1.8eq) were added, the temperature was raised to 30-35 ℃ for reaction, and the reaction was monitored by TLC. After the reaction, 80mL of 10% acetic acid aqueous solution and 200mL of dichloromethane are added, stirring is carried out for 30min, layers are separated, an organic phase is taken out, the organic phase is respectively washed by saturated sodium bicarbonate aqueous solution (100mL multiplied by 1) and saturated sodium chloride aqueous solution (100mL multiplied by 1), anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is decompressed and concentrated to obtain a solid crude product. The crude product was recrystallized from 150mL of ethyl acetate and n-hexane (2:1) to yield 17.2g of VP4 as a solid product. Yield: 88 percent.
Step five, preparing Velpatasvir:
under the protection of nitrogen, intermediate VP4(17.2g, 19mmol, 1.0eq) and 200mL of tetrahydrofuran were added to a 500mL reaction flask, stirred to dissolve, cooled to 0-5 deg.C, glacial acetic acid was added, and 50mL of DDQ solution in tetrahydrofuran (8.6g, 38mmol, 2.0eq) was added dropwise. After the addition, the reaction was carried out at 0-5 ℃ and monitored by TLC. After the reaction is finished, dropwise adding 10% sodium hydroxide solution to adjust the pH to be nearly neutral, adding 100mL of water and 300mL of dichloromethane, stirring, standing and layering; the aqueous layer was extracted with dichloromethane (150 mL. times.3), the organic phases were combined, washed with saturated aqueous sodium chloride (150 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude solid. The crude product was recrystallized from 150mL of isopropanol and water (2:1) to give 15.1g of Velpatasvir as a solid product. Yield: 88 percent.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. However, the above description is only an example of the present invention, the technical features of the present invention are not limited thereto, and any other embodiments that can be obtained by those skilled in the art without departing from the technical solution of the present invention should be covered by the claims of the present invention.
Claims (10)
2. The method for preparing NS5A inhibitor, wipatasvir, according to claim 1, wherein the specific synthetic steps are:
1) preparation of intermediate VP 1: carrying out butt-joint reaction on reaction starting raw materials VPM1, VPM2 and VPM3 under the catalytic action of an alkali reagent to prepare an intermediate VP 1;
2) preparation of intermediate VP 2: removing amino protecting groups from the intermediate VP1 by a deprotection reagent to obtain an intermediate VP 2;
3) preparation of intermediate VP 3: intermediate VP2 and amine compound are cyclized to prepare intermediate VP 3;
4) preparation of intermediate VP 4: the intermediate VP3 reacts with (R) -2- (methoxycarbonylamino) -2-phenylacetic acid under the action of a condensing agent to prepare an amide compound intermediate VP 4;
5) and carrying out oxidation reaction on the intermediate VP4 under the action of an oxidant to prepare Velpatasvir.
3. The method of claim 2, wherein in step 1, VPM1 is selected from the group consisting of 9-bromo-3- (2-bromoacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one, 9-bromo-3- (2-chloroacetyl) -10, 11-dihydro-5H-benzo [ D ] naphtho [2,3-B ] pyran-8 (9H) -one; the selection range of VPM2 includes (2S,4S) -1- (tert-butoxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid, (2S,4S) -1- (benzyloxycarbonyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid and (2S,4S) -1- (benzoyl) -4- (methoxymethyl) -pyrrolidine-2-carboxylic acid.
4. The method for preparing NS5A inhibitor-vipatavir as claimed in claim 2, wherein VPM1, VPM2 and VPM3 are fed in a molar ratio of: 1:1.02: 1.02-1: 1.05: 1.05.
5. The method of claim 2, wherein in step 1, the base reagent is selected from the group consisting of sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide; the feeding molar ratio of the alkali reagent to the VPM1 is as follows: 2:1 to 3: 1.
6. The method of claim 2, wherein in step 2, the deprotecting reagent is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, sodium methoxide, sodium ethoxide, ammonia methanol, palladium on charcoal/hydrogen.
7. The method for preparing NS5A inhibitor wiepatasvir as claimed in claim 6, wherein when the deprotecting reagent is other than palladium on carbon, the molar ratio of deprotecting reagent to VP1 is: 1.05: 1-10.0: 1; when the deprotection reagent is palladium carbon, the mass of the palladium carbon is 10% of the mass of the substrate.
8. The method of claim 2, wherein in step 3, the amine compound is selected from the group consisting of ammonium carbonate, ammonium formate, ammonium acetate, ammonium propionate; the feeding molar ratio of the amine compound to the VP2 is as follows: 3.0:1 to 5.0: 1.
9. The process of claim 2, wherein in step 4, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N '-carbonyldiimidazole or a combination of N, N' -dicyclohexylcarbodiimide and 1-hydroxybenzotriazole; the charging molar ratio of VP3, VPM4 and the condensing agent is as follows: 1.0:1.1: 1.5-1.0: 1.5: 1.8.
10. The method of claim 2, wherein in step 5, the oxidizing agent is selected from the group consisting of dichlorodicyanoquinone, tetrachlorobenzoquinone; the feeding molar ratio of the intermediate VP4 to the oxidant is as follows: 1.0: 1.5-1.0: 2.5.
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CN113072615A (en) * | 2021-03-24 | 2021-07-06 | 上海法默生物科技有限公司 | Preparation method of vipatavir intermediate |
CN113072615B (en) * | 2021-03-24 | 2023-01-10 | 上海法默生物科技有限公司 | Preparation method of vipatavir intermediate |
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