CN110143891B - Preparation method of aceclofenac - Google Patents
Preparation method of aceclofenac Download PDFInfo
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- CN110143891B CN110143891B CN201910424338.2A CN201910424338A CN110143891B CN 110143891 B CN110143891 B CN 110143891B CN 201910424338 A CN201910424338 A CN 201910424338A CN 110143891 B CN110143891 B CN 110143891B
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- 229960004420 aceclofenac Drugs 0.000 title claims abstract description 22
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000019253 formic acid Nutrition 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- 229940125782 compound 2 Drugs 0.000 claims abstract description 8
- 229940126214 compound 3 Drugs 0.000 claims abstract description 6
- 229940125904 compound 1 Drugs 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims 1
- QIQFYYWKRUYDTH-UHFFFAOYSA-N [2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl] 2-[2-(2,6-dichloroanilino)phenyl]acetate Chemical compound CC(C)(C)OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl QIQFYYWKRUYDTH-UHFFFAOYSA-N 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 239000011259 mixed solution Substances 0.000 abstract description 2
- 239000012046 mixed solvent Substances 0.000 abstract description 2
- 208000012839 conversion disease Diseases 0.000 abstract 1
- 229960001259 diclofenac Drugs 0.000 abstract 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 5
- -1 tert-butyl aceclofenac Chemical compound 0.000 description 5
- 229960001193 diclofenac sodium Drugs 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 2
- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A preparation method of aceclofenac under the assistance of microwaves comprises the following steps: under the microwave condition, reacting the compound 2 with the compound 3 under the catalysis of KI to generate a compound 4; under the microwave condition, reacting the compound 4 in a mixed solvent of formic acid and acetone to generate a compound 1; the invention adopts the microwave condition to carry out acidolysis on aceclofenac tert-butyl ester in the mixed solution of formic acid and acetone, the acidolysis method has high selectivity, reduces the breakage of the ethoxy group of the aceclofenac tert-butyl ester to the lowest limit, has high acidolysis reaction conversion rate, has extremely low diclofenac content in the product, is easy to refine the product and has high purity.
Description
(I) technical field
The invention relates to a preparation method of an anti-inflammatory analgesic drug, in particular to a preparation method of aceclofenac under the assistance of microwaves, belonging to the fields of chemical pharmacy and microwave reaction.
(II) background of the invention
Aceclofenac, chemical name 2- ((2, 6-dichlorophenyl) amino) phenylacetoxyacetic acid, english name: aceclofenac, structural formula:
in the traditional aceclofenac synthesis reaction, a heat conduction heating method is adopted, the reaction is usually heated to a higher temperature, the energy consumption is high, the traditional reaction time is longer, more impurities are generated in the acidolysis process, and the aftertreatment is difficult.
CN2007192213 discloses a preparation method of aceclofenac, which comprises the steps of using diclofenac sodium and tert-butyl chloroacetate, heating and reacting under the action of triethylamine to obtain tert-butyl aceclofenac, and carrying out acidolysis with formic acid to obtain aceclofenac. The method has the advantages of low reaction rate and low reaction yield.
The microwave is electromagnetic wave with frequency of 300 MHz-300 KMHz. The vibration frequency of the microwave is similar to the dipole vibration frequency of the substance molecules. In a microwave magnetic field, the molecular dipoles vibrate in a manner that the magnetic field vibrates in a manner that matches the vibration of the magnetic field, but the vibration lags behind the magnetic field, so that the molecules of matter absorb electromagnetic energy and vibrate at high speed, billions of times per second, to generate heat energy.
Most of the existing organic matters are polar and nonpolar compounds, polar molecular organic matters have a dipole effect, and when microwaves encounter polar molecules, high-speed violent oscillation of the molecules can be caused to generate a large amount of molecular heat; the nonpolar molecules generate induced and dispersed dipoles due to the existence of polar medium molecules, and can also generate vibration under the action of a high-frequency alternating electric field such as microwave to generate molecular heat. The traditional heating mode is to heat the substance from outside to inside by conduction, convection, radiation and other modes, the heating process is slow, and the system is heated unevenly. The chemical reaction under the assistance of the microwave generates molecular heat by promoting the vibration of substance molecules, so that the heating efficiency is high, and the system is uniformly heated. The reaction has the characteristics of low energy consumption, short reaction time, high reaction yield and the like.
