CN107805256B - Wipatasvir intermediate, preparation method and application - Google Patents

Wipatasvir intermediate, preparation method and application Download PDF

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CN107805256B
CN107805256B CN201710917345.7A CN201710917345A CN107805256B CN 107805256 B CN107805256 B CN 107805256B CN 201710917345 A CN201710917345 A CN 201710917345A CN 107805256 B CN107805256 B CN 107805256B
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CN107805256A (en
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应述欢
皮红军
公绪栋
于冲冲
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Shanghai Yunshengyan Neoplasm Technology Co ltd
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Shanghai Bocimed Pharmaceutical Co Ltd
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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
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a vipatavir intermediate, a preparation method and application thereof. The invention provides a compound 5The preparation method comprises the following steps: and under the protection of protective gas, carrying out condensation reaction on the compound 15 and ammonium salt in an organic solvent to obtain the compound 5. The preparation method disclosed by the invention is mild in reaction conditions, simple and safe in operation, free of special purification equipment, free of column chromatography separation operation in a post-treatment process, and easy in control of chiral isomers, the yield of the preparation of the vipatavir by taking the compound 15 disclosed by the invention as an intermediate is high, the chemical and optical purity of the prepared vipatavir is more than 99.50%, all impurities are less than 0.10%, the drug substance standard can be achieved, the cost is low, and the preparation method is suitable for industrial production.

Description

Wipatasvir intermediate, preparation method and application
Technical Field
The invention relates to a vipatavir intermediate, a preparation method and application thereof.
Background
Another anti-hepatitis C virus drug Epclusa (Sofosbuvir 400mg + Velpatasvir 100mg) was approved by Gilidd scientific at 2016 (6 months) and the first anti-hepatitis C drug was used to treat the major genotype 1-6. Is known as the third generation anti-hepatitis C heavy explosive after searching for non-Buwei and Harvoni.
The 2016 10-month Jilide science company announced 4 global clinical research results in that the three-in-one tablet of sofosbuvir, vipatavir (Velpatasvir) and Voxilaprevir has obvious curative effect on the patients with gene 1-6 type HCV infection. The novel compound drug for resisting hepatitis C, which takes Velpatasvir as a compound drug, is approved by FDA to be on the market in 7 months in 2017, has drug names Vosevi and Vosevi, can quickly become a star drug in the field of resisting hepatitis C, and has wide market prospect.
US20150361073 of gillidd science discloses a preparation method of vipatavir (Velpatasvir or GS5816), which has weak fluorescence of raw materials, and is difficult to control chirality in a synthesis process, so that an intermediate with high chiral purity is difficult to obtain, and further, API preparation cost is high and difficulty is high.
Figure BDA0001426055360000021
Therefore, the problem to be solved at present is to find a preparation method of Velpatasvir (Velpatasvir or GS5816) which is convenient for controlling chiral isomers in the reaction process, high in chiral purity and chemical purity of the prepared product, high in total yield, simple and convenient to operate, low in production cost and suitable for industrial production, and meets the standards of raw material medicines.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, chiral isomers are difficult to control in the reaction process of a preparation method of wipatasvir (Velpatasvir or GS5816), the obtained product has poor chiral purity which cannot reach the standard of raw material medicines, the total yield is low, the production cost is high, and the preparation method and application of the intermediate are provided for overcoming the defects that the industrial production is not suitable and the like. The preparation method disclosed by the invention is mild in reaction conditions, short in steps, high in yield, high in purity of the prepared product, low in production cost and suitable for industrial production, and can reach the standard of raw material medicines (API).
A method of preparing compound 5, comprising the steps of: under the protection of protective gas, carrying out condensation reaction on a compound 15 and ammonium salt in an organic solvent to obtain a compound 5;
Figure BDA0001426055360000022
p is an amino protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz) or P-toluenesulfonyl (Tosyl).
The preparation method of the compound 5 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 5, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 5, the organic solvent is preferably an aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent is preferably toluene.
In the method for producing the compound 5, the ammonium salt is an ionic compound formed by an ammonium ion and an acid ion generated by reacting ammonia with an acid. The ammonium salt is preferably one or more of ammonium acetate, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate.
In the preparation method of the compound 5, the molar ratio of the ammonium salt to the compound 15 is preferably 1 to 40, more preferably 15 to 25, for example 20.
In the method for producing the compound 5, the condensation reaction temperature is preferably 50 to 120 ℃, more preferably 60 to 110 ℃, for example 80 to 100 ℃.
In the method for preparing the compound 5, the progress of the condensation reaction can be monitored by a conventional monitoring method in the art (for example, TLC, HPLC, or NMR), and is generally the end point of the reaction when the compound 15 and the intermediate state disappear, and the time of the condensation reaction is preferably 5 hours to 24 hours, more preferably 15 hours to 22 hours, for example 20 hours.
The preparation method of the compound 5 can adopt the following post-treatment steps: and after the reaction is finished, adding an alcohol solvent, washing and removing the solvent to obtain the purified compound 5. The alcohol solvent is preferably n-butanol. The washing and removal of the solvent may be carried out by methods conventional in the art for such procedures. The washing is preferably carried out with water and/or a saturated aqueous sodium chloride solution. The solvent removal is preferably carried out by distillation under reduced pressure.
Said process for the preparation of compound 5 further preferably comprises a process for the preparation of compound 15 comprising the steps of: under the protection of protective gas, in an organic solvent and in the presence of alkali, carrying out nucleophilic substitution reaction on a compound 16 and a compound 7 to obtain a compound 15;
Figure BDA0001426055360000041
wherein, the definition of P is the same as that of the previous description; l represents a leaving group, e.g., p-toluenesulfonyl (Tos), methanesulfonyl (-OMs), trifluoromethanesulfonyl (-OSO)2CF3) Br, Cl or I.
