CN108864003B - Preparation method of dapoxib intermediate and dapoxib - Google Patents
Preparation method of dapoxib intermediate and dapoxib Download PDFInfo
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- CN108864003B CN108864003B CN201810618418.7A CN201810618418A CN108864003B CN 108864003 B CN108864003 B CN 108864003B CN 201810618418 A CN201810618418 A CN 201810618418A CN 108864003 B CN108864003 B CN 108864003B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
Abstract
The invention discloses an ereoxib intermediate and a preparation method of ereoxib, wherein the preparation method comprises the steps of reacting p-methylphenylacetic acid with α -dibromo-4-methylsulfonylacetophenone in an organic solvent in the presence of organic alkali to generate the ereoxib intermediate, wherein the raw materials are added in a mode that the organic alkali, the organic solvent and the p-methylphenylacetic acid are mixed to obtain a mixed solution, α -dibromo-4-methylsulfonylacetophenone is added or dripped into the mixed solution in batches, the feeding amount of the organic alkali relative to α -dibromo-4-methylsulfonylacetophenone is excessive, and the ereoxib is prepared under the action of an acidic medium after the prepared ereoxib intermediate reacts with n-propylamine.
Description
Technical Field
The invention belongs to the field of synthesis, and particularly relates to an erexib intermediate and a preparation method of erexib.
Background
Ereoxib (english name: imrech) is a nonsteroidal anti-inflammatory analgesic (NSAIDs) that can be used to relieve the pain symptoms of osteoarthritis, and has the following structural formula:
for the ereoxib, the prior art discloses more preparation methods, and the currently common method is to use 4-methylsulfonylacetophenone as a raw material to generate bromoacetophenone by bromination, then generate a dihydrofuranone compound with p-toluenesulfonic acid under the action of an alkaline medium, and then react with n-propylamine and n-propylamine salt to generate pyrrolidone so as to obtain the ereoxib, although the method realizes the preparation of the ereoxib by fewer steps, the problems of unsatisfactory yield, complicated operation and the like still exist, for example, Chinese invention patent CN102206178B discloses a method for preparing the ereoxib, which specifically comprises 1) preparing α -bromomethylsulfonylacetophenone by bromination by using methylsulfonylacetophenone as a raw material, 2) condensing the prepared compound with p-tolylacetic acid to form dihydrofuranone under the action of an alkaline medium, and 3) reacting the dihydrofuranone with n-propylamine and n-propylamine salt to generate the pyrrolidone so as to prepare the ereoxib, wherein the route is as follows:
although the patent realizes the preparation of the ereoxib by fewer steps, the yields of the first step and the third step are not high, especially the first step reaction, because the methylsulfonyl acetophenone is very expensive and even reaches dozens of ten thousand yuan per ton, the lower yield of the first step reaction causes great obstruction to the expansion of the production scale;
also for the second reaction, two methods are provided in the examples:
firstly, adding alkaline substances into the same reaction solution twice and controlling different reaction temperatures, so that the realized yield is 11% -53%, but according to the embodiment, the intermediate is actually generated firstly, and then the product with the structure shown in the formula b is obtained by adding alkali, so that the process operation is complex, the reaction conditions need to be adjusted for many times, and the operation difficulty is increased;
the second method comprises two steps, wherein an intermediate a is prepared in the first step, and then a compound shown as a formula b is generated under the action of alkali in the second step, although the second step realizes higher yield under specific conditions, the raw material DBU is expensive and not beneficial to expanding production, and the implementation mode has the defects of complex operation, need of regulating and controlling reaction conditions for many times and increased process control difficulty;
therefore, in view of the above problems, those skilled in the art need to find a preparation method that can reduce the operation difficulty and achieve a more desirable yield.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art, and provide an improved preparation method for preparing an ereoxib intermediate, which can obtain a relatively ideal product yield, is simple to operate and is suitable for large-scale production.
The invention also provides a preparation method of the ereoxib.
In order to solve the technical problems, the invention adopts a technical scheme as follows:
a preparation method of an ereoxib intermediate shown as a formula I comprises the steps of reacting p-methylphenylacetic acid with α -dibromo-4-methylsulfonylacetophenone shown as a formula II in an organic solvent in the presence of an organic base to generate the ereoxib intermediate shown as the formula I;
the raw materials in the preparation method are added in a mode that the organic base, the organic solvent and the p-methyl phenylacetic acid are mixed to obtain a mixed solution, and then α -dibromo-4-methylsulfonyl acetophenone shown in the formula II is added into the mixed solution in batches or dropwise, wherein the feeding amount of the organic base is excessive relative to α -dibromo-4-methylsulfonyl acetophenone shown in the formula II.
