CN110872247A - Xofluza sulfur-containing heterocyclic compound, intermediate thereof and preparation method - Google Patents
Xofluza sulfur-containing heterocyclic compound, intermediate thereof and preparation method Download PDFInfo
- Publication number
- CN110872247A CN110872247A CN201810997345.7A CN201810997345A CN110872247A CN 110872247 A CN110872247 A CN 110872247A CN 201810997345 A CN201810997345 A CN 201810997345A CN 110872247 A CN110872247 A CN 110872247A
- Authority
- CN
- China
- Prior art keywords
- solvent
- formula
- compound shown
- compound
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/12—[b,e]-condensed
Abstract
The invention discloses an Xofluza sulfur-containing heterocyclic compound, an intermediate and a preparation method thereof. The invention also provides a preparation method of the compound shown in the formula 5. The preparation method has the advantages of mild reaction conditions, low energy consumption and cost, high utilization rate of the reaction kettle, less peculiar smell of raw materials, wide sources and suitability for industrial production.
Description
Technical Field
The invention relates to Xofluza sulfur-containing heterocyclic compounds, intermediates thereof and a preparation method thereof.
Background
Influenza is a potential major public health problem, and can bring about 300 to 500 ten thousand serious cases each year, so that about 25 to 50 ten thousand people die. The effects of influenza are more severe for children under 2 years of age, elderly people over 65 years of age, pregnant women, and other people with low immunity.
24/2/2018, a message of heavy pounds was sent by salt wild meaning pharmacy (Shionogi). Innovative anti-influenza drug Xofluza (baloxavir marboxil, great name S-033188) was given accelerated approval and is marketed in Japan, and its structural formula is shown below. The partner Roche (Roche) is expected to bring the new influenza medicine in more regions.
Approval of Xofluza is expected to bring about major changes in the treatment of influenza patients. Xofluza is an innovative Cap-dependent endonuclease inhibitor and is a small number of new drugs which can inhibit the proliferation of influenza viruses in the world. The compound can inhibit the CAP structure at the 5' end of host mRNA obtained from host cells aiming at the key link of the replication of the influenza virus, thereby inhibiting the transcription of the self mRNA of the influenza virus. Since there is no protease with a similar mechanism in the host cell, this drug theoretically has no effect on the host cell.
In the last 10 months, the phase 3 clinical result of the new medicine is published. Patients receiving Xofluza treatment resolved the fever trouble one day later (24.5 hours) compared to the control group patients. This data for the control group was 42 hours. In addition, the patients receiving the drug returned to pre-influenza health after 129.2 hours, which is 168.8 hours in the control group, with a difference of nearly 40 hours. Some experts point out that 1 tablet of the new drug can reach up to 10 tablets of the current standard therapy and can continue to take effect for 10 days. This allows people in any region of the world to fight the severe epidemic influenza in a simple and quick manner.
The synthesis of sulfur-containing heterocycles as key intermediates of Xofluza is less documented at present, and only one patent (TW201802097A) reports as follows:
the synthetic route is as follows:
in the report, the intermediate sulfur-containing heterocyclic compound 7 of Xofluza is synthesized in five steps, because the peculiar smell of thiophenol is large, a large amount of thiophenol is not supplied in the current Chinese chemical market, and the intermediate sulfur-containing heterocyclic compound needs to be prepared from sodium thiophenol, and the actual steps are six steps, and are as follows:
the method comprises the following steps of selectively extracting hydrogen from lithium diisopropylamide generated in a reaction at a carboxylic acid ortho-position, carrying out two substitution reactions to obtain a compound 2, substituting the compound 2 with thiophenol under the catalysis of camphorsulfonic acid to obtain a compound 4, breaking a carbon-oxygen bond of the compound 4 under the action of aluminum trichloride to obtain a compound 5, carrying out a Friedel-crafts reaction with polyphosphoric acid to obtain a sulfur heterocycle 6, and reducing the compound 6 to obtain a compound 7.
The prior art has three major disadvantages, which limit the industrial applicability of the technology. (1) Butyl lithium is used in the first step of reaction, the reaction is carried out at the temperature of minus 40 ℃, the requirement on a reaction kettle is higher in industry, fewer pharmaceutical and chemical manufacturers with the matched facility are provided in China, the energy consumption is higher, and the cost is directly increased. (2) In the first step of reaction, the authors can only reduce the reaction concentration in order to avoid intermolecular reaction, which results in that only 300g of raw material can be fed into a 20L reaction kettle, and the utilization rate of the reaction kettle is too low. (3) The key raw material thiophenol in the route belongs to highly toxic products, has heavy peculiar smell, has more limit on purchase and use, and does not have a large amount of thiophenol available in the domestic chemical industry market.
Therefore, there is a need to develop a new Xofluza sulfur-containing heterocyclic compound and a preparation method of an intermediate thereof.
Disclosure of Invention
The invention aims to overcome the defects of harsh reaction conditions, high energy consumption and cost, low utilization rate of a reaction kettle, large toxic and side effects of raw materials, difficult obtainment and the like in the conventional preparation method of the Xofluza intermediate. Therefore, the Xofluza sulfur-containing heterocyclic compound, the intermediate and the preparation method thereof provided by the invention are all completed at 0-120 ℃, low-temperature reaction is avoided, energy consumption and cost are reduced, the utilization rate of a reaction kettle is higher, sodium thiophenolate is used for replacing thiophenol as a raw material, the peculiar smell is less, the source is wide, and the Xofluza sulfur-containing heterocyclic compound is suitable for industrial production.