The preparation method of the compound 15 can be a conventional method of nucleophilic substitution reaction in the field, and the following reaction conditions are particularly preferred in the invention:
in the preparation method of the compound 15, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 15, the organic solvent is preferably an amide solvent, and the amide solvent is preferably N, N-Dimethylformamide (DMF).
In the preparation method of the compound 15, the base is preferably an inorganic base, and the inorganic base is preferably potassium carbonate.
In the method for preparing the compound 15, the molar ratio of the base to the compound 16 is preferably 1.00 to 3.00, more preferably 1.00 to 1.50, for example, 1.05.
In the preparation method of the compound 15, the molar ratio of the compound 7 to the compound 16 is preferably 1.00 to 3.00, more preferably 1.00 to 1.50, for example, 1.05.
In the method for producing the compound 15, the temperature of the nucleophilic substitution reaction is preferably 10 to 60 ℃, and more preferably 20 to 40 ℃.
In the preparation method of the compound 15, the progress of the nucleophilic substitution reaction can be monitored by a conventional monitoring method in the art (such as HPLC, TLC or NMR), and generally the disappearance of the compound 16 is taken as a reaction end point, and the time of the nucleophilic substitution reaction is preferably 10 hours to 30 hours, more preferably 12 hours to 20 hours, such as 16 hours.
In the process for the preparation of compound 15, the following work-up steps are preferably employed: after the reaction is finished, cooling, adding water, stirring, filtering and drying to obtain the compound 15. The temperature reduction is preferably to a temperature of-5 ℃ to 10 ℃, for example 5 ℃ to 10 ℃. The water is preferably added dropwise, and the dropwise adding speed is based on the system temperature not exceeding 10 ℃. The stirring, filtration and drying can be carried out by methods conventional in the art for such procedures.
Said process for the preparation of compound 5 further preferably comprises a process for the preparation of compound 16, comprising the steps of: in an organic solvent, carrying out substitution reaction on the compound 17 and a halogenated reagent to obtain the compound 16;
Figure BDA0001426055360000051
wherein L is as defined above; the halogenating reagent is p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, tribromopyridine, trichloropyridine or triiodopyridine.
The preparation method of the compound 16 can be a conventional method of the substitution reaction in the field, and the following reaction conditions are particularly preferred in the invention:
in the preparation method of the compound 16, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method for preparing the compound 16, the molar ratio of the halogenating agent to the compound 17 is preferably 1 to 3, more preferably 1.1 to 1.5, for example 1.1.
In the preparation method of the compound 16, when tribromopyridine is used as a halogenating reagent, the tribromopyridine can be a commercially available tribromopyridine reagent conventional in the art, such as a methanol solution of tribromopyridine.
In the method for producing compound 16, the temperature of the substitution reaction is preferably 0 to 40 ℃, and more preferably 10 to 15 ℃.
In the preparation method of compound 16, the progress of the substitution reaction can be monitored by a detection method (such as HPLC, TLC or NMR) which is conventional in the art, and generally the disappearance of compound 17 is taken as a reaction end point, and the time of the substitution reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 5 hours, for example 3 hours.
The preparation method of the compound 16 preferably adopts the following steps: and (3) dropwise adding a halogenated reagent into a mixed solution formed by the compound 17 and an organic solvent at 0-5 ℃ to perform substitution reaction to obtain the compound 16.
In the preparation method of the compound 16, the following post-treatment steps are preferably adopted: after the reaction is finished, the compound 16 is obtained by filtering, washing and drying. The filtration, washing and drying can be carried out by methods conventional in the art for such procedures. The washing is preferably performed by using an alcohol solvent, and the alcohol solvent is preferably methanol.
Said process for the preparation of compound 5 further preferably comprises a process for the preparation of compound 17, comprising the steps of: under the protection of protective gas, carrying out condensation reaction on the compound 12 and ammonium salt in an organic solvent to obtain a compound 17;
Figure BDA0001426055360000061
the preparation method of the compound 17 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 17, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 17, the organic solvent is preferably an aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent is preferably toluene.
In the preparation method of the compound 17, the ammonium salt is an ionic compound formed by an ammonium ion and an acid radical ion generated by the reaction of ammonia and acid. The ammonium salt is preferably one or more of ammonium acetate, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate.
In the preparation method of the compound 17, the molar ratio of the ammonium salt to the compound 12 is preferably 1 to 40, more preferably 15 to 25, for example 20.
In the method for producing the compound 17, the condensation reaction is preferably carried out at a temperature of 50 to 120 ℃ such as 80 to 100 ℃.
In the preparation method of compound 17, the progress of the condensation reaction can be monitored by a conventional detection method in the art (e.g., TLC, HPLC, or NMR), and is generally the end point of the reaction when compound 12 and the intermediate state disappear, and the time of the condensation reaction is preferably 5 hours to 24 hours, more preferably 15 hours to 22 hours, e.g., 20 hours.
The preparation method of the compound 17 can adopt the following post-treatment steps: after the reaction is finished, adding an alcohol solvent, washing and removing the solvent to obtain the purified compound 17. The alcohol solvent is preferably n-butanol. The washing and removal of the solvent may be carried out by methods conventional in the art for such procedures. The washing is preferably carried out with water and/or a saturated aqueous sodium chloride solution. The solvent removal is preferably carried out by distillation under reduced pressure.
Said process for the preparation of compound 5 further preferably comprises a process for the preparation of compound 12 comprising the steps of: in an organic solvent, in the presence of a condensing agent, carrying out a condensation reaction on a compound 13 and a compound 9 to obtain a compound 12;
Figure BDA0001426055360000071
the preparation method of the compound 12 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 12, the organic solvent is preferably an amide solvent; the amide solvent is preferably N, N-Dimethylformamide (DMF).
