WO2022126826A1 - 塞利尼索及其中间体的制备方法 - Google Patents

塞利尼索及其中间体的制备方法 Download PDF

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WO2022126826A1
WO2022126826A1 PCT/CN2021/073127 CN2021073127W WO2022126826A1 WO 2022126826 A1 WO2022126826 A1 WO 2022126826A1 CN 2021073127 W CN2021073127 W CN 2021073127W WO 2022126826 A1 WO2022126826 A1 WO 2022126826A1
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formula
compound represented
solvent
preparation
reaction
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PCT/CN2021/073127
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English (en)
French (fr)
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徐亮
卢彪
陈昌龙
周炳乾
张绮琳
蔡祥
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佛山奕安赛医药科技有限公司
中山奕安泰医药科技有限公司
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Publication of WO2022126826A1 publication Critical patent/WO2022126826A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a preparation method of selinesol and an intermediate thereof.
  • Selinexor is shown in formula I, and its chemical name is: (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2 , 4-Triazol-1-yl)-N'-(pyrazin-2-yl)acrylohydrazide.
  • the above synthetic route 1 takes 3,5-bistrifluoromethyl benzonitrile as raw material to obtain intermediate (III) through addition and condensation reaction, and takes propyonic acid as raw material to obtain intermediate (IV) through esterification and addition reaction. ), intermediate (III) and intermediate (IV) are subjected to a substitutional condensation reaction to obtain intermediate (V), which is further hydrolyzed to obtain intermediate (II), and intermediate (II) and pyrazine-2-hydrazine are subjected to amidation reaction The target compound selinisol (I) was prepared.
  • the synthetic route has relatively long process steps, and requires the use of raw materials such as propyolic acid with poor stability.
  • intermediate (III) hydrogen sulfide waste gas with strong irritating odor will be produced;
  • intermediate (III) and intermediate (IV) Using N,N-dimethylformamide as a solvent, it is difficult to recover, and a large amount of waste water will be generated;
  • the preparation of intermediate (V) will produce by-product trans isomers, which need to be separated and purified by column chromatography, using a large amount of elution Solvent, and a large amount of silica solid waste is generated; the overall yield of the preparation intermediate (II) is low and the trans-isomer impurities are difficult to control.
  • World Patent WO2017118940 discloses an improved Selinexor and its intermediate (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2 , The preparation method of 4-triazol-1-yl) acrylic acid is shown in the synthetic route two.
  • World patent WO2018129227 discloses another improved Selinexor and its intermediate (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1, The preparation method of 2,4-triazol-1-yl)acrylic acid is shown in synthetic route three.
  • R 1 is selected from C 1-9 alkyl, cycloalkyl having 3-8 ring atoms, heterocyclyl having 3-8 ring atoms, aryl having 5-20 ring atoms or 5-20 Heteroaryl with ring atoms;
  • X is halogen
  • R 1 is selected from methyl, ethyl or isopropyl; X is chlorine or bromine.
  • R 1 is selected from C 1-9 alkyl, cycloalkyl with 3-8 ring atoms, heterocyclyl with 3-8 ring atoms, aryl with 5-20 ring atoms or 5 - Heteroaryl with 20 ring atoms;
  • R 2 is selected from alkali metals or alkaline earth metals
  • R 3 is selected from: C 1-9 alkyl, C 1-9 alkoxy or hydroxyl; and two R 3 can form a substituted or unsubstituted cyclic structure together with B;
  • X is halogen
  • R 1 is selected from methyl, ethyl or isopropyl
  • R is selected from lithium, sodium , potassium, magnesium or calcium;
  • R 3 is selected from: C 1-4 alkoxy or hydroxyl; and two R 3 can form together with B structure, R 4 , R 5 , R 6 , R 7 are each independently C 1-4 alkyl; and/or
  • X is chlorine or bromine.
  • providing the compound represented by formula (II-3) comprises the following steps:
  • R 2 is selected from alkali metals or alkaline earth metals, preferably R 2 is lithium, sodium, potassium, magnesium or calcium.
  • the step of reacting the compound represented by the formula (II-1) with the compound represented by the formula (II-2) includes the following steps
  • the acid is at least one of acetic acid and trifluoroacetic acid, preferably acetic acid.
  • the step of reacting the compound represented by the formula (II-3) and the compound represented by the formula (II-4) comprises the following steps:
  • the alkali is selected from: at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine or triethylenediamine and;
  • the solvent is selected from at least one of ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and dimethylsulfoxide. A sort of.
  • the alkali is: the combination of sodium carbonate and triethylamine, or the combination of potassium carbonate and triethylamine;
  • the solvent is selected from ethanol or tetrahydrofuran.
  • the step of reacting the compound represented by the formula (II-5) and the compound represented by the formula (II-6) comprises the following steps:
  • the catalyst is selected from: palladium catalyst or nickel catalyst;
  • the solvent is at least one of alcohol, ethanol, tetrahydrofuran, 1,4-dioxane, toluene and water;
  • the alkali is at least one of sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide and barium hydroxide.
  • the catalyst is tetrakis(triphenylphosphorus)palladium or tris(dibenzylideneacetone)dipalladium;
  • the solvent is a combination of tetrahydrofuran and water, or a combination of toluene and water.
  • the step of reacting the compound represented by formula (II-7) comprises the following steps:
  • the alkali is at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide;
  • the solvent is at least one of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetone and water, and the solvent contains at least water.
  • a kind of preparation method of celinisol comprises the following steps:
  • the preparation method of the intermediate of the structure represented by the above formula (II) innovatively uses the compound represented by the formula (II-3) and the compound represented by the formula (II-4) to carry out a substitution reaction to prepare the compound represented by the formula (II-5).
  • the compound represented by the formula (II-5) is then coupled with the compound represented by the formula (II-6) to obtain the compound represented by the formula (II-7), and then the compound represented by the formula (II-7)
  • the compound shown can be hydrolyzed and acidified to obtain the intermediate of the structure shown in (II).
  • the entire synthesis route is short, the reaction conditions are mild, no malodorous gas is generated during the reaction process, and the safety is high, and the solvent of each reaction type has a wide acceptable range, and a solvent with high safety and simple post-processing can be selected for the reaction. , effectively avoiding the problem of large amount of waste water caused by the use of solvents such as N,N-dimethylformamide in the traditional route.
  • the product obtained in each step has high purity and simple post-processing, which can effectively avoid the increase of industrial cost caused by high separation and purification difficulty, has high environmental protection and economic benefits, and is especially suitable for industrial production.
  • alkyl refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, for example, "C 1-9 alkyl” refers to an alkyl group containing 1 to 9 carbon atoms, each occurrence of which may independently be C 1 alkyl, C 2 alkyl, C 3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl or C9 alkyl.
  • Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ) , 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 ) )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 ) CH 2 CH 2 CH 3 ), 2-p
  • alkoxy refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom. Phrases containing this term, for example, "C 1-9 alkoxy” means that the alkyl moiety contains 1 to 9 carbon atoms, and each occurrence may independently be C 1 alkoxy, C 4 alkoxy group, C 5 alkoxy, C 6 alkoxy, C 7 alkoxy, C 8 alkoxy or C 9 alkoxy.
