CN114790154B - Preparation method of antitumor drug imatinib intermediate (2-methyl-5-nitrophenyl) guanidine nitrate - Google Patents
Preparation method of antitumor drug imatinib intermediate (2-methyl-5-nitrophenyl) guanidine nitrate Download PDFInfo
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- CN114790154B CN114790154B CN202210231325.5A CN202210231325A CN114790154B CN 114790154 B CN114790154 B CN 114790154B CN 202210231325 A CN202210231325 A CN 202210231325A CN 114790154 B CN114790154 B CN 114790154B
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- nitrophenyl
- methyl
- silica gel
- guanidine nitrate
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- IINMQQJNRFDBMV-UHFFFAOYSA-N 2-(2-methyl-5-nitrophenyl)guanidine;nitric acid Chemical compound O[N+]([O-])=O.CC1=CC=C([N+]([O-])=O)C=C1N=C(N)N IINMQQJNRFDBMV-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 8
- 239000005517 L01XE01 - Imatinib Substances 0.000 title claims abstract description 7
- 229960002411 imatinib Drugs 0.000 title claims abstract description 7
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000741 silica gel Substances 0.000 claims abstract description 15
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 15
- 238000003756 stirring Methods 0.000 claims abstract description 15
- DSBIJCMXAIKKKI-UHFFFAOYSA-N 5-nitro-o-toluidine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1N DSBIJCMXAIKKKI-UHFFFAOYSA-N 0.000 claims abstract description 13
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 12
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000012065 filter cake Substances 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 2
- 238000007664 blowing Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000010992 reflux Methods 0.000 abstract description 8
- 238000010438 heat treatment Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000011010 flushing procedure Methods 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 238000000967 suction filtration Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229960003685 imatinib mesylate Drugs 0.000 description 3
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
Abstract
The invention discloses a preparation method of an antitumor drug imatinib intermediate, (2-methyl-5-nitrophenyl) guanidine nitrate, which comprises the following steps: adding 2-amino-4-nitrotoluene into absolute ethyl alcohol, then adding nitric acid and inorganic silica gel, uniformly stirring, adding cyanamide, and purifying after the reaction is finished to obtain an intermediate A, (2-methyl-5-nitrophenyl) guanidine nitrate. According to the invention, the silica gel is added in the process of preparing the intermediate in the formula A, so that the reaction temperature is reduced from reflux to room temperature, firstly, accidents caused by flushing in the heating process are effectively avoided, secondly, side reactions under the condition of high-temperature reflux reaction are reduced, the product yield is improved, the product quality is improved, and the production cost is reduced.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an antitumor drug imatinib intermediate (2-methyl-5-nitrophenyl) guanidine nitrate.
Background
Imatinib mesylate is the first anticancer drug for molecular targeted therapy developed by northwest pharmacy, is the first line therapeutic drug for chronic granulocytic leukemia, and imatinib mesylate is an important intermediate for producing imatinib mesylate. A common method for the preparation of imazamide is shown in figure 1.
In the preparation process of the imamine, an intermediate A is obtained by reflux reaction of 2-amino-4-nitrotoluene and cyanamide in ethanol under an acidic condition. The specific operation is that ethanol and 2-amino-4-nitrotoluene are added into a reactor, nitric acid is added dropwise, cyanamide is added after uniform stirring, and heating reflux reaction is carried out. Under the laboratory pilot scale condition, the reaction is stable and the process is controllable. However, when the experiment is amplified to be more than kilogram level, the temperature is not well controlled at the stage of heating, and the heat is rapidly released in the heating process, so that the problems of production accidents and the like are caused. Even if the material is washed without causing accidents, the yield and the product quality are greatly affected, and the production of the medicine enterprise is greatly puzzled, so that the problem needs to be solved.
Disclosure of Invention
Aiming at the technical problems, the invention provides a preparation method of an anti-tumor drug imatinib intermediate (2-methyl-5-nitrophenyl) guanidine nitrate.
Through a great number of researches, analysis and test verification, the inventor finally finds that when silica gel is added into a reaction system, the reaction can be carried out under the room temperature condition, so that the reaction does not need to be heated, the problem of material flushing caused by heating is solved, meanwhile, due to low reaction temperature, side reactions which occur under the high-temperature reflux reaction condition are avoided, the corresponding reaction yield is improved, and the product quality is also improved.