In the preparation method of the compound 12, the condensing agent is preferably 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), benzotriazol-NN, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (BOP), chlorotriazolylphosphonium hexafluorophosphate (PyClOP), benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBOP), N, N ' -Dicyclohexylcarbodiimide (DCC), (2-oximo-cyanoethyl acetate) -N, N-dimethyl-morpholinyluronium hexafluorophosphate (COMU), ethyl 2-oxime cyanoacetate (Oxyma) and propylphosphoric anhydride (T-Bu)3P) is selected. Said propyl phosphoric anhydride (T)3P) may be conventional commercially available propyl phosphoric anhydride (T)3P) reagent, e.g. propylphosphoric anhydride (T) at 50% by mass3P) N, N-Dimethylformamide (DMF) solution, wherein the mass concentration refers to the mass percentage of the propyl phosphoric anhydride to the total mass of the propyl phosphoric anhydride N, N-dimethylformamide solution.
In the method for preparing the compound 12, the molar ratio of the condensing agent to the compound 13 is preferably 1 to 3, more preferably 1 to 1.5, for example, 1.1.
In the preparation method of the compound 12, the molar ratio of the compound 9 to the compound 13 is preferably 1 to 3, more preferably 1 to 1.5, for example 1.1.
In the method for producing compound 12, the condensation reaction temperature is preferably 0 to 40 ℃, more preferably 10 to 30 ℃, for example, 20 to 25 ℃.
In the method for preparing the compound 12, the progress of the condensation reaction can be monitored by a detection method (for example, HPLC, TLC or NMR) which is conventional in the art, and generally the time when the compound 13 disappears is used as the end point of the reaction, and the time of the condensation reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 8 hours, for example 5 hours to 6 hours.
The preparation method of the compound 12 preferably adopts the following steps: and (2) dripping a mixture formed by the compound 10 and the organic solvent into a mixture formed by the compound 9, the condensing agent and the organic solvent at 0-10 ℃ to perform condensation reaction to obtain the compound 12.
The preparation method of the compound 12 preferably adopts the following post-treatment steps: after the reaction is finished, cooling, dripping water, stirring, filtering and washing to obtain the compound 12. The temperature reduction is preferably carried out to 5-10 ℃. The stirring is preferably carried out for 2 to 3 hours.
Said process for the preparation of compound 5 further preferably comprises a process for the preparation of compound 13, comprising the steps of: in an organic solvent, carrying out a reaction of removing an amino protecting group on the compound 14 and an acid to prepare the compound 13;
Figure BDA0001426055360000081
wherein P is as defined above.
The preparation method of the compound 13 can be a conventional method of the reaction for removing the amino protecting group in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 13, the organic solvent is preferably an ester solvent; the ester solvent is preferably isopropyl acetate.
In the preparation method of the compound 13, the acid is preferably an inorganic acid; the inorganic acid is preferably hydrogen chloride. The hydrogen chloride may be used in gaseous form or as a solution thereof, preferably as a solution of hydrogen chloride in isopropyl acetate.
In the preparation method of the compound 13, the molar ratio of the acid to the compound 14 is preferably 1 to 10, more preferably 4 to 6, for example 5.
In the method for producing compound 13, the reaction temperature for removing the amino protecting group is preferably 40 to 100 ℃, more preferably 50 to 70 ℃, for example, 60 to 65 ℃.
In the preparation method of compound 13, the progress of the amino protecting group removing reaction can be monitored by a conventional detection method in the art (e.g., HPLC, TLC or NMR), and generally, the end point of the reaction is the time when compound 14 disappears, and the time of the amino protecting group removing reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 8 hours, for example 2 hours to 6 hours.
Said process for the preparation of compound 5 further preferably comprises a process for the preparation of compound 14 comprising the steps of: under the protection of protective gas, in an organic solvent and in the presence of alkali, carrying out condensation reaction on a compound 25 and a compound 24 to obtain the compound 14;
Figure BDA0001426055360000091
wherein P is as defined above.
The preparation method of the compound 14 can be a conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 14, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 14, the organic solvent is preferably an amide solvent; the amide solvent is preferably N, N-Dimethylformamide (DMF).
In the preparation method of the compound 14, the base is preferably an inorganic base; the inorganic base is preferably potassium carbonate.
In the preparation method of the compound 14, the molar ratio of the base to the compound 25 is preferably 1 to 3, more preferably 1 to 1.5, for example, 1.05.
In the preparation method of the compound 14, the molar ratio of the compound 24 to the compound 25 is preferably 1 to 3, more preferably 1 to 1.5, for example, 1.05.
In the method for producing compound 14, the condensation reaction temperature is preferably 10 to 50 ℃, and more preferably 20 to 40 ℃.
In the preparation method of the compound 14, the progress of the condensation reaction can be monitored by a detection method (for example, HPLC, TLC or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound 25 disappears, and the time of the condensation reaction is preferably 1 hour to 5 hours, more preferably 2 hours to 4 hours, for example 3 hours.
The invention also provides a preparation method of the compound 4, which comprises the following steps: after the compound 5 is prepared according to the preparation method, the compound 5 and an oxidant are subjected to oxidation reaction in an organic solvent under the protection of protective gas to obtain a compound 4;
Figure BDA0001426055360000101
p is as defined above.
The preparation method of the compound 4 can be a conventional method of the oxidation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound 4, the protective gas is preferably nitrogen and/or argon.
In the preparation method of the compound 4, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method for preparing the compound 4, the oxidizing agent is preferably manganese dioxide, dichlorodicyanoquinone (DDQ), chloranil, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) and Pd/Al2O3/O2One or more of (a). The manganese dioxide is preferably active manganese dioxide which is currently used. The preparation method of the manganese dioxide can adopt a conventional preparation method in the field.
In the preparation method of the compound 4, the molar ratio of the oxidant to the compound 5 is preferably 1 to 20, more preferably 5 to 15, for example 10.
In the method for producing the compound 4, the temperature of the oxidation reaction is preferably 0 to 40 ℃, more preferably 1 to 20 ℃, for example, 5 to 10 ℃.
