CN108947884B - Preparation method of ereoxib and intermediate thereof - Google Patents
Preparation method of ereoxib and intermediate thereof Download PDFInfo
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- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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Abstract
The invention discloses a preparation method of ereoxib and an intermediate thereof, which comprises the following steps: 1) carrying out amidation reaction on 2-amino-1-p-methylsulfonyl acetophenone and p-methylphenylacetoxy halide to obtain N- [ 2-oxo-2- (4-methylsulfonylphenyl) ] ethyl-4-methylphenylacetamide; 2) carrying out condensation cyclization reaction on N- [ 2-oxo-2- (4-methylsulfonylphenyl) ] ethyl-4-methylphenylacetamide to obtain 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone; 3) carrying out substitution reaction on 3-p-methylphenyl-4-p-methylsulfonyl phenyl-3-pyrrolidine-2-ketone and 1-halopropane or hydrocarbon propyl sulfonate derivative to obtain the ereoxib; and preparing an intermediate of the ereoxib: n- [ 2-oxo-2- (4-methanesulfonylphenyl) ] ethyl-4-methylphenylacetamide or 3-p-methylphenyl-4-p-methanesulfonylphenyl-3-pyrrolidin-2-one; the synthetic route of the invention optimizes the reaction process, so that the separation of each step is simpler, the purity is higher, and the ideal product yield can be obtained.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of erexib and an intermediate thereof.
Background
Novel COX-2 selective inhibitor Irecoxib (Imrechoxib) is a national class 1.1 innovative drug for treating and relieving pain symptoms of osteoarthritis and postoperative inflammation, and is approved by the national FDA to be marketed at present. The chemical name of the compound is N-N-propyl-3-p-methylphenyl-4-p-methylsulfonyl phenyl-3-pyrrolidine-2-ketone, and the chemical structural formula is as follows:
the first line of osteoarthritis will change in the future and specific COX-2 (a cyclooxygenase enzyme that causes joint pain and inflammation) inhibitors may replace the current acetaminophen as the first line of osteoarthritis.
At present, a plurality of patents have been reported on methods for preparing ereoxib, for example, a synthetic route for preparing ereoxib disclosed in patents CN1134413C and US20040029951, wherein 4-methanesulfonyl styrene oxide is used as a starting material, and ereoxib is obtained through steps of nucleophilic ring opening, amidation, oxidation, cyclization and the like, as shown below:
the oxidation reaction involved in the method uses Jones reagent or pyridine chromium trioxide and other oxidants, but the yield of the oxidation reaction is low, the product is not easy to separate and purify, and the residue of metal chromium can influence the product quality of the raw material medicine. For example, patent CN107586268A modifies some compounds based on the above-mentioned route, and the second step uses 4-methylphenylacetic acid instead of its acid chloride reagent, so expensive condensing agent such as CDI is used to promote the completion of the reaction, which is not favorable for further popularization of industrial production.
Meanwhile, the method for preparing the ereoxib, disclosed in chinese patent CN102206178B, adopts different synthetic routes, but the synthesis implementation with a better yield still uses an expensive condensing agent DBU to perform condensation cyclization reaction, and the process is complex to regulate and control, needs to regulate reaction conditions for many times, is also not beneficial to large-scale production, and the synthetic route is as follows:
also as a synthetic route for preparing the ereoxib disclosed in the Chinese patent CN104193664B, the following is shown:
in the formula R1、R2In the first route, the used raw material n-propylamine is a high-toxicity chemical, the operation process and the wastewater are high in toxicity, the wastewater is nitrogen-containing wastewater which is difficult to treat, and in the second route, the intermediate reaction product is a liquid oily substance which is difficult to purify, impurities in the step are brought into a final product prepared by subsequent reaction and can continue to generate side reaction, the separation difficulty of a target product is further increased, and the difficulty is brought to the impurity control and research of the raw material medicines.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel preparation method of the erexib.
The invention also provides an intermediate for preparing the ereoxib.
