CN112250589A - Aceclofenac synthesis refining process - Google Patents
Aceclofenac synthesis refining process Download PDFInfo
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- CN112250589A CN112250589A CN202011153001.1A CN202011153001A CN112250589A CN 112250589 A CN112250589 A CN 112250589A CN 202011153001 A CN202011153001 A CN 202011153001A CN 112250589 A CN112250589 A CN 112250589A
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- 229960004420 aceclofenac Drugs 0.000 title claims abstract description 122
- 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 121
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 35
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000008569 process Effects 0.000 title claims abstract description 23
- 238000007670 refining Methods 0.000 title claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 47
- 239000003960 organic solvent Substances 0.000 claims abstract description 27
- 238000005406 washing Methods 0.000 claims abstract description 26
- 238000002791 soaking Methods 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 21
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 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
- 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 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000002386 leaching Methods 0.000 claims abstract description 9
- 238000000967 suction filtration Methods 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 239000000047 product Substances 0.000 claims abstract description 4
- 238000000746 purification Methods 0.000 claims description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 34
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 230000000052 comparative effect Effects 0.000 description 19
- 230000002194 synthesizing effect Effects 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960005142 alclofenac Drugs 0.000 description 2
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- -1 tert-butyl aceclofenac Chemical compound 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
Classifications
-
- 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
- C07C227/16—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 not involving the amino or carboxyl groups
-
- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
Abstract
The application relates to the field of raw material medicine synthesis, and particularly discloses an aceclofenac synthesis refining process, which comprises the following steps: (1) adding aceclofenac tert-butyl ester into formic acid, heating for acidolysis reaction, cooling to normal temperature, performing suction filtration and water washing, leaching until the pH of discharged water is more than 5.0, and performing centrifugal drying to obtain a crude aceclofenac product; (2) putting the aceclofenac crude product into a reaction vessel, adding an organic solvent to cover the aceclofenac crude product, wherein the aceclofenac is insoluble or slightly soluble in the organic solvent, soaking, stirring and washing, centrifuging and spin-drying, and drying to obtain the aceclofenac. The process has the advantage of improving the purity and whiteness of aceclofenac.
Description
Technical Field
The application relates to the field of raw material medicine synthesis, in particular to an aceclofenac synthesis refining process.
Background
Aceclofenac, the chemical name is 2- ((2, 6-dichlorophenyl) amino) phenylacetoxyacetic acid, this product is a new synthetic oral effective nonsteroidal anti-inflammatory analgesic, belong to phenylacetic acid anti-inflammatory, antipyretic, analgesic drug, structurally, with diclofenac, alclofenac and alclofenac are relevant, in clinical practice, its pharmacological action compares with other nonsteroidal drugs, it has apparent extensive anti-inflammatory action, powerful analgesia and antipyretic and stomach toxicity effects as the characteristic in acute, chronic inflammation experimental model.
In the presence of triethylamine, diclofenac and tert-butyl bromoacetate are condensed to prepare tert-butyl aceclofenac, and the tert-butyl aceclofenac is then acidolyzed with formic acid to prepare aceclofenac.
In view of the above-mentioned related art, the above-mentioned method generates a lot of by-products, and the inventors consider that there is a defect that the purity of aceclofenac is to be improved.
Disclosure of Invention
In order to improve the purity of aceclofenac, the application provides a process for synthesizing and refining aceclofenac.
The aceclofenac synthesis refining process provided by the application adopts the following technical scheme:
an aceclofenac synthesis and refining process comprises the following steps:
(1) adding aceclofenac tert-butyl ester into formic acid, heating for acidolysis reaction, cooling to normal temperature, performing suction filtration and water washing, leaching until the pH of discharged water is more than 5.0, and performing centrifugal drying to obtain a crude aceclofenac product;
(2) putting the aceclofenac crude product into a reaction vessel, adding an organic solvent to cover the aceclofenac crude product, wherein the aceclofenac is insoluble or slightly soluble in the organic solvent, soaking, stirring and washing, centrifuging and spin-drying, and drying to obtain the aceclofenac.
By adopting the technical scheme, the aceclofenac crude product is soaked and washed by adopting the organic solvent, the aceclofenac is insoluble or slightly soluble in the organic solvent, impurities and colored impurities on the surface of the crude product can be dissolved in the organic solvent, and the speed of removing the impurities can be accelerated by stirring and washing, so that the effect of improving the purity of the aceclofenac is obtained, and meanwhile, the whiteness of the aceclofenac can be improved by the process.
