CN111807978B - Preparation method of Robecoxib - Google Patents
Preparation method of Robecoxib Download PDFInfo
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Abstract
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' 6' -tetrafluorophenyl) -5-ethylindole-2-ketone, and further synthesizing to obtain the synthesis of the robucoxide. Compared with the prior art, the invention has the beneficial effects that: 1. a palladium-containing catalyst or butyl lithium with high risk is not needed to be used for preparing the diarylamine compound, the reaction condition is mild, the process is safe, and the problem of heavy metal residue is avoided; 2. the use of expensive and dangerous dichloroethylaluminum is avoided, and the production cost is greatly reduced; 3. the method has short process route and cheap and easily-obtained raw materials.
Description
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 robesine is mainly carried out by the following routes:
(1) Roebecoxib is prepared by a coupling reaction, a substitution reaction or a rearrangement reaction to N- (2 '3' 6' -tetrafluorophenyl) -4-ethylaniline, followed by acylation, F-C alkylation and hydrolysis reactions in this order (U.S. Pat. No. 6291523, CN 102311355, organic Process research and 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) Diarylamine compounds are prepared by coupling 2-iodophenylacetic acid derivatives with 2,3,5,6-tetrafluoroaniline, and then the diarylamine compounds are subjected to acylation, reduction and hydrolysis reactions to prepare the robecoxib (U.S. Pat. No. 6,1523). 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 self-made, so that the total reaction route is longer 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 technical scheme adopted by the invention is as follows: 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' 6' -tetrafluorophenyl) -5-ethylindole-2-ketone, and further synthesizing to obtain the synthesis of the robucoxide.
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-ethylindole-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 'to 3' to 5'6' -tetrafluorophenyl) -5-ethylindole-2-ketone, a solvent and an alkali into a reaction vessel, heating for reaction, adjusting the pH 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-ethylindol-2-one to the 2,3,5, 6-tetrafluoroiodobenzene is 1.
According to the scheme: the heating reaction is carried out at 60-100 ℃ for 3-24h.
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 1-2, the molar ratio of 2-indolone to acetyl chloride is 1-3, and the reaction time is 2-18h.
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 to 10ml, the molar ratio of the 5-acetylindole-2-ketone to triethylsilane is 1 to 3, and the reaction time is 3 to 16 hours.
According to the scheme: in the synthesis step of the robecoxib, the alkali is sodium hydroxide or potassium hydroxide, the solvent is a mixture of an alcohol solvent and water, and the heating reaction condition is 80-100 ℃ for reaction for 3-12h.
The reaction equation involved in the invention is as follows:
compared with the prior art, the invention has the beneficial effects that:
1. directly preparing a key intermediate 4 by the Ullmann coupling reaction of 5-ethylindole-2-ketone and 2,3,5, 6-tetrafluoroiodobenzene, preparing a diarylamine compound without using a palladium-containing catalyst or butyl lithium with high risk, having mild reaction conditions and safe process, and avoiding the problem of heavy metal residue;
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 the Robecoxib compound prepared in example 1 of the present invention 1 H 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.
Example 1
(1) Synthesis of 5-acetylindol-2-one (2):
into a 250mL three-necked flask was added 32.0g of AlCl 3 And 100mL of dichloroethane, cooling to 0 ℃ in an ice bath, dropwise adding 17.7g of acetyl chloride while controlling the temperature not to exceed 10 ℃, keeping the temperature and stirring for 1h after the dropwise adding is finished, then adding 10g of 2-indolone while controlling the temperature to be 0-15 ℃, slowly returning to room temperature and stirring for 6h after the dropwise adding is finished, after the reaction is finished, slowly adding the reaction solution into 400g of ice water while stirring vigorously, stirring for 30min, washing the filtered solid with water, and drying to obtain 12.2g of 5-acetylindol-2-one with the yield of 92.8%.