The technical scheme provided by the invention is as follows:
the preparation method of the antitumor drug imatinib intermediate (2-methyl-5-nitrophenyl) guanidine nitrate comprises the following steps:
adding 2-amino-4-nitrotoluene into absolute ethyl alcohol, then adding nitric acid and inorganic silica gel, uniformly stirring, adding cyanamide, and purifying after the reaction is finished to obtain (2-methyl-5-nitrophenyl) guanidine nitrate.
Further, the inorganic silica gel is colloidal particles with the particle size of 300-400 meshes.
Further, the mass ratio of the 2-amino-4-nitrotoluene, the absolute ethyl alcohol and the nitric acid is 1:2-10:1-2.
Further, the mass of the inorganic silica gel is 10-80% of the mass of the 2-amino-4-nitrotoluene.
Further, the reaction temperature of the reaction was room temperature.
Further, the structural formula A of the (2-methyl-5-nitrophenyl) guanidine nitrate is shown as the following formula:
further, the purification method comprises the following steps: concentrating the reaction solution under reduced pressure, cooling to the temperature of <5 ℃, and suction filtering; and (3) stirring and washing the filter cake with ethyl acetate, repeating the operation, stirring and washing the filter cake with 1L of water, carrying out suction filtration, and carrying out forced air drying on the filter cake.
The beneficial effects of the invention are as follows:
according to the invention, the silica gel is added in the process of preparing the intermediate in the formula A, so that the reaction temperature is reduced from reflux to room temperature, firstly, the problem of possible material flushing caused by a heating process is effectively avoided, secondly, the side reaction under the condition of high-temperature reflux reaction is reduced, the product yield is improved, the product quality is improved, and the production cost is reduced.
Drawings
FIG. 1 is a general method for preparing imazamide.
Detailed Description
The invention is further illustrated below in connection with specific examples, the content of which is not limited at all.
In the following examples, nitric acid was concentrated nitric acid, inorganic silica gel was AR grade colloidal particles, and silica gel having a particle size of 300 to 400 mesh.
Example 1
75.0g of 2-amino-4-nitrotoluene and 50g of silica gel are added into 180ml of absolute ethyl alcohol, 49.0g of nitric acid is slowly added dropwise under stirring, and the temperature of the dropping process is controlled between 20 ℃ and 25 ℃. After the completion of the dropping, stirring was continued for 15 minutes, 72.0g of cyanamide was added, and the reaction was stirred at room temperature. After the reaction was completed, the mixture was filtered, and the cake was washed with ethanol. The filtrate was concentrated under reduced pressure. Cooling the residual liquid to less than or equal to 5 ℃ and carrying out suction filtration. The filter cake is stirred and washed by ethyl acetate, then by water, and suction filtration is carried out. The filter cake is dried to obtain intermediate A,108.3g, yield of 85.4% and purity higher than 98%.
Example 2
75.0g of 2-amino-4-nitrotoluene and 7.5g of silica gel are added into 180ml of absolute ethyl alcohol, 49.0g of nitric acid is slowly added dropwise under stirring, and the temperature of the dropping process is controlled between 20 ℃ and 25 ℃. After the completion of the dropping, stirring was continued for 15 minutes, 72.0g of cyanamide was added, and the reaction was stirred at room temperature. After the reaction was completed, the mixture was filtered, and the cake was washed with ethanol. The filtrate was concentrated under reduced pressure. Cooling the residual liquid to less than or equal to 5 ℃ and carrying out suction filtration. The filter cake is stirred and washed by ethyl acetate, then by water, and suction filtration is carried out. The filter cake is dried to obtain intermediate A,105.7g, yield of 83.4% and purity higher than 98%.
Example 3
75.0g of 2-amino-4-nitrotoluene and 60g of silica gel are added into 180ml of absolute ethyl alcohol, 49.0g of nitric acid is slowly added dropwise under stirring, and the temperature of the dropping process is controlled between 20 ℃ and 25 ℃. After the completion of the dropping, stirring was continued for 15 minutes, 72.0g of cyanamide was added, and the reaction was stirred at room temperature. After the reaction was completed, the mixture was filtered, and the cake was washed with ethanol. The filtrate was concentrated under reduced pressure. Cooling the residual liquid to less than or equal to 5 ℃ and carrying out suction filtration. The filter cake is stirred and washed by ethyl acetate, then by water, and suction filtration is carried out. The filter cake is dried to obtain intermediate A,107.4g, with yield of 84.7% and purity higher than 98%.