  • Suitable examples include, but are not limited to: methoxy (-O- CH3 or -OMe), ethoxy (-O- CH2CH3 or -OEt) and tert-butoxy (-OC( CH3 ) 3 or -OtBu).
  • cycloalkyl refers to a non-aromatic hydrocarbon containing ring carbon atoms, which may be monocycloalkyl, or spirocycloalkyl, or bridged cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Additionally, “cycloalkyl” may also contain one or more double bonds, and representative examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl .
  • Aryl refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom, which can be a single-ring aryl group, a fused-ring aryl group, or a polycyclic aryl group.
  • polycyclic ring species at least One is an aromatic ring system.
  • aryl having 5-20 ring atoms refers to an aryl group containing 5-20 carbon atoms, and each occurrence may independently be C 5 aryl, C 6 aryl, C 10 aryl group, C 14 aryl, C 18 aryl or C 20 aryl.
  • Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof. It will be appreciated that multiple aryl groups can also be interrupted by short non-aromatic units (eg ⁇ 10% non-H atoms, such as C, N or O atoms), specifically such as acenaphthene, fluorene, or 9,9-diaryl Fluorene, triarylamine, diaryl ether systems should also be included in the definition of aryl.
  • non-aromatic units eg ⁇ 10% non-H atoms, such as C, N or O atoms
  • Heteroaryl means that on the basis of an aryl group, at least one carbon atom is replaced by a non-carbon atom, and the non-carbon atom can be N atom, O atom, S atom and the like.
  • aryl having 5-20 ring atoms refers to a heteroaryl group containing 5-20 carbon atoms.
  • Suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrrolo imidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furanofuran, thienofuran, benzisoxazole, benziisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine , triazine, quinoline, isoquinoline, naphthalene, quinoxaline, phenanthridine, primary pyridine, quinazoline and quinazolinone.
  • Heterocyclyl means that at least one carbon atom is replaced by a non-carbon atom on the basis of a cycloalkyl group. Suitable examples include, but are not limited to: dihydropyridyl, tetrahydropyridyl (piperidinyl), tetrahydrothienyl, sulfur-oxidized tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinoline base, indoline.
  • Halogen or halo refers to F, Cl, Br or I.
  • R 1 is selected from C 1-9 alkyl, cycloalkyl having 3-8 ring atoms, heterocyclyl having 3-8 ring atoms, aryl having 5-20 ring atoms or 5-20 Heteroaryl of ring atoms;
  • X is halogen
  • R 1 is selected from C 1-6 alkyl, cyclohexyl or phenyl; further, R 1 is selected from C 1-4 alkyl; further, R 1 is selected from methyl, ethyl or iso- propyl.
  • X is chlorine or bromine.
  • One embodiment of the present invention provides a method for preparing an intermediate of a structure represented by formula (II), comprising the following steps:
  • the compound represented by the formula (II-3) can be prepared by the existing method, preferably the compound represented by the formula (II-3) is prepared by the following method:
  • the compound represented by formula (II-1) can be a commercially available substance, or can be prepared by an existing method.
  • R 2 is selected from alkali metal or alkaline earth metal;
  • X is halogen; further, R 2 is selected from lithium, sodium, potassium, magnesium or calcium; further, R 2 is selected from sodium or potassium; further, X is Bromine or iodine.
  • step S1012 is an addition reaction, by mixing the compound represented by formula (II-2) with an acid to generate hydrogen halide, and performing addition reaction with the compound represented by formula (II-1) to obtain formula (II) -3) The compound shown.
  • step S1012 includes the following steps: mixing the compound represented by formula (II-1), the compound represented by formula (II-2), an acid and a solvent, and performing an addition reaction.
  • the acid is at least one of acetic acid and trifluoroacetic acid, preferably acetic acid.
  • the temperature of the addition reaction is 40-110°C, particularly preferably 60-80°C.
  • the molar ratio of the compound represented by the formula (II-1) and the compound represented by the formula (II-2) is 1:(1-2); further, the compound represented by the formula (II-1) and the formula ( The molar ratio of the compound shown in II-2) is 1:(1.3-1.6);
  • the mol ratio of compound shown in formula (II-1) and acid is 1:(3-8); Further, the mol ratio of compound shown in formula (II-1) and acid is 1:(5- 7).
  • step S102 the compound represented by formula (II-3) and the compound represented by formula (II-4) undergo a substitution reaction.
  • step S102 includes the following steps: mixing the compound represented by the formula (II-3), the compound represented by the formula (II-4), a base and a solvent, and performing a substitution reaction;
  • step S102 includes the following steps: mixing the compound represented by the formula (II-4), the base and the solvent to form a mixed solution, and gradually adding the formula at a temperature of -20 to 40°C (preferably -10 to 10°C) dropwise.
  • the compound represented by (II-3) after the dropwise addition is completed, the reaction is kept at a temperature, and after the reaction is completed, post-processing is performed to obtain the compound represented by the formula (II-5).
  • the alkali is at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine or triethylenediamine and; in one embodiment , the alkali is the combination of sodium carbonate and triethylamine; Further, the mass ratio of sodium carbonate and triethylamine is 1:0.1-1:10; In one embodiment, the alkali is the combination of potassium carbonate and triethylamine; Further, the mass ratio of potassium carbonate and triethylamine is 1:0.1-1:10.
  • the solvent is selected from: ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide. at least one; in one embodiment, the solvent is ethanol. In one embodiment, the solvent is tetrahydrofuran.
  • step S102 the molar ratio of the compound represented by the formula (II-3) and the compound represented by the formula (II-4) is 1:(0.5-1); further, the compound represented by the formula (II-3) The molar ratio of the compound to the compound represented by formula (II-4) is 1:(0.7-0.9).
  • One embodiment of the present invention provides a method for preparing an intermediate of the structure represented by formula (II), comprising the following steps:
  • R 1 is selected from C 1-9 alkyl, cycloalkyl with 3-8 ring atoms, heterocyclyl with 3-8 ring atoms, aryl with 5-20 ring atoms or 5 -Heteroaryl with 20 ring atoms; further, R 1 is selected from C 1-6 alkyl, cyclohexyl or phenyl; further, R 1 is selected from C 1-4 alkyl; further, R 1 is selected from methyl, ethyl or isopropyl.
  • the compound represented by formula (II-1) can be a commercially available substance, or can be prepared by an existing method.
  • the compound represented by the formula (II-1) is cheap and easy to obtain, and using it as a raw material can reduce the production cost.
  • R 2 is selected from alkali metal or alkaline earth metal;
  • X is halogen; further, R 2 is selected from lithium, sodium, potassium, magnesium or calcium; further, R 2 is selected from sodium or potassium; further, X is Bromine or iodine.
  • step S202 is an addition reaction, by mixing the compound represented by formula (II-2) with an acid to generate hydrogen halide, and performing addition reaction with the compound represented by formula (II-1) to obtain formula (II) -3) The compound shown.
  • step S202 includes the following steps: mixing the compound represented by formula (II-1), the compound represented by formula (II-2), an acid and a solvent, and performing an addition reaction.
  • the acid is at least one of acetic acid and trifluoroacetic acid, preferably acetic acid.