In order to solve the technical problems, the invention adopts a technical scheme as follows:
a preparation method of ereoxib, comprising the following steps:
(1) carrying out amidation reaction on a compound shown as a formula (I) and a compound shown as a formula (II) in a first solvent in the presence of an acid-binding agent to generate a compound shown as a formula (III); wherein the acid-binding agent is one or more of triethylamine, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, N-methylmorpholine and N-ethylmorpholine;
in the formula (II), X1Is fluorine, chlorine, bromine or iodine;
(2) subjecting the compound represented by the formula (III) to a condensation cyclization reaction in a second solvent in the presence of a basic substance to produce a compound represented by the formula (IV); wherein the alkaline substance is one or more of sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide;
(3) carrying out substitution reaction on the compound shown in the formula (IV) and the compound shown in the formula (V) in a third solvent in the presence of a basic substance to prepare the ereoxib shown in the formula (VI); wherein the alkaline substance is one or more of sodium hydride, potassium hydride, sodium amide, sodium bis (trimethylsilyl) amide, sodium tert-butoxide and potassium tert-butoxide;
in the formula (V), X2Is fluorine, chlorine, bromine, iodine or
Wherein X3Is C1-6Alkyl, halogenated C of1-6Alkyl or
In the present invention, the step (1), the step (2) and the step (3) can obtain a more desirable yield in the presence of the specific acid-binding agent or the basic substance than other acid-binding agents or basic substances.
According to some specific aspects of the invention, X3Is methyl, ethyl, propyl, isopropyl, perfluoro-substituted methyl, perfluoro-substituted ethyl, perfluoro-substituted propyl, perfluoro-substituted isopropyl or
According to some preferred aspects of the present invention, in the step (1), the amidation reaction is performed at a temperature of 10 to 100 ℃. More preferably, in the step (1), the amidation reaction is performed at a temperature of 20 to 80 ℃. Further preferably, in the step (1), the amidation reaction is performed at a temperature of 20 to 60 ℃.
According to some specific and preferred aspects of the present invention, in the step (1), the reaction time of the amidation reaction is controlled to be 6 to 16 hours.
According to some preferred aspects of the present invention, in the step (1), the compound represented by the formula (i), the compound represented by the formula (ii) and the acid-binding agent are charged at a molar ratio of 1: 1.2 to 1.5: 1.5 to 2.5.
According to some specific and preferred aspects of the present invention, in the step (1), the first solvent is a combination of one or more selected from the group consisting of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, toluene, N-dimethylformamide, methyl t-butyl ether, 1, 4-dioxane and acetonitrile.
According to some preferred aspects of the present invention, in the step (2), the compound represented by the formula (iii) and the basic substance are charged at a molar ratio of 1: 1.1-1.5.
According to some preferred aspects of the present invention, in step (2), the condensation cyclization reaction is carried out at a temperature of 10 to 120 ℃. More preferably, in step (2), the condensation cyclization reaction is carried out at a temperature of 10 to 100 ℃. Further preferably, in the step (2), the condensation-cyclization reaction is carried out at a temperature of 20 to 90 ℃.
According to some specific and preferred aspects of the present invention, in the step (2), the reaction time of the condensation-cyclization reaction is controlled to 6 to 12 hours.
According to some specific and preferred aspects of the present invention, in the step (2), the second solvent is a combination of one or more selected from the group consisting of alcohol, ethanol, N-propanol, isopropanol, N-butanol, t-amyl alcohol, tetrahydrofuran, N-dimethylformamide, 2-methyltetrahydrofuran, methyl t-butyl ether, and toluene.
According to some preferred aspects of the present invention, in the step (3), the compound represented by the formula (iv), the compound represented by the formula (v), and the basic substance are charged at a molar ratio of 1: 1.1-1.5-1.5-2.0.
According to some preferred aspects of the invention, in step (3), the substitution reaction is carried out at a temperature of 30 to 130 ℃. More preferably, in step (3), the substitution reaction is carried out at a temperature of 40 to 110 ℃. Further preferably, in step (3), the substitution reaction is carried out at a temperature of 50 to 100 ℃.
According to some specific and preferred aspects of the present invention, in the step (3), the reaction time of the substitution reaction is controlled to be 12 to 24 hours.
According to some specific and preferred aspects of the present invention, in the step (3), the third solvent is a combination of one or more selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl t-butyl ether, acetonitrile and N-methylpyrrolidone.
The invention provides another technical scheme that: an intermediate for preparing ereoxib, the intermediate having a structure represented by formula (iii):
the invention provides another technical scheme that: an intermediate for preparing ereoxib, the intermediate having a structure represented by formula (iv):
due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention optimizes the reaction process by providing a new synthesis route of the ereoxib, has simple process operation, no pollutant generation and avoids the defect of using heavy metal oxidation reagents, meets the current high standard requirement on environmental protection, also ensures that each step can separate high-purity intermediate products or target products by a simple separation method, obtains ideal product yield, meets the high standard requirement of raw material medicines, avoids using expensive condensing agents, reduces the production cost and is beneficial to industrial large-scale production.