Disclosure of the invention
The invention aims to provide a preparation method of aceclofenac under the assistance of microwaves.
The technical scheme of the invention is as follows:
a preparation method of aceclofenac under the assistance of microwaves comprises the following steps:
(a) under the microwave condition, the compound 2 (diclofenac sodium) and the compound 3 (tert-butyl bromoacetate) react under the catalysis of KI to generate a compound 4 (tert-butyl aceclofenac);
specifically, the operation method of the step (a) comprises the following steps:
mixing a compound 2, a compound 3, KI (catalyst) and acetonitrile (solvent), reacting for 5-30 min (preferably 15min) under the conditions of microwave power of 50-300W (preferably 100W) and microwave reaction temperature of 20-50 ℃ (preferably 30 ℃), and then carrying out aftertreatment to obtain a compound 4;
the ratio of the amount of the compound 2, the compound 3 and the KI is 1: 1-1.5: 0.03 to 0.1, preferably 1: 1.2: 0.05;
the volume dosage of the acetonitrile is 3-10 mL/g, preferably 3mL/g, based on the mass of the compound 2;
the post-treatment method comprises the following steps: after the reaction is finished, pouring the reaction solution into purified water with the volume of 3-5 times, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake with purified water to obtain a crude product, adding the crude product into ethanol for refining, heating to 75 ℃, cooling to 10 ℃ while stirring after the solid is completely dissolved, crystallizing for 2 hours, carrying out suction filtration, washing the filter cake with ethanol, and drying to obtain a compound 4;
(b) under the microwave condition, the compound 4 reacts in a mixed solvent of formic acid and acetone to generate a compound 1 (aceclofenac);
specifically, the operation method of the step (b) is as follows:
mixing the compound 4, formic acid and acetone, reacting for 5-30 min (preferably 10min) under the conditions of microwave power of 50-400W (preferably 200W) and microwave reaction temperature of 30-80 ℃ (preferably 65 ℃), and then carrying out post-treatment to obtain a compound 1;
the mass ratio of the compound 4 to formic acid is 1: 20-25, preferably 1: 22;
the volume dosage of the acetone is 0.5-1 mL/g, preferably 0.5mL/g, based on the mass of the compound 4;
the post-treatment method comprises the following steps: after the reaction is finished, pouring the reaction solution into purified water of which the amount is 4-6 times that of the reaction solution, stirring for 10min, carrying out suction filtration, washing a filter cake with the purified water to obtain a crude product, and recrystallizing the crude product with toluene to obtain a compound 1;
the invention has the beneficial effects that: the invention provides a microwave-assisted aceclofenac preparation method, which comprises the step of acidolysis of aceclofenac tert-butyl ester in a mixed solution of formic acid and acetone under the microwave condition.
(IV) detailed description of the preferred embodiments
The present invention is further illustrated by the following specific examples, but the scope of the invention is not limited thereto.
Example 1: preparation of tert-butyl 2- ((2, 6-dichlorophenyl) amino) phenylacetoxyacetate (tert-butyl aceclofenac)
Diclofenac sodium (10g, 33.8mmol), tert-butyl bromoacetate (7.85g, 40.3mmol), KI (0.26g, 1.6mmol), acetonitrile (30mL) were added to a 100mL flask. Setting microwave conditions, wherein the power is 100W, the temperature is 30 ℃, and the reaction time is 15 min. After the reaction is finished, pouring the reaction liquid into 100mL of purified water, and stirring for crystallization for 2 h. And (4) carrying out suction filtration, and washing a filter cake twice by using 100mL of purified water to obtain a crude product of aceclofenac tert-butyl ester.
Adding the crude product and ethanol (280mL) into a 500mL three-necked flask, heating to 75 ℃, cooling to 10 ℃ while stirring until the solid is completely dissolved, crystallizing for 2h, performing suction filtration, washing a filter cake twice with 100mL of ethanol, and drying to obtain 12.70g of white solid with the yield of 91.6%.