According to some preferred aspects of the invention, the molar charge ratio of the organic base to the α -dibromo-4-methylsulfonylacetophenone is 2-10: 1.
According to some preferred aspects of the invention, the feed molar ratio of the p-methylphenylacetic acid to the α -dibromo-4-methylsulfonylacetophenone is 0.9-1.1: 1.
According to some preferred aspects of the invention, the reaction is carried out at 70-90 ℃. More preferably, the reaction is carried out at 75-88 ℃. According to a particular aspect of the invention, the reaction is carried out at 78-82 ℃.
According to some preferred aspects of the invention, the organic base is a combination of one or more selected from triethylamine, diisopropylethylamine, pyridine, N-lutidine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride and sodium amide.
According to some preferred aspects of the present invention, the organic solvent is a combination of one or more selected from acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, toluene, N-methylpyrrolidone, and ethylene glycol dimethyl ether.
According to some specific aspects of the invention, the preparation method is implemented by adding the p-methylphenylacetic acid and the organic base into the organic solvent to obtain a mixed solution, heating, preparing α -dibromo-4-methylsulfonylacetophenone shown in the formula II into a solution, adding the solution in batches or dropwise into the mixed solution, and continuing reflux reaction after dropwise addition to obtain the dapoxib intermediate shown in the formula I.
According to some preferred aspects of the invention, the preparation method further comprises the steps of subjecting the 4-methylsulfonylacetophenone of formula III to a bromination reaction to produce α -dibromo-4-methylsulfonylacetophenone of formula II;
according to some preferred aspects of the invention, the bromination reaction is carried out in a halogenated hydrocarbon. This mode facilitates the reaction and the recycling of the halogenated hydrocarbons.
According to some specific and preferred aspects of the present invention, the halogenated hydrocarbon is a combination of one or more selected from the group consisting of dichloromethane, chloroform, and dichloroethane.
According to some preferred aspects of the invention, the bromination reaction is carried out at 50-55 ℃.
The invention provides another technical scheme that: a preparation method of ereoxib, which comprises the following steps:
step 1), preparing an ereoxib intermediate shown in a formula I by the preparation method;
step 2), reacting the intermediate of the ereoxib shown in the formula I prepared in the step 1) with n-propylamine to generate the ereoxib shown in the formula IV under the action of an acidic medium;
according to some preferred aspects of the present invention, in step 2), a combination of one or more of ethanol, methanol, tetrahydrofuran and toluene is further added at the initial stage of the reaction of the ereoxib intermediate represented by formula i and the n-propylamine.
According to some specific and preferred aspects of the invention, in step 2), the acidic medium is a combination of one or more selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid.
According to some specific and preferred aspects of the present invention, in the step (2), the reaction is controlled to be carried out at 50 to 120 ℃.
According to some specific and preferred aspects of the present invention, in step (2), the charging molar ratio of the n-propylamine to the dapoxib intermediate represented by formula i is 1-20: 1.
According to some specific and preferred aspects of the present invention, in step (2), the feeding molar ratio of the acidic medium to the dapoxib intermediate represented by formula i is 1-50: 1.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the preparation method of the ereoxib intermediate shown in the formula I has the advantages that p-methylphenylacetic acid is reacted with α -dibromo-4-methylsulfonylacetophenone shown in the formula II, the addition mode of the raw materials is further controlled, the reaction selectivity is improved, the ideal yield of the required product is obtained, the operation is simple, the reaction condition is mild, and the industrial production is facilitated.
Drawings
FIG. 1 is a nuclear magnetic spectrum of α -dibromo-4-methylsulfonylacetophenone represented by the formula II of the present invention;
FIG. 2 is a nuclear magnetic spectrum of an ereoxib intermediate (4- (4-methylsulfonylphenyl) -3- (4-methylphenyl) -2, 5-dihydrofuran-2-one) shown in formula I.
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.
EXAMPLE 1 preparation of α -dibromo-4-methylsulfonylacetophenone of formula II
Dissolving 19.8g of 4-methylsulfonylacetophenone in 100ml of chloroform, slowly dropwise adding 35.2g of bromine at 50-55 ℃, keeping the temperature for reaction for 15min after dropwise adding, cooling, adding 100ml of water at 0-5 ℃, layering, drying a lower organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure until the lower organic phase is dry, adding 50ml of ethyl acetate, heating and refluxing for 2h, cooling to 10-15 ℃ for crystallization for 2h, filtering, and drying to obtain 32.6g of α -dibromo-4-methylsulfonylacetophenone, wherein the yield is 91.7%, and the purity is 98.3%.