The invention mainly solves the technical problems through the following technical scheme.
The invention provides a preparation method of a compound shown as a formula 5, which comprises the following steps:
(1) in a solvent, under the action of a Grignard reagent, a compound shown as a formula 9 and a carbon source are subjected to a reaction shown as the following to obtain a compound shown as a formula 10; wherein, X1Is chlorine, bromine or iodine;
(2) in a solvent, carrying out a halogenation reaction on a compound shown as a formula 10 and a halogenating reagent as shown in the specification to obtain a compound shown as a formula 11; wherein, X2Is chlorine, bromine or iodine;
(3) in a solvent, under the action of a nucleophilic reagent, carrying out nucleophilic substitution reaction on a compound shown as a formula 11 as shown in the specification to obtain a compound shown as a formula 5;
in step (1), the grignard reagent may be a grignard reagent that is conventional in the above reaction in the art, preferably one or more of isopropyl magnesium chloride, ethyl magnesium chloride and cyclohexyl magnesium chloride, and more preferably isopropyl magnesium chloride.
In step (1), the carbon source may be a carbon source conventional in the above reaction in the art, preferably carbon dioxide gas and/or methyl chloroformate, more preferably carbon dioxide gas.
In step (1), the solvent may be a solvent conventional in the above-mentioned reaction in the art, and further may be an organic solvent conventional in the above-mentioned reaction in the art, and is preferably a halogenated hydrocarbon solvent and/or an ether solvent. The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, chloroform, carbon tetrachloride and dichloroethane. The ethereal solvent is preferably tetrahydrofuran.
In a preferred embodiment of the present invention, in step (1), the solvent is preferably an ether solvent, such as tetrahydrofuran.
In the step (1), the molar ratio of the grignard reagent to the compound represented by the formula 9 may be a molar ratio conventionally used in the above reaction in the art, and is preferably 0.8 to 2.5:1, and more preferably 1.5: 1.
In the step (1), the molar ratio of the carbon source to the compound represented by the formula 9 may be a molar ratio conventionally used in the above-mentioned reaction in the art.
In a preferred embodiment of the present invention, in the step (1), the molar ratio of the carbon source to the compound represented by the formula 9 is greater than 1: 1.
In a preferred embodiment of the present invention, in the step (1), carbon dioxide gas is continuously introduced into the reaction solution.
In the step (1), the molar concentration of the compound represented by formula 9 in the solvent may be a molar concentration conventionally used in the above reaction in the art, and is preferably 0.5 to 5mol/L, more preferably 0.8 to 1.0mol/L, for example (128/149) mol/L.
In the step (1), the reaction temperature may be a temperature that is conventional in the above-mentioned reaction in the art, preferably 0 to 40 ℃, and more preferably room temperature.
In step (1), the progress of the reaction can be monitored by detection methods conventional in the art (e.g., HPLC), and the end point of the reaction is generally determined when compound 9 disappears. The reaction time is preferably 10 to 60min, and more preferably 30 min.
In a preferred embodiment of the present invention, step (1) comprises the steps of: compound 9 is mixed with a solvent, and a mixture of a grignard reagent and the solvent is added dropwise thereto.
In the step (1), after the reaction is finished, preferably, a post-treatment operation may be further included. The methods and conditions of the work-up may be those conventional in the art for such reactions, and preferably include the steps of: mixing with water, concentrating, adjusting pH to strong acidity (such as pH 1), precipitating solid, filtering with suction, washing, and drying. The conditions and operations for the concentration may be those conventional in the art, and concentration under reduced pressure is preferred. The acid used to adjust the pH may be an acid conventional in the art, preferably hydrochloric acid, more preferably concentrated hydrochloric acid. The conditions and operations of the suction filtration may be those conventional in the art. The washing conditions and operations may be those conventional in the art, and the washing solvent is preferably water and n-heptane. The drying conditions and operations may be those conventional in the art, and vacuum drying is preferred.
In step (2), when X is present2In the case of bromine, the halogenation is preferably carried out under the action of a free radical initiator; the radical initiator may be a radical initiator conventional to the halogenation reaction described above in the art, preferably m-chlorobenzoyl peroxide and/or azobisisobutyronitrile, more preferably azobisisobutyronitrile; the molar ratio of the free radical initiator to the compound represented by formula 10 may be a molar ratio conventionally used in the above-mentioned halogenation reaction in the art, and is preferably 1:10 to 50, more preferably 1:18 to 20, for example 1 (1127/60).
In step (2), when X is present2In the case of bromine, the halogenating agent may be a halogenating agent conventionally used in the above-mentioned halogenation reaction in the art, and is preferably one or more of dibutyl itaconate (DBI), N-bromosuccinimide (NBS) and dibromohydantoin, more preferably N-bromosuccinimide.