(2) Synthesis of 5-ethylindol-2-one (3):
to a 250mL three-necked flask was added 10.0g of intermediate 2, dissolved with 75mL of TFA, and 14g of triethylsilane was slowly added under ice bath and stirred at room temperature overnight. The reaction solution was poured into ice water, and the obtained precipitate was filtered, washed thoroughly with water, and dried to obtain 8.3g of 5-ethylindole-2-one with a yield of 90.2%. 1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),7.12–6.98(m,2H),6.81(d,J＝8.0Hz,1H),3.52(s,2H),2.61(q,J＝7.6Hz,2H),1.22(t,J＝7.6Hz,3H)。
(3) Synthesis of N- (2 '3'5'6' -tetrafluorophenyl) -5-ethylindol-2-one (4):
to a 250mL three-necked flask, 150mg of CuI,8.0g of Compound 3, 11.0g of 2,3,5, 6-tetrafluoroiodobenzene and 11.0g of anhydrous K were added 2 CO 3 455mg of trans-N, N' -dimethyl-1, 2-cyclohexanediamine and 50ml of 1, 4-dioxane were replaced with argon in a reaction flask and stirred at 100 ℃ for 6 hours, after the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered through silica gel, the silica gel was washed with ethyl acetate, the filtrates were combined and concentrated and recrystallized from petroleum ether/ethyl acetate to give 10.9g of Compound 4, with a yield of 88.4%. 1 H NMR(400MHz,DMSO-d 6 )δ8.17(tt,J＝10.8,7.6Hz,1H),7.25(s,1H),7.12–7.06(m,1H),6.75(d,J＝8.0Hz,1H),3.91(s,2H),2.60(q,J＝7.6Hz,2H),1.17(t,J＝7.6Hz,3H)。
(4) Synthesis of robecoxib:
adding 50mL of water, 10mL of ethanol, 4g of sodium hydroxide and 10g of compound 4 into a 250mL three-necked flask, heating to 80 ℃, and keeping the temperatureAnd reacting for 6 hours, cooling the reaction solution, adjusting the pH value to 3-4 by using hydrochloric acid, filtering, washing the obtained solid product by using water, and recrystallizing to obtain 10.3g of the robecoxib with the yield of 97.4%. 1 H NMR(400MHz,DMSO-d 6 )δ12.50(s,1H),7.64(s,1H),7.32(tt,J＝10.8,7.2Hz,1H),7.07(d,J＝2.0Hz,1H),7.01(dd,J＝8.4,2.0Hz,1H),6.83–6.76(m,1H),3.67(s,2H),2.54(q,J＝7.6Hz,2H),1.16(t,J＝7.6Hz,3H)。
FIG. 1 is a graphic representation of the Robecoxib compound prepared in example 1 of the present invention 1 H NMR chart, broad peak at 12.50ppm is chemical shift of carboxylic acid active H, single peak at 7.64ppm is chemical shift of-NH-, tt peak at 7.32ppm is chemical shift of tetrafluorobenzene ring H, chemical shift of HC (6) at 7.07ppm, chemical shift of HC (4) at 7.01ppm, multiple peak at 6.83-6.76ppm is chemical shift of HC (3), single peak at 3.67ppm is-CH 2 Chemical shift of methylene H in-COOH, triplet at 2.54ppm is-CH 2 -CH 3 Chemical shift of the intermediate methylene H, a quartet at 1.16ppm is-CH 2 -CH 3 Chemical shift of the middle methyl group H. As can be seen from the peak types and the chemical shifts of all groups of peaks in a nuclear magnetic spectrum, the structure of the compound prepared in the embodiment 1 of the invention is completely consistent with that of a target molecule, and the purity of the Roebeixib prepared in the invention is up to 99.7 percent as shown in a figure 2.
Example 2
(1) Synthesis of 5-acetylindol-2-one (2):
into a 250mL three-necked flask, 30.0g of AlCl was added 3 And 100mL of dichloroethane, cooling to 0 ℃ in an ice bath, dropwise adding 11.8g of acetyl chloride while controlling the temperature not to exceed 10 ℃, keeping the temperature and stirring for 1h after the dropwise adding is finished, then adding 10g of 2-indolone while controlling the temperature to be 0-15 ℃, slowly returning to room temperature after the dropwise adding is finished, stirring overnight, after the reaction is finished, slowly adding the reaction solution into 400g of ice water while stirring vigorously, stirring for 30min, washing the filtered solid with water, and drying to obtain 12.4g of 5-acetylindole-2-one with the yield of 94.3%.
