阅读说明：本技术 一种罗贝考昔的制备方法 (Preparation method of Robecoxib ) 是由 施川 王靖 于 2020-07-29 设计创作，主要内容包括：本发明涉及一种罗贝考昔的制备方法,包括以下步骤：在惰性气体保护下,向反应容器中加入5-乙基吲哚-2-酮、2,3,5,6-四氟碘苯、催化剂、碱、配体和溶剂,加热反应；反应完成后将反应液冷却至室温,稀释后经过滤,洗涤,有机相浓缩后重结晶即得N-(2’3’5’6’-四氟苯基)-5-乙基吲哚-2-酮,并进一步合成得到罗贝考昔的合成。与现有工艺相比,本发明的有益效果在于：1、无需使用含钯催化剂或危险性较大的丁基锂来制备二芳胺化合物,反应条件温和,工艺安全,且避免了重金属残留的问题；2、避免了使用价格昂贵且危险的二氯乙基铝,大幅降低了生产成本；3、该方法工艺路线短,原料廉价易得。(The invention relates to a preparation method of Robecoxib, which comprises the following steps: under the protection of inert gas, adding 5-ethylindole-2-ketone, 2,3,5, 6-tetrafluoroiodobenzene, a catalyst, alkali, a ligand and a solvent into a reaction vessel, and heating for reaction; and after the reaction is finished, cooling the reaction liquid to room temperature, diluting, filtering, washing, concentrating an organic phase, recrystallizing to obtain N- (2 '3' 5 '6' -tetrafluorophenyl) -5-ethylindole-2-ketone, and further synthesizing to obtain the synthesis of the Roebeckib. Compared with the prior art, the invention has the beneficial effects that: 1. the diarylamine compound is prepared without using a palladium-containing catalyst or butyl lithium with high risk, the reaction condition is mild, the process is safe, and the problem of heavy metal residue is avoided; 2. expensive and dangerous dichloroethylaluminum is avoided, and production cost is greatly reduced; 3. the method has short process route and cheap and easily-obtained raw materials.)

1. A method of preparing robecoxib comprising the steps of:

under the protection of inert gas, adding 5-ethylindole-2-ketone, 2,3,5, 6-tetrafluoroiodobenzene, a catalyst, alkali, a ligand and a solvent into a reaction vessel, and heating for reaction; and after the reaction is finished, cooling the reaction liquid to room temperature, diluting, filtering, washing, concentrating an organic phase, recrystallizing to obtain N- (2 '3' 5 '6' -tetrafluorophenyl) -5-ethylindole-2-ketone, and further synthesizing to obtain the synthesis of the Roebeckib.

2. A method of preparing robesicoxib according to claim 1 wherein: the synthesis of the 5-ethylindole-2-ketone comprises the following steps:

1) synthesis of 5-acetylindol-2-one: dispersing anhydrous aluminum trichloride with 1, 2-dichloroethane, cooling in an ice water bath, dropwise adding acetyl chloride, keeping the temperature and stirring, then adding 2-indolone, reacting at room temperature, pouring the reaction liquid into ice water, stirring, filtering, washing the obtained solid, and drying to obtain 5-acetylindole-2-one;

2) synthesis of 5-ethylindol-2-one: dissolving 5-acetyl indole-2-ketone with trifluoroacetic acid, adding triethylsilane in an ice water bath, reacting at room temperature, pouring the reaction liquid into ice water after the reaction is finished, filtering the obtained precipitate, washing and drying to obtain the 5-ethyl indole-2-ketone.

3. A method of preparing robesicoxib according to claim 1 wherein: the synthesis of the robecoxib comprises the following specific steps: adding N- (2 '3' 5 '6' -tetrafluorophenyl) -5-ethylindole-2-ketone, a solvent and alkali into a reaction vessel, heating for reaction, adjusting the pH value of a reaction solution to 3-4 after the reaction is finished, filtering, washing the obtained solid with water, and recrystallizing to obtain the robecoxib.

4. A method of preparing robesicoxib according to claim 1 wherein: the catalyst is cuprous iodide or cuprous oxide, the alkali is anhydrous potassium carbonate or anhydrous potassium phosphate, the ligand is N, N '-dimethylethylenediamine, trans-N, N' -dimethyl-1, 2-cyclohexanediamine or glycine, and the solvent is 1, 4-dioxane or acetonitrile.