Example 2: preparation of aceclofenac
Tert-butyl aceclofenac (7.0g, 17.1mmol), formic acid (14mL, 371.3mmol) and acetone (3.5mL) were added to a 50mL three-necked flask. Setting microwave conditions, wherein the power is 200W, the temperature is 65 ℃, and the reaction time is 10 min. After the reaction is finished, slowly pouring the reaction liquid into 80mL of purified water, stirring for 10 minutes, carrying out suction filtration, and washing the filter cake twice with 20mL of purified water to obtain a crude product. Dissolving the crude product in toluene (12mL), heating to 90 ℃, cooling to 10 ℃ while stirring until the solid is completely dissolved, crystallizing, growing the crystal for 2h, filtering, washing the filter cake twice with 10mL of toluene, and drying to obtain 5.83g of white solid with the yield of 96.3%.
Comparative example
Acetonitrile (120mL) and diclofenac sodium (19.2g,0.06mol) are added into a 250mL reaction flask, stirred and heated to reflux, tert-butyl chloroacetate (10.8g,0.07mol) is added dropwise, and after the dropwise addition, the mixture is stirred and refluxed for reaction for 24 hours. Suction filtration is carried out, and the solvent is removed by evaporation from the filtrate, thus obtaining crude aceclofenac tert-butyl ester (22.8 g). Directly used for the next reaction.
Adding toluene (20mL) and concentrated hydrochloric acid (5mL) into the crude aceclofenac tert-butyl ester, heating to 60 ℃, stirring and reacting for 1.5h at 55-60 ℃ after all solids are dissolved, stirring and cooling to room temperature after the reaction is finished, and precipitating a large amount of white crystals. Suction filtration and washing of the filter cake with water 2 times, drying and recrystallization from toluene gave a white solid (17.4g, 82.2% yield over two steps).
Claims (4)
1. A preparation method of aceclofenac under the assistance of microwaves is characterized by comprising the following steps:
(a) mixing the compound 2, the compound 3, KI and acetonitrile, reacting for 15min under the conditions of microwave power of 100W and microwave reaction temperature of 30 ℃, and then carrying out post-treatment to obtain a compound 4;
the ratio of the amount of the compound 2, the compound 3 and the KI is 1: 1.2: 0.05;
(b) mixing the compound 4, formic acid and acetone, reacting for 10min under the conditions of microwave power of 200W and microwave reaction temperature of 65 ℃, and then carrying out post-treatment to obtain a compound 1;
the mass ratio of the compound 4 to formic acid is 1: 22; the volume dosage of the acetone is 0.5mL/g based on the mass of the compound 4;
2. the microwave-assisted aceclofenac production method according to claim 1, wherein in the step (a), the volume of acetonitrile is 3 to 10mL/g based on the mass of the compound 2.
3. The method for preparing aceclofenac under microwave assistance according to claim 1, wherein the post-treatment in the step (a) is carried out by: after the reaction is finished, pouring the reaction solution into purified water with the volume being 3-5 times of that of the reaction solution, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake with purified water to obtain a crude product, adding the crude product into ethanol for refining, heating to 75 ℃, cooling to 10 ℃ while stirring after the solid is completely dissolved, crystallizing for 2 hours, carrying out suction filtration, washing the filter cake with ethanol, and drying to obtain a compound 4.
4. The method for preparing aceclofenac under microwave assistance according to claim 1, wherein the post-treatment in the step (b) is carried out by: and after the reaction is finished, pouring the reaction solution into purified water of which the volume is 4-6 times that of the reaction solution, stirring for 10min, carrying out suction filtration, washing a filter cake with the purified water to obtain a crude product, and recrystallizing the crude product with toluene to obtain the compound 1.
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| CN111848426B (en) * | 2020-07-17 | 2023-02-10 | 宁波斯迈克制药有限公司 | Industrial production method of aceclofenac |
| CN112250589A (en) * | 2020-10-23 | 2021-01-22 | 陕西恒诚制药有限公司 | Aceclofenac synthesis refining process |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101531607A (en) * | 2009-01-20 | 2009-09-16 | 鲁南制药集团股份有限公司 | Improved method for preparing aceclofenac |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531607A (en) * | 2009-01-20 | 2009-09-16 | 鲁南制药集团股份有限公司 | Improved method for preparing aceclofenac |
Non-Patent Citations (1)
| Title |
|---|
| Ultrasound-promoted synthesis of aceclofenac;Patra, S.等;《Journal of Scientific & Industrial Research》;20151231;第74卷(第10期);第582页右栏最后一段 * |
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