Optionally, the organic solvent is selected from any one of cyclohexane, benzene, toluene, cyclohexane mixed with acetone.
By adopting the technical scheme, the organic solvent can dissolve impurities generated in the synthesis process, and the purity and whiteness of the aceclofenac are improved.
Optionally, the volume ratio of acetone in the cyclohexane mixed with acetone is 1-10%.
By adopting the technical scheme, acetone is used as a polar solvent, cyclohexane is used as a non-polar solvent, different impurities are respectively dissolved, and the purity and whiteness of aceclofenac are further improved.
Optionally, the weight ratio of the organic solvent to the crude aceclofenac is (0.6-1.5): 1.
By adopting the technical scheme, the organic solvent is too little to remove impurities, and too much organic solvent can dissolve part of aceclofenac on one hand and cause solvent waste on the other hand.
Optionally, the soaking time is 10-30 min.
Optionally, the soaking time is 15-25 min.
By adopting the technical scheme, the soaking time is controlled, so that more impurities are removed.
Optionally, the stirring and washing time is 1-30 min.
Optionally, the stirring and washing time is 5-15 min.
Through adopting above-mentioned technical scheme, wash under the condition of stirring, wash the impurity on the surface of aceclofenac more easily.
Optionally, the stirring speed of the stirring washing is 5-65 rpm.
Optionally, the stirring speed of the stirring washing is 30-45 rpm.
By adopting the technical scheme, the speed of dissolving impurities in the organic solvent can be increased at the stirring speed.
In summary, the present application has the following beneficial effects:
1. because this application adopts organic solvent to soak the aceclofenac crude and washes, aceclofenac is insoluble or slightly soluble in organic solvent, and impurity and the colored impurity on crude surface can be dissolved in organic solvent, stirs the speed that the washing can accelerate the impurity to get rid of, consequently, obtains the effect that improves aceclofenac purity.
2. The organic solvent is adopted in the application to remove the colored impurities on the surface of the aceclofenac, and the whiteness of the aceclofenac can be improved.
Detailed Description
The present application will be described in further detail with reference to examples.
Examples
Example 1
An aceclofenac synthesis and refining process comprises the following steps:
(1) adding 80ml of formic acid and 40g of aceclofenac tert-butyl ester into a three-neck flask, heating to 72 ℃, preserving heat, reacting for 4 hours, cooling to normal temperature, carrying out suction filtration and water washing, leaching in a centrifuge until the pH of drained water is above 5.0, and centrifuging and spin-drying to obtain 33g of crude aceclofenac;
(2) putting 33g of crude aceclofenac into a beaker, adding 19.8ml of cyclohexane to cover the crude aceclofenac, soaking for 20min, stirring and washing at the stirring speed of 30rpm for 15min, centrifuging and drying at 80 ℃, and obtaining 32.5g of aceclofenac, wherein the refining yield is 98.5%, and the HPLC purity is 99.993%.
Example 2
An aceclofenac synthesis and refining process comprises the following steps:
(1) adding 80ml of formic acid and 40g of aceclofenac tert-butyl ester into a three-neck flask, heating to 75 ℃, preserving heat, reacting for 3 hours, cooling to normal temperature, carrying out suction filtration and water washing, leaching in a centrifuge until the pH of drained water is above 5.0, and centrifuging and spin-drying to obtain 32g of crude aceclofenac;
(2) putting 32g of crude aceclofenac into a beaker, adding 32ml of cyclohexane to cover the crude aceclofenac, soaking for 20min, stirring and washing at the stirring speed of 30rpm for 15min, centrifuging and drying at 80 ℃ to obtain 31.7g of aceclofenac, wherein the refining yield is 98.8 percent, and the HPLC purity is 99.985 percent.
Example 3
An aceclofenac synthesis and refining process comprises the following steps:
(1) adding 80ml of formic acid and 40g of aceclofenac tert-butyl ester into a three-neck flask, heating to 78 ℃, preserving heat, reacting for 3 hours, cooling to normal temperature, carrying out suction filtration and water washing, leaching in a centrifuge until the pH of drained water is above 5.0, and centrifuging and spin-drying to obtain 31g of crude aceclofenac;
(2) putting 31g of crude aceclofenac into a beaker, adding 46.5ml of cyclohexane to cover the crude aceclofenac, soaking for 20min, stirring and washing at the stirring speed of 30rpm for 15min, centrifuging and drying at 80 ℃, and obtaining 30.4g of aceclofenac, wherein the refining yield is 98.1%, and the HPLC purity is 99.986%.