  • the temperature of the addition reaction is 40-110°C, particularly preferably 60-80°C.
  • the molar ratio of the compound represented by the formula (II-1) and the compound represented by the formula (II-2) is 1:(1-2); further, the compound represented by the formula (II-1) and the formula ( The molar ratio of the compound shown in II-2) is 1:(1.3-1.6);
  • the mol ratio of compound shown in formula (II-1) and acid is 1:(3-8); Further, the mol ratio of compound shown in formula (II-1) and acid is 1:(5- 7).
  • step S203 the compound represented by formula (II-3) and the compound represented by formula (II-4) undergo a substitution reaction.
  • steps S201 and S202 can be omitted, which should not be construed as a limitation of the present invention, and the methods of S201 and S202 are preferably used to prepare the formula (II-3) compound shown.
  • step S203 includes the following steps: mixing the compound represented by the formula (II-3), the compound represented by the formula (II-4), a base and a solvent, and performing a substitution reaction;
  • step S203 includes the following steps: mixing the compound represented by the formula (II-4), the base and the solvent to form a mixed solution, and gradually adding the formula at a temperature of -20 to 40°C (preferably -10 to 10°C) dropwise.
  • the compound represented by (II-3) after the dropwise addition is completed, the reaction is kept at a temperature, and after the reaction is completed, post-processing is performed to obtain the compound represented by the formula (II-5).
  • the alkali is at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine or triethylenediamine and; in one embodiment , the alkali is the combination of sodium carbonate and triethylamine; Further, the mass ratio of sodium carbonate and triethylamine is 1:0.1-1:10; In one embodiment, the alkali is the combination of potassium carbonate and triethylamine; Further, the mass ratio of potassium carbonate and triethylamine is 1:0.1-1:10.
  • the solvent is selected from: ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide. at least one; in one embodiment, the solvent is ethanol. In one embodiment, the solvent is tetrahydrofuran.
  • step S203 the molar ratio of the compound represented by the formula (II-3) and the compound represented by the formula (II-4) is 1:(0.5-1); further, the compound represented by the formula (II-3) The molar ratio of the compound to the compound represented by formula (II-4) is 1:(0.7-0.9).
  • R 3 is selected from: C 1-9 alkyl, C 1-9 alkoxy or hydroxyl; and two R 3 can form a substituted or unsubstituted cyclic structure together with B; further, R 3 selects From: C 1-6 alkyl, C 1-6 alkoxy or hydroxy; further, R 3 is selected from: C 1-4 alkoxy or hydroxy, and two R 3 and B together can be formed by a or multiple C 1-4 alkyl substituted 5-membered cyclic structures; furthermore, two R 3 can be formed together with B; Structure; R 4 , R 5 , R 6 , R 7 are each independently C 1-4 alkyl; further, R 4 , R 5 , R 6 , and R 7 are each independently methyl or ethyl. Still further, R 3 is selected from hydroxyl.
  • the two R 3 in -B(R 3 ) 2 may be the same or different from each other, which should be understood as being within the protection scope of the present invention.
  • step S204 the compound represented by the formula (II-5) and the compound represented by the formula (II-6) are subjected to a coupling reaction to obtain the compound represented by the formula (II-7).
  • step S204 includes the following steps: mixing the compound represented by the formula (II-5), the compound represented by the formula (II-6), a catalyst, a base and a solvent to carry out a coupling reaction.
  • the catalyst is selected from: palladium catalyst or nickel catalyst; preferably, the catalyst is tetrakis(triphenylphosphorus) palladium or tris(dibenzylideneacetone)dipalladium.
  • the solvent is selected from at least one of alcohol, ethanol, tetrahydrofuran, 1,4-dioxane, toluene or water; in one embodiment, the solvent is a combination of tetrahydrofuran and water; further, the volume of tetrahydrofuran and water The ratio is (1-2): 1; further, the volume ratio of tetrahydrofuran and water is (1.3-1.8): 1; in one embodiment, it is dissolved in a combination of toluene and water; further, toluene and water The volume ratio of toluene is (1-2):1; further, the volume ratio of toluene and water is (1.3-1.8):1.
  • the alkali is at least one of sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide and barium hydroxide; preferably the alkali is selected from sodium carbonate or potassium carbonate.
  • step S204 the molar ratio of the compound represented by formula (II-5) and the compound represented by formula (II-6) is 1:(1-1.3).
  • the temperature of the coupling reaction is 50-100°C, particularly preferably 60-80°C.
  • step S205 the compound represented by the formula (II-7) can be hydrolyzed first to obtain the salt of the structure represented by the formula (II), and then an acid is added to obtain the structure represented by the formula (II) the intermediate.
  • step S205 includes the following steps: mixing the compound shown in formula (II-7), the base and the solvent, carrying out a hydrolysis reaction, adding an acid after the reaction is completed, and adjusting the pH value of the reaction solution to less than 5 (preferably 2- 3).
  • step S205 includes the following steps: dissolving the compound represented by formula (II-7) in the first solvent, then cooling to 0-10° C., and then slowly adding an aqueous solution of alkali dropwise, and after the dropping is completed, keeping the temperature for 1 -2h, after the reaction is complete, add acid to adjust the pH to 2-3, a solid is precipitated, filtered, and dried to obtain an intermediate of the structure shown in formula (II), wherein the first solvent is an organic solvent that is miscible with water , and further, the first solvent is at least one of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane and acetone.
  • the base is lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; preferably the base is lithium hydroxide or sodium hydroxide.
  • the solvent is at least one of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetone and water.
  • the solvent in step S205, is a mixed solvent composed of ethanol and water; further, the volume ratio of ethanol and water is (1.5-5): 1; further, the volume ratio of ethanol and water is ( 2-3): 1.
  • the solvent in step S105, is a mixed solvent composed of tetrahydrofuran and water; further, the volume ratio of tetrahydrofuran and water is (1.5-5): 1; further, the volume ratio of tetrahydrofuran and water is ( 2-3): 1.
  • the mol ratio of the compound shown in formula (II-7) and the base is 1:(1.5-5); Further, the mol ratio of the compound shown in formula (II-7) and the base is 1:(1.8- 2.2).
  • the acid is an inorganic acid; further, the acid is at least one of hydrochloric acid and sulfuric acid.
  • the preparation method of the intermediate of the structure represented by the above formula (II) innovatively uses the cheap and easily available compound represented by the formula (II-1) as the raw material, and firstly obtains the compound represented by the formula (II-3) through an addition reaction. , and then through the substitution reaction, the compound represented by the formula (II-5) is prepared, and then the compound represented by the formula (II-5) and the compound represented by the formula (II-6) are subjected to a coupling reaction to prepare the formula (II- 7) the compound represented by the formula (II-7), and then the compound represented by the formula (II-7) is subjected to hydrolysis reaction and acidified to obtain the intermediate of the structure represented by (II).
  • the entire synthesis route is short, the reaction conditions are mild, no malodorous gas is generated during the reaction process, and the safety is high, and the solvent of each reaction type has a wide acceptable range, and a solvent with high safety and simple post-processing can be selected for the reaction. , effectively avoiding the problem of large amount of waste water caused by the use of solvents such as N,N-dimethylformamide in the traditional route. And in the above reaction, the product obtained in each step has high purity, simple post-processing, can effectively avoid the increase of industrial cost caused by high separation and purification difficulty, has high environmental protection and economic benefits, and is especially suitable for industrial production.