5. A method of preparing robesicoxib according to claim 1 wherein: the molar ratio of the 5-ethylindole-2-ketone to the 2,3,5, 6-tetrafluoroiodobenzene is 1:0.8-1.2, the molar ratio of the 5-ethylindole-2-ketone to the catalyst is 1:0.01-0.2, the molar ratio of the 5-ethylindole-2-ketone to the ligand is 1:0.02-0.2, and the molar ratio of the 5-ethylindole-2-ketone to the alkali is 1: 1.5-3.

6. A method of preparing robesicoxib according to claim 1 wherein: the heating reaction is carried out at 60-100 ℃ for 3-24 h.

7. A method of preparing robesicoxib according to claim 2 wherein: in the synthesis process of the 5-ethylindole-2-ketone, the molar ratio of acetyl chloride to anhydrous aluminum trichloride is 1:1-2, the molar ratio of 2-indolone to acetyl chloride is 1:1-3, and the reaction time is 2-18 h.

8. A method of preparing robesicoxib according to claim 2 wherein: in the synthesis process of the 5-ethylindole-2-ketone, the mass volume ratio of the 5-acetylindole-2-ketone to trifluoroacetic acid is 1g:5-10ml, the molar ratio of the 5-acetylindole-2-ketone to triethylsilane is 1:1-3, and the reaction time is 3-16 h.

9. A method of preparing robesicoxib according to claim 3 wherein: the base in the synthesis step of the Robecoxib is sodium hydroxide or potassium hydroxide, the solvent is a mixture of an alcohol solvent and water, and the heating reaction condition is that the reaction is carried out for 3-12h at 80-100 ℃.

Technical Field

The invention relates to a preparation method of Robecoxib.

Background

Robecoxib is a nonsteroidal anti-inflammatory drug which can selectively inhibit cyclooxygenase (COX-2) and has a slight inhibition effect on cyclooxygenase (COX-1). Therefore, compared with other non-selective non-steroidal anti-inflammatory drugs, the product has less adverse reaction to gastrointestinal tract or kidney.

The synthesis of the currently reported robesicoxib mainly comprises the following routes:

(1) n- (2 '3' 5 '6' -tetrafluorophenyl) -4-ethylaniline is prepared by a coupling reaction, a substitution reaction or a rearrangement reaction, and then robecoxib is prepared by acylation, F-C alkylation and hydrolysis reactions in sequence (U.S. Pat. No. 6,1523, CN 102311355, Organic Process Research & Development 2009,13,1608). The specific reaction equation is as follows:

in the method, the coupling reaction is realized by palladium catalysis, the cost is high, and a large amount of heavy metal residues are difficult to remove; if the substitution reaction is carried out, butyl lithium is needed to be used as alkali, so that the method has great danger and is not beneficial to large-scale production; the rearrangement reaction has a long route and the used raw materials are expensive. Furthermore, the ethyl aluminum dichloride used in this route to perform the F-C alkylation reaction is expensive and hazardous.

(2) The diarylamine compound is prepared by coupling 2-iodophenylacetic acid derivative and 2,3,5, 6-tetrafluoroaniline, and then the robecoxib is prepared by acylation, reduction and hydrolysis (U.S. Pat. No. 6,629,1523). The specific reaction equation is as follows:

the method also needs to use palladium for catalysis, has the problem of heavy metal residue, and the used tetrafluoroaniline is very expensive. In addition, the 2-iodophenylacetic acid derivative has no commercial source and needs to be prepared by self, so that the total reaction route is long and the production cost is overhigh.

In addition, CN109503399A, CN109694330A and the like adopt methods similar to the method 1 to prepare the Robecoxib, and the methods also have the defects of long reaction route, complex process, high production cost and the like.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of the Roebeside aiming at the defects in the prior art, shorten the reaction route, simplify the reaction conditions, improve the process safety and prepare the Roebeside with high yield and high purity at lower cost.

In order to solve the technical problems, the invention adopts the technical scheme that: a method of preparing robecoxib comprising the steps of:

under the protection of inert gas, adding 5-ethylindole-2-ketone, 2,3,5, 6-tetrafluoroiodobenzene, a catalyst, alkali, a ligand and a solvent into a reaction vessel, and heating for reaction; and after the reaction is finished, cooling the reaction liquid to room temperature, diluting, filtering, washing, concentrating an organic phase, recrystallizing to obtain N- (2 '3' 5 '6' -tetrafluorophenyl) -5-ethylindole-2-ketone, and further synthesizing to obtain the synthesis of the Roebeckib.