(2) Synthesis of 5-ethylindol-2-one (3):
to a 250mL three-necked flask was added 10.0g of intermediate 2, dissolved with 100mL of TFA, and 20g of triethylsilane was slowly added under ice-bath, and stirred at room temperature for 3h. The reaction solution was poured into ice water, and the obtained precipitate was filtered, washed thoroughly with water, and dried to obtain 8.6g of 5-ethylindole-2-one with a yield of 93.5%.
(3) Synthesis of N- (2 '3'5'6' -tetrafluorophenyl) -5-ethylindol-2-one (4):
into a 250mL three-necked flask were charged 480mg of CuI,8.0g of the compound 3, 13.8g of 2,3,5, 6-tetrafluoroiodobenzene and 21.2g of anhydrous K 3 PO 4 440mg of N, N' -dimethylethylenediamine and 100ml of acetonitrile, the inside of a reaction flask was replaced with argon, and then stirred at 80 ℃ for 12 hours, after the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through silica gel, and the silica gel was washed with ethyl acetate, and the filtrates were combined, concentrated and recrystallized from petroleum ether/ethyl acetate to obtain 13.2g of compound 4, with a yield of 85.4%.
(4) Synthesis of robecoxib:
adding 50mL of water, 10mL of methanol, 6g of potassium hydroxide and 10g of compound 4 into a 250mL three-necked flask, heating to 80 ℃, preserving the temperature, reacting for 5 hours, cooling the reaction solution, adjusting the pH to 3-4 by hydrochloric acid, filtering, washing the obtained solid product by using water, and recrystallizing to obtain 10.4g of robecoxib with the yield of 98.3%.
Example 3
(1) Synthesis of 5-acetylindol-2-one (2):
into a 250mL three-necked flask was added 20.0g of AlCl 3 And 70mL of dichloroethane, cooling to 0 ℃ in an ice bath, dropwise adding 8.8g of acetyl chloride while controlling the temperature not to exceed 10 ℃, keeping the temperature and stirring for 1h after the dropwise adding is finished, then adding 10g of 2-indolone while controlling the temperature to be 0-15 ℃, slowly returning to room temperature after the dropwise adding is finished, stirring overnight, after the reaction is finished, slowly adding the reaction solution into 300g of ice water while stirring vigorously, stirring for 30min, washing the filtered solid with water, and drying to obtain 11.9g of 5-acetylindole-2-one with the yield of 91.5%.
(2) Synthesis of 5-ethylindol-2-one (3):
a250 mL three-necked flask was charged with 10.0g of intermediate 2, dissolved with 60mL of TFA, and slowly added with 11g of triethylsilane under ice bath, and stirred at room temperature for 8h. The reaction solution was poured into ice water, and the obtained precipitate was filtered, washed thoroughly with water, and dried to obtain 8.1g of 5-ethylindole-2-one with a yield of 88.2%.
(3) Synthesis of N- (2 '3'5'6' -tetrafluorophenyl) -5-ethylindol-2-one (4):
into a 250mL three-necked flask was added 0.72g of Cu 2 O,8.0g of Compound 3, 16.0g of 2,3,5, 6-tetrafluoroiodobenzene and 23g of anhydrous K 3 PO 4 Replacing glycine 0.75g and 1, 4-dioxane 50ml in a reaction bottle by argon gas, stirring at 100 ℃ for 24 hours, cooling the reaction liquid to room temperature after the reaction is finished, diluting the reaction liquid by ethyl acetate, filtering the reaction liquid by silica gel, washing the silica gel by ethyl acetate, combining the filtrates, and recrystallizing the filtrate by petroleum ether/ethyl acetate to obtain a compound 4 12.5g with the yield of 80.9 percent.
(4) Synthesis of robecoxib:
50mL of water, 10mL of methanol, 4g of sodium hydroxide and 10g of compound 4 are added into a 250mL three-necked flask, the temperature is raised to 90 ℃ for reaction overnight, then the reaction liquid is cooled, the pH is adjusted to 3-4 by hydrochloric acid, the solution is filtered, the obtained solid product is washed by water and then recrystallized to obtain 10.0g of robecoxib, and the yield is 94.5%.