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Abstract

一种塞利尼索及其中间体的制备方法，该方法整个合成路线较短，反应条件温和，反应过程中无恶臭气体的产生，安全性较高，且各反应类型溶剂可接受范围较广，可以选择安全性较高、且后处理简单的溶剂进行反应，有效地避免了传统路线中需要使用N,N-二甲基甲酰胺等溶剂而导致的废水量大的问题。且上述反应中，各步骤所得到的产品纯度较高，后处理简单，能够有效地避免分离纯化难度较高而导致的工业成本的增加，具有较高环保经济效益，特别适合工业化生产。

Description

塞利尼索及其中间体的制备方法 技术领域
本发明涉及药物化学技术领域，特别涉及塞利尼索及其中间体的制备方法。
背景技术
塞利尼索(Selinexor)的结构如式I所示，其化学名为：(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-N’-(吡嗪-2-基)丙烯酰肼。
Figure PCTCN2021073127-appb-000001
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸是制备塞利尼索(Selinexor)原料药关键中间体，其结构如中间体(I)所示：
Figure PCTCN2021073127-appb-000002
美国专利US9079865首先报道了塞利尼索(Selinexor)及其中间体(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸的制备方法如合成路线一所示。
合成路线一：
Figure PCTCN2021073127-appb-000003
上述合成路线一，以3,5-双三氟甲基苯腈为原料通过加成和缩合反应得到中间体(Ⅲ)，以丙炔酸为原料通过酯化和加成反应得到中间体(Ⅳ)，中间体(Ⅲ)和中间体(Ⅳ)通过取代缩合反应得中间体(Ⅴ)，进步水解反应得中间体(II)，中间体(II)和吡嗪-2-肼通过酰胺化反应制备得到目标化合物塞利尼索(I)。
该合成路线工艺步骤较长，需要用到稳定性差的丙炔酸等原料，制备中间体(Ⅲ)过程中会产生强烈刺激性臭味的硫化氢废气；制备中间体(Ⅲ)和中间(Ⅳ)用到N,N-二甲基甲酰胺为溶剂，难回收，且会产生大量废水；制备中间体(Ⅴ)会产生副产物反式异构体需通过柱色谱分离纯化，使用大量洗脱溶剂，且产生大量硅胶固废；制备中间体(II)总收率低且反式异构体杂质难控制。
世界专利WO2017118940公开了一种改进的塞利尼索(Selinexor)及其中间体(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸的制备方法如合成路线二所示。
合成路线二：
Figure PCTCN2021073127-appb-000004
上述合成路线二，相对于上述合成路线一，仅在溶剂选择，以及中间体(II)收率和纯度等有所改进，但是没有根本性改变合成路线，也没有公开市场难购得的中间体(Ⅲ)的制备方法，且其还增加了中间体(II)通过成二环己胺盐再用硫酸调酸纯化除副产物反式异构体的繁琐步骤，且反应过程中仍然需要使用N,N-二甲基甲酰胺等溶剂，后处理难度较大，会产生大量废水，不利于工业生产应用。
世界专利WO2018129227公开了另一种改进的塞利尼索(Selinexor)及其中间体(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸的制备方法如合成路线三所示。
合成路线三：
Figure PCTCN2021073127-appb-000005
上述合成路线三，相对于上述合成路线一和合成路线二，仍没有根本性改变合成路线，仅制备中间体(Ⅲ)反应试剂有所改变，例如采用双氧水替代硫氢化钠，以及用中间体(Ⅵ)替代中间体(Ⅳ)。但上述合成路线中所采用的双氧水在工业生产中属于危险品，安全性较低，且反应中需要使用DMSO等溶剂，不适宜工业放大生产。
综上所述，中间体(II)(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸是制备塞利尼索(I，Selinexor)原料药关键中间体，现有合成路线仍然存在反应步骤多、原料市场难购得、工艺危险性高、“三废”多、副反应难控制及成本较高等弊端。寻求原料易得、工艺简洁、环保经济、适合工业化生产的工艺路线，有利于促进塞利尼索(I，Selinexor)原料药的经济技术发展
发明内容
基于此，有必要提供一种塞利尼索及其中间体的制备方法，该方法原料易得、工艺简洁、环保经济，特别适合工业化生产。
一种化合物，具有以下结构：
Figure PCTCN2021073127-appb-000006
R 1选自C 1-9烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或具有5-20个环原子的杂芳基；
X为卤素。
在其中一实施例中，R 1选自甲基、乙基或异丙基；X为氯或溴。
一种式(II)所示结构的中间体的制备方法，包括以下步骤：
Figure PCTCN2021073127-appb-000007
提供式(II-3)所示化合物；
将式(II-3)所示化合物和式(II-4)所示化合物进行反应，制得式(II-5)所示化合物；
将式(II-5)所示化合物和式(II-6)所示化合物进行反应，制得式(II-7)所示化合物；
将式(II-7)所示化合物进行反应，制得式(II)所示结构的中间体；
其中，R 1选自C 1-9烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或具有5-20个环原子的杂芳基；
R 2选自碱金属或碱土金属；
R 3选自：C 1-9烷基、C 1-9烷氧基或羟基；且两个R 3可与B一起形成取代或未取代的环状结构；
X为卤素。
在其中一实施例中，R 1选自甲基、乙基或异丙基；和/或
R 2选自锂、钠、钾、镁或钙；和/或
R 3选自：C 1-4烷氧基或羟基；且两个R 3可与B一起形成
Figure PCTCN2021073127-appb-000008
结构，R 4、R 5、R 6、R 7各自独立地为C 1-4烷基；和/或
X为氯或溴。
在其中一实施例中，所述提供式(II-3)所示化合物包括以下步骤：
Figure PCTCN2021073127-appb-000009
将式(II-1)所示化合物和式(II-2)所示化合物进行反应，制得式(II-3)所示化合物；
R 2选自碱金属或碱土金属，优选R 2为锂、钠、钾、镁或钙。
在其中一实施例中，将式(II-1)所示化合物和式(II-2)所示化合物进行反应的步骤包括以下步骤
将式(II-1)所示化合物、式(II-2)所示化合物、酸和溶剂混合，进行加成反应。
在其中一实施例中，所述酸为乙酸和三氟乙酸中至少一种，优选为乙酸。
在其中一实施例中，将式(II-3)所示化合物和式(II-4)所示化合物进行反应的步骤包括以下步骤：
将式(II-3)所示化合物、式(II-4)所示化合物、碱和溶剂混合，进行取代反应；
其中，所述碱选自：碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙胺或三乙烯二胺及中的至少一种；
所述溶剂选自：乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、四氢呋喃、1，4-二氧六环、N,N-二甲基甲酰胺和二甲基亚砜中的至少一种。