Detailed Description
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
In the following, all starting materials are either commercially available or prepared by conventional methods in the art, unless otherwise specified. Wherein the starting material 2-amino-1-p-methylsulfonylacetophenone can be prepared by amination of 2-bromo-1-p-methylsulfonylacetophenone (CAS 50413-24-6), see WO2015187088 and WO2015187089 for preparation of the same compound; the starting materials p-methylphenylacetyl chloride and p-methylphenylacetyl bromide can be prepared by acylchlorination and acylbromination, respectively, of p-methylphenylacetic acid (CAS 622-47-9), see patent US20060100263 for the preparation of the same compounds.
In the following examples, the synthetic route for ereoxib (compound (vi)) is as follows:
example 1
A) Preparation of N- [ 2-oxo-2- (4-methanesulfonylphenyl) ] ethyl-4-methylphenylacetamide (Compound (III)):
dissolving 2-amino-1-p-methylsulfonylacetophenone (10.0g, compound (I)) in acetonitrile (60mL), adding triethylamine (7.1g), stirring, cooling in an ice bath to 5-10 ℃, and dropwise adding p-methylphenylacetoxy chloride (9.5g, compound (II), X)1Chlorine) solution in acetonitrile (15mL), heating to 40 ℃, reacting for 12h until the reaction is complete, cooling to room temperature, adjusting to neutrality by using 1N hydrochloric acid, decompressing and rotary-steaming to remove the organic solvent, adding ethyl acetate and water for extraction, separating out the organic phase, washing by using water and saturated salt in sequence, drying by using anhydrous sodium sulfate, decompressing and rotary-steaming for concentration to be dry, recrystallizing the obtained crude product by using ethanol to obtain N- [ 2-oxo-2- (4-methylsulfonylphenyl)]Ethyl-4-methylphenylacetamide, an off-white solid 14.9g, a yield 92.0%, a purity of 99.2%.
B) Preparation of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (Compound (IV)):
dissolving N- [ 2-oxo-2- (4-methylsulfonylphenyl) ] ethyl-4-methylbenzoacetamide (12.0g, compound (III)) prepared according to the method of the step A) in DMF (50mL), controlling the temperature to be 0-5 ℃, adding sodium tert-butoxide (5.1g), raising the temperature of the reaction mixture to 25 ℃, reacting for 2 hours till the reaction is completed, adjusting the reaction mixture to be neutral by using 1N hydrochloric acid, decompressing and carrying out rotary evaporation to remove an organic solvent, adding ethyl acetate for extraction, drying by using anhydrous sodium sulfate, decompressing and carrying out rotary evaporation to concentrate until the reaction is dried, and recrystallizing by using isopropanol to obtain the 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-one, wherein the off-white solid is 9.9g, the yield is 87.0%, and the purity is 98.5%.
C) Preparation of ericoxib (compound (vi)):
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (8.0g, compound (IV)) prepared according to step B) in N, N-dimethylformamide (40mL), displacing with nitrogen, adding sodium hydride (1.5g, content 60%) dispersed in mineral oil, reacting at 0-5 ℃ for 1h, heating to room temperature, dropwise adding 1-chloropropane (2.1g, compound (V), X)2Chlorine), heating to 50 ℃, reacting for 22 hours until the reaction is complete, reducing the temperature to 5-10 ℃, dropwise adding 1N hydrochloric acid to adjust to be neutral, carrying out reduced pressure rotary evaporation to remove the organic solvent, adding ethyl acetate for extraction, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to concentrate to be dry, and recrystallizing with a mixed solvent of ethanol and isopropanol to obtain the erexib, wherein the content of the off-white solid is 8.3g, the yield is 91.9%, and the purity is 99.6%.
Example 2
A) Preparation of N- [ 2-oxo-2- (4-methanesulfonylphenyl) ] ethyl-4-methylphenylacetamide (Compound (III)):
2-amino-1-p-methylsulfonylacetophenone (18.0g, Compound (I)) was dissolved in methyl tert-butyl ether (100mL), N-diisopropylethylamine (27.3g) was added, the mixture was stirred and cooled to 5 to 10 ℃ in an ice bath, and p-methylphenylacetyl bromide (27.0g, Compound (II), X)1Bromine) is heated to 20 ℃, the reaction is carried out for 16 hours till the reaction is complete, 1N hydrochloric acid is used for adjusting the reaction to be neutral, the organic solvent is removed by reduced pressure rotary evaporation, ethyl acetate and water are added for extraction, the organic phase is separated, water and saturated salt water are sequentially used for washing,drying with anhydrous sodium sulfate, rotary steaming under reduced pressure, concentrating to dryness, recrystallizing the obtained crude product with ethanol to obtain N- [ 2-oxo-2- (4-methylsulfonylphenyl)]Ethyl-4-methylphenylacetamide as an off-white solid (26.1 g), 89.5% yield and 99.0% purity.