It is apparent that the above embodiments are only examples for clearly illustrating and do not limit the embodiments. It will be apparent to those skilled in the art that the above data illustrates that other variations and modifications may be made on the basis of the above description without necessarily requiring or implying an exhaustive enumeration of all such embodiments. And obvious variations or modifications are therefore intended to be included within the scope of the invention as claimed.
Claims (6)
1. A method of preparing robecoxib comprising the steps of:
1) Synthesis of 5-ethylindol-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; 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 5-ethyl indole-2-ketone;
2) Synthesis of N- (2 '3'5'6' -tetrafluorophenyl) -5-ethylindol-2-one: 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; cooling the reaction liquid to room temperature after the reaction is finished, diluting, filtering, washing, concentrating an organic phase, and recrystallizing to obtain N- (2 '3' 6' -tetrafluorophenyl) -5-ethylindole-2-ketone, wherein the catalyst is cuprous iodide or cuprous oxide, the base is anhydrous potassium carbonate or anhydrous potassium phosphate, and the ligand is anhydrous potassium carbonate or anhydrous potassium phosphateN,N '-dimethylethylenediamine, trans-N,N ’-dimethyl-1, 2-cyclohexanediamine or glycine, the solvent being 1, 4-dioxane or acetonitrile;
3) Synthesis of robecoxib: adding N- (2 'to 3' to 5'6' -tetrafluorophenyl) -5-ethylindole-2-ketone, a solvent and an alkali into a reaction vessel, heating for reaction, adjusting the pH 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; the alkali is sodium hydroxide or potassium hydroxide, and the solvent is a mixture of an alcohol solvent and water.
2. A method of preparing robesicoxib according to claim 1 wherein: step 2) the molar ratio of 5-ethylindol-2-one to 2,3,5, 6-tetrafluoroiodobenzene is 1.
3. A method of preparing robesicoxib according to claim 1 wherein: the heating reaction in the step 2) is carried out for 3-24h at the temperature of 60-100 ℃.
4. A method of preparing a rofecoxib compound in accordance with claim 1, wherein: the molar ratio of acetyl chloride to anhydrous aluminum trichloride in the step 1) is 1-2, the molar ratio of 2-indolone to acetyl chloride is 1-3, and the reaction time is 2-18h.
5. A method of preparing robesicoxib according to claim 1 wherein: the mass volume ratio of the 5-acetyl indole-2-ketone to the trifluoroacetic acid in the step 1) is 1g to 10ml, the molar ratio of the 5-acetyl indole-2-ketone to the triethylsilane is 1 to 3, and the reaction time is 3 to 16 hours.
6. A method of preparing a rofecoxib compound in accordance with claim 1, wherein: the heating reaction condition in the step 3) is that the reaction is carried out for 3 to 12 hours at a temperature of between 80 and 100 ℃.
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| CN1268112A (en) * | 1997-08-28 | 2000-09-27 | 诺瓦提斯公司 | Certain 5-alkyl-2-arylaminophenylacetic acids and their derivatives |
| CN102311355A (en) * | 2011-09-26 | 2012-01-11 | 扬州天和药业有限公司 | Preparation method of rofecoxib |
| CN109503399A (en) * | 2018-12-29 | 2019-03-22 | 江苏天和制药有限公司 | A kind of preparation method of rofecoxib |
| WO2020021077A1 (en) * | 2018-07-27 | 2020-01-30 | Krka, D.D., Novo Mesto | A process for the preparation of polymorphic form of robenacoxib |
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| CN1268112A (en) * | 1997-08-28 | 2000-09-27 | 诺瓦提斯公司 | Certain 5-alkyl-2-arylaminophenylacetic acids and their derivatives |
| CN102311355A (en) * | 2011-09-26 | 2012-01-11 | 扬州天和药业有限公司 | Preparation method of rofecoxib |
| WO2020021077A1 (en) * | 2018-07-27 | 2020-01-30 | Krka, D.D., Novo Mesto | A process for the preparation of polymorphic form of robenacoxib |
| CN109503399A (en) * | 2018-12-29 | 2019-03-22 | 江苏天和制药有限公司 | A kind of preparation method of rofecoxib |
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