In the step (2), the solvent may be a solvent conventional to the halogenation reaction described above in the art, and further may be an organic solvent conventional to the halogenation reaction described above in the art, and is preferably one or more of an amide-based solvent, a nitrile-based solvent, and a halogenated hydrocarbon-based solvent. The amide solvent is preferably N, N-dimethylformamide. The nitrile solvent is preferably acetonitrile. The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
In a preferred embodiment of the present invention, in step (2), the solvent is preferably a nitrile solvent, such as acetonitrile.
In the step (2), the molar ratio of the halogenating reagent to the compound represented by formula 10 may be a molar ratio conventionally used in the above-mentioned halogenation reaction in the art, and is preferably 0.9-1.8: 1, more preferably 1.1-1.3: 1, for example (1352/1127: 1).
In the step (2), the molar concentration of the compound represented by formula 10 in the solvent may be a molar concentration conventionally used in the halogenation reaction in the art, and is preferably 0.1 to 0.8mol/L, more preferably 0.5 to 0.7mol/L, for example (1427/1940) mol/L.
In step (2), when X is present2In the case of bromine, the temperature of the halogenation reaction may be a temperature conventional for the halogenation reaction in the art, and is preferably 75 to 125 ℃, and more preferably 85 ℃.
In step (2), the progress of the halogenation reaction can be monitored by detection methods conventional in the art (e.g., HPLC), and is generally the end point of the reaction when compound 10 disappears. The time of the halogenation reaction is preferably 1 to 3 hours, and more preferably 2 hours.
In a preferred embodiment of the present invention, the step (2) comprises the steps of: compound 10 is mixed with a solvent and the halogenating agent and free radical initiator are added.
In a preferred embodiment of the present invention, the step (2) comprises the steps of: the compound 10 is mixed with a solvent, and then a halogenated reagent and a free radical initiator are sequentially added.
In the step (2), after the halogenation reaction is finished, preferably, the method may further include a post-treatment operation. The methods and conditions of the work-up may be those conventional in the art for such reactions, and preferably include the steps of: mixing with an inorganic salt solution (the inorganic salt solution is preferably 5% sodium bisulfite), concentrating, extracting, drying, concentrating to obtain a white solid crude product, mixing the crude product with a solvent (the solvent is preferably dichloromethane), heating and refluxing for 2-4h (preferably 3h), cooling to 20-30 ℃, performing suction filtration, washing, and concentrating the filtrate to obtain a white solid compound 11. The conditions and operations for the concentration may be those conventional in the art, and concentration under reduced pressure is preferred. The conditions and operation of the extraction may be those conventional in the art, and the extraction solvent is preferably dichloromethane. The washing conditions and operations may be those conventional in the art, and the washing solvent is preferably dichloromethane.
In step (3), the nucleophile may be a nucleophile conventional in the art as described above, preferably sodium and/or potassium thiophenolate, more preferably sodium thiophenolate.
In the step (3), the solvent may be a solvent conventional in the above-mentioned reaction in the art, and further may be an organic solvent conventional in the above-mentioned reaction in the art, and is preferably one or more of an amide solvent, a nitrile solvent and a halogenated hydrocarbon solvent. The amide solvent is preferably N, N-dimethylformamide. The nitrile solvent is preferably acetonitrile. The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, trichloromethane and dichloroethane.
In a preferred embodiment of the present invention, in step (3), the solvent is preferably an amide-based solvent, such as N, N-dimethylformamide.
In the step (3), the molar ratio of the nucleophilic reagent to the compound represented by formula 11 may be a molar ratio conventionally used in the above reaction in the art, and is preferably 1 to 5:1, more preferably 1.1 to 2:1, and further more preferably 1.1: 1.
In the step (3), the molar concentration of the compound represented by formula 11 in the solvent may be a molar concentration conventionally used in the above reaction in the art, and is preferably 0.4 to 1.0mol/L, more preferably 0.7 to 0.9mol/L, such as (90/113) mol/L.
In the step (3), the reaction temperature may be a temperature conventional in the above reaction in the art, preferably 0 to 40 ℃, and more preferably room temperature;
in step (3), the progress of the nucleophilic substitution reaction can be monitored by detection methods conventional in the art (e.g., HPLC), and is generally terminated when compound 11 disappears. The time of the nucleophilic substitution reaction is preferably 1.5 to 2.5 hours, and more preferably 2 hours.
In a preferred embodiment of the present invention, the step (3) comprises the steps of: compound 11 is mixed with a solvent and the nucleophile is added.
In the step (3), after the nucleophilic substitution reaction is completed, preferably, a post-treatment operation may be further included. The methods and conditions of the work-up may be those conventional in the art for such reactions, and preferably include the steps of: extracting, drying, concentrating to obtain crude product, recrystallizing, vacuum filtering, washing, and drying. The conditions and operation of the extraction may be those conventional in the art, and the extraction solvent is preferably dichloromethane. The concentration conditions and operations may be those conventional in the art, more preferably concentration under reduced pressure. The conditions and operation of the recrystallization may be those conventional in the art, and the recrystallization solvent is more preferably a mixed solvent of ethyl acetate and n-heptane. The washing conditions and operations may be those conventional in the art, and the washing solvent is more preferably n-heptane. The drying conditions and operations may be those conventional in the art, preferably reduced pressure rotary evaporation.
