CN108794392B - Method for synthesizing sorafenib by solid-state ball milling - Google Patents
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- 238000000498 ball milling Methods 0.000 title claims abstract description 40
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 239000005511 L01XE05 - Sorafenib Substances 0.000 title claims abstract description 29
- 229960003787 sorafenib Drugs 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000007788 liquid Substances 0.000 claims abstract description 13
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims abstract description 11
- RXZZBPYPZLAEFC-UHFFFAOYSA-N 4-(4-aminophenoxy)-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(N)=CC=2)=C1 RXZZBPYPZLAEFC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- ASPDJZINBYYZRU-UHFFFAOYSA-N 5-amino-2-chlorobenzotrifluoride Chemical compound NC1=CC=C(Cl)C(C(F)(F)F)=C1 ASPDJZINBYYZRU-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- DNPVYSKMZNWRGW-UHFFFAOYSA-N n-[4-chloro-3-(trifluoromethyl)phenyl]imidazole-1-carboxamide Chemical compound C1=C(Cl)C(C(F)(F)F)=CC(NC(=O)N2C=NC=C2)=C1 DNPVYSKMZNWRGW-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NBJZEUQTGLSUOB-UHFFFAOYSA-N 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(N=C=O)=CC=C1Cl NBJZEUQTGLSUOB-UHFFFAOYSA-N 0.000 claims description 5
- MCMNRKCIXSYSNV-UHFFFAOYSA-N ZrO2 Inorganic materials O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 5
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- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
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- 230000035484 reaction time Effects 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910001220 stainless steel Inorganic materials 0.000 claims description 2
- 239000010935 stainless steel Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims 1
- 239000000428 dust Substances 0.000 abstract description 2
- 230000036632 reaction speed Effects 0.000 abstract 1
- -1 diaryl semicarbazone Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
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- 238000001308 synthesis method Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 238000004128 high performance liquid chromatography Methods 0.000 description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
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- 229910020323 ClF3 Inorganic materials 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
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- 108010091528 Proto-Oncogene Proteins B-raf Proteins 0.000 description 1
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- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
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- 238000006053 organic reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a method for synthesizing sorafenib by solid-state ball milling. The method comprises the steps of taking a compound 4- (4-aminophenoxy) -N-methylpyridine-2-formamide and a compound 4-chloro-3-trifluoromethyl isocyanate as raw materials, or taking a compound 4-chloro-3-trifluoromethylaniline, a compound N, N' -carbonyldiimidazole and a compound 4- (4-aminophenoxy) -N-methylpyridine-2-formamide as raw materials, and synthesizing the sorafenib by solid ball milling in a ball mill under the catalysis of a small amount of liquid (and alkali). The method has the main innovation point that the sorafenib is synthesized by solid-state ball milling in a ball mill for the first time, and compared with the original method for synthesizing the sorafenib in a liquid solvent, the method has the advantages of high reaction speed, no dust overflow, good reaction controllability, simplicity in operation, high reaction yield, less pollution, strong feasibility and the like.
Description
Technical Field
The invention relates to the technical field of preparation of sorafenib, in particular to a method for synthesizing sorafenib by solid-state ball milling.
Background
Sorafenib is a novel diaryl semicarbazone with the chemical name 4- {4- [ ({ [4 chloro-3- (trifluoromethyl) phenyl ] carbonyl]Amino } carbonyl) amino]Phenoxy } -N-methylpyridine-2-carboxamide having the formula C21H16ClF3N4O3Molecular weight is 464.83, and the structural formula is formula I.
Sorafenib is a multi-target targeted therapeutic drug and has dual anti-tumor effects: the method can block a RAF/MEK/ERK signal conduction pathway and inhibit the proliferation of tumor cells by inhibiting the serine/threonine kinase activity of RAF-1 and B-RAF, and can also block the formation of tumor neovessels and cut off the nutrition supply of tumor cells by inhibiting the tyrosine kinase activity of vascular endothelial growth factor receptors VEGFR and PDGFR so as to achieve the purpose of inhibiting the tumor growth.