B) Preparation of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (Compound (IV)):
dissolving N- [ 2-oxo-2- (4-methylsulfonylphenyl) ] ethyl-4-methylbenzoacetamide (25.0g, compound (III)) prepared according to the method of the step A) in N, N-dimethylformamide (100mL), replacing nitrogen, adding sodium hydride (6.0g, the content is 60%) dispersed in mineral oil, keeping the temperature of a reaction mixture at 20 ℃ for 12 hours until the reaction is completed, adjusting the temperature to be neutral by using 1N hydrochloric acid, carrying out reduced pressure rotary evaporation to remove an organic solvent, adding ethyl acetate for extraction, drying by using anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to concentrate until the reaction is completed, and recrystallizing by using isopropanol to obtain the 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-one, wherein the off-white solid is 20.0g, the yield is 84.4%, and the purity is 98.4%.
C) Preparation of ericoxib (compound (vi)):
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (18.0g, Compound (IV)) prepared according to step B) in methyl-tert-butyl ether (70mL), adding potassium tert-butoxide (11.1g), refluxing the mixture for 1h, cooling to room temperature, dropwise adding 1-iodopropane (12.1g, Compound (V), X)2Iodine) is added, the temperature is increased to 80 ℃, the reaction is carried out for 16 hours until the reaction is complete, the temperature is reduced to 5-10 ℃, 1N hydrochloric acid is dripped to adjust the reaction to be neutral, the organic solvent is removed by reduced pressure rotary evaporation, ethyl acetate is added for extraction, anhydrous sodium sulfate is dried, the reduced pressure rotary evaporation is carried out for concentration until the mixture is dry, ethanol and isopropanol mixed solvent is recrystallized to obtain the erexib, 17.5g of white-like solid is obtained, the yield is 86.1%, and the purity is 99.5%.
Example 3
A) Preparation of N- [ 2-oxo-2- (4-methanesulfonylphenyl) ] ethyl-4-methylphenylacetamide (Compound (III)):
2-amino-1-p-methylsulfonylacetophenone (20.0g, Compound (I)) was dissolved in chloroform (110mL), pyridine (14.8g) was added, the mixture was stirred and cooled to 5 to 10 ℃ in an ice bath, and p-methylphenylacetoxy chloride (20.6g, Compound (I)) was added dropwise(Ⅱ)，X1Chlorine) solution in chloroform (30mL), rising to 60 ℃, reacting for 6h until the reaction is complete, cooling to room temperature, adjusting to neutral by 1N hydrochloric acid, decompressing and rotary-steaming to remove the organic solvent, adding ethyl acetate and water for extraction, separating out the organic phase, washing by water and saturated salt in turn, drying by anhydrous sodium sulfate, decompressing and rotary-steaming to concentrate to be dry, recrystallizing the obtained crude product by ethanol to obtain N- [ 2-oxo-2- (4-methylsulfonylphenyl)]Ethyl-4-methylphenylacetamide as an off-white solid (30.1 g), yield 92.9%, purity 99.0%.
B) Preparation of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (Compound (IV)):
dissolving N- [ 2-oxo-2- (4-methylsulfonylphenyl) ] ethyl-4-methylphenylacetamide (30.0g, compound (III)) prepared according to the method of the step A) in methanol (110mL), adding sodium methoxide (6.1g), raising the temperature of a reaction mixture to 50 ℃, reacting for 9 hours until the reaction is completed, cooling to room temperature, adjusting to be neutral by using 1N hydrochloric acid, decompressing and carrying out rotary evaporation to remove an organic solvent, adding ethyl acetate for extraction, drying by using anhydrous sodium sulfate, decompressing and carrying out rotary evaporation and concentration until the organic solvent is dried, and recrystallizing by using isopropanol to obtain the 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone, wherein the off-white to light yellow solid is 25.0g, the yield is 87.9%, and the purity is 98.7%.