As shown in fig. 1, the product nmr data is:1HNMR(300MHz,CDCl3)δ8.32(d,J＝8.6Hz,2H),8.11(d,J＝8.7Hz,2H),6.64(s,1H),3.13(s,3H)。
EXAMPLE 2 preparation of α -dibromo-4-methylsulfonylacetophenone of formula II
Dissolving 19.8g of 4-methylsulfonylacetophenone in 100ml of chloroform, slowly dropwise adding 32.2g of bromine at 50-55 ℃, keeping the temperature for reaction for 15min after dropwise adding, cooling, adding 100ml of water at 0-5 ℃, layering, drying a lower organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure until the lower organic phase is dry, adding 50ml of ethyl acetate, heating and refluxing for 2h, cooling to 10-15 ℃ for crystallization for 2h, filtering, and drying to obtain 31.6g of α -dibromo-4-methylsulfonylacetophenone, wherein the yield is 88.9%, and the purity is 97.8%.
EXAMPLE 34 preparation of- (4-methanesulfonylphenyl) -3- (4-methylphenyl) -2, 5-dihydrofuran-2-one (intermediate of Ericoxib, formula I)
Adding 13.5g of p-methylphenylacetic acid and 27.3g of triethylamine into 50ml of acetonitrile, heating to 78-82 ℃, slowly dropwise adding a solution prepared by using 32.0g of α -dibromo-4-methylsulfonylacetophenone and 60ml of acetonitrile in advance, continuously carrying out reflux reaction for 1h after dropwise adding, cooling to 20-25 ℃, adding saturated saline solution for layering, concentrating an organic layer to dryness, adding ethyl acetate and ethanol, stirring for 2h, carrying out suction filtration, and drying a solid to obtain 27.2g, wherein the yield is 92.1%, and the purity is 98.5%.
As shown in fig. 2, the product nmr data is:1HNMR(300MHz,CDCl3)δ7.95(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.32(d,J＝7.8Hz,2H),7.23(d,J＝7.9Hz,2H),5.20(s,2H),3.10(s,3H),2.41(s,3H)。
EXAMPLE 44 preparation of- (4-methanesulfonylphenyl) -3- (4-methylphenyl) -2, 5-dihydrofuran-2-one (intermediate of Ericoxib, formula I)
Adding 13.5g of p-methylphenylacetic acid and 34.8g of diisopropylethylamine into 50ml of acetonitrile, heating to 78-82 ℃, slowly dropwise adding a solution prepared by using 32.0g of α -dibromo-4-methylsulfonylacetophenone and 60ml of acetonitrile in advance, continuously carrying out reflux reaction for 1h after dropwise adding is finished, cooling to 20-25 ℃, adding saturated saline solution for layering, concentrating an organic layer to be dry, adding ethyl acetate and ethanol, stirring for 2h, carrying out suction filtration, drying a solid to obtain 26.7g, wherein the yield is 90.5%, and the purity is 98.1%.
EXAMPLE 54 preparation of (4-methanesulfonylphenyl) -3- (4-methylphenyl) -2, 5-dihydrofuran-2-one (intermediate of Ericoxib, formula I)
Adding 14.7g of p-methylphenylacetic acid and 27.3g of triethylamine into 50ml of acetonitrile, heating to 78-82 ℃, slowly dropwise adding a solution prepared by using 32.0g of α -dibromo-4-methylsulfonylacetophenone and 60ml of acetonitrile in advance, continuously carrying out reflux reaction for 1h after dropwise adding is finished, cooling to 20-25 ℃, adding saturated saline solution for layering, concentrating an organic layer to be dry, adding ethyl acetate and ethanol, stirring for 2h, carrying out suction filtration, and drying a solid to obtain 24.7g, wherein the yield is 83.7%, and the purity is 98.5%.
Example 6 preparation of Ehrexib
10g of 4- (4-methanesulfonylphenyl) -3- (4-methylphenyl) -2, 5-dihydrofuran-2-one preparation (an intermediate of ereoxib represented by formula I) and 50ml of toluene were charged into a reaction flask, and 14.6g of n-propylamine was added and heated to 50 ℃ for reaction for 3 hours. Cooling to room temperature, concentrating, adding 50ml acetic acid, heating to 120 deg.C, stirring, reacting for 3 hr, cooling the reaction solution to 20 deg.C, adding water, precipitating solid, filtering, and drying to obtain solid compound 9.53g with yield of 84.7%;
the solid compound was recrystallized from ethanol to give 8.83g of a white solid compound, yield 74.0%, purity 98.2%.