The preparation method of the compound shown in the formula 5 can also comprise the following steps:
in a solvent, under the action of a catalyst, performing halogenation reaction on a compound shown as a formula 8 and a halogenating reagent as shown in the specification to obtain a compound shown as a formula 9; wherein, X1Is chlorine, bromine or iodine;
the methods and conditions for the halogenation are the same as those conventional in the art for such reactions.
The invention also provides a preparation method of the compound shown in the formula 5, which comprises the following steps:
in a solvent, under the action of a nucleophilic reagent, carrying out nucleophilic substitution reaction on a compound shown as a formula 11 as shown in the specification; wherein, X2Is chlorine, bromine or iodine;
the conditions of the nucleophilic substitution reaction are the same as those of the nucleophilic substitution reaction in the aforementioned step (3).
The preparation method of the compound shown in the formula 5 can also comprise the following steps: in the solvent, the solvent is added with a solvent,performing halogenation reaction on a compound shown as a formula 10 and a halogenating reagent as shown in the specification; wherein, X2Is chlorine, bromine or iodine;
the conditions of the halogenation reaction are the same as those of the halogenation reaction in the step (2).
In the present invention, Xofluza sulfur-containing heterocyclic compounds and intermediates thereof can be prepared by any one of the following synthetic routes, as shown in synthetic route a, synthetic route B and synthetic route C; wherein, X1、X2Independently chlorine, bromine or iodine.
Scheme a:
scheme B:
scheme C:
the invention also provides a compound shown as the formula I, and the structure of the compound is shown as follows:
wherein R may be one of halogen, hydroxyl, and a hydroxyl-related leaving group; the halogen can be chlorine, bromine or iodine; the hydroxyl-related leaving group may be p-toluenesulfonyl or methanesulfonyl.
In a preferred embodiment of the invention, R is preferably halogen; the halogen is chlorine, bromine or iodine.
The invention also provides application of the compound shown as the formula I as an anti-influenza medicament Xofluza intermediate.
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.
"h" in the present invention represents "hour".
If the temperature is not particularly emphasized, the reaction is usually carried out at room temperature, and the room temperature in the present invention is 20 to 30 ℃.
The positive progress effects of the invention are as follows:
(1) compared with the prior art, the preparation method provided by the invention has the advantages of cheap and easily available raw materials, mild reaction conditions, avoidance of low-temperature reaction, reduction of energy consumption and cost, high product yield, higher utilization rate of a reaction kettle and suitability for industrial production.
(2) The thiophenol belongs to highly toxic products and has heavy peculiar smell, and sodium thiophenol is used for replacing the thiophenol in the production process of the invention, so that the method has less peculiar smell and is safer and more environment-friendly. In addition, the purchase and use of thiophenol have a plurality of limitations, a large amount of thiophenol is not available in domestic markets, but sodium thiophenol is available in large quantities in markets, and the raw material sources are wider.
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. If the temperature is not particularly emphasized, the reaction is usually carried out at room temperature, and the room temperature in the present invention is 20 to 30 ℃.
LCMS detection method
Shimadazu LCMS models LC-DGU-20A5, SPD-M205, LCMS-2010EU
Chromatographic column conditions: CDL 250 deg.C, Nebulizing Gas 3L/min, heat block 200 deg.C
A chromatographic column: agela Venusil ASB C18.3 μm,150A, 4.6X 50mm
Mobile phase: a (0.001 aqueous formic acid); b (0.001 acetonitrile formate solution)
Flow rate: pump A Total flow Rate 1mL/min
The method comprises the following steps: 0.01min, 10% of B; 1min, 10% of B; 4min, and the percentage of B is 90 percent; 5min, and the percentage of B is 90 percent; 5.5min, 10% of B; 7min, B% is 10%
Detection wavelength: 254nm
Example 1
Compound 8(20g, 156.1mmol) and dichloromethane (60mL) were added to a 250mL three-necked flask and cooled to 0 ℃ on an ice bath. To the reaction solution was added aluminum trichloride (0.2g, 1.6mmol) at 0 ℃ followed by slowly dropping a mixed solution of liquid bromine (24.95g, 156.1mmol) and dichloromethane (20 mL). After detection of less than 5% compound 8 by HPLC, the reaction was quenched by slow addition of water (60 mL). The organic phase was washed with 1M hydrochloric acid (20mL) and 5% sodium bisulfite (20mL) respectively for 1 time, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and spin-dried to give crude compound 9 (30 g). And (3) carrying out reduced pressure rectification, purification and collection on the crude compound 9 product, and collecting 75-85 ℃ fractions to obtain the colorless liquid compound 9(26.5g, yield 82%).1H-NMR(400MHz,DMSO-d6):δ7.44(m,1H),7.26(m,1H),2.28(d,3H).