C) Preparation of ericoxib (compound (vi)):
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (25.0g, compound (IV)) prepared according to step B) in toluene (130mL), adding sodium amide (6g), refluxing the mixture for 1h, cooling to room temperature, and adding propyl p-toluenesulfonate (24.5g, compound (V), X) dropwise2P-toluenesulfonyloxy), heating to 100 ℃, reacting for 12 hours until the reaction is complete, cooling to 5-10 ℃, dropwise adding 1N hydrochloric acid to adjust to be neutral, carrying out reduced pressure rotary evaporation to remove the organic solvent, adding ethyl acetate for extraction, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation and concentration to be dry, and recrystallizing with a mixed solvent of ethanol and isopropanol to obtain the erexib, wherein the off-white solid is 23.4g, the yield is 83.6%, and the purity is 99.7%.
Example 4
A) Preparation of N- [ 2-oxo-2- (4-methanesulfonylphenyl) ] ethyl-4-methylphenylacetamide (Compound (III)):
2-amino-1-p-methylsulfonylacetophenone (20.0g, Compound (I)) was dissolved in chloroform (110mL), pyridine (14.8g) was added, the mixture was stirred and cooled to 5 to 10 ℃ in an ice bath, and p-methylphenylacetyl chloride (19.0g, Compound (II), X) was added dropwise1Chlorine) solution in chloroform (30mL), rising to 60 ℃, reacting for 6h until the reaction is complete, cooling to room temperature, adjusting to neutral by 1N hydrochloric acid, decompressing and rotary-steaming to remove the organic solvent, adding ethyl acetate and water for extraction, separating out the organic phase, washing by water and saturated salt in turn, drying by anhydrous sodium sulfate, decompressing and rotary-steaming to concentrate to be dry, recrystallizing the obtained crude product by ethanol to obtain N- [ 2-oxo-2- (4-methylsulfonylphenyl)]Ethyl-4-methylphenylacetamide as an off-white solid (30.0 g), yield 92.6%, purity 99.1%.
B) Preparation of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (Compound (IV)):
dissolving N- [ 2-oxo-2- (4-methylsulfonylphenyl) ] ethyl-4-methylphenylacetamide (30.0g, compound (III)) prepared according to the method of the step A) in methanol (110mL), adding sodium methoxide (5.2g), raising the temperature of a reaction mixture to 50 ℃, reacting for 9 hours until the reaction is completed, cooling to room temperature, adjusting to be neutral by using 1N hydrochloric acid, decompressing and carrying out rotary evaporation to remove an organic solvent, adding ethyl acetate for extraction, drying by using anhydrous sodium sulfate, decompressing and carrying out rotary evaporation and concentration until the organic solvent is dried, and recrystallizing by using isopropanol to obtain 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone, wherein the off-white to light yellow solid is 24.3g, the yield is 85.5%, and the purity is 98.6%.
C) Preparation of ericoxib (compound (vi)):
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (12.0g, Compound (IV)) prepared according to step B) in toluene (60mL), adding sodium amide (2.9g), refluxing the mixture for 1h, cooling to room temperature, dropwise adding propyl methanesulfonate (7.6g, Compound (V), X)2Methylsulfonyloxy), heating to 100 ℃, reacting for 12 hours until the reaction is complete, cooling to 5-10 ℃, dropwise adding 1N hydrochloric acid to adjust to be neutral, decompressing and rotary-steaming to remove the organic solvent, adding ethyl acetate for extraction, drying with anhydrous sodium sulfate, decompressing and rotary-steaming for concentration to be dry, recrystallizing with ethanol and isopropanol mixed solvent to obtain erexib, wherein the similar white solid is 10.9g, the yield is 80.5%, and the purity is 99.5%。
Example 5
Preparation of ericoxib (compound (vi)):
will be provided withExample 4Dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one (12.0g, compound (IV)) prepared by the method of step B) in toluene (60mL), adding sodium amide (2.9g), refluxing the mixture for 1h, cooling to room temperature, dropwise adding propyl trifluoromethanesulfonate (7.6g, compound (V), X)2Trifluoromethanesulfonyloxy), heating to 100 ℃, reacting for 12 hours until the reaction is complete, cooling to 5-10 ℃, dropwise adding 1N hydrochloric acid to adjust to be neutral, carrying out reduced pressure rotary evaporation to remove the organic solvent, adding ethyl acetate for extraction, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation and concentration to be dry, and recrystallizing with a mixed solvent of ethanol and isopropanol to obtain the erexib, wherein the off-white solid accounts for 11.4g, the yield is 84.2%, and the purity is 99.7%.