在其中一实施例中，所述碱为：碳酸钠和三乙胺的组合，或碳酸钾和三乙胺的组合；
所述溶剂选自乙醇或四氢呋喃。
在其中一实施例中，将式(II-5)所示化合物和式(II-6)所示化合物进行反应的步骤包括以下步骤：
将式(II-5)所示化合物、式(II-6)所示化合物、催化剂、碱和溶剂混合，进行偶联反应；
其中，所述催化剂选自：钯催化剂或镍催化剂；
所述溶剂为醇、乙醇、四氢呋喃、1，4-二氧六环、甲苯和水中至少一种；
所述碱为碳酸钠、碳酸钾、乙酸钠、氢氧化钠、氢氧化钾和氢氧化钡中至少一种。
在其中一实施例中，所述催化剂为四(三苯基磷)钯或三(二亚苄基丙酮)二钯；
所述溶剂为四氢呋喃和水的组合，或甲苯与水的组合。
在其中一实施例中，将式(II-7)所示化合物进行反应的步骤包括以下步骤：
将式(II-7)所示化合物、碱和溶剂混合，进行水解反应，反应完成后加入酸，将反应液的pH调至pH值小于5；
其中，所述碱为氢氧化锂、氢氧化钠、氢氧化钾和氢氧化钙中至少一种；
所述溶剂为甲醇、乙醇、异丙醇、四氢呋喃、1，4-二氧六环、丙酮和水中至少一种，且所述溶剂中至少含有水。
一种塞利尼索的制备方法，包括以下步骤：
根据上述制备方法制备式(II)所示结构的中间体；
将式(II)所示结构的中间体和吡嗪-2-肼进行反应，制得式(I)所示化合物；
Figure PCTCN2021073127-appb-000010
有益效果：
上述式(II)所示结构的中间体的制备方法创新性地以式(II-3)所示化合物与式(II-4)所示化合物进行取代反应，制得式(II-5)所示化合物，再将式(II-5)所示化合物和式(II-6)所示化合物进行偶联反应，制得式(II-7)所示化合物，然后再将式(II-7)所示化合物经水解反应，并酸化即可获得(II)所示结构的中间体。整个合成路线较短，反应条件温和，反应过程中无恶臭气体的产生，安全性较高，且各反应类型溶剂可接受范围较广，可以选择安全性较 高、且后处理简单的溶剂进行反应，有效地避免了传统路线中需要使用N,N-二甲基甲酰胺等溶剂而导致的废水量大的问题。且上述反应中，各步骤所得到的产品纯度较高，后处理简单，能够有效地避免分离纯化难度较高而导致的工业成本的增加，具有较高环保经济效益，特别适合工业化生产。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述，并给出了本发明的较佳实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
术语
除非另外说明或存在矛盾之处，本文中使用的术语或短语具有以下含义：
术语“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其组合的饱和烃。包含该术语的短语，例如，“C 1-9烷基”是指包含1～9个碳原子的烷基，每次出现时，可以互相独立地为C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基或C 9烷基。合适的实例包括但不限于：甲基(Me、-CH 3)、乙基(Et、-CH 2CH 3)、1-丙基(n-Pr、n-丙基、-CH 2CH 2CH 3)、2-丙基(i-Pr、i-丙基、-CH(CH 3) 2)、1-丁基(n-Bu、n-丁基、-CH 2CH 2CH 2CH 3)、2-甲基-1-丙基(i-Bu、i-丁基、-CH 2CH(CH 3) 2)、2-丁基(s-Bu、s-丁基、-CH(CH 3)CH 2CH 3)、2-甲基-2-丙基(t-Bu、t-丁基、-C(CH 3) 3)、1-戊基(n-戊基、-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)、2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)、1-己基(-CH 2CH 2CH 2CH 2CH 2CH 3)、2-己基 (-CH(CH 3)CH 2CH 2CH 2CH 3)、3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))、2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)、4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)、3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)、2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)、2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)、3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3和辛基(-(CH 2) 7CH 3)。
术语“烷氧基”是指具有-O-烷基的基团，即如上所定义的烷基经由氧原子连接至母核结构。包含该术语的短语，例如，“C 1- 9烷氧基”是指烷基部分包含1～9个碳原子，每次出现时，可以互相独立地为C 1烷氧基、C 4烷氧基、C 5烷氧基、C 6烷氧基、C 7烷氧基、C 8烷氧基或C 9烷氧基。合适的实例包括但不限于：甲氧基(-O-CH 3或-OMe)、乙氧基(-O-CH 2CH 3或-OEt)和叔丁氧基(-O-C(CH 3) 3或-OtBu)。
术语“环烷基”是指包含环碳原子的非芳香族烃，可以为单环烷基、或螺环烷基、或桥环烷基。合适的实例包括但不限于：环丙基、环丁基、环戊基、环己基和环庚基。另外，“环烷基”还可含有一个或多个双键，含有双键的环烷基的代表性实例包括环戊烯基、环己烯基、环己二烯基和环丁二烯基。
“芳基”是指在芳香环化合物的基础上除去一个氢原子衍生的芳族烃基，可以为单环芳基、或稠环芳基、或多环芳基，对于多环的环种，至少一个是芳族环系。例如，“具有5-20个环原子的芳基”是指包含5～20个碳原子的芳基，每次出现时，可以互相独立地为C 5芳基、C 6芳基、C 10芳基、C 14芳基、C 18芳基或C 20芳基。合适的实例包括但不限于：苯、联苯、萘、蒽、菲、二萘嵌苯、三亚苯及其衍生物。可以理解地，多个芳基也可以被短的非芳族单元间断(例如<10％的非H原子，比如C、N或O原子)，具体如苊、芴，或者9,9-二芳基芴、三芳胺、二芳基醚体系也应该包含在芳基的定义中。
“杂芳基”是指在芳基的基础上至少一个碳原子被非碳原子所替代，非碳原子可以为N原子、O原子、S原子等。例如，“具有5-20个环原子的芳基”是指包含5～20个碳原子的杂芳基。合适的实例包括但不限于：呋喃、苯并呋喃、噻吩、苯并噻吩、吡咯、吡唑、三唑、咪唑、噁唑、噁二唑、噻唑、四唑、吲哚、咔唑、吡咯并咪唑、吡咯并吡咯、噻吩并吡咯、噻吩并噻吩、呋喃并吡咯、 呋喃并呋喃、噻吩并呋喃、苯并异噁唑、苯并异噻唑、苯并咪唑、吡啶、吡嗪、哒嗪、嘧啶、三嗪、喹啉、异喹啉、邻二氮萘、喹喔啉、菲啶、伯啶、喹唑啉和喹唑啉酮。
“杂环基”是指在环烷基的基础上至少一个碳原子被非碳原子所替代，非碳原子可以为N原子、O原子、S原子等，可以为饱和环或部分不饱和环。合适的实例包括但不限于：二氢吡啶基、四氢吡啶基(哌啶基)、四氢噻吩基、硫氧化的四氢噻吩基、四氢呋喃基、四氢喹啉基、四氢异喹啉基、二氢吲哚基。
“卤素”或“卤基”是指F、Cl、Br或I。
详细解释
本发明一实施方式提供了一种化合物，具有以下结构：
