CN112679477B - Preparation method of celecoxib and intermediate thereof - Google Patents
Preparation method of celecoxib and intermediate thereof Download PDFInfo
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- CN112679477B CN112679477B CN202011494689.XA CN202011494689A CN112679477B CN 112679477 B CN112679477 B CN 112679477B CN 202011494689 A CN202011494689 A CN 202011494689A CN 112679477 B CN112679477 B CN 112679477B
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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Abstract
The invention relates to a preparation method of celecoxib and an intermediate thereof, which has the advantages of short whole synthetic route, mild reaction conditions, no generation of malodorous gas in the reaction process, high safety, wide acceptable range of solvents of various reaction types, capability of selecting solvents with high safety and simple post-treatment for reaction, and effectively avoiding the problem of large waste water amount caused by the need of using solvents such as N, N-dimethylformamide and the like in the traditional route. In the reaction, the product obtained in each step has high purity, the post-treatment is simple, the increase of industrial cost caused by high separation and purification difficulty can be effectively avoided, and the method has high environmental protection economic benefit and is particularly suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of celecoxib and an intermediate thereof.
Background
The structure of Seriensol (Selinexor) is shown as formula I, and the chemical name is as follows: (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -N' - (pyrazin-2-yl) propenylhydrazide.
(Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazole-1-yl) acrylic acid is a key intermediate for preparing bulk drug of Serinixol (Selinexor), and the structure of the (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazole-1-yl) acrylic acid is shown as an intermediate (I):
U.S. Pat. No. 5,9079865 first reported a preparation method of Seriensoe (Selinexor) and its intermediate (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylic acid as shown in synthetic route one.
The first synthetic route is as follows:
according to the first synthetic route, 3, 5-bis (trifluoromethyl) benzonitrile is used as a raw material to obtain an intermediate (III) through addition and condensation reactions, propiolic acid is used as a raw material to obtain an Intermediate (IV) through esterification and addition reactions, the intermediate (III) and the Intermediate (IV) are subjected to substitution and condensation reactions to obtain an intermediate (V), hydrolysis reactions are further carried out to obtain an intermediate (II), and the intermediate (II) and pyrazine-2-hydrazine are subjected to amidation reactions to prepare the target compound, namely celecoxib (I).
The synthesis route has longer process steps, raw materials such as propiolic acid with poor stability and the like are needed, and hydrogen sulfide waste gas with strong pungent odor is generated in the process of preparing the intermediate (III); n, N-dimethylformamide is used as a solvent for preparing the intermediate (III) and the Intermediate (IV), so that the intermediate (III) and the Intermediate (IV) are difficult to recover and can generate a large amount of wastewater; the trans-isomer produced as a byproduct in the preparation of the intermediate (V) needs to be separated and purified by column chromatography, a large amount of elution solvent is used, and a large amount of silica gel solid waste is produced; the total yield of the intermediate (II) is low and the trans-isomer impurities are difficult to control.
World patent WO2017118940 discloses an improved preparation method of celecoxib (Selinexor) and its intermediate (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylic acid as shown in synthetic route two.
The second synthetic route is as follows:
compared with the first synthesis route, the second synthesis route only selects a solvent, improves the yield and purity of the intermediate (II), does not fundamentally change the synthesis route, does not disclose a preparation method of the intermediate (III) which is difficult to purchase in the market, increases the complicated step of removing the trans-isomer of the byproduct by the intermediate (II) through dicyclohexylamine salt formation and then acid adjustment by sulfuric acid purification, still needs to use solvents such as N, N-dimethylformamide and the like in the reaction process, has high post-treatment difficulty, generates a large amount of waste water, and is not beneficial to industrial production and application.
World patent WO2018129227 discloses another improved preparation method of celecoxib (Selinexor) and its intermediate (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylic acid as shown in synthetic route three.
The third synthetic route is as follows:
in the third synthetic route, the synthetic route is not fundamentally changed relative to the first synthetic route and the second synthetic route, and only the reaction reagent for preparing the intermediate (III) is changed, such as hydrogen peroxide instead of sodium hydrosulfide and intermediate (VI) instead of Intermediate (IV). However, the hydrogen peroxide adopted in the synthetic route belongs to dangerous goods in industrial production, the safety is low, and solvents such as DMSO (dimethyl sulfoxide) and the like are required in the reaction, so that the method is not suitable for industrial large-scale production.