Currently, there are two main synthetic methods for sorafenib, one of which is to prepare sorafenib by condensing 4-chloro-3-trifluoromethylphenyl isocyanate and 4- (4-aminophenoxy) -N-methylpyridine-2-formamide (U.S. Pat. No. 4, 7235576). Another method is to react 4-chloro-3-trifluoromethylaniline with N, N' -Carbonyldiimidazole (CDI) to produce an active intermediate N- (4-chloro-3-trifluoromethylphenyl) -1H-imidazole-1-amide, which reacts with 4- (4-aminophenoxy) -N-methylpyridine-2-carboxamide to obtain the final product sorafenib (US 7235576). In the synthesis process, organic solvents such as dichloromethane and the like are generally used for reaction in a liquid phase, organic reagents such as dichloromethane and the like easily cause environmental pollution, and the reaction also has the defects of time consumption, solvent consumption, high risk and high danger in industrial production and the like.
The solid-state ball milling reaction of compounds in a ball mill is a novel non-liquid phase reaction and has been applied to many organic reactions. Because the danger caused by using toxic reagents can be effectively avoided, the reaction materials can be fully and uniformly mixed, the contact surface and the frequency of reactants are increased, and the reaction rate is accelerated, so that the method is widely concerned. In addition, because a solvent is hardly used, the reaction is relatively safe and clean, the efficiency is high, the operation is simple, the reaction condition is mild, no dust overflows, and the solid ball milling synthesis method in the ball mill can be said to be a synthesis method conforming to the principle of green chemistry. The core technology of the solid ball-milling synthesis method in the ball mill is the application of the catalyst to control the synthesis reactivity, and the catalyst not only has a solid catalyst, but also has a small amount of liquid to catalyze and accelerate the reaction. At present, no solid-state ball milling method for synthesizing sorafenib is reported.
Disclosure of Invention
The invention aims to provide a method for synthesizing sorafenib by solid-state ball milling in a ball mill.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method for synthesizing sorafenib by solid-state ball milling comprises the following steps: (1) 4-chloro-3-trifluoromethylphenyl isocyanate (compound II) and 4- (4-aminophenoxy) -N-methylpyridine-2-formamide (compound III) are used as raw materials, and solid-state ball milling reaction is carried out in a ball mill under the catalysis of a small amount of liquid. After the ball milling is finished, dissolving the sorafenib by using a solvent, concentrating and purifying to obtain sorafenib (compound I); (2) 4-chloro-3-trifluoromethylaniline (compound IV) and N, N' -carbonyldiimidazole (compound V) are used as raw materials, and an intermediate N- (4-chloro-3-trifluoromethylphenyl) -1H-imidazole-1-amide (compound VI) is obtained through ball milling reaction under the catalysis of a small amount of liquid; and carrying out ball milling reaction on the compound VI and the compound III in a ball mill in the presence of a small amount of liquid and alkali, and after the ball milling is finished, dissolving and concentrating by using a solvent, and purifying to obtain the sorafenib (compound I).
The synthetic route of the invention is as follows:
route one:
and a second route:
the molar ratio of the compound II (4-chloro-3-trifluoromethylphenyl isocyanate) to the compound III (4- (4-aminophenoxy) -N-methylpyridine-2-formamide) is 1: 1-1: 1.05; the molar ratio of the compound IV (4-chloro-3-trifluoromethylaniline) to the compound V (N, N' -carbonyldiimidazole) is 1: 1-1: 2; the molar ratio of the compound VI (N- (4-chloro-3-trifluoromethylphenyl) -1H-imidazole-1-amide) to the compound III is 1: 1-1: 1.05.
In the method, a small amount of liquid for catalyzing and accelerating reaction is selected from one or more of acetonitrile, methanol, dichloromethane and ethyl acetate, and the dosage is 0.01-1.00 mu l/mg of solid compound.