In the preparation method of the compound 4, the progress of the oxidation reaction can be monitored by a detection method (such as TLC, HPLC or NMR) which is conventional in the art, and generally the time when the compound 5 disappears is taken as the end point of the reaction, and the time of the oxidation reaction is preferably 5 hours to 24 hours, such as 10 hours to 15 hours.
The preparation method of the compound 4 preferably adopts the following post-treatment steps: after the reaction is finished, adding diatomite into the reaction solution, stirring, filtering, removing the solvent, then adding the ether solvent and the inorganic alkaline water solution, refluxing, filtering, removing part of the solvent, adding seed crystals, and crystallizing to obtain the compound 4. The stirring, filtration and removal of the solvent can be carried out by methods conventional in the art for such procedures. The ether solvent may be methyl t-butyl ether. The inorganic base is preferably sodium hydroxide or potassium hydroxide. The mass concentration of the aqueous inorganic alkali solution is preferably 5% to 40%, more preferably 5% to 15%, for example 10%, and the mass concentration is a percentage of the mass of the inorganic alkali to the total mass of the aqueous inorganic alkali solution. The term "removing part of the solvent" means that the ratio of the volume of the removed solvent to the total volume of the solvent in the filtrate is 0.2-0.7. The temperature of the crystallization is preferably 0-20 ℃. Preferably, after partial solvent is removed, adding an adverse solvent for crystallization; the poor solvent is preferably an alkane solvent, and the alkane solvent is preferably n-heptane.
The invention also provides a preparation method of the compound 3, which comprises the following steps: after the compound 4 is prepared according to the preparation method, the compound 4 and acid are subjected to deamination protecting group reaction to obtain the compound 3;
Figure BDA0001426055360000111
wherein P is an amino protecting group such as t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz) or P-toluenesulfonyl (Tosyl).
The preparation method of the compound 3 can be a conventional method for the deamination protecting group reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
the preparation method of the compound 3 can be carried out in a solvent or under the condition of no solvent; when carried out in a solvent, the solvent is preferably one or more of an alcohol solvent, a halogenated hydrocarbon solvent and an ether solvent. The alcohol solvent is preferably methanol. The halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The ether solvent is preferably tetrahydrofuran.
In the preparation method of the compound 3, the acid can be an organic acid or an inorganic acid. The organic acid is preferably one or more of trifluoromethanesulfonic acid, benzenesulfonic acid and methanesulfonic acid. The inorganic acid is preferably hydrochloric acid and/or sulfuric acid. The hydrochloric acid can be a conventional commercially available hydrochloric acid reagent, the mass concentration of the hydrochloric acid can be 20-37%, and the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the hydrochloric acid solution.
In the preparation method of the compound 3, the molar ratio of the acid to the compound 4 is preferably 1 to 20, more preferably 5 to 15, for example 10.
In the method for producing the compound 3, the reaction temperature of the deamination protecting group is preferably 40 to 70 ℃, for example, 60 to 65 ℃.
In the preparation method of the compound 3, the progress of the reaction of the deamination protecting group can be monitored by a conventional detection method in the field (such as TLC, HPLC or NMR), and generally the end point of the reaction is the time when the compound 4 disappears, and the reaction time of the deamination protecting group is preferably 1 to 10 hours, such as 2 to 6 hours.
The preparation method of the compound 3 preferably adopts the following post-treatment steps: and after the reaction is finished, adding a solvent, stirring, filtering, suspending the solid in an organic solvent, adjusting the pH to 11-12, washing, and removing the solvent to obtain the purified compound 3. The solvent is preferably an ether solvent, and the ether solvent is preferably methyl tert-butyl ether. The organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The pH is preferably adjusted by using an organic base; the organic base is preferably ammonia. The ammonia water can be a conventional commercial ammonia water reagent in the field, the mass concentration of the ammonia water can be 5% -25%, and the mass concentration refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution. The washing and removal of the solvent may be carried out by methods conventional in the art for such procedures. The washing is preferably carried out with water and/or a saturated aqueous sodium chloride solution. The solvent removal is preferably carried out by distillation under reduced pressure.
The invention also provides a preparation method of the vipatavir 1, which comprises the following steps: after the compound 3 is prepared according to the preparation method, the compound 3 and MOC-L-valine are subjected to condensation reaction in an organic solvent in the presence of alkali, a catalyst and a condensing agent to obtain the wipatavir 1;
Figure BDA0001426055360000131
the preparation method of the vipatavir 1 can be a conventional method in the field of condensation reaction, and the following reaction methods and conditions are particularly preferred in the invention:
in the preparation method of the wipatavir 1, the organic solvent is preferably a polar organic solvent; the polar organic solvent is preferably one or more of a nitrile solvent, an amide solvent and an ether solvent. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-Dimethylformamide (DMF). The ethereal solvent is preferably Tetrahydrofuran (THF).
In the preparation method of the vipetavir 1, the catalyst is preferably 1-hydroxybenzotriazole (HOBt).
In the preparation method of the vipetavir 1, the molar ratio of the catalyst to the compound 3 is preferably 1 to 5, more preferably 2 to 4, for example 2.6.
In the preparation method of the vipatavir 1, the condensing agent is preferably 1-ethyl- (3-di-ethyl)Methylaminopropyl) carbonyl diimine hydrochloride (EDCI), 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-tris (trimethylamino) -trifluorophosphate (BOP), chlorotris-azolidinylphosphonium hexafluorophosphate (PyClOP), benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyP), BOP N, N ' -Dicyclohexylcarbodiimide (DCC), (2-oximidoethyl cyanoacetate) -N, N-dimethyl-morpholinyluronium hexafluorophosphate (COMU), 2-Oxime Ethylcyanoacetate (Oxyma) and propylphosphoric anhydride (T)3P) is selected.
In the preparation method of the vipetavir 1, the molar ratio of the condensing agent to the compound 3 is preferably 1 to 5, more preferably 2 to 4, for example 2.5.