Example 4
An aceclofenac synthesis purification process, which is different from that of example 1 in that cyclohexane was replaced with equal volumes of cyclohexane mixed with acetone, 0.12mL of acetone and 19.60mL of cyclohexane, the purification yield was 98.0% and the HPLC purity was 99.997%.
Example 5
An aceclofenac synthesis purification process which differs from example 1 in that cyclohexane was replaced with equal volumes of cyclohexane mixed with acetone, 1.98mL of acetone and 17.82mL of cyclohexane. The purification yield was 97.2% and the HPLC purity was 99.996%.
Example 6
An aceclofenac synthesis purification process which differs from example 1 in that cyclohexane was replaced with equal volumes of cyclohexane mixed with acetone, 2.97mL of acetone, and 16.83mL of cyclohexane. The purification yield was 96.8% and the HPLC purity was 99.992%.
Example 7
A process for synthesizing and purifying aceclofenac, which is different from that of example 1 in that the amount of cyclohexane added is 13.2 mL. The purification yield was 97.7% and the HPLC purity was 99.982%.
Example 8
A process for synthesizing and purifying aceclofenac, which is different from that of example 1 in that the amount of cyclohexane to be added is 66 mL. The purification yield was 98.1% and the HPLC purity was 99.993%.
Example 9
The difference between the aceclofenac synthesis and purification process and the example 1 is that the soaking time is 25 min. The purification yield was 98.6% and the HPLC purity was 99.994%.
Example 10
The difference between the aceclofenac synthesis and purification process and the example 1 is that the soaking time is 5 min. The purification yield was 98.3% and the HPLC purity was 99.980%.
Example 11
The difference between the aceclofenac synthesis and purification process and the example 1 is that the soaking time is 40 min. The purification yield was 97.6% and the HPLC purity was 99.993%.
Example 12
The difference between the aceclofenac synthesis and purification process and the example 1 is that the stirring time is 5 min. The purification yield was 98.1% and the HPLC purity was 99.994%.
Example 13
The difference between the aceclofenac synthesis and purification process and the example 1 is that the stirring time is 30 s. The purification yield was 97.5% and the HPLC purity was 99.983%.
Example 14
The difference between the aceclofenac synthesis and purification process and the example 1 is that the stirring time is 40 min. The purification yield was 97.9% and the HPLC purity was 99.993%.
Example 15
A process for synthesizing and purifying aceclofenac, which is different from that of example 1, is carried out at a stirring speed of 45 rpm. The purification yield was 98.4% and the HPLC purity was 99.994%.
Example 16
A process for synthesizing and purifying aceclofenac, which is different from that of example 1, is carried out at a stirring speed of 3 rpm. The purification yield was 96.8% and the HPLC purity was 99.990%.
Example 17
A process for synthesizing and refining aceclofenac, which is different from that of example 1, is carried out at a stirring speed of 80 rpm. The purification yield was 96.5% and the HPLC purity was 99.994%.
Comparative example
Comparative example 1
An aceclofenac synthesis and refining process comprises the following steps: adding 80ml of formic acid and 40g of aceclofenac tert-butyl ester into a three-neck flask, heating to 72 ℃, preserving heat, reacting for 4 hours, cooling to normal temperature, carrying out suction filtration and washing, leaching in a centrifuge until the pH of drained water is above 5.0, centrifuging, drying, and drying at 80 ℃ to obtain 30.1g of aceclofenac. The purification yield was 90.1% and the HPLC purity was 99.000%.
Comparative example 2
An aceclofenac synthesis and purification process was different from that in example 1 in that cyclohexane was replaced with n-hexane of the same volume. The purification yield was 95.2% and the HPLC purity was 99.453%.
Comparative example 3
An aceclofenac synthesis and refining process comprises the following steps:
(1) adding 80ml of formic acid and 40g of aceclofenac tert-butyl ester into a three-neck flask, heating to 72 ℃, preserving heat, reacting for 4 hours, cooling to normal temperature, carrying out suction filtration and water washing, leaching in a centrifuge until the pH of drained water is above 5.0, and centrifuging and spin-drying to obtain 32.1g of crude aceclofenac;
(2) putting 32.1g of crude aceclofenac into a beaker, adding 19.8ml of cyclohexane to cover the crude aceclofenac, stirring and washing at the stirring speed of 30rpm for 15min, centrifuging and spin-drying, and drying at 80 ℃ to obtain 30.4g of aceclofenac. The purification yield was 94.7% and the HPLC purity was 99.389%.