In the method, the base used for catalytic reaction is one or a mixture of more of potassium carbonate, sodium hydroxide and potassium tert-butoxide, and the molar ratio of the compound III (4- (4-aminophenoxy) -N-methylpyridine-2-formamide) to the base is 1: 1-1: 2.
The ball used in the ball milling reaction is made of one or more of stainless steel, agate or zirconium dioxide. The ball milling reaction adopts grinding balls with large, medium and small diameters of 3 specifications for common grinding, wherein the larger diameter accounts for 30 percent, the medium diameter accounts for 50 percent, and the smaller diameter accounts for 20 percent. The diameter of the grinding ball is 3 mm-40 mm.
The ball milling reaction time is 2-8 hours. The ball milling speed is 300-500 r/min.
In the second synthetic route, the ball milling reaction is carried out to obtain an intermediate compound VI (N- (4-chloro-3-trifluoromethylphenyl) -1H-imidazole-1-amide), and the post-treatment method comprises adding water, stirring vigorously, filtering, and drying the filter cake.
After the ball milling reaction is finished, the organic solvent used for dissolving the product is selected from one or more of methanol, ethyl acetate, dichloromethane, acetonitrile, ethanol and acetone.
Compared with the prior art, the invention has the beneficial effects that:
the sorafenib is synthesized by solid-state ball milling in the ball mill, so that the synthetic reaction in a solvent is avoided, the reaction is relatively safe and clean, and meanwhile, the reaction rate is accelerated by using a catalyst (such as a small amount of liquid and alkali), so that the reaction time is greatly shortened. The method has the advantages of high reaction efficiency, short reaction time, simple and convenient operation, low cost, less pollution, environmental protection and the like, and is suitable for industrial popularization and application.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1:
preparation of 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenoxy } -N-methylpyridine-2-carboxamide
In a 100mL polytetrafluoroethylene ball mill containing about 100g of zirconium dioxide milling balls, 0.50g (2.06mmol) of 4- (4-aminophenoxy) -N-methylpyridine-2-carboxamide, 0.46g (2.06mmol) of 4-chloro-3-trifluoromethylphenyl isocyanate, and 240. mu.l acetonitrile (0.25. mu.l/mg of solid compound) were added. The rotation speed of the ball mill is set to 400r/min, and the reaction is stopped for 4h under the state that the tank body is sealed. After the reaction, the product was dissolved in methanol in a ball mill, and the mixture was evaporated to dryness by rotation and purified to obtain 0.92g (yield: 96%) of a brown powder with a purity of 99% (HPLC method). 1H NMR (600MHz, DMSO-d6) delta: 2.79(d, J ═ 4.9Hz, 3H), 7.18(m, 3H), 7.38(d, J ═ 2.6Hz, 1H), 7.62(m, 4H), 8.13(d, J ═ 2.5Hz, 1H), 8.51(d, J ═ 5.6Hz, 1H), 8.78(q, J ═ 4.8Hz, 1H), 9.02(s, 1H), 9.24(s, 1H).
Example 2:
preparation of N- (4-chloro-3-trifluoromethylphenyl) -1H-imidazole-1-amide
In a 100mL polytetrafluoroethylene ball mill pot containing about 100g of zirconium dioxide milling balls, 1g (5.113mmol) of 4-chloro-3-trifluoromethylaniline, 0.83g (5.118mmol) of N, N' -carbonyldiimidazole and 460. mu.l of acetonitrile (0.25. mu.l/mg of solid compound) were added. The rotating speed of the ball mill is set to be 400r/min, the TLC method tracks until the reaction is complete, and the reaction is stopped for 5 hours under the state that the tank body is sealed. After completion of the reaction, the reaction mixture was vigorously stirred with water, filtered under suction, the filtrate was discarded, and the mixture was dried overnight to obtain 1.18g of a white powder (yield 80%).