In conclusion, the intermediate (II) (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazole-1-yl) acrylic acid is a key intermediate for preparing the bulk drug of the Serienosol (I, Selinexor), and the existing synthetic route still has the defects of more reaction steps, difficult acquisition of raw material markets, high process risk, more three wastes, difficult control of side reactions, higher cost and the like. The process route which has the advantages of easily obtained raw materials, simple process, environmental protection and economy and is suitable for industrial production is sought, and the economic and technical development of the bulk drug of the Seriendox (I) is promoted
Disclosure of Invention
Therefore, the preparation method of the celecoxib and the intermediate thereof is needed to be provided, and the method has the advantages of easily available raw materials, simple process, environmental friendliness and economy, and is particularly suitable for industrial production.
A compound having the structure:
R1is selected from C1-9An alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group having 3 to 8 ring atoms, an aryl group having 5 to 20 ring atoms, or a heteroaryl group having 5 to 20 ring atoms;
x is halogen.
In one embodiment, R1Selected from methyl, ethyl or isopropyl; x is chlorine or bromine.
A preparation method of an intermediate with a structure shown in a formula (II) comprises the following steps:
providing a compound represented by formula (II-3);
reacting a compound shown as a formula (II-3) with a compound shown as a formula (II-4) to obtain a compound shown as a formula (II-5);
reacting a compound shown as a formula (II-5) with a compound shown as a formula (II-6) to obtain a compound shown as a formula (II-7);
reacting a compound shown as a formula (II-7) to prepare an intermediate with a structure shown as a formula (II);
wherein R is1Is selected from C1-9An alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group having 3 to 8 ring atoms, an aryl group having 5 to 20 ring atoms, or a heteroaryl group having 5 to 20 ring atoms;
R2selected from alkali metals or alkaline earth metals;
R3selected from: c1-9Alkyl radical, C1-9Alkoxy or hydroxy; and two R3May be taken together with B to form substituted or unsubstitutedA cyclic structure;
x is halogen.
In one embodiment, R1Selected from methyl, ethyl or isopropyl; and/or
R2Selected from lithium, sodium, potassium, magnesium or calcium; and/or
R3Selected from: c1-4Alkoxy or hydroxy; and two R3May be formed together with B
Structure R4、R5、R6、R7Each independently is C1-4An alkyl group; and/or
X is chlorine or bromine.
In one embodiment, the providing of the compound of formula (II-3) comprises the steps of:
reacting a compound shown as a formula (II-1) with a compound shown as a formula (II-2) to obtain a compound shown as a formula (II-3);
R2selected from alkali metals or alkaline earth metals, preferably R2Is lithium, sodium, potassium, magnesium or calcium.
In one embodiment, the step of reacting the compound represented by the formula (II-1) with the compound represented by the formula (II-2) comprises the following steps
A compound represented by the formula (II-1), a compound represented by the formula (II-2), an acid and a solvent are mixed and subjected to an addition reaction.
In one embodiment, the acid is at least one of acetic acid and trifluoroacetic acid, preferably acetic acid.
In one embodiment, the step of reacting the compound represented by the formula (II-3) with the compound represented by the formula (II-4) comprises the steps of:
mixing a compound shown as a formula (II-3), a compound shown as a formula (II-4), alkali and a solvent for substitution reaction;
wherein the base is selected from: at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, N-diisopropylethylamine or triethylene diamine;
the solvent is selected from: at least one of ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, and dimethyl sulfoxide.
In one embodiment, the base is: a combination of sodium carbonate and triethylamine, or a combination of potassium carbonate and triethylamine;
the solvent is selected from ethanol or tetrahydrofuran.
In one embodiment, the step of reacting the compound represented by the formula (II-5) with the compound represented by the formula (II-6) comprises the steps of:
mixing a compound shown as a formula (II-5), a compound shown as a formula (II-6), a catalyst, alkali and a solvent, and carrying out a coupling reaction;
wherein the catalyst is selected from: a palladium catalyst or a 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.
In one embodiment, the catalyst is tetrakis (triphenylphosphine) palladium or tris (dibenzylideneacetone) dipalladium;
the solvent is a combination of tetrahydrofuran and water, or a combination of toluene and water.
In one embodiment, the step of reacting the compound represented by the formula (II-7) comprises the steps of:
mixing a compound shown as a formula (II-7), alkali and a solvent, carrying out hydrolysis reaction, adding acid after the reaction is finished, and adjusting the pH value of a reaction solution to be less than 5;
wherein 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 at least contains water.