Comparative example 4
An aceclofenac synthesis and refining process comprises the following steps:
(1) adding 80ml of formic acid and 40g of aceclofenac tert-butyl ester into a three-neck flask, heating to 72 ℃, preserving heat, reacting for 4 hours, cooling to normal temperature, carrying out suction filtration and water washing, leaching in a centrifuge until the pH of drained water is above 5.0, and centrifuging and spin-drying to obtain 31.6g of crude aceclofenac;
(2) 31.6g of crude aceclofenac was put into a beaker, 19.8ml of cyclohexane was added to cover the crude aceclofenac, and the mixture was soaked for 20min, centrifuged, and dried at 80 ℃ to obtain 29.6g of aceclofenac, with a purification yield of 93.87% and an HPLC purity of 99.212%.
Table 1 examples 1-10 test design comparison table
TABLE 2 test design comparison tables for examples 11-17 and comparative examples 1-4
Detection test
The test method comprises the following steps: the aceclofenac in examples 1 to 17 and comparative examples 1 to 4 was evaluated for its color, and the full score was 10.0, and the aceclofenac standard was white or off-white crystalline powder, and the closer to the color of the standard, the higher the score.
TABLE 3 color scores for examples 1-17 and comparative examples 1-4
| Example/comparative example 1 numbering | Color scoring |
| Example 1 | 9.4 |
| Example 2 | 9.2 |
| Example 3 | 9.3 |
| Example 4 | 9.6 |
| Example 5 | 9.6 |
| Example 6 | 9.5 |
| Example 7 | 9.1 |
| Example 8 | 9.4 |
| Example 9 | 9.4 |
| Example 10 | 8.9 |
| Example 11 | 9.4 |
| Example 12 | 9.5 |
| Example 13 | 9.2 |
| Example 14 | 9.4 |
| Example 15 | 9.4 |
| Example 16 | 9.3 |
| Example 17 | 9.4 |
| Comparative example 1 | 6.1 |
| Comparative example 2 | 8.2 |
| Comparative example 3 | 7.8 |
| Comparative example 4 | 7.3 |
As can be seen by combining examples 1 to 17 and comparative examples 1 to 4 with Table 3, the aceclofenac of examples 1 to 3 had a purity of 99.985 or more, a low impurity content, a high purity, and a high whiteness score. In contrast, in comparative example 1, when the refining treatment was not performed, the purity of aceclofenac was only 99.000%, and the impurity content was high; in comparative example 2, when n-hexane is used for impurity removal, the purity is reduced compared with that in example 1, which shows that the selection of the solvent has a large influence on the impurity removal; comparative example 3, without the soaking step, showed a 0.604% reduction in purity compared to example 1, and comparative example 4, without the stirring step, showed a 0.781% reduction in purity compared to example 1, indicating that the soaking and stirring steps had a greater effect on impurity removal.
Examples 4 to 5 show that the purity of aceclofenac is further improved by using a small amount of acetone mixed with cyclohexane as an organic solvent, as compared with example 1, and that the purity of aceclofenac can be further improved by dissolving different kinds of impurities in the organic solvent of acetone and cyclohexane. However, when the amount of acetone added in example 6 exceeded 10%, the purity of aceclofenac did not improve, but the yield of aceclofenac decreased significantly, and it was likely that some of aceclofenac dissolved in acetone and wasted.
Example 7 compared with example 1, the purity of aceclofenac decreased with the addition of less organic solvent, indicating that the amount of organic solvent used was too small to remove impurities; example 8 compared with example 1, the purity of aceclofenac was not significantly improved by adding more organic solvent, which indicates that the use of too much organic solvent could not remove more impurities and would cause waste.
Example 9 compared with example 1, the soaking time was increased, the purity of aceclofenac was slightly improved, and example 10 compared with example 1, the soaking time was less than 10min, and the purity of aceclofenac was reduced, indicating that too short soaking time was insufficient to sufficiently dissolve impurities; example 11 compared with example 1, the soaking time is more than 30min, the purity of aceclofenac is not obviously improved, which indicates that the soaking time is too long to remove more impurities, and the time is wasted. The comprehensive comparison shows that the aceclofenac has higher purity when the soaking time is 15-25 min.