Example 3:
preparation of 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenoxy } -N-methylpyridine-2-carboxamide
In a 100mL polytetrafluoroethylene ball mill jar containing about 100g of zirconium dioxide milling balls were added 0.12g (0.49mmol) of 4- (4-aminophenoxy) -N-methylpyridine-2-carboxamide, 0.14g (0.48mmol) of N- (4-chloro-3-trifluoromethylphenyl) -1H-imidazole-1-amide, 0.14g (1.01mmol) of potassium carbonate, and 65. mu.l of methylene chloride (0.25. mu.l/mg of solid compound). The rotation speed of the ball mill is set to 400r/min, and the reaction is stopped for 8h under the state that the tank body is sealed. After the reaction was completed, methanol was added to the ball mill pot to dissolve the product, and the liquid was transferred to a pear-shaped bottle, heated to completely dissolve, evaporated to dryness by rotation, and purified to obtain 0.17g (yield 72%) of brown powder with a purity of 99% (HPLC method). 1H NMR (500MHz, DMSO-d 6): δ 2.81(d, J ═ 4.9Hz, 3H), 7.18(m, 3H), 7.40(d, J ═ 2.6Hz, 1H), 7.66(m, 4H), 8.14(d, J ═ 2.5Hz, 1H), 8.53(d, J ═ 5.6Hz, 1H), 8.78(d, J ═ 4.9Hz, 1H), 9.02(s, 1H), 9.24(s, 1H).
Claims (6)
1. A method for synthesizing sorafenib by solid-state ball milling is characterized in that the synthesis route is divided into two types:
(1) taking 4-chloro-3-trifluoromethylphenyl isocyanate (compound II) and 4- (4-aminophenoxy) -N-methylpyridine-2-formamide (compound III) as raw materials, and carrying out solid ball milling reaction in a ball mill under the catalysis of a small amount of liquid; after the ball milling is finished, dissolving the sorafenib by using a solvent, concentrating and purifying to obtain sorafenib (compound I);
(2) 4-chloro-3-trifluoromethylaniline (compound IV) and N, N' -carbonyldiimidazole (compound V) are used as raw materials, and are subjected to ball milling reaction in a ball mill under the catalysis of a small amount of liquid to obtain an intermediate N- (4-chloro-3-trifluoromethylphenyl) -1H-imidazole-1-amide (compound VI); carrying out ball milling reaction on the compound VI and the compound III in a ball mill in the presence of a small amount of liquid and alkali, and after the ball milling is finished, dissolving and concentrating by using a solvent, and purifying to obtain sorafenib (compound I);
a small amount of liquid for catalyzing and accelerating reaction is selected from one or a mixture of more of acetonitrile, methanol, dichloromethane and ethyl acetate, and the dosage is 0.01-1 mu l/mg of solid compound; the base used for catalytic reaction is one or a mixture of more of potassium carbonate, sodium hydroxide and potassium tert-butoxide, and the molar ratio of the compound III to the base is 1: 1-1: 2;
the structural formulas of the compounds I, II, III, IV, V and VI are shown as follows:
2. the method for solid-state ball-milling synthesis of sorafenib according to claim 1, characterized in that: the molar ratio of the compound II to the compound III is 1: 1-1: 1.05; the molar ratio of the compound IV to the compound V is 1: 1-1: 2; the molar ratio of the compound VI to the compound III is 1: 1-1: 1.05.
3. The method for solid-state ball-milling synthesis of sorafenib according to claim 1, characterized in that: the ball material used in the ball milling reaction is one or more selected from stainless steel, agate or zirconium dioxide, and the diameter of the grinding ball is 3-40 mm.
4. The method for solid-state ball-milling synthesis of sorafenib according to claim 1, characterized in that: the ball milling reaction time is 2-8 hours; the ball milling speed is 300-500 r/min.
5. The method for solid-state ball-milling synthesis of sorafenib according to claim 1, characterized in that: in the synthetic route (2), after the intermediate compound VI is obtained through ball milling reaction, water is added for violent stirring, and the mixture is subjected to suction filtration and drying.
6. The method for solid-state ball-milling synthesis of sorafenib according to claim 1, characterized in that: after the ball milling