A preparation method of celecoxib comprises the following steps:
preparing an intermediate having a structure represented by formula (II) according to the above preparation method;
reacting an intermediate with a structure shown in a formula (II) with pyrazine-2-hydrazine to prepare a compound shown in a formula (I);
has the advantages that:
the preparation method of the intermediate with the structure shown in the formula (II) is characterized in that a compound shown in the formula (II-3) and a compound shown in the formula (II-4) are innovatively subjected to substitution reaction to prepare a compound shown in the formula (II-5), the compound shown in the formula (II-5) and a compound shown in the formula (II-6) are subjected to coupling reaction to prepare a compound shown in the formula (II-7), and the compound shown in the formula (II-7) is subjected to hydrolysis reaction and acidification to obtain the intermediate with the structure shown in the formula (II). The whole synthetic route is short, the reaction conditions are mild, no malodorous gas is generated in the reaction process, the safety is high, the acceptable range of solvents of each reaction type is wide, the solvents with high safety and simple post-treatment can be selected for reaction, and the problem of large wastewater amount caused by the need of using solvents such as N, N-dimethylformamide and the like in the traditional route is effectively solved. In the reaction, the product obtained in each step has high purity, the post-treatment is simple, the increase of industrial cost caused by high separation and purification difficulty can be effectively avoided, and the method has high environmental protection economic benefit and is particularly suitable for industrial production.
Detailed Description
In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Term(s) for
Unless otherwise stated or contradicted, terms or phrases used herein have the following meanings:
the term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing the term, e.g., "C1-9Alkyl "refers to an alkyl group containing 1 to 9 carbon atoms, which may be independently at each occurrence C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl radical, C6Alkyl radical, C7Alkyl radical, C8Alkyl or C9An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) 1-propyl (n-Pr, n-propyl, -CH)2CH2CH3) 2-propyl (i-Pr, i-propyl, -CH (CH)3)2) 1-butyl (n-Bu, n-butyl, -CH)2CH2CH2CH3) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)2CH(CH3)2) 2-butyl (s-Bu, s-butyl, -CH (CH)3)CH2CH3) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)3)3) 1-pentyl (n-pentyl, -CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) 1-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3And octyl (- (CH)2)7CH3)。
The term "alkoxy" refers to a group having an-O-alkyl group, i.e., an alkyl group as defined above attached to the parent core structure via an oxygen atom. Phrases containing the term, e.g., "C1-9Alkoxy "means that the alkyl moiety contains 1 to 9 carbon atoms and, at each occurrence, may be independently C1Alkoxy radical, C4Alkoxy radical, C5Alkoxy radical, C6Alkoxy radical, C7Alkoxy radical, C8Alkoxy or C9An alkoxy group. Suitable examples include, but are not limited to: methoxy (-O-CH)3or-OMe), ethoxy (-O-CH)2CH3or-OEt) and tert-butoxy (-O-C (CH)3)3or-OtBu).
The term "cycloalkyl" refers to a non-aromatic hydrocarbon containing ring carbon atoms and may be a monocycloalkyl, or spirocycloalkyl, or bridged cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In addition, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyl groups containing a double bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.
"aryl" refers to an aromatic hydrocarbon group derived by removing one hydrogen atom from the aromatic ring compound and may be a monocyclic aryl group, or a fused ring aryl group, or a polycyclic aryl group, at least one of which is an aromatic ring system for polycyclic ring species. For example, "aryl having 5 to 20 ring atoms" means an aryl group containing 5 to 20 carbon atoms, which at each occurrence, may be independently C5Aryl radical, C6Aryl radical, C10Aryl radical, C14Aryl radical, C18Aryl or C20And (4) an aryl group. 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 may also be interrupted by short non-aromatic units (e.g. by short non-aromatic units)<10% of atoms other than H, such as C, N or O atoms), such as in particular acenaphthene, fluorene, or 9, 9-diarylfluorene, triarylamine, diaryl ether systems should also be included in the definition of aryl.
"heteroaryl" means that on the basis of an aryl at least one carbon atom is replaced by a non-carbon atom which may be a N atom, an O atom, an S atom, etc. For example, "aryl group having 5 to 20 ring atoms" means a heteroaryl group containing 5 to 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, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, phthalazine, quinoxaline, phenanthridine, primadine, quinazoline, and quinazolinone.
"Heterocyclyl" means that at least one carbon atom is replaced with a non-carbon atom, which may be a N atom, an O atom, an S atom, etc., and may be a saturated ring or a partially unsaturated ring, in addition to a cycloalkyl group. Suitable examples include, but are not limited to: dihydropyridinyl, tetrahydropyridinyl (piperidinyl), tetrahydrothienyl, thiooxidised tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl.
"halogen" or "halo" refers to F, Cl, Br, or I.
Detailed explanation
One embodiment of the present invention provides a compound having the structure:
R1is selected from C1-9An alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group having 3 to 8 ring atoms, an aryl group having 5 to 20 ring atoms, or a heteroaryl group having 5 to 20 ring atoms; x is halogen
Further, R1Is selected from C1-6Alkyl, cyclohexyl or phenyl; further, R1Is selected from C1-4An alkyl group; further, R1Selected from methyl, ethyl or isopropyl.