Example 12 has a slightly higher purity of aceclofenac with a lower stirring time than example 1, and example 13 has a lower purity of aceclofenac with a lower stirring time than example 1, indicating that too short a stirring time is insufficient to sufficiently dissolve the impurities; example 14 the stirring time was increased compared to example 1, and the purity of aceclofenac was not significantly improved, indicating that the stirring time was too long to remove more impurities, and time was wasted. The comprehensive comparison shows that when the stirring time is 5-15min, the purity of the aceclofenac is higher.
The purity of aceclofenac was slightly improved with an increase in the stirring speed in example 15 as compared with example 1, and with a decrease in the stirring speed and a decrease in the purity of aceclofenac in example 16 as compared with example 1, indicating that the stirring speed was too slow to sufficiently dissolve the impurities; example 17 compared to example 1, the purity of aceclofenac was not significantly improved by increasing the stirring speed, indicating that too high a stirring speed could not remove more impurities, and compared to a total stirring speed of 30-45rpm, the purity of aceclofenac was higher.
The change tendency of the whiteness scores of aceclofenac of examples 1 to 17 and comparative examples 1 to 4 was substantially consistent with the purity, and it can be seen that the process of the present application improved the purity of aceclofenac and also improved the whiteness of aceclofenac.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. An aceclofenac synthesis and refining process is characterized in that: the method comprises the following steps:
(1) adding aceclofenac tert-butyl ester into formic acid, heating for acidolysis reaction, cooling to normal temperature, performing suction filtration and water washing, leaching until the pH of discharged water is more than 5.0, and performing centrifugal drying to obtain a crude aceclofenac product;
(2) putting the aceclofenac crude product into a reaction vessel, adding an organic solvent to cover the aceclofenac crude product, wherein the aceclofenac is insoluble or slightly soluble in the organic solvent, soaking, stirring and washing, centrifuging and spin-drying, and drying to obtain the aceclofenac.
2. The aceclofenac synthesis and purification process according to claim 1, wherein: the organic solvent is selected from any one of cyclohexane, benzene, toluene and cyclohexane mixed with acetone.
3. The aceclofenac synthesis and purification process according to claim 2, wherein: in the cyclohexane mixed with acetone, the volume ratio of the acetone is 1-10%.
4. The aceclofenac synthesis and purification process according to claim 1, wherein: the weight ratio of the organic solvent to the crude aceclofenac is (0.6-1.5) to 1.
5. The aceclofenac synthesis and purification process according to claim 1, wherein: the soaking time is 10-30 min.
6. The aceclofenac synthesis and purification process according to claim 1, wherein: the soaking time is 15-25 min.
7. The aceclofenac synthesis and purification process according to claim 1, wherein: the time for stirring and washing is 1-30 min.
8. The aceclofenac synthesis and purification process according to claim 1, wherein: the stirring and washing time is 5-15 min.
9. The aceclofenac synthesis and purification process according to claim 1, wherein: the stirring speed of the stirring washing is 5-65 rpm.
10. The aceclofenac synthesis and purification process according to claim 1, wherein: the stirring speed of the stirring washing is 30-45 rpm.
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| CN202011153001.1A CN112250589A (en) | 2020-10-23 | 2020-10-23 | Aceclofenac synthesis refining process |
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| CN202011153001.1A CN112250589A (en) | 2020-10-23 | 2020-10-23 | Aceclofenac synthesis refining process |
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| CN202011153001.1A Pending CN112250589A (en) | 2020-10-23 | 2020-10-23 | Aceclofenac synthesis refining process |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999055660A1 (en) * | 1998-04-28 | 1999-11-04 | Russinsky Limited | Process for the preparation of aceclofenac |
| CN110143891A (en) * | 2019-05-21 | 2019-08-20 | 浙江工业大学 | A kind of preparation method of Aceclofenac |
| KR20200098992A (en) * | 2019-02-13 | 2020-08-21 | 한국바이오켐제약 주식회사 | Methods for preparing aceclofenac and pharmaceutical composition comprising the same |
-
2020
- 2020-10-23 CN CN202011153001.1A patent/CN112250589A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999055660A1 (en) * | 1998-04-28 | 1999-11-04 | Russinsky Limited | Process for the preparation of aceclofenac |
| KR20200098992A (en) * | 2019-02-13 | 2020-08-21 | 한국바이오켐제약 주식회사 | Methods for preparing aceclofenac and pharmaceutical composition comprising the same |
| CN110143891A (en) * | 2019-05-21 | 2019-08-20 | 浙江工业大学 | A kind of preparation method of Aceclofenac |
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