In the preparation method of the vipetavir 1, the base is preferably an organic base; the organic base is preferably N, N-Diisopropylethylamine (DIPEA) and/or triethylamine.
In the preparation method of wipatavir 1, the molar ratio of the base to the compound 3 is preferably 1 to 5, more preferably 2 to 4, such as 3.5.
In the preparation method of wipatavir 1, the condensation reaction temperature is preferably-5 ℃ to 30 ℃, more preferably 0 ℃ to 20 ℃, for example 0 ℃ to 15 ℃.
In the preparation method of vipetavir 1, the progress of the condensation reaction may be monitored by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and is generally the end point of the reaction when compound 3 disappears, and the time of the condensation reaction is preferably 5 hours to 24 hours, more preferably 10 hours to 20 hours, e.g., 12 hours to 16 hours.
The preparation method of the vipetavir 1 preferably adopts the following reaction steps: and (3) sequentially adding the compound 3 and alkali into a mixture formed by MOC-L-valine, a catalyst, a condensing agent and an organic solvent, and carrying out condensation reaction to obtain the wipatavir 1.
The preparation method of the vipetavir 1 can adopt the following post-treatment steps: and after the reaction is finished, extracting, filtering, washing and removing the solvent to obtain the purified wipatavir 1. The extraction, filtration, washing and removal of the solvent can be carried out by methods conventional in the art for such procedures. The solvent used for extraction can be isopropyl acetate and water. The washing may be performed by using an aqueous sodium hydroxide solution, a saturated aqueous sodium chloride solution and water in this order. The molar concentration of the sodium hydroxide aqueous solution can be 0.5mol/L (namely 0.5N); the molar concentration refers to the ratio of the molar weight of the sodium hydroxide to the total volume of the sodium hydroxide aqueous solution. The solvent removal can be carried out by distillation under reduced pressure.
The preparation method of the vipatavir 1 can adopt the following routes:
Figure BDA0001426055360000151
the invention also provides intermediate compounds 3, 4, 5, 12, 13, 14, 15, 16 and 17 for preparing the wipatavir 1, wherein the structural formula is shown as follows:
Figure BDA0001426055360000152
the invention also provides a preparation method of the intermediate compounds 3, 4, 5, 12, 13, 14, 15, 16 and 17 for preparing the wipatavir, and the reaction steps are the same as those described above.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method disclosed by the invention is mild in reaction conditions, simple and safe in operation, free of special purification equipment, high in yield (up to 67%) and suitable for industrial production, avoids column chromatography separation operation in a post-treatment process, and the vipetavir prepared by taking the compound 15 disclosed by the invention as an intermediate is high in purity (the chemical and optical purity is more than 99.50%, all impurities are less than 0.10%, and the purity can reach the raw material drug standard).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of Compound 14 (P is Boc)
Figure BDA0001426055360000161
Compound 25(1.96kg, 5.29mol,1.0eq) and compound 24(1.37kg, 1.05eq) were dissolved in N, N-Dimethylformamide (DMF), potassium carbonate (730.8g,1.05eq) was added, nitrogen was replaced three times in vacuo, and the mixture was heated to 20-40 ℃ and stirred for 3 hours. TLC showed complete reaction of compound 25. Cooling to 5-10 deg.C, dropping water, 5-10 deg.C, stirring for 2-3 hr, filtering, washing filter cake with water, and drying to obtain 2.85kg of compound 14 with yield 98.0% and HPLC purity 98.56%.
EXAMPLE 2 preparation of Compound 13 (P is Boc, i.e.t-butyloxycarbonyl)
Figure BDA0001426055360000171
Dissolving compound 14(2.85kg, 5.18mol, 1eq) in isopropyl acetate, adding isopropyl acetate/hydrogen chloride (1.33L,5eq), heating under reflux (60-65 ℃), reacting for 2-6 hours, TLC shows complete reaction, cooling to room temperature, slowly dropping methyl tert-butyl ether, stirring at 0-10 ℃ for 2-5 hours after dropping, filtering, suspending the solid in dichloromethane, adding saturated sodium bicarbonate, stirring for 1 hour, filtering, washing the organic phase with water and saturated sodium chloride, concentrating and drying to obtain 2.21kg of compound 13, yield 95.0%, and HPLC purity 98.86%.
EXAMPLE 3 preparation of Compound 12
Figure BDA0001426055360000172
Compound 13(2.21kg,4.92mol,1.0eq) was dissolved in N, N-Dimethylformamide (DMF) for use.
Compound 9(1.3kg, 1.1eq) was added at a mass concentration of 50% propyl phosphoric anhydride (T)3P) N, N-Dimethylformamide (DMF) solution (5.02kg,1.1eq) (the mass concentration refers to the mass percentage of the propyl phosphoric anhydride to the total mass of the propyl phosphoric anhydride N, N-dimethylformamide solution), dissolving in DMF, reducing to 0-10 ℃, dropping the prepared solution, stirring for 5-6 hours at 20-25 ℃, TLC shows that the compound 13 is completely reacted, reducing to 5-10 ℃, dropping water, 5-10 ℃, stirring for 2-3 hours, filtering, washing a filter cake with water, and drying to obtain 3.06kg of the compound 12, wherein the yield is 97.0%, and the HPLC purity is 98.71%.
EXAMPLE 4 preparation of Compound 17
Figure BDA0001426055360000173
Compound 12(3.06kg, 4.77mol,1.0eq) was dissolved in toluene, ammonium acetate (7.40kg, 20eq) was added, nitrogen was vacuum-replaced three times, and the mixture was heated to 80-100 deg.C (external temperature) and stirred for 20 hours. TLC showed complete reaction, and was cooled to room temperature (20 ℃ -25 ℃). Adding n-butanol, washing with water and saturated brine, and concentrating to obtain 2.93kg of compound 17 with yield of 99.0% and HPLC purity of 98.95%.