Further, X is chlorine or bromine.
One embodiment of the present invention provides a method for preparing an intermediate having a structure represented by formula (II), comprising the steps of:
s101: providing a compound represented by formula (II-3);
the compound represented by the formula (II-3) can be produced by a conventional method, and preferably, the compound represented by the formula (II-3) is produced by the following method:
s1011: providing a compound shown as a formula (II-1);
it is understood that the compound represented by the formula (II-1) may be a commercially available compound or may be prepared by a conventional method.
S1012: reacting a compound shown as a formula (II-1) with a compound shown as a formula (II-2) to obtain a compound shown as a formula (II-3);
wherein R is2Selected from alkali metals or alkaline earth metals; x is halogen; further, R2Selected from lithium, sodium, potassium, magnesium or calcium; further, R2Selected from sodium or potassium; further, X is bromine or iodine.
It is understood that step S1012 is an addition reaction in which a compound represented by the formula (II-3) is produced by mixing a compound represented by the formula (II-2) with an acid to generate a hydrogen halide and performing an addition reaction with a compound represented by the formula (II-1).
Further, step S1012 includes the steps of: a compound represented by the formula (II-1), a compound represented by the formula (II-2), an acid and a solvent are mixed and subjected to an addition reaction.
Further, the acid is at least one of acetic acid and trifluoroacetic acid, preferably acetic acid.
Further, the temperature of the addition reaction is 40 to 110 ℃ and particularly preferably 60 to 80 ℃.
Further, the molar ratio of the compound represented by the formula (II-1) to the compound represented by the formula (II-2) is 1 (1-2); further, the molar ratio of the compound represented by the formula (II-1) to the compound represented by the formula (II-2) is 1 (1.3-1.6);
further, the molar ratio of the compound shown in the formula (II-1) to the acid is 1 (3-8); further, the molar ratio of the compound represented by the formula (II-1) to the acid is 1 (5-7).
S102: reacting a compound shown as a formula (II-3) with a compound shown as a formula (II-4) to obtain a compound shown as a formula (II-5);
it is understood that, in step S102, the compound represented by the formula (II-3) and the compound represented by the formula (II-4) are subjected to substitution reaction.
Further, step S102 includes the steps of: mixing a compound shown as a formula (II-3), a compound shown as a formula (II-4), alkali and a solvent for substitution reaction;
further, step S102 includes the steps of: mixing a compound shown as a formula (II-4), alkali and a solvent to form a mixed solution, gradually dropwise adding the compound shown as the formula (II-3) at the temperature of-20-40 ℃ (preferably-10 ℃), after dropwise adding, carrying out heat preservation reaction, and after the reaction is completed, carrying out post-treatment to obtain the compound shown as the formula (II-5).
Further, the alkali is at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, N-diisopropylethylamine or triethylene diamine; in one embodiment, the base is a combination of sodium carbonate and triethylamine; further, the mass ratio of the sodium carbonate to the triethylamine is 1:0.1-1: 10; in one embodiment, the base is a combination of potassium carbonate and triethylamine; further, the mass ratio of potassium carbonate to triethylamine is 1:0.1-1: 10.
Further, the solvent is selected from: at least one of ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, and dimethyl sulfoxide; in one embodiment, the solvent is ethanol. In one embodiment, the solvent is tetrahydrofuran.
Further, in step S102, the molar ratio of the compound represented by the formula (II-3) to the compound represented by the formula (II-4) is 1 (0.5-1); further, the molar ratio of the compound represented by the formula (II-3) to the compound represented by the formula (II-4) is 1 (0.7-0.9).
One embodiment of the present invention provides a method for preparing an intermediate having a structure represented by formula (II), comprising the steps of:
s201: providing a compound shown as a formula (II-1);
wherein R is1Is selected from C1-9An alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group having 3 to 8 ring atoms, an aryl group having 5 to 20 ring atoms, or a heteroaryl group having 5 to 20 ring atoms; further, R1Is selected from C1-6Alkyl, cyclohexyl or phenyl; further, R1Is selected from C1-4An alkyl group; further, R1Selected from methyl, ethyl or isopropyl.
It is understood that the compound represented by the formula (II-1) may be a commercially available compound or may be prepared by a conventional method.
The compound shown in the formula (II-1) is cheap and easy to obtain, and the production cost can be reduced by using the compound as a raw material.