Example 2
Compound 9(26.5g, 128.0mmol) and tetrahydrofuran (53mL) were added to a 250mL three-necked flask and cooled to 0 ℃ on an ice bath. The reaction mixture was slowly added dropwise to a 2M solution of isopropyl magnesium chloride in tetrahydrofuran (96mL, 192.0mmol) at 0 ℃. After the addition, the reaction solution was warmed to room temperature and stirred for 6 hours. The reaction solution was cooled to 0 ℃ in an ice bath, carbon dioxide gas was introduced into the reaction solution for 30 minutes, and then the reaction solution was warmed to room temperature and stirred for 30 minutes. After detecting less than 5% of compound 9 by HPLC, the reaction was cooled to 0 ℃ in an ice bath and quenched by slowly adding water (106mL) dropwise. Vacuum concentrating the mixtureThe organic solvent is removed, the pH of the rotary drying substance is adjusted to 1 by concentrated hydrochloric acid, and white solid is separated out. The suspension was filtered with suction and the filter cake was washed 1 time with water (26.5mL) and pre-cooled n-heptane (26.5 mL). The filter cake was dried at 50 ℃ under vacuum to give compound 10 as a white solid (19.4g, 88%). The peak position: 4.233 min; LC-MS [ M-H ]]-:170.7。1H-NMR(400MHz,DMSO-d6):δ13.3(s,1H),7.71(m,1H),7.35(q,1H),2.48(s,3H).
Example 3
Compound 10(19.4g, 112.7mmol) and acetonitrile (194mL) were added to a 500mL three-necked flask and dissolved with stirring. N-bromosuccinimide (24.1g, 135.2mmol) and azobisisobutyronitrile (1.0g, 6mmol) were then added. The reaction solution is heated to 80-85 ℃ and refluxed for 2 hours. After less than 5% of compound 10 was detected by HPLC, the reaction was cooled to 0 ℃ in an ice bath and quenched by the addition of 5% sodium bisulfite (97 mL). The reaction solution was concentrated under reduced pressure to remove acetonitrile, the dried product was extracted 3 times with dichloromethane (3X 97mL), the organic phases were combined and washed 1 time with water (97mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound 11 as a white solid. Crude compound 11 and dichloromethane (58mL) were added to a 100mL three-necked flask and heated to reflux for 3 hours, then cooled to room temperature and stirred for 1 hour, filtered, the filter cake was rinsed 1 time with dichloromethane (10mL), and the filtrate was concentrated under reduced pressure to give compound 11 as a white solid (22.6g, 80%). The peak position: 4.383 min; LC-MS [2M + Na ]]+:522.1。1H-NMR(400MHz,DMSO-d6):δ11.2(br,1H),7.82(m,1H),7.57(q,1H),5.07(s,2H).
Example 4
Compound 11(22.6g, 90.0mmol) and N, N-dimethylformamide (113mL) were added to a 250mL three-necked flask and dissolved with stirring. Subsequently, sodium thiophenolate (11.9g, 99.0mmol) was added and stirred at 30-40 ℃ for 2 hours. After less than 5% of Compound 11 was detected by HPLC, the reaction was runThe solution was extracted 2 times with water (226mL) and dichloromethane (2X 226mL), and the organic phases were combined and washed 1 time with water (113 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 5 as a white solid. Crude compound 5 and ethyl acetate (45mL) were added to a 500mL three-necked flask, warmed to 50 ℃, followed by dropwise addition of n-heptane (136mL) and stirring for 1 hour, cooled to room temperature and stirred for 1 hour, the suspension was filtered with suction, and the filter cake was rinsed once with n-heptane (23 mL). The filter cake was rotary evaporated to dryness under reduced pressure to give Compound 5(23.0g, 91%) as a white solid. The peak position: 4.714 min; LCMS [ M-H ]]-:278.7。1H-NMR(400MHz,DMSO-d6):δ13.4(br,1H),7.75(m,1H),7.43(m,1H),7.25-7.33(m,5H),4.59(s,2H).
Example 5
Polyphosphoric acid (115g) was added to a 500mL three-necked flask and the temperature was raised to 80 ℃. Compound 5(23.0g, 82.1mmol) was then added. The reaction solution was heated to 120 ℃ and kept at that temperature for 4 hours. After detection of less than 5% of compound 5 by HPLC, the reaction was cooled to 80 ℃ and water (54mL) was added slowly. The reaction mixture was further cooled to 30 ℃ and water (230mL) was added to extract the mixture with ethyl acetate (230 mL). The organic phase was washed 1 time with water (115mL) and 10% aqueous sodium bicarbonate (69mL), respectively. The organic phase was concentrated to dryness under reduced pressure and the azeotropic removal of the solvent with n-heptane (92mL) was continued. After addition of n-heptane (23mL) to the rotary dry and stirring at 10 ℃ for 1 hour, the suspension was filtered by suction, the filter cake was washed 1 time with n-heptane (12mL) and the filter cake was rotary evaporated under reduced pressure to give Compound 6 as a brown solid (20.9g, 97%). The peak position: 5.136 min; LCMS (liquid Crystal display Module) [ M + H ]]+:262.6。1H-NMR(400MHz,DMSO-d6):δ8.07(m,1H),7.36-7.54(m,5H),4.34(s,2H).