Example 7 preparation of Ehrexib
10g of 4- (4-methanesulfonylphenyl) -3- (4-methylphenyl) -2, 5-dihydrofuran-2-one preparation (intermediate of ereoxib represented by formula I) and 50ml of ethanol were charged into a reaction flask, 14.6g of n-propylamine was added, and the mixture was heated to 50 ℃ for reaction for 3 hours. Cooling to room temperature, concentrating, adding 50ml acetic acid, heating to 120 deg.C, stirring, reacting for 3 hr, cooling the reaction solution to 20 deg.C, adding water, precipitating solid, filtering, and drying to obtain solid compound 10.5g with yield of 93.3%;
the solid compound was recrystallized from ethanol to give 9.69g of a white solid compound, yield 86.1%, purity 98.9%.
Comparative example 1
The method is basically the same as example 3, except that the feeding method is different, specifically, p-methylphenylacetic acid and α -dibromo-4-methylsulfonylacetophenone are mixed to obtain a mixed solution, triethylamine is added into the mixed solution dropwise, and the product, namely the intermediate of the erexib shown in the formula I, is 21.0g, the yield is 71.1%, and the purity is 98.1%.
Comparative example 2
Essentially the same as example 3 except that the starting material α -dibromo-4-methylsulfonylacetophenone was replaced with α -bromomethylsulfonylacetophenone (shown below);
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 (10)
1. The preparation method of the ereoxib intermediate shown in the formula I is characterized by comprising the following steps of reacting p-methylphenylacetic acid with α -dibromo-4-methylsulfonylacetophenone shown in the formula II in an organic solvent in the presence of an organic base to generate the ereoxib intermediate shown in the formula I;
the raw materials in the preparation method are added in a mode that the organic base, the organic solvent and the p-methyl phenylacetic acid are mixed to obtain a mixed solution, and then α -dibromo-4-methylsulfonyl acetophenone shown in the formula II is added into the mixed solution in batches or dropwise, wherein the feeding amount of the organic base is excessive relative to α -dibromo-4-methylsulfonyl acetophenone shown in the formula II.
2. The preparation method of the dapoxib intermediate shown in the formula I as claimed in claim 1, wherein the feeding molar ratio of the organic base to the α -dibromo-4-methylsulfonylacetophenone is 2-10: 1.
3. The preparation method of the dapoxib intermediate shown as the formula I in claim 1, wherein the feeding molar ratio of the p-methylphenylacetic acid to the α -dibromo-4-methylsulfonylacetophenone is 0.9-1.1: 1.
4. The process for the preparation of the intermediate of formula i according to claim 1, characterized in that the reaction is carried out at 70-90 ℃.
5. The method for preparing the intermediate of the dapoxib of formula i according to claim 1, wherein the organic base is one or more selected from triethylamine, diisopropylethylamine, pyridine, N-lutidine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; and/or the organic solvent is one or more of acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, toluene, N-methylpyrrolidone and ethylene glycol dimethyl ether.
6. The method for preparing the ereoxib intermediate shown in the formula I as claimed in claim 1, is characterized in that the preparation method specifically comprises the steps of adding the p-methylphenylacetic acid and the organic base into the organic solvent to obtain a mixed solution, heating, preparing α -dibromo-4-methylsulfonylacetophenone shown in the formula II into a solution, adding the solution in batches or dropwise into the mixed solution, and continuing reflux reaction after dropwise addition is finished to obtain the ereoxib intermediate shown in the formula I.
7. The preparation method of the intermediate of the ereoxib shown in the formula I is characterized by further comprising the following steps of carrying out bromination reaction on the 4-methylsulfonylacetophenone shown in the formula III to generate α -dibromo-4-methylsulfonylacetophenone shown in the formula II;
8. the process for the preparation of the intermediate of formula i according to claim 7, characterized in that the bromination is carried out in a halogenated hydrocarbon; and/or, allowing the bromination reaction to proceed at 50-55 ℃.
9. A preparation method of ereoxib is characterized by comprising the following steps:
step 1), preparing an ereoxib intermediate shown as a formula I by the preparation method disclosed by any one of claims 1-8;
step 2), reacting the intermediate of the ereoxib shown in the formula I prepared in the step 1) with n-propylamine to generate the ereoxib shown in the formula IV under the action of an acidic medium;
10. the method for preparing ereoxib according to claim 9, wherein in step 2), one or more of ethanol, methanol, tetrahydrofuran and toluene are further added in the initial stage of the reaction between the intermediate of ereoxib represented by formula i and n-propylamine.
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