S202: reacting a compound shown as a formula (II-1) with a compound shown as a formula (II-2) to obtain a compound shown as a formula (II-3);
wherein R is2Selected from alkali metals or alkaline earth metals; x is halogen; further, R2Selected from lithium, sodium, potassium, magnesium or calcium; further, R2Selected from sodium or potassium; further, X is bromine or iodine.
It is understood that step S202 is an addition reaction in which a compound represented by the formula (II-2) is mixed with an acid to generate a hydrogen halide, and the hydrogen halide is subjected to an addition reaction with a compound represented by the formula (II-1) to produce a compound represented by the formula (II-3).
Further, step S202 includes the steps of: a compound represented by the formula (II-1), a compound represented by the formula (II-2), an acid and a solvent are mixed and subjected to an addition reaction.
Further, the acid is at least one of acetic acid and trifluoroacetic acid, preferably acetic acid.
Further, the temperature of the addition reaction is 40 to 110 ℃ and particularly preferably 60 to 80 ℃.
Further, the molar ratio of the compound represented by the formula (II-1) to the compound represented by the formula (II-2) is 1 (1-2); further, the molar ratio of the compound represented by the formula (II-1) to the compound represented by the formula (II-2) is 1 (1.3-1.6);
further, the molar ratio of the compound shown in the formula (II-1) to the acid is 1 (3-8); further, the molar ratio of the compound represented by the formula (II-1) to the acid is 1 (5-7).
S203: reacting a compound shown as a formula (II-3) with a compound shown as a formula (II-4) to obtain a compound shown as a formula (II-5);
it is understood that, in step S203, the compound represented by the formula (II-3) and the compound represented by the formula (II-4) are subjected to substitution reaction. In addition, when the compound represented by the formula (II-3) is prepared by a conventional method, steps S201 and S202 may be omitted, and it is not to be construed as limiting the present invention, and it is preferable to prepare the compound represented by the formula (II-3) by the methods of S201 and S202.
Further, step S203 includes the steps of: mixing a compound shown as a formula (II-3), a compound shown as a formula (II-4), alkali and a solvent for substitution reaction;
further, step S203 includes the steps of: mixing a compound shown as a formula (II-4), alkali and a solvent to form a mixed solution, gradually dropwise adding the compound shown as the formula (II-3) at the temperature of-20-40 ℃ (preferably-10 ℃), after dropwise adding, carrying out heat preservation reaction, and after the reaction is completed, carrying out post-treatment to obtain the compound shown as the formula (II-5).
Further, the alkali is at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, N-diisopropylethylamine or triethylene diamine; in one embodiment, the base is a combination of sodium carbonate and triethylamine; further, the mass ratio of the sodium carbonate to the triethylamine is 1:0.1-1: 10; in one embodiment, the base is a combination of potassium carbonate and triethylamine; further, the mass ratio of potassium carbonate to triethylamine is 1:0.1-1: 10.
Further, the solvent is selected from: at least one of ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, and dimethyl sulfoxide; in one embodiment, the solvent is ethanol. In one embodiment, the solvent is tetrahydrofuran.
Further, in step S203, the molar ratio of the compound represented by the formula (II-3) to the compound represented by the formula (II-4) is 1 (0.5-1); further, the molar ratio of the compound represented by the formula (II-3) to the compound represented by the formula (II-4) is 1 (0.7-0.9).
S204: reacting a compound shown as a formula (II-5) with a compound shown as a formula (II-6) to obtain a compound shown as a formula (II-7);
wherein R is3Selected from: c1-9Alkyl radical, C1-9Alkoxy or hydroxy; and two R3May form a substituted or unsubstituted cyclic structure together with B; further, R3Selected from: c1-6Alkyl radical, C1-6Alkoxy or hydroxy; further, R3Selected from: c1-4Alkoxy or hydroxy, and two R3Together with B may form C or C1-4An alkyl-substituted 5-membered cyclic structure; further, two R3May be formed together with B;
structure; r4、R5、R6、R7Each independently is C1-4An alkyl group; further, R4、R5、R6、R7Each independently being methyl or ethyl. Further, R3Selected from hydroxyl groups.
Understandably, in the present invention-B (R)3)2Two of R3May be the same or different from each other and are understood to be within the scope of the present invention.
It is understood that, in 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 produce the compound represented by the formula (II-7).
Further, step S204 includes the steps of: mixing a compound represented by the formula (II-5), a compound represented by the formula (II-6), a catalyst, a base and a solvent, and carrying out a coupling reaction.
Further, the catalyst is selected from: a palladium catalyst or a nickel catalyst; preferably the catalyst is tetrakis (triphenylphosphine) palladium or tris (dibenzylideneacetone) dipalladium.