Example 6
Sodium borohydride (0.24g,6.2mmol) was dissolved in isopropanol (20mL), water (2.25mL) and 0.5% sodium hydroxide (1.8mL) and cooled to 0 deg.C and addedCompound 6(4.5g,17.2mmol) was heated to 40 ℃ and reacted until the starting material disappeared completely, water (40mL) and 62% sulfuric acid (0.46mL) were added, cooled to 5 ℃ and a solid precipitated, and filtered to give product 7(4.4g, yield 97%).1H-NMR(CDCl3)：δ7.44-7.49(m,1H),7.12-7.21(m,4H),7.02(dt,1H),4.68(dd,2H),4.20(dd,2H),2.67(d,1H)。
Comparative example 1
Dissolving 4-methyl-2, 3-difluorobenzoic acid ((1.724g,6.869mmol) in carbon tetrachloride (10mL), adding N-bromosuccinimide (1.189g,6.682mmol) and azobisisobutyronitrile (43.9mg,0.267mmol), heating the reaction solution to 90 ℃ for reaction for 30min, heating to 100 ℃ for reaction for 2.5h, cooling to 0 ℃ after the reaction is finished, precipitating a precipitate, carrying out suction filtration on the precipitate, washing a filter cake with N-hexane and water to obtain a crude product, dissolving the crude product in ethyl acetate (5mL), adding N-hexane (10mL), precipitating a solid, carrying out suction filtration, and drying under reduced pressure to obtain a light yellow solid, namely 4- (bromomethyl) -2, 3-difluorobenzoic acid (627.5mg, 3.599mmol, the yield is 25.2%).
Comparative example 2
2, 3-difluoro-1-methoxy-4-methylbenzene (39.5g,0.25mol), N-bromosuccinimide (44.5g,0.25mol) and azobisisobutyronitrile (0.41g,2.5mmol) were dissolved in carbon tetrachloride (300mL) and stirred for 3.5 h. The succinimide is then removed by suction filtration and the filtrate is concentrated in vacuo. The rotaries were dissolved in ethyl acetate (200mL) and then concentrated to 100 mL. Cooling in an ice bath precipitated a precipitate which was filtered off with suction, the filter cake was washed with precooled ethyl acetate and dried in vacuo as a white solid (36.0g, 61%).
Claims (10)
1. A preparation method of a compound shown as a formula 5 is characterized by comprising the following steps:
(1) in a solvent, under the action of a Grignard reagent,carrying out the following reaction on a compound shown as a formula 9 and a carbon source to obtain a compound shown as a formula 10; wherein, X1Is chlorine, bromine or iodine;
(2) in a solvent, carrying out a halogenation reaction on a compound shown as a formula 10 and a halogenating reagent as shown in the specification to obtain a compound shown as a formula 11; wherein, X2Is chlorine, bromine or iodine;
(3) in a solvent, under the action of a nucleophilic reagent, carrying out nucleophilic substitution reaction on a compound shown as a formula 11 as shown in the specification to obtain a compound shown as a formula 5;
2. the process according to claim 1 for preparing a compound represented by the formula 5,
in the step (1), the Grignard reagent is one or more of isopropyl magnesium chloride, ethyl magnesium chloride and cyclohexyl magnesium chloride;
and/or, in the step (1), the carbon source is carbon dioxide gas and/or methyl chloroformate;
and/or, in the step (1), the solvent is an organic solvent, preferably a halogenated hydrocarbon solvent and/or an ether solvent;
and/or in the step (1), the molar ratio of the Grignard reagent to the compound shown in the formula 9 is 0.8-2.5: 1;
and/or, in the step (1), the molar ratio of the carbon source to the compound shown in the formula 9 is a conventional molar ratio;
and/or in the step (1), the molar concentration of the compound shown in the formula 9 in the solvent is 0.5-5 mol/L;
and/or in the step (1), the reaction temperature is 0-40 ℃;
and/or, in step (2), when X is2When the halogen is bromine, the halogenation reaction is carried out under the action of a free radical initiator; the free radical initiator is preferably m-chloro benzoyl peroxide and/or azobisisobutyronitrile; the free radical initiator and the compound of formula 10The molar ratio of the compound is preferably 1: 10-50;
and/or, in step (2), when X is2When the halogen reagent is bromine, the halogen reagent is one or more of dibutyl itaconate, N-bromosuccinimide and dibromohydantoin;
and/or, in the step (2), the solvent is an organic solvent, preferably one or more of an amide solvent, a nitrile solvent and a halogenated hydrocarbon solvent;
and/or in the step (2), the molar ratio of the halogenated reagent to the compound shown in the formula 10 is 0.9-1.8: 1;
and/or in the step (2), the molar concentration of the compound shown in the formula 10 in the solvent is 0.1-0.8 mol/L;
and/or, in step (2), when X is2When the bromine is used, the temperature of the halogenation reaction is 75-125 ℃;
and/or, in the step (3), the nucleophilic reagent is sodium thiophenol and/or potassium thiophenol;
and/or, in the step (3), the solvent is an organic solvent, preferably one or more of an amide solvent, a nitrile solvent and a halogenated hydrocarbon solvent;
and/or in the step (3), the molar ratio of the nucleophilic reagent to the compound shown in the formula 11 is 1-5: 1;
and/or in the step (3), the molar concentration of the compound shown in the formula 11 in the solvent is 0.4-1.0 mol/L;
and/or in the step (3), the reaction temperature is 0-40 ℃.
3. The process according to claim 2 for preparing a compound represented by the formula 5,
in the step (1), the halogenated hydrocarbon solvent is one or more of dichloromethane, chloroform, carbon tetrachloride and dichloroethane; the ether solvent is tetrahydrofuran;
and/or, in the step (2), the amide solvent is N, N-dimethylformamide; the nitrile solvent is acetonitrile; the halogenated hydrocarbon solvent is one or more of dichloromethane, dichloroethane, chloroform and carbon tetrachloride;
and/or, in the step (3), the amide solvent is N, N-dimethylformamide; the nitrile solvent is acetonitrile; the halogenated hydrocarbon solvent is one or more of dichloromethane, trichloromethane and dichloroethane.