Figure PCTCN2021073127-appb-000011
R 1选自C 1-9烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或具有5-20个环原子的杂芳基；X为卤素
进一步地，R 1选自C 1-6烷基、环己基或苯基；更进一步地，R 1选自C 1-4烷基；更进一步地，R 1选自甲基、乙基或异丙基。
进一步地，X为氯或溴。
本发明一实施方式提供了一种式(II)所示结构的中间体的制备方法，包括以下步骤：
S101：提供式(II-3)所示化合物；
Figure PCTCN2021073127-appb-000012
可以采用现有的方法制备式(II-3)所示化合物，优选采用以下方法制备式(II-3)所示化合物：
S1011：提供式(II-1)所示化合物；
Figure PCTCN2021073127-appb-000013
可理解的，式(II-1)所示化合物可以为市售物质，也可以采用现有的方法制备而成。
S1012：将式(II-1)所示化合物和式(II-2)所示化合物进行反应，制得式(II-3)所示化合物；
Figure PCTCN2021073127-appb-000014
其中，R 2选自碱金属或碱土金属；X为卤素；进一步地，R 2选自锂、钠、钾、镁或钙；更进一步地，R 2选自钠或钾；进一步地，X为溴或碘。
可理解的，步骤S1012为加成反应，通过使式(II-2)所示化合物和酸混合，产生卤化氢，与式(II-1)所示化合物进行加成反应，制得式(II-3)所示化合物。
进一步地，步骤S1012包括以下步骤：将式(II-1)所示化合物、式(II-2)所示化合物、酸和溶剂混合，进行加成反应。
进一步地，酸为乙酸和三氟乙酸中至少一种，优选为乙酸。
进一步地，加成反应的温度为40-110℃，特别优选60-80℃。
进一步地，式(II-1)所示化合物和式(II-2)所示化合物的摩尔比为1:(1-2)；更进一步地，式(II-1)所示化合物和式(II-2)所示化合物的摩尔比为1:(1.3-1.6)；
进一步地，式(II-1)所示化合物和酸的摩尔比为1:(3-8)；更进一步地，式(II-1)所示化合物和酸的摩尔比为1:(5-7)。
S102：将式(II-3)所示化合物和式(II-4)所示化合物进行反应，制得式(II-5)所示化合物；
Figure PCTCN2021073127-appb-000015
可理解的，步骤S102中，式(II-3)所示化合物和式(II-4)所示化合物进行取代反应。
进一步地，步骤S102包括以下步骤：将式(II-3)所示化合物、式(II-4)所示化合物、碱和溶剂混合，进行取代反应；
更进一步地，步骤S102包括以下步骤：将式(II-4)所示化合物、碱和溶剂混合形成混合液，在-20～40℃(优选-10～10℃)温度下，逐渐滴加式(II-3)所示化合物，滴加完成后，保温反应，待反应完全后，后处理，制得式(II-5)所示化合物。
进一步地，碱为碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙胺或三乙烯二胺及中的至少一种；在一实施例中，碱为碳酸钠和三乙胺的组合；进一步地，碳酸钠和三乙胺的质量比为1:0.1-1:10；在一实施例中，碱为碳酸钾和三乙胺的组合；进一步地，碳酸钾和三乙胺的质量比为1:0.1-1:10。
进一步地，溶剂选自：乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、四氢呋喃、1，4-二氧六环、N,N-二甲基甲酰胺和二甲基亚砜中的至少一种；在一实施例中，溶剂为乙醇。在一实施例中，溶剂为四氢呋喃。
进一步地，步骤S102中，式(II-3)所示化合物和式(II-4)所示化合物的摩尔比为1:(0.5-1)；更进一步地，式(II-3)所示化合物和式(II-4)所示化合物的摩尔比为1:(0.7-0.9)。
本发明一实施方式提供了式(II)所示结构的中间体的制备方法，包括以下步骤：
S201：提供式(II-1)所示化合物；
Figure PCTCN2021073127-appb-000016
其中，R 1选自C 1-9烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或具有5-20个环原子的杂芳基；进一步地，R 1选自C 1-6烷基、环己基或苯基；更进一步地，R 1选自C 1-4烷基；更进一步地，R 1选自甲基、乙基或异丙基。
可理解的，式(II-1)所示化合物可以为市售物质，也可以采用现有的方法制备而成。
式(II-1)所示化合物廉价易得，以其作为原料能够降低生产成本。
S202：将式(II-1)所示化合物和式(II-2)所示化合物进行反应，制得式(II-3)所示化合物；
Figure PCTCN2021073127-appb-000017
其中，R 2选自碱金属或碱土金属；X为卤素；进一步地，R 2选自锂、钠、钾、镁或钙；更进一步地，R 2选自钠或钾；进一步地，X为溴或碘。
可理解的，步骤S202为加成反应，通过使式(II-2)所示化合物和酸混合，产生卤化氢，与式(II-1)所示化合物进行加成反应，制得式(II-3)所示化合物。
进一步地，步骤S202包括以下步骤：将式(II-1)所示化合物、式(II-2)所示化合物、酸和溶剂混合，进行加成反应。
进一步地，酸为乙酸和三氟乙酸中至少一种，优选为乙酸。
进一步地，加成反应的温度为40-110℃，特别优选60-80℃。
进一步地，式(II-1)所示化合物和式(II-2)所示化合物的摩尔比为1:(1-2)；更进一步地，式(II-1)所示化合物和式(II-2)所示化合物的摩尔比为1:(1.3-1.6)；
进一步地，式(II-1)所示化合物和酸的摩尔比为1:(3-8)；更进一步地，式(II-1)所示化合物和酸的摩尔比为1:(5-7)。
S203：将式(II-3)所示化合物和式(II-4)所示化合物进行反应，制得式(II-5)所示化合物；
Figure PCTCN2021073127-appb-000018
可理解的，步骤S203中，式(II-3)所示化合物和式(II-4)所示化合物进 行取代反应。另外，当采用现有的方法制备式(II-3)所示化合物时，可以省略步骤S201和S202，不应理解为对本发明的限制，优选采用S201和S202的方法制备式(II-3)所示化合物。
进一步地，步骤S203包括以下步骤：将式(II-3)所示化合物、式(II-4)所示化合物、碱和溶剂混合，进行取代反应；
更进一步地，步骤S203包括以下步骤：将式(II-4)所示化合物、碱和溶剂混合形成混合液，在-20～40℃(优选-10～10℃)温度下，逐渐滴加式(II-3)所示化合物，滴加完成后，保温反应，待反应完全后，后处理，制得式(II-5)所示化合物。
进一步地，碱为碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙胺或三乙烯二胺及中的至少一种；在一实施例中，碱为碳酸钠和三乙胺的组合；进一步地，碳酸钠和三乙胺的质量比为1:0.1-1:10；在一实施例中，碱为碳酸钾和三乙胺的组合；进一步地，碳酸钾和三乙胺的质量比为1:0.1-1:10。
进一步地，溶剂选自：乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、四氢呋喃、1，4-二氧六环、N,N-二甲基甲酰胺和二甲基亚砜中的至少一种；在一实施例中，溶剂为乙醇。在一实施例中，溶剂为四氢呋喃。