Further, the solvent is at least one selected from alcohol, ethanol, tetrahydrofuran, 1, 4-dioxane, toluene or water; in one embodiment, the solvent is a combination of tetrahydrofuran and water; further, the volume ratio of the tetrahydrofuran to the water is (1-2) to 1; further, the volume ratio of tetrahydrofuran to water is (1.3-1.8) to 1; in one embodiment, the dissolution is a combination of toluene and water; further, the volume ratio of toluene to water is (1-2) to 1; further, the volume ratio of toluene to water is (1.3-1.8): 1.
Further, the alkali is at least one of sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide and barium hydroxide; preferably, the base is selected from sodium carbonate or potassium carbonate.
Further, in step S204, the molar ratio of the compound represented by the formula (II-5) to the compound represented by the formula (II-6) is 1 (1-1.3).
Further, in step S204, the temperature of the coupling reaction is 50-100 ℃, and particularly preferably 60-80 ℃.
S205: and (3) reacting the compound shown as the formula (II-7) to obtain an intermediate with the structure shown as the formula (II).
It is understood that in step S205, the compound of formula (II-7) may be hydrolyzed to obtain a salt of formula (II), and then an acid is added to obtain an intermediate of formula (II).
Further, step S205 includes the steps of: mixing the compound shown in the formula (II-7), alkali and solvent, carrying out hydrolysis reaction, adding acid after the reaction is finished, and adjusting the pH value of the reaction liquid to be less than 5 (preferably 2-3).
Further, step S205 includes the steps of: dissolving a compound shown as a formula (II-7) in a first solvent, then cooling to 0-10 ℃, then slowly dripping an alkali water solution, preserving heat for 1-2h after dripping is finished, adding an acid to adjust the pH to 2-3 after reaction is completed, separating out solids, filtering, and drying to obtain an intermediate shown as a formula (II), wherein the first solvent is an organic solvent mutually soluble with water, and further is at least one of methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane and acetone.
Further, the alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; preferably, the base is lithium hydroxide or sodium hydroxide.
Further, the solvent is at least one of methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane, acetone and water. In one embodiment, in step S205, the solvent is a mixed solvent of ethanol and water; further, the volume ratio of the ethanol to the water is (1.5-5) to 1; furthermore, the volume ratio of the ethanol to the water is (2-3): 1. In one embodiment, in step S105, the solvent is a mixed solvent of tetrahydrofuran and water; further, the volume ratio of the tetrahydrofuran to the water is (1.5-5) to 1; furthermore, the volume ratio of the tetrahydrofuran to the water is (2-3): 1.
Further, the molar ratio of the compound represented by the formula (II-7) to the base is 1 (1.5-5); further, the molar ratio of the compound represented by the formula (II-7) to the base is 1 (1.8-2.2).
Further, 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 with the structure shown in the formula (II) innovatively takes a cheap and easily-obtained compound shown in the formula (II-1) as a raw material, firstly prepares a compound shown in the formula (II-3) through an addition reaction, then prepares a compound shown in the formula (II-5) through a substitution reaction, then carries out a coupling reaction on the compound shown in the formula (II-5) and the compound shown in the formula (II-6) to prepare a compound shown in the formula (II-7), and then carries out a hydrolysis reaction on the compound shown in the formula (II-7) and acidification to obtain the intermediate with the structure shown in the formula (II). The whole synthetic route is short, the reaction conditions are mild, no malodorous gas is generated in the reaction process, the safety is high, the acceptable range of solvents of each reaction type is wide, the solvents with high safety and simple post-treatment can be selected for reaction, and the problem of large wastewater amount caused by the need of using solvents such as N, N-dimethylformamide and the like in the traditional route is effectively solved. In the reaction, the product obtained in each step has high purity, the post-treatment is simple, the increase of industrial cost caused by high separation and purification difficulty can be effectively avoided, and the method has high environmental protection economic benefit and is particularly suitable for industrial production.
The present invention will be described below with reference to specific examples.
Example 1
Preparation of Compound (2) (Z) -3-iodoacrylic acid Ethyl ester
Adding glacial acetic acid (232g, 3.86mol), ethyl propiolate (58g, 0.591mol) and sodium iodide (133g, 0.887mol) into a 500ml reaction bottle, stirring, heating to 60-80 ℃, preserving heat for 5-7 hours, sampling, analyzing by TLC, and finishing conversion of the raw material ethyl propiolate; concentrating under reduced pressure to recover glacial acetic acid; the temperature of the residue was reduced to 15 to 25 ℃ and water (116ml) and methyl t-butyl ether (174ml) were added for extraction washing, the organic layer was separated and washed with water (116ml), and the organic layer was concentrated to dryness to recover methyl t-butyl ether, to give ethyl (Z) -3-iodoacrylate (112.2g, 0.496mol) as a yellow liquid in 84% yield and 95.0% purity by HPLC.