4. The process for preparing a compound of formula 5 as claimed in claim 1 or 2,
in the step (1), the Grignard reagent is isopropyl magnesium chloride;
and/or, in the step (1), the carbon source is carbon dioxide gas;
and/or, in the step (1), the solvent is an ether solvent, preferably tetrahydrofuran;
and/or, in the step (1), the molar ratio of the Grignard reagent to the compound shown in the formula 9 is 1.5: 1;
and/or in the step (1), the molar concentration of the compound shown in the formula 9 in the solvent is 0.8-1.0 mol/L;
and/or, in the step (1), the reaction temperature is room temperature;
and/or, in step (2), when X is2When the halogen is bromine, the halogenation reaction is carried out under the action of a free radical initiator; the radical initiator is preferably azobisisobutyronitrile; the molar ratio of the free radical initiator to the compound shown in the formula 10 is preferably 1: 18-20;
and/or, in step (2), when X is2When the halogenated reagent is bromine, the halogenated reagent is N-bromosuccinimide;
and/or, in step (2), the solvent is a nitrile solvent, preferably acetonitrile;
and/or in the step (2), the molar ratio of the halogenated reagent to the compound shown in the formula 10 is 1.1-1.3: 1;
and/or in the step (2), the molar concentration of the compound shown in the formula 10 in the solvent is 0.5-0.7 mol/L;
and/or, in step (2), when X is2When the bromine is used, the temperature of the halogenation reaction is 85 ℃;
and/or, in the step (3), the nucleophilic reagent is sodium thiophenolate;
and/or, in the step (3), the solvent is an amide solvent, preferably N, N-dimethylformamide;
and/or in the step (3), the molar ratio of the nucleophilic reagent to the compound shown in the formula 11 is 1.1-2: 1, preferably 1.1: 1;
and/or in the step (3), the molar concentration of the compound shown in the formula 11 in the solvent is 0.7-0.9 mol/L;
and/or, in the step (3), the temperature of the reaction is room temperature.
5. The method of claim 1, further comprising the steps of:
in a solvent, under the action of a catalyst, performing halogenation reaction on a compound shown as a formula 8 and a halogenating reagent as shown in the specification to obtain a compound shown as a formula 9; wherein, X1Is chlorine, bromine or iodine;
6. a preparation method of a compound shown as a formula 5 is characterized by comprising the following steps:
in a solvent, under the action of a nucleophilic reagent, carrying out nucleophilic substitution reaction on a compound shown as a formula 11 as shown in the specification; wherein, X2Is chlorine, bromine or iodine;
the conditions of the nucleophilic substitution reaction are the same as those of the nucleophilic substitution reaction in step (3) in any one of claims 1 to 4.
7. The compound of claim 6, represented by formula 5The preparation method is characterized in that the preparation method shown as the formula 5 further comprises the following steps: in a solvent, performing a halogenation reaction on a compound shown as a formula 10 and a halogenating reagent as shown in the specification; wherein, X2Is chlorine, bromine or iodine;
the conditions of the halogenation reaction are the same as those of the halogenation reaction in the step (2) in any one of claims 1 to 4.
8. A preparation method of Xofluza sulfur-containing heterocyclic compound shown as a formula 6 comprises the following synthetic route:
wherein, X1、X2Independently chlorine, bromine or iodine.
9. A compound of formula I, having the structure:
wherein R is halogen, preferably chlorine, bromine or iodine.
10. An application of a compound shown as a formula I as an intermediate of an anti-influenza medicament Xofluza.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810997345.7A CN110872247A (en) | 2018-08-29 | 2018-08-29 | Xofluza sulfur-containing heterocyclic compound, intermediate thereof and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810997345.7A CN110872247A (en) | 2018-08-29 | 2018-08-29 | Xofluza sulfur-containing heterocyclic compound, intermediate thereof and preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110872247A true CN110872247A (en) | 2020-03-10 |
Family
ID=69714698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810997345.7A Pending CN110872247A (en) | 2018-08-29 | 2018-08-29 | Xofluza sulfur-containing heterocyclic compound, intermediate thereof and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110872247A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110872225A (en) * | 2019-10-29 | 2020-03-10 | 广东东阳光药业有限公司 | Preparation method of Barosavir intermediate |
| CN111808069A (en) * | 2020-07-21 | 2020-10-23 | 中国药科大学 | Preparation method of baroxavir key intermediate and intermediate thereof |
| CN112062750A (en) * | 2020-07-22 | 2020-12-11 | 和鼎（南京）医药技术有限公司 | Process for preparing a Barosavir intermediate and intermediate obtained by this process |
| CN112939932A (en) * | 2021-02-09 | 2021-06-11 | 上海应用技术大学 | Preparation method of sulfur-containing hetero seven-membered ring compound |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4397790A (en) * | 1980-12-03 | 1983-08-09 | Monsanto Company | Isophosphinolinone derivatives |