Comparative example 1
Essentially the same procedure as in step A) of example 1, except that triethylamine was replaced with an equimolar amount of sodium carbonate, N- [ 2-oxo-2- (4-methanesulfonylphenyl) ] ethyl-4-methylbenzylacetamide was obtained in the form of an off-white solid (12.9 g), yield 79.6% and purity 98.8%.
Comparative example 2
Essentially the same as step B) of example 1, except that sodium tert-butoxide was replaced with an equimolar amount of triethylamine to give 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one as an off-white to pale yellow solid, 8.3g, 73.0% yield, 98.3% purity.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (6)
1. A preparation method of ereoxib is characterized by comprising the following steps:
(1) carrying out amidation reaction on a compound shown as a formula (I) and a compound shown as a formula (II) in a first solvent in the presence of an acid-binding agent to generate a compound shown as a formula (III); wherein the acid-binding agent is one or a combination of more of triethylamine, N-diisopropylethylamine and pyridine; the first solvent is one or more of chloroform, methyl tert-butyl ether and acetonitrile; the amidation reaction is carried out at a temperature of 10-100 ℃;
in the formula (II), X1Is fluorine, chlorine, bromine or iodine;
(2) subjecting the compound represented by the formula (III) to a condensation cyclization reaction in a second solvent in the presence of a basic substance to produce a compound represented by the formula (IV); wherein, the alkaline substance is one or more of sodium hydride, sodium methoxide and sodium tert-butoxide; the second solvent is one or more selected from methanol and N, N-dimethylformamide; the condensation cyclization reaction is carried out at the temperature of 10-120 ℃;
(3) carrying out substitution reaction on the compound shown in the formula (IV) and the compound shown in the formula (V) in a third solvent in the presence of a basic substance to prepare the ereoxib shown in the formula (VI); wherein the alkaline substance is one or more of sodium hydride, potassium hydride, sodium amide, sodium bis (trimethylsilyl) amide, sodium tert-butoxide and potassium tert-butoxide;
2. The method for preparing the dapoxib according to claim 1, wherein in step (1), the compound represented by formula (I), the compound represented by formula (II) and the acid-binding agent are fed at a molar ratio of 1: 1.2-1.5: 1.5-2.5.
3. The method for preparing dapoxib according to claim 1, wherein in step (2), the feeding molar ratio of the compound represented by formula (III) to the alkaline substance is 1: 1.1-1.5.
4. The method for preparing dapoxib according to claim 1, wherein in step (3), the compound of formula (IV), the compound of formula (V) and the basic substance are fed in a molar ratio of 1: 1.1-1.5: 1.5-2.0.
5. The method for preparing ereoxib according to claim 1, wherein in step (3), the substitution reaction is carried out at a temperature of 30 to 130 ℃.
6. The method according to claim 1, wherein in step (3), the third solvent is a combination of one or more selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl t-butyl ether, acetonitrile, and N-methylpyrrolidone.
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| CN111747879B (en) * | 2019-03-29 | 2023-03-21 | 成都同心纵横生物医药有限公司 | Large-process synthesis method of erexib |
| CN111747873B (en) * | 2019-03-29 | 2022-04-08 | 成都同心纵横生物医药有限公司 | Ericoxib intermediate and preparation method and application thereof |
| CN114702425B (en) * | 2022-03-28 | 2024-04-19 | 苏州汉酶生物技术有限公司 | Process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives and intermediates |
| CN115073350B (en) * | 2022-07-04 | 2023-09-12 | 苏州富士莱医药股份有限公司 | Preparation method of eremophilone |
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| GB770277A (en) * | 1952-08-23 | 1957-03-20 | Parke Davis & Co | Amino-propanediols and their derivatives |
| US20040029951A1 (en) * | 2002-08-08 | 2004-02-12 | Research Institute Of Material Medica, Chinese Academy Of Medical Sciences; | Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof |
| CN102206178A (en) * | 2010-03-30 | 2011-10-05 | 上海源力生物技术有限公司 | Method for preparing imrecoxib |
| CN107586268A (en) * | 2016-07-07 | 2018-01-16 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of imrecoxib and its intermediate |
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| US20040029951A1 (en) * | 2002-08-08 | 2004-02-12 | Research Institute Of Material Medica, Chinese Academy Of Medical Sciences; | Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof |
| CN102206178A (en) * | 2010-03-30 | 2011-10-05 | 上海源力生物技术有限公司 | Method for preparing imrecoxib |
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