Example 2
Preparation of compound (4) (Z) -3- (3-bromo-1H-1, 2, 4-triazole-1-yl) ethyl acrylate
Adding 3-bromo-1H-1, 2, 4-triazole (20g, 0.135mol), ethanol (120ml) and potassium carbonate (37.6g, 0.27mol) into a 500ml reaction bottle, stirring and cooling to-10 ℃, dropwise adding (Z) -3-iodoethyl acrylate (36.6g, 0.162mol), keeping the temperature for 1-2 hours after adding, sampling and analyzing by TLC, and finishing the conversion of the raw material 3-bromo-1H-1, 2, 4-triazole; concentrating under reduced pressure to recover ethanol; cooling the residue to 15-25 deg.C, adding water (60ml) and ethyl acetateEster (100ml) was extracted and washed, the organic layer separated and washed with water (60 ml); the organic layer was concentrated under reduced pressure to dryness to recover ethyl acetate, and the residue was crystallized with methanol (40ml), filtered, washed, and dried to give (Z) -ethyl 3- (3-bromo-1H-1, 2, 4-triazol-1-yl) acrylate (25.2g, 0.103mol) as an off-white solid powder in 76% yield and 98.6% HPLC purity.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)。
Example 3
Preparation of Compound (6), ethyl (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylate
Adding (Z) -ethyl 3- (3-bromo-1H-1, 2, 4-triazole-1-yl) acrylate (10g, 0.041mol), 3, 5-bis (trifluoromethyl) phenylboronic acid (12.6g, 0.049mol), toluene (80ml), water (50ml), sodium carbonate (10.4g, 0.098mol), tetrabutylammonium bromide (0.1g, 0.4mmol), tetrakis (triphenylphosphine) palladium (0.5g, 0.4mmol) into a 250ml reaction bottle, stirring and heating to 60-80 ℃, preserving heat for 16-24 hours, sampling and analyzing by TLC, and basically converting the raw material (Z) -ethyl 3- (3-bromo-1H-1, 2, 4-triazole-1-yl) acrylate; adding activated carbon (1g), cooling to 15-25 deg.C, filtering to obtain activated carbon, standing to separate organic layer, and washing with water (30 ml); the organic layer was concentrated under reduced pressure to dryness to recover toluene, and the residue was crystallized from methanol (20ml), filtered, washed, and dried to give (Z) -ethyl 3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylate (13.2g, 0.035mol) as an off-white solid powder with a yield of 85% and an HPLC purity of 98.2%. 1H NMR (CDCl3) Δ 1.33-1.37(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).
Example 4
Preparation of intermediate (II) (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylic acid
Adding (Z) -ethyl 3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylate (8g, 0.021mol) and ethanol (24ml) into a 100ml reaction bottle, stirring to dissolve, cooling to 0-10 ℃, dropwise adding a solution of sodium hydroxide (1.7g, 0.042mol) dissolved in water (10ml), keeping the temperature for 1-2 hours after adding, sampling and analyzing by TLC, and finishing the conversion of the raw material (Z) -ethyl 3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylate; 40ml of water was added thereto, and 3mol/L hydrochloric acid (14ml, 0.042mol) was added dropwise to adjust the pH to 2-3, thereby precipitating a white solid, which was then filtered, washed and dried to obtain a white solid powder of celecoxib intermediate (II) (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylic acid (6.7g, 0.019mol), yield 91% and HPLC purity 98.9%. 1H NMR (CDCl3) delta 5.85-5.88(d, 1H), 7.32-7.35(d, 1H), 7.97(s, 1H), 8.59(s, 2H), 9.35(s, 1H).
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (11)
1. A compound having the structure:
R1is selected from C1-9An alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group having 3 to 8 ring atoms, an aryl group having 5 to 20 ring atoms, or a heteroaryl group having 5 to 20 ring atoms;
x is halogen.
2. A compound of claim 1, wherein R is1Selected from methyl, ethyl or isopropyl; x is chlorine or bromine.
3. A process for the preparation of a compound according to claim 1, comprising the steps of:
providing a compound represented by formula (II-3);
reacting the compound shown in the formula (II-3) with the compound shown in the formula (II-4) to obtain the compound shown in the formula (II-5).