| CN1148385A (en) * | 1994-05-17 | 1997-04-23 | 罗纳-普朗克农业有限公司 | 4-benzoylisoxazole derivatives and their use as herbicides |
| WO2017072341A1 (en) * | 2015-10-30 | 2017-05-04 | F. Hoffmann-La Roche Ag | Pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease |
| WO2017221869A1 (en) * | 2016-06-20 | 2017-12-28 | 塩野義製薬株式会社 | Method for producing substituted polycyclic pyridone derivative and crystal of same |
| WO2018030463A1 (en) * | 2016-08-10 | 2018-02-15 | 塩野義製薬株式会社 | Substituted polycyclic pyridone derivative and pharmaceutical composition containing prodrug thereof |
| CN107709321A (en) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | The polycyclic Pyridione derivatives and its prodrug being substituted |
-
2018
- 2018-08-29 CN CN201810997345.7A patent/CN110872247A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4397790A (en) * | 1980-12-03 | 1983-08-09 | Monsanto Company | Isophosphinolinone derivatives |
| CN1148385A (en) * | 1994-05-17 | 1997-04-23 | 罗纳-普朗克农业有限公司 | 4-benzoylisoxazole derivatives and their use as herbicides |
| CN107709321A (en) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | The polycyclic Pyridione derivatives and its prodrug being substituted |
| WO2017072341A1 (en) * | 2015-10-30 | 2017-05-04 | F. Hoffmann-La Roche Ag | Pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease |
| WO2017221869A1 (en) * | 2016-06-20 | 2017-12-28 | 塩野義製薬株式会社 | Method for producing substituted polycyclic pyridone derivative and crystal of same |
| WO2018030463A1 (en) * | 2016-08-10 | 2018-02-15 | 塩野義製薬株式会社 | Substituted polycyclic pyridone derivative and pharmaceutical composition containing prodrug thereof |
Non-Patent Citations (4)
| Title |
|---|
| IDREES MOHAMMED等: "SAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis Inhibitor", 《ACS MEDICINAL CHEMISTRY LETTERS》 * |
| SRIRAM NAGANATHAN等: "Process Development and Scale-Up of a Benzoxazepine-Containing Kinase Inhibitor", 《ORG. PROCESS RES. DEV》 * |
| STN REGISTRY数据库: "1824062-47-6，1807273-66-0", 《STN REGISTRY数据库》 * |
| 郑凤然 等: "对溴甲基苯甲酸合成工艺研究", 《广东化工》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110872225A (en) * | 2019-10-29 | 2020-03-10 | 广东东阳光药业有限公司 | Preparation method of Barosavir intermediate |
| CN111808069A (en) * | 2020-07-21 | 2020-10-23 | 中国药科大学 | Preparation method of baroxavir key intermediate and intermediate thereof |
| CN111808069B (en) * | 2020-07-21 | 2022-05-17 | 中国药科大学 | Preparation method of baroxavir key intermediate and intermediate thereof |
| CN112062750A (en) * | 2020-07-22 | 2020-12-11 | 和鼎（南京）医药技术有限公司 | Process for preparing a Barosavir intermediate and intermediate obtained by this process |
| CN112939932A (en) * | 2021-02-09 | 2021-06-11 | 上海应用技术大学 | Preparation method of sulfur-containing hetero seven-membered ring compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110872247A (en) | Xofluza sulfur-containing heterocyclic compound, intermediate thereof and preparation method | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN100391945C (en) | S-(-)-indolyl-2-carboxylic acid synthesizing method | |
| US11773073B2 (en) | Method for synthesizing myricetin | |
| CN103254201B (en) | A kind of preparation method of asenapine | |
| CN105541819A (en) | Preparation method and intermediate of brexpiprazole and preparation method of intermediate | |
| CN106397235A (en) | Bromfenac sodium preparation method | |
| WO2018214676A1 (en) | Buagafuran active pharmaceutical ingredient and preparation method and application thereof | |
| CN105622380B (en) | Preparation method of apremilast and intermediate thereof | |
| CN106008316A (en) | New method for synthesizing Ledipasvir chiral intermediate | |
| CN112062669A (en) | Process for preparing aromatic compounds | |
| CN106831863B (en) | Montelukast sodium intermediate and its preparation method and application | |
| CN109651238A (en) | A kind of new method preparing picosulfate sodium | |
| CN114380732B (en) | Preparation method of fluoroindole carboxylic acid compound | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| CN111138349A (en) | Synthesis method of tirofiban hydrochloride intermediate III | |
| CN102942542B (en) | The preparation method of 2,3-Dihydrobenzofuranes compounds | |
| WO2016127874A1 (en) | Method for preparing vorapaxar sulfate, and intermediate and preparation method therefor | |
| CN112390707B (en) | Preparation and application of (Z) -3, 5-dihydroxy-4-isopropyl stilbene | |
| CN103980135A (en) | Preparation method of 4-amino-2-fluorobenzoic acid | |
| CN113956268B (en) | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method | |
| CN110862311B (en) | Synthesis method of 1-hydroxycyclopropanecarboxylic acid and carboxylate | |
| CN111349012B (en) | Preparation method of halogenated aromatic compound and intermediate thereof | |
| Walton et al. | Studies in the Quinoline Series. II. The Monoaminophenylquinaldylcarbinols | |
| CN109836425B (en) | Preparation process of synthetic pemetrexed |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200310 |