According to the scheme: the synthesis of the 5-ethylindole-2-ketone comprises the following steps:

1) synthesis of 5-acetylindol-2-one: dispersing anhydrous aluminum trichloride with 1, 2-dichloroethane, cooling in an ice water bath, dropwise adding acetyl chloride, keeping the temperature and stirring, then adding 2-indolone, reacting at room temperature, pouring the reaction liquid into ice water, stirring, filtering, washing the obtained solid, and drying to obtain 5-acetylindole-2-one;

2) synthesis of 5-ethylindol-2-one: dissolving 5-acetyl indole-2-ketone with trifluoroacetic acid, adding triethylsilane in an ice water bath, reacting at room temperature, pouring the reaction liquid into ice water after the reaction is finished, filtering the obtained precipitate, washing and drying to obtain the 5-ethyl indole-2-ketone.

According to the scheme: the synthesis of the robecoxib comprises the following specific steps: adding N- (2 '3' 5 '6' -tetrafluorophenyl) -5-ethylindole-2-ketone, a solvent and alkali into a reaction vessel, heating for reaction, adjusting the pH value of a reaction solution to 3-4 after the reaction is finished, filtering, washing the obtained solid with water, and recrystallizing to obtain the robecoxib.

According to the scheme: the catalyst is cuprous iodide or cuprous oxide, the alkali is anhydrous potassium carbonate or anhydrous potassium phosphate, the ligand is N, N '-dimethylethylenediamine, trans-N, N' -dimethyl-1, 2-cyclohexanediamine or glycine, and the solvent is 1, 4-dioxane or acetonitrile.

According to the scheme: the molar ratio of the 5-ethylindole-2-ketone to the 2,3,5, 6-tetrafluoroiodobenzene is 1:0.8-1.2, the molar ratio of the 5-ethylindole-2-ketone to the catalyst is 1:0.01-0.2, the molar ratio of the 5-ethylindole-2-ketone to the ligand is 1:0.02-0.2, and the molar ratio of the 5-ethylindole-2-ketone to the alkali is 1: 1.5-3.

According to the scheme: the heating reaction is carried out at 60-100 ℃ for 3-24 h.

According to the scheme: in the synthesis process of the 5-ethylindole-2-ketone, the molar ratio of acetyl chloride to anhydrous aluminum trichloride is 1:1-2, the molar ratio of 2-indolone to acetyl chloride is 1:1-3, and the reaction time is 2-18 h.

According to the scheme: in the synthesis process of the 5-ethylindole-2-ketone, the mass volume ratio of the 5-acetylindole-2-ketone to trifluoroacetic acid is 1g:5-10ml, the molar ratio of the 5-acetylindole-2-ketone to triethylsilane is 1:1-3, and the reaction time is 3-16 h.

According to the scheme: the base in the synthesis step of the Robecoxib is sodium hydroxide or potassium hydroxide, the solvent is a mixture of an alcohol solvent and water, and the heating reaction condition is that the reaction is carried out for 3-12h at 80-100 ℃.

The reaction equation involved in the invention is as follows:

compared with the prior art, the invention has the beneficial effects that:

1. the key intermediate 4 is directly prepared from 5-ethylindole-2-ketone and 2,3,5, 6-tetrafluoroiodobenzene through Ullmann coupling reaction, a palladium-containing catalyst or butyl lithium with high risk is not needed to be used for preparing a diarylamine compound, the reaction condition is mild, the process is safe, and the problem of heavy metal residue is avoided;

2. 2-indolone which is rich in source, cheap and easy to obtain is used as a starting material, and an F-C alkylation reaction is not needed, so that expensive and dangerous ethylene aluminum dichloride is avoided, and the production cost is greatly reduced;

3. the method has the advantages of short process route, cheap and easily-obtained raw materials, mild reaction conditions, simple operation and low production cost, and is suitable for industrial production.

Drawings

FIG. 1 is a graphic representation of Robecoxib prepared in example 1 of the present invention¹H NMR chart;

FIG. 2 is a liquid chromatogram of Robecoxib prepared in example 1 of the present invention;

Detailed Description

In order to make the technical solutions of the present invention better understood, the present invention is further described in detail below with reference to the accompanying drawings.