EXAMPLE 5 preparation of Compound 16 (L is Br)
Figure BDA0001426055360000181
Compound 17(2.93kg, 4.72mol, 1.0eq) was dissolved in dichloromethane, and a solution of tribromopyridine (1.66kg, 1.1eq) in methanol was added under ice-cooling (0 ℃ C. -5 ℃ C.), stirred at 10 ℃ C. -15 ℃ C. for 3 hours, and TLC showed completion of the reaction. Filtering, leaching a filter cake with Dichloromethane (DCM), leaching with methanol, and drying at 50 ℃ to obtain 3.19kg of bright yellow solid compound 16 with the yield of 96.7 percent and the HPLC purity of 98.92 percent.
EXAMPLE 6 preparation of Compound 15 (P is Boc; L is Br)
Figure BDA0001426055360000182
Compound 16(3.19kg, 4.71mol,1.0eq) and compound 7(1.13kg, 1.05eq) were dissolved in N, N-Dimethylformamide (DMF), potassium carbonate (682.3g,1.05eq) was added, nitrogen was replaced three times in vacuo, and the mixture was heated to 20-40 ℃ and stirred for 16 hours. TLC showed compound 16 was completely reacted. Cooling to 5-10 deg.C, dropping water, 5-10 deg.C, stirring for 2-3 hr, filtering, washing filter cake with water, and drying to obtain 3.79kg of compound 15 with yield 95.0% and HPLC purity 98.57%.
EXAMPLE 7 preparation of Compound 5 (P is Boc)
Figure BDA0001426055360000183
Compound 6(2.25kg, 2.59mol,1.0eq) was dissolved in toluene, ammonium acetate (4.01kg, 20eq) was added, nitrogen was vacuum-replaced three times, and the mixture was heated to 80-100 deg.C (external temperature) and stirred for 20 hours. TLC shows complete reaction, the temperature is reduced to 20-25 ℃, n-butyl alcohol and organic phase are added, water and saturated saline are used for washing, and 2.13kg of compound 5 is obtained by concentration, the yield is 99.0%, and the HPLC purity is 98.87%.
EXAMPLE 8 preparation of Compound 5 (P is Boc)
Figure BDA0001426055360000191
Compound 15(3.79kg, 4.47mol,1.0eq) was dissolved in toluene, ammonium acetate (6.40kg, 20eq) was added, nitrogen was replaced three times in vacuo, and the mixture was heated to 80-100 deg.C (external temperature) and stirred for 20 hours. TLC showed complete reaction, and was cooled to room temperature (20 ℃ -25 ℃). Adding n-butanol, washing with water and saturated brine, and concentrating to obtain 3.63kg of compound 5 with yield 98.0% and HPLC purity 99.04%.
EXAMPLE 9 preparation of Compound 4 (P is Boc)
Figure BDA0001426055360000192
Adding a raw material compound 5(2.13kg,2.55mol,1.0eq) into dichloromethane, adding at 10-20 ℃, adding active manganese dioxide (2.22kg,10eq) under the protection of nitrogen, stirring at 15-20 ℃ for 10-15 hours, monitoring the complete reaction of the compound 5 by HPLC, adding diatomite into a reaction solution, stirring, filtering, leaching by dichloromethane, concentrating to dryness, adding methyl tert-butyl ether and 10% potassium hydroxide aqueous solution (the mass concentration refers to the mass percentage of potassium hydroxide in the total mass of the potassium hydroxide aqueous solution), refluxing at 60 ℃ overnight, filtering, concentrating the filtrate to a small volume (the ratio of the volume of the removed solvent to the total volume of the filtrate is 0.7), adding seed crystals, stirring for 2-3 hours, then dropwise adding n-heptane, stirring at 0-20 ℃ for 1-2 hours, filtering to obtain 2.05kg of a compound 4 with the yield of 99.29%, HPLC purity 99.15%.
EXAMPLE 10 preparation of Compound 4 (P is Boc)
Figure BDA0001426055360000201
Adding a raw material compound 5(3.63kg,4.38mol,1.0eq) into dichloromethane, adding at 10-20 ℃, adding activated manganese dioxide (3.81kg,10eq) under the protection of nitrogen, stirring at 5-10 ℃ for 10-15 hours, monitoring the complete reaction of the compound 5 by HPLC, adding diatomite into a reaction solution, stirring, filtering, leaching by dichloromethane, concentrating to dryness, adding methyl tert-butyl ether and 10% potassium hydroxide aqueous solution (the mass concentration refers to the mass percentage of potassium hydroxide in the total mass of the potassium hydroxide aqueous solution), refluxing at 60 ℃ overnight, filtering, concentrating the filtrate to a small volume (the ratio of the volume of the removed solvent to the total volume of the filtrate is 0.7), adding seed crystals, stirring for 2-3 hours, then dropwise adding n-heptane, stirring at 0-20 ℃ for 1-2 hours, filtering to obtain 3.62kg of a compound 4 with the yield of 90.0%, HPLC purity 99.30%.
Preparation of active manganese dioxide: weighing 20g of manganese sulfate, dissolving in 500mL of distilled water, adding 10mL of concentrated ammonia water, shaking up, adding 90mL of ammonium persulfate solution, stirring while adding, boiling for 10min, adding 1-2 drops of ammonia water, and standing until the solution is clear. And (3) carrying out suction filtration by using a Buchner funnel, washing for 10 times by using ammonia water, washing for 2-3 times by using hot water, washing for 12 times by using sulfuric acid, and finally washing by using hot water until no sulfuric acid reaction exists. Drying at 110 +/-5 ℃ for 3-4 h, and storing in a dryer for later use.