进一步地，步骤S203中，式(II-3)所示化合物和式(II-4)所示化合物的摩尔比为1:(0.5-1)；更进一步地，式(II-3)所示化合物和式(II-4)所示化合物的摩尔比为1:(0.7-0.9)。
S204：将式(II-5)所示化合物和式(II-6)所示化合物进行反应，制得式(II-7)所示化合物；
Figure PCTCN2021073127-appb-000019
其中，R 3选自：C 1-9烷基、C 1-9烷氧基或羟基；且两个R 3可与B一起形成取代或未取代的环状结构；更进一步地，R 3选自：C 1-6烷基、C 1-6烷氧基或羟基； 更进一步地，R 3选自：C 1-4烷氧基或羟基，且两个R 3与B一起可形成被一个或多个C 1-4烷基取代的5元环状结构；更进一步地，两个R 3可与B一起形成；
Figure PCTCN2021073127-appb-000020
结构；R 4、R 5、R 6、R 7各自独立地为C 1-4烷基；更进一步地，R 4、R 5、R 6、R 7各自独立地为甲基或乙基。更进一步地，R 3选自羟基。
可理解的，本发明中-B(R 3) 2中两个R 3可以彼此相同或不同，应理解为均在本发明的保护范围内。
可理解的，步骤S204中，式(II-5)所示化合物和式(II-6)所示化合物进行偶联反应，制得式(II-7)所示化合物。
进一步地，步骤S204包括以下步骤：将式(II-5)所示化合物、式(II-6)所示化合物、催化剂、碱和溶剂混合，进行偶联反应。
进一步地，催化剂选自：钯催化剂或镍催化剂；优选催化剂为四(三苯基磷)钯或三(二亚苄基丙酮)二钯。
进一步地，溶剂选自醇、乙醇、四氢呋喃、1，4-二氧六环、甲苯或水中至少一种；在一实施例中，溶剂为四氢呋喃和水的组合；进一步地，四氢呋喃和水的体积比为(1-2):1；更进一步地，四氢呋喃和水的体积比为(1.3-1.8):1；在一实施例中，溶解为甲苯与水的组合；更进一步地，甲苯和水的体积比为(1-2):1；更进一步地，甲苯和水的体积比为(1.3-1.8):1。
进一步地，碱为碳酸钠、碳酸钾、乙酸钠、氢氧化钠、氢氧化钾和氢氧化钡中至少一种；优选碱为选碳酸钠或碳酸钾。
进一步地，步骤S204中，式(II-5)所示化合物和式(II-6)所示化合物的摩尔比为1:(1-1.3)。
进一步地，步骤S204中，偶联反应的温度为50～100℃，特别优选60～80℃。
S205：将式(II-7)所示化合物进行反应，制得式(II)所示结构的中间体。
可理解的，步骤S205中，式(II-7)所示化合物可以先进行水解反应，制得式(II)所示结构的盐，然后再加入酸，即可获得式(II)所示结构的中间体。
进一步地，步骤S205包括以下步骤：将式(II-7)所示化合物、碱和溶剂 混合，进行水解反应，反应完成后加入酸，将反应液的pH值调节至小于5(优选为2-3)。
更进一步地，步骤S205包括以下步骤：将式(II-7)所示化合物溶于第一溶剂中，然后降温至0-10℃，然后缓慢滴加碱的水溶液，滴加完毕后，保温1-2h，待反应完全后，加入酸调pH至2-3，有固体析出，过滤，干燥，制得式(II)所示结构的中间体，其中，第一溶剂为与水互溶的有机溶剂，进一步地，第一溶剂为甲醇、乙醇、异丙醇、四氢呋喃、1，4-二氧六环和丙酮中至少一种。
进一步地，碱为氢氧化锂、氢氧化钠、氢氧化钾或氢氧化钙；优选碱为氢氧化锂或氢氧化钠。
进一步地，溶剂为甲醇、乙醇、异丙醇、四氢呋喃、1，4-二氧六环、丙酮和水中至少一种。在一实施例中，步骤S205中，溶剂为乙醇和水组成的混合溶剂；进一步地，乙醇和水的体积比为(1.5-5):1；更进一步地，乙醇和水的体积比为(2-3):1。在一实施例中，步骤S105中，溶剂为四氢呋喃和水组成的混合溶剂；进一步地，四氢呋喃和水的体积比为(1.5-5):1；更进一步地，四氢呋喃和水的体积比为(2-3):1。
进一步地，式(II-7)所示化合物和碱的摩尔比为1:(1.5-5)；更进一步地，式(II-7)所示化合物和碱的摩尔比为1:(1.8-2.2)。
进一步地，酸为无机酸；更进一步地，酸为盐酸和硫酸中至少一种。
上述式(II)所示结构的中间体的制备方法创新性地以廉价易得的式(II-1)所示化合物为原料，先通过加成反应制得式(II-3)所示化合物，然后经取代反应，制得式(II-5)所示化合物，再将式(II-5)所示化合物和式(II-6)所示化合物进行偶联反应，制得式(II-7)所示化合物，然后再将式(II-7)所示化合物经水解反应，并酸化即可获得(II)所示结构的中间体。整个合成路线较短，反应条件温和，反应过程中无恶臭气体的产生，安全性较高，且各反应类型溶剂可接受范围较广，可以选择安全性较高、且后处理简单的溶剂进行反应，有效地避免了传统路线中需要使用N,N-二甲基甲酰胺等溶剂而导致的废水量大的问题。且上述反应中，各步骤所得到的产品纯度较高，后处理简单，能够有效地避免分离纯化难度较高而导致的工业成本的增加，具有较高环保经济效益， 特别适合工业化生产。
下面列举具体实施例来对本发明进行说明。
实施例1
式化合物(2)(Z)-3-碘丙烯酸乙酯的制备
Figure PCTCN2021073127-appb-000021
于500ml反应瓶，加入冰乙酸(232g，3.86mol)，丙炔酸乙酯(58g，0.591mol)，碘化钠(133g，0.887mol)，搅拌升温至60-80℃，保温5-7小时，取样TLC分析，原料丙炔酸乙酯转化完；减压浓缩回收冰乙酸；残留物降温15-25℃，加入水(116ml)和甲基叔丁基醚(174ml)萃洗，分出有机层再用水(116ml)洗，浓缩有机层至干回收甲基叔丁基醚，得到黄色液体(Z)-3-碘丙烯酸乙酯(112.2g，0.496mol)，收率84％，HPLC纯度95.0％。
实施例2
化合物(4)(Z)-3-(3-溴-1H-1,2,4-三氮唑-1-基)丙烯酸乙酯的制备
Figure PCTCN2021073127-appb-000022
于500ml反应瓶，加入3-溴-1H-1,2,4-三氮唑(20g，0.135mol)，乙醇(120ml)，碳酸钾(37.6g，0.27mol)，搅拌降温至-10～10℃，滴加(Z)-3-碘丙烯酸乙酯(36.6g，0.162mol)，加完保温1-2小时，取样TLC分析，原料3-溴-1H-1,2,4-三氮唑转化完；减压浓缩回收乙醇；残留物降温15-25℃，加入水(60ml)和乙酸乙酯(100ml)萃洗，分出有机层再用水(60ml)洗；减压浓缩有机层至干回收乙酸乙酯，残留物加入甲醇(40ml)结晶，过滤，洗涤，干燥得到类白色固体粉末(Z)-3-(3-溴-1H-1,2,4-三氮唑-1-基)丙烯酸乙酯(25.2g，0.103mol)，收率76％，HPLC纯度98.6％。 1H NMR(CDCl3)δ1.30-1.34(t，3H)，4.22-4.27(q，2H)，5.69-5.72(d，1H)，7.14-7.17(d，1H)，9.57(s，1H)。
实施例3
化合物(6)(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸乙酯的制备
Figure PCTCN2021073127-appb-000023