4. The preparation method of the intermediate with the structure shown in the formula (II) is characterized by comprising the following steps:
providing a compound represented by formula (II-3);
reacting a compound shown as a formula (II-3) with a compound shown as a formula (II-4) to obtain a compound shown as a formula (II-5);
reacting a compound shown as a formula (II-5) with a compound shown as a formula (II-6) to obtain a compound shown as a formula (II-7);
reacting a compound shown as a formula (II-7) to prepare an intermediate with a structure shown as a formula (II);
wherein R is1Is selected from C1-9Alkyl, cycloalkyl having 3 to 8 ring atoms, heterocyclyl having 3 to 8 ring atoms, aryl having 5 to 20 ring atoms orA heteroaryl group;
R3is selected from C1-9Alkyl radical, C1-9Alkoxy or hydroxy; and two R3May form a substituted or unsubstituted cyclic structure together with B;
x is halogen.
5. The method of claim 4, wherein R is1Selected from methyl, ethyl or isopropyl; and/or
R3Selected from: c1-4Alkoxy or hydroxy; and two R3May be formed together with B
Structure R4、R5、R6、R7Each independently is C1-4An alkyl group; and/or
X is chlorine or bromine.
6. The method according to claim 3 or 4, wherein the step of providing the compound represented by formula (II-3) comprises the steps of:
reacting a compound shown as a formula (II-1) with a compound shown as a formula (II-2) to obtain a compound shown as a formula (II-3);
R2selected from alkali metals or alkaline earth metals.
7. The production method according to claim 6,
the step of reacting the compound represented by the formula (II-1) with the compound represented by the formula (II-2) comprises the steps of:
mixing a compound shown in a formula (II-1), a compound shown in a formula (II-2), acid and a solvent, and carrying out addition reaction;
wherein the acid is at least one of acetic acid and trifluoroacetic acid.
8. The production method according to claim 4 or 5, wherein the step of reacting the compound represented by the formula (II-3) with the compound represented by the formula (II-4) comprises the steps of:
mixing a compound shown as a formula (II-3), a compound shown as a formula (II-4), alkali and a solvent for substitution reaction;
wherein the base is selected from: at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, N-diisopropylethylamine, and triethylenediamine;
the solvent is selected from: at least one of ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, and dimethyl sulfoxide.
9. The production method according to claim 4 or 5, wherein the step of reacting the compound represented by the formula (II-5) with the compound represented by the formula (II-6) comprises the steps of:
mixing a compound shown as a formula (II-5), a compound shown as a formula (II-6), a catalyst, alkali and a solvent, and carrying out a coupling reaction;
wherein the catalyst is selected from: a palladium catalyst or a nickel catalyst;
the solvent is selected from: at least one of ethanol, tetrahydrofuran, 1, 4-dioxane, toluene and water;
the base is selected from: at least one of sodium carbonate, potassium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide and barium hydroxide.
10. The production method according to claim 4 or 5, wherein the step of reacting the compound represented by the formula (II-7) comprises the steps of:
mixing a compound shown as a formula (II-7), alkali and a solvent, carrying out hydrolysis reaction, adding acid after the reaction is finished, and adjusting the pH value of a reaction solution to be less than 5;
wherein the base is selected from: at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide;
the solvent is selected from: methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane, acetone and water.
11. The preparation method of the celecoxib is characterized by comprising the following steps:
preparing an intermediate having a structure represented by formula (II) according to the preparation method of any one of claims 4 to 10;
reacting an intermediate with a structure shown in a formula (II) with pyrazine-2-hydrazine to prepare a compound shown in a formula (I);
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| WO2017118940A1 (en) * | 2016-01-08 | 2017-07-13 | Dr. Reddy's Laboratories Limited | Solid forms of selinexor and process for their preparation |
| CN107072992A (en) * | 2014-08-15 | 2017-08-18 | 卡尔约药物治疗公司 | Sai Lingkesi polymorph |
| WO2018129227A1 (en) * | 2017-01-05 | 2018-07-12 | Watson Laboratories Inc. | Novel crystalline forms of selinexor and process for their preparation |
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| CR20210590A (en) * | 2019-05-01 | 2022-03-11 | Karyopharm Therapeutics Inc | Process for preparing xpo1 inhibitors and intermediates for use in the preparation of xp01 inhibitors |
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| US9079865B2 (en) * | 2011-07-29 | 2015-07-14 | Karyopharm Therapeutics Inc. | Hydrazide containing nuclear transport modulators and uses thereof |
| CN107072992A (en) * | 2014-08-15 | 2017-08-18 | 卡尔约药物治疗公司 | Sai Lingkesi polymorph |
| WO2017118940A1 (en) * | 2016-01-08 | 2017-07-13 | Dr. Reddy's Laboratories Limited | Solid forms of selinexor and process for their preparation |
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