Comparative example 1
75.0g of 2-amino-4-nitrotoluene is added into 180ml of absolute ethyl alcohol, 49.0g of nitric acid is slowly added dropwise, and the temperature of the dropwise adding process is controlled to be 20-25 ℃. After the completion of the dropping, stirring was continued for 15 minutes, 72.0g of cyanamide was added, and the reaction was heated under reflux overnight. After the reaction, the mixture was concentrated under reduced pressure. Cooling the residual liquid to less than or equal to 5 ℃ and carrying out suction filtration. The filter cake is stirred and washed by ethyl acetate, then stirred and washed by water, suction filtration is carried out, and the filter cake is dried to obtain intermediate A,77.1g, the yield is 61%, and the purity is 94.3%.
The present invention is not limited to the above-mentioned embodiments, but any modifications, equivalents, improvements and modifications within the scope of the invention will be apparent to those skilled in the art.
Claims (3)
1. The preparation method of the antitumor drug imatinib intermediate (2-methyl-5-nitrophenyl) guanidine nitrate is characterized by comprising the following steps:
adding 2-amino-4-nitrotoluene into absolute ethyl alcohol, then adding nitric acid and inorganic silica gel, uniformly stirring, adding cyanamide, and purifying after the reaction is finished to obtain (2-methyl-5-nitrophenyl) guanidine nitrate;
the inorganic silica gel is colloidal particles, and the particle size range is 300-400 meshes; the mass of the inorganic silica gel is 10% -80% of the mass of the 2-amino-4-nitrotoluene;
the reaction temperature was room temperature.
2. The method according to claim 1, wherein the mass ratio of the 2-amino-4-nitrotoluene, the cyanamide and the nitric acid is 1:2-10:1-2.
3. The method according to claim 1, wherein the purification method is: filtering the reaction solution, and washing a filter cake with ethanol; concentrating the filtrate under reduced pressure, cooling to below 5deg.C, and vacuum filtering; stirring and washing the filter cake with ethyl acetate, stirring and washing with water, filtering, and drying the filter cake by blowing air.
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| CN202210231325.5A CN114790154B (en) | 2022-03-10 | 2022-03-10 | Preparation method of antitumor drug imatinib intermediate (2-methyl-5-nitrophenyl) guanidine nitrate |
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| CN202210231325.5A CN114790154B (en) | 2022-03-10 | 2022-03-10 | Preparation method of antitumor drug imatinib intermediate (2-methyl-5-nitrophenyl) guanidine nitrate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911157A (en) * | 2011-08-02 | 2013-02-06 | 沈阳药科大学 | (E)-3-[2-bromo-5-(3-substituted propoxy)]phenyl-N-{4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl acrylamide compound |
| CN111039921A (en) * | 2019-12-17 | 2020-04-21 | 杭州沧海帆医药科技有限公司 | Synthesis process of imatinib and imatinib mesylate |
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- 2022-03-10 CN CN202210231325.5A patent/CN114790154B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911157A (en) * | 2011-08-02 | 2013-02-06 | 沈阳药科大学 | (E)-3-[2-bromo-5-(3-substituted propoxy)]phenyl-N-{4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl acrylamide compound |
| CN111039921A (en) * | 2019-12-17 | 2020-04-21 | 杭州沧海帆医药科技有限公司 | Synthesis process of imatinib and imatinib mesylate |
Non-Patent Citations (5)
| Title |
|---|
| Formation of Pyrimidin-2-ylcyanamide and 2-Aminopyrimidine in the Reaction of Aniline Derivatives with Cyanamide and Dimethylamino-1-pyridyl-2-propenone;E. V. Koroleva 等;Russian Journal of Organic Chemistry;第47卷(第8期);1222-1226 * |
| Koroleva, E. V.等.Substituted 2-aryl aminopyrimidines - key intermediates for directed synthesis of biomolecules.Vestsi Natsyyanal'nai Akademii Navuk Belarusi, Seryya Khimichnykh Navuk.2013,第3卷79-86. * |
| 伊马替尼衍生物的合成及细胞毒活性研究;陈仕杰 等;有机化学;第35卷;2377-2382 * |
| 李建颖 等.食品添加剂速查手册.2017,64. * |
| 甲磺酸伊马替尼的合成;郭家林 等;中国医药工业杂志;第44卷(第7期);644-647 * |
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