于250ml反应瓶，加入(Z)-3-(3-溴-1H-1,2,4-三氮唑-1-基)丙烯酸乙酯(10g，0.041mol)，3,5-双(三氟甲基)苯硼酸(12.6g，0.049mol)，甲苯(80ml)，水(50ml)，碳酸钠(10.4g，0.098mol)，四丁基溴化铵(0.1g，0.4mmol)，四(三苯基磷)钯(0.5g，0.4mmol)，搅拌升温至60-80℃，保温16-24小时，取样TLC分析，原料(Z)-3-(3-溴-1H-1,2,4-三氮唑-1-基)丙烯酸乙酯基本转化完；加入活性炭(1g)，降温15-25℃，过滤出活性炭，静置分出有机层再用水(30ml)洗；减压浓缩有机层至干回收甲苯，残留物加入甲醇(20ml)结晶，过滤，洗涤，干燥得到类白色固体粉末(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸乙酯(13.2g，0.035mol)，收率85％，HPLC纯度98.2％。1H NMR(CDCl3)δ1.33-1.37(t，3H)，4.26-4.32(q，2H)，5.76-5.79(d，1H)，7.28-7.31(d，1H)，7.93(s，1H)，8.60(s，2H)，9.74(s，1H)。
实施例4
中间体(II)(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸的制备
Figure PCTCN2021073127-appb-000024
于100ml反应瓶，加入(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸乙酯(8g，0.021mol)，乙醇(24ml)，搅拌溶解，降温至0-10℃，滴加氢氧化钠(1.7g，0.042mol)溶于水(10ml)的溶液，加完保温1-2小时，取样 TLC分析，原料(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸乙酯转化完；加入水40ml，滴加3mol/L盐酸(14ml，0.042mol)调pH＝2-3，析出白色固体，过滤，洗涤，干燥得到白色固体粉末塞利尼索中间体(II)(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸(6.7g，0.019mol)，收率91％，HPLC纯度98.9％。1H NMR(CDCl3)δ5.85-5.88(d，1H)，7.32-7.35(d，1H)，7.97(s，1H)，8.59(s，2H)，9.35(s，1H)。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种化合物，其特征在于，具有以下结构：
    Figure PCTCN2021073127-appb-100001
    R 1选自C 1-9烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或具有5-20个环原子的杂芳基；优选R 1选自甲基、乙基或异丙基
    X为卤素，优选X为氯或溴。
  2. 权利要求1所述的化合物的制备方法，包括以下步骤：
    Figure PCTCN2021073127-appb-100002
    提供式(II-3)所示化合物；
    将式(II-3)所示化合物和式(II-4)所示化合物进行反应，制得式(II-5)所示化合物。
  3. 式(II)所示结构的中间体的制备方法，其特征在于，包括以下步骤：
    Figure PCTCN2021073127-appb-100003
    提供式(II-3)所示化合物；
    将式(II-3)所示化合物和式(II-4)所示化合物进行反应，制得式(II-5)所示化合物；
    将式(II-5)所示化合物和式(II-6)所示化合物进行反应，制得式(II-7)所示化合物；
    将式(II-7)所示化合物进行反应，制得式(II)所示结构的中间体；
    其中，R 1选自C 1-9烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或具有5-20个环原子的杂芳基；
    R 3选自C 1-9烷基、C 1-9烷氧基或羟基；且两个R 3可与B一起形成取代或未取代的环状结构；
    X为卤素。
  4. 根据权利要求3所述的制备方法，其特征在于，R 1选自甲基、乙基或异丙基；和/或
    R 3选自：C 1-4烷氧基或羟基；且两个R 3可与B一起形成
    Figure PCTCN2021073127-appb-100004
    结构，R 4、R 5、R 6、R 7各自独立地为C 1-4烷基；和/或
    X为氯或溴。
  5. 根据权利要求2或3所述的制备方法，其特征在于，所述提供式(II-3)所示化合物包括以下步骤：
    Figure PCTCN2021073127-appb-100005
    将式(II-1)所示化合物和式(II-2)所示化合物进行反应，制得式(II-3)所示化合物；
    R 2选自碱金属或碱土金属，优选R 2为锂、钠、钾、镁或钙。
  6. 根据权利要求5所述的制备方法，其特征在于，
    将式(II-1)所示化合物和式(II-2)所示化合物进行反应的步骤包括以下 步骤
    将式(II-1)所示化合物、式(II-2)所示化合物、酸和溶剂混合，进行加成反应；
    其中，所述酸为乙酸和三氟乙酸中至少一种，优选为乙酸。
  7. 根据权利要求3或4所述的制备方法，其特征在于，将式(II-3)所示化合物和式(II-4)所示化合物进行反应的步骤包括以下步骤：
    将式(II-3)所示化合物、式(II-4)所示化合物、碱和溶剂混合，进行取代反应；
    其中，所述碱选自：碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙胺或三乙烯二胺及中的至少一种；优选，碱为碳酸钠和三乙胺的组合，或碳酸钾和三乙胺的组合；
    所述溶剂选自：乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、四氢呋喃、1，4-二氧六环、N,N-二甲基甲酰胺和二甲基亚砜中的至少一种；优选溶剂为乙醇或四氢呋喃。
  8. 根据权利要求3或4所述的制备方法，其特征在于，将式(II-5)所示化合物和式(II-6)所示化合物进行反应的步骤包括以下步骤：
    将式(II-5)所示化合物、式(II-6)所示化合物、催化剂、碱和溶剂混合，进行偶联反应；
    其中，所述催化剂选自：钯催化剂或镍催化剂；优选催化剂为四(三苯基磷)钯或三(二亚苄基丙酮)二钯；
    所述溶剂选自：醇、乙醇、四氢呋喃、1，4-二氧六环、甲苯和水中至少一种；优选所述溶剂为四氢呋喃和水的组合，或甲苯与水的组合；
    所述碱选自：碳酸钠、碳酸钾、乙酸钠、氢氧化钠、氢氧化钾和氢氧化钡中至少一种。
  9. 根据权利要求3或4所述的制备方法，其特征在于，将式(II-7)所示化合物进行反应的步骤包括以下步骤：
    将式(II-7)所示化合物、碱和溶剂混合，进行水解反应，反应完成后加入酸，将反应液的pH值调节至小于5；
    其中，所述碱选自：氢氧化锂、氢氧化钠、氢氧化钾和氢氧化钙中至少一种；
    所述溶剂选自：甲醇、乙醇、异丙醇、四氢呋喃、1，4-二氧六环、丙酮和水中至少一种。
  10. 一种塞利尼索的制备方法，其特征在于，包括以下步骤：
    根据权利要求3-9任一项所述的制备方法制备式(II)所示结构的中间体；
    将式(II)所示结构的中间体和吡嗪-2-肼进行反应，制得式(I)所示化合物；
    Figure PCTCN2021073127-appb-100006
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