EXAMPLE 11 preparation of Compound 3 (P is Boc)
Figure BDA0001426055360000202
Dissolving compound 4(2.05kg, 2.45mol, 1.0eq) in methanol, adding trifluoromethanesulfonic acid (3.67kg, 10eq), heating under reflux (60 ℃ -65 ℃) for 2-6 hours, TLC shows that compound 4 is completely reacted, cooling to room temperature, slowly dropping methyl tert-butyl ether, stirring at 0-10 ℃ for 2-5 hours after dropping, filtering, suspending the solid in dichloromethane, adding ammonia water, adjusting pH to 11-12, stirring for 1 hour, filtering, washing the organic phase with water and saturated sodium chloride, and concentrating to obtain 1.66kg of compound 3, yield 93.5%, and HPLC purity 99.30%.
EXAMPLE 12 preparation of Wiepatasvir 1
Figure BDA0001426055360000211
MOC-L-valine (1.01kg 2.5eq), 1-hydroxybenzotriazole (HOBt) (0.84kg,2.6eq), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI) (1.1kg,2.5eq) and acetonitrile were added to the reaction vessel and stirred at 10-15 ℃ for 1 hour. Cooled to 0-10 ℃ and compound 3(1.66kg,2.29mol, 1eq) was added followed by dropwise addition of N, N-Diisopropylethylamine (DIPEA) (1.18kg, 3.5 eq). Stirring for 12-16 hours at 0-15 ℃. TLC checked complete reaction of compound 3. Slowly adding isopropyl acetate and water, filtering, separating liquid, washing organic phase with 0.5N sodium hydroxide, saturated sodium chloride aqueous solution and water, concentrating dry solvent to obtain 1.98kg of the vitaspiravir 1, wherein the yield is 98.0%, the HPLC purity is 99.80%, and the maximum single impurity content is 0.05%.

Claims (21)

1. A method for preparing compound 5, comprising the steps of: under the protection of protective gas, carrying out condensation reaction on a compound 15 and ammonium salt in an organic solvent to obtain a compound 5; the molar ratio of the ammonium salt to the compound 15 is 1-40;
Figure FDA0002361056890000011
wherein P is an amino protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl or P-toluenesulfonyl.
2. A process for the preparation of compound 5 according to claim 1, characterized in that:
in the preparation method of the compound 5, the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
in the preparation method of the compound 5, the organic solvent is an aromatic hydrocarbon solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 5, the ammonium salt is one or more of ammonium acetate, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate;
and/or the presence of a gas in the gas,
in the preparation method of the compound 5, the condensation reaction temperature is 50-120 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 5, the condensation reaction is carried out for 5 to 24 hours.
3. A process for the preparation of compound 5 according to claim 1, characterized in that:
the preparation method of the compound 5 further comprises a preparation method of a compound 15, which comprises the following steps: under the protection of protective gas, in an organic solvent and in the presence of alkali, carrying out nucleophilic substitution reaction on a compound 16 and a compound 7 to obtain a compound 15;
Figure FDA0002361056890000021
wherein P is as defined in claim 1; l represents a leaving group.
4. A process for the preparation of compound 5 according to claim 3, characterized in that:
l represents p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, Br, Cl or I;
and/or the presence of a gas in the gas,
in the preparation method of the compound 15, the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
in the preparation method of the compound 15, the organic solvent is an amide solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 15, the base is an inorganic base;
and/or the presence of a gas in the gas,
in the preparation method of the compound 15, the molar ratio of the alkali to the compound 16 is 1.00-3.00;
and/or the presence of a gas in the gas,
in the preparation method of the compound 15, the molar ratio of the compound 7 to the compound 16 is 1.00-3.00;
and/or the presence of a gas in the gas,
in the preparation method of the compound 15, the temperature of the nucleophilic substitution reaction is 10-60 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 15, the time of the nucleophilic substitution reaction is 10 to 30 hours.
5. A process for the preparation of compound 5 according to claim 3, characterized in that:
the method for preparing compound 5 further comprises a method for preparing compound 16, which comprises the following steps: in an organic solvent, carrying out substitution reaction on the compound 17 and a halogenated reagent to obtain the compound 16;
Figure FDA0002361056890000031
wherein L is as defined in claim 3 or 4.
6. A process for the preparation of compound 5 according to claim 5, characterized in that:
in the preparation method of the compound 16, the halogenating reagent is p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, tribromopyridine, trichloropyridine or triiodopyridine;
and/or the presence of a gas in the gas,
in the preparation method of the compound 16, the organic solvent is a halogenated hydrocarbon solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 16, the molar ratio of the halogenated reagent to the compound 17 is 1-3;
and/or the presence of a gas in the gas,
in the preparation method of the compound 16, the temperature of the substitution reaction is 0-40 ℃;
and/or the presence of a gas in the gas,
in the method for producing compound 16, the time of the substitution reaction is 1 to 10 hours;
and/or the presence of a gas in the gas,
the preparation method of the compound 16 comprises the following steps: and (3) dropwise adding a halogenated reagent into a mixed solution formed by the compound 17 and an organic solvent at 0-5 ℃ to perform substitution reaction to obtain the compound 16.
7. A process for the preparation of compound 5 according to claim 5, characterized in that:
the preparation method of the compound 5 further comprises a preparation method of a compound 17, which comprises the following steps: under the protection of protective gas, carrying out condensation reaction on the compound 12 and ammonium salt in an organic solvent to obtain a compound 17;
Figure FDA0002361056890000041
8. a process for the preparation of compound 5 according to claim 7, wherein:
in the preparation method of the compound 17, the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
in the preparation method of the compound 17, the organic solvent is an aromatic hydrocarbon solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 17, the ammonium salt is one or more of ammonium acetate, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate;
and/or the presence of a gas in the gas,
in the preparation method of the compound 17, the molar ratio of the ammonium salt to the compound 12 is 1-40;
and/or the presence of a gas in the gas,
in the preparation method of the compound 17, the condensation reaction temperature is 50-120 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 17, the condensation reaction is carried out for 5 to 24 hours.
9. A process for the preparation of compound 5 according to claim 7, wherein:
the preparation method of the compound 5 further comprises a preparation method of a compound 12, which comprises the following steps: in an organic solvent, in the presence of a condensing agent, carrying out a condensation reaction on a compound 13 and a compound 9 to obtain a compound 12;
Figure FDA0002361056890000051
10. a process for the preparation of compound 5 according to claim 9, wherein:
in the preparation method of the compound 12, the organic solvent is an amide solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride, 2- (7-azobenzotriazol) -N, N '-tetramethyluronium hexafluorophosphate, benzotriazol-N, N' -tetramethyluronium hexafluorophosphate, O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate, benzotriazol-1-tris (trimethylamino) -trifluorophosphate, chlorotrifluoromethylphosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, N' -dicyclohexylcarbodiimide, (2-oximido-ethyl cyanoacetate) -N, one or more of N-dimethyl-morpholinylurea hexafluorophosphate, ethyl 2-oxime cyanoacetate and propylphosphoric anhydride;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the molar ratio of the condensing agent to the compound 13 is 1-3;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the molar ratio of the compound 9 to the compound 13 is 1-3;
and/or the presence of a gas in the gas,
in the preparation method of the compound 12, the condensation reaction temperature is 0-40 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 12, the condensation reaction is carried out for 1 to 10 hours;
and/or the presence of a gas in the gas,
the preparation method of the compound 12 adopts the following steps: and (3) dripping a mixture of the compound 13 and an organic solvent into a mixture of the compound 9, a condensing agent and the organic solvent at 0-10 ℃ to perform condensation reaction to obtain the compound 12.
11. A process for the preparation of compound 5 according to claim 9, wherein:
the preparation method of the compound 5 further comprises a preparation method of a compound 13, which comprises the following steps: in an organic solvent, carrying out a deamination protecting group reaction on the compound 14 and acid to prepare the compound 13;
Figure FDA0002361056890000061
wherein P is defined as in claim 1.
12. A process for the preparation of compound 5 according to claim 11, wherein:
in the preparation method of the compound 13, the organic solvent is an ester solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the acid is an inorganic acid;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the molar ratio of the acid to the compound 14 is 1-10;
and/or the presence of a gas in the gas,
in the preparation method of the compound 13, the reaction temperature for removing the amino protecting group is 40-100 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 13, the reaction time for removing the amino protecting group is 1 to 10 hours.
13. A process for the preparation of compound 5 according to claim 11, wherein: the preparation method of the compound 5 further comprises a preparation method of a compound 14, which comprises the following steps: under the protection of protective gas, in an organic solvent and in the presence of alkali, carrying out condensation reaction on a compound 25 and a compound 24 to obtain the compound 14;
Figure FDA0002361056890000071
wherein P is defined as in claim 1.
14. A process for the preparation of compound 5 according to claim 13, wherein:
in the preparation method of the compound 14, the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the organic solvent is an amide solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the base is an inorganic base;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the molar ratio of the alkali to the compound 25 is 1-3;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the molar ratio of the compound 24 to the compound 25 is 1-3;
and/or the presence of a gas in the gas,
in the preparation method of the compound 14, the condensation reaction temperature is 10-50 ℃;
and/or the presence of a gas in the gas,
in the method for producing the compound 14, the condensation reaction is carried out for 1 to 5 hours.
15. An intermediate compound 15 for preparing the vipatavir has a structural formula as shown in the specification:
Figure FDA0002361056890000072
wherein P is an amino protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl or P-toluenesulfonyl.
16. A process for the preparation of compound 15, characterized by comprising the steps of: under the protection of protective gas, in an organic solvent and in the presence of alkali, carrying out nucleophilic substitution reaction on a compound 16 and a compound 7 to obtain a compound 15;
Figure FDA0002361056890000081
wherein P is as defined in claim 15; l is as defined in claim 3 or 4; the reaction conditions are as defined in claim 3 or 4.
17. A process for the preparation of compound 15 according to claim 16, wherein:
the method for preparing compound 15 further comprises a method for preparing compound 16, which comprises the following steps: in an organic solvent, carrying out substitution reaction on the compound 17 and a halogenated reagent to obtain the compound 16;
Figure FDA0002361056890000082
wherein L is as defined in claim 3 or 4 and the reaction conditions are as defined in claim 5 or 6.
18. A process for the preparation of compound 15 according to claim 17, wherein:
the method of preparing compound 15 further includes a method of preparing compound 17, comprising the steps of: under the protection of protective gas, carrying out condensation reaction on the compound 12 and ammonium salt in an organic solvent to obtain a compound 17;
Figure FDA0002361056890000083
wherein the reaction conditions are as defined in claim 7 or 8.
19. A process for the preparation of compound 15 according to claim 18, wherein:
the method for preparing compound 15 further comprises a method for preparing compound 12, which comprises the following steps: in an organic solvent, in the presence of a condensing agent, carrying out a condensation reaction on a compound 13 and a compound 9 to obtain a compound 12;
Figure FDA0002361056890000091
wherein the reaction conditions are as defined in claim 9 or 10.
20. A process for the preparation of compound 15 according to claim 19, wherein:
the method for preparing compound 15 further comprises a method for preparing compound 13, which comprises the following steps: in an organic solvent, carrying out a deamination protecting group reaction on the compound 14 and acid to prepare the compound 13;
Figure FDA0002361056890000092
wherein P is as defined in claim 15; the reaction conditions are as defined in claim 11 or 12.
21. A process for the preparation of compound 15 according to claim 20, wherein: the method for preparing compound 15 further comprises a method for preparing compound 14, which comprises the following steps: under the protection of protective gas, in an organic solvent and in the presence of alkali, carrying out condensation reaction on a compound 25 and a compound 24 to obtain the compound 14;
Figure FDA0002361056890000093
wherein P is as defined in claim 15; the reaction conditions are as defined in claim 13 or 14.
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CN107501280A (en) * 2017-09-05 2017-12-22 安徽华昌高科药业有限公司 A kind of Wei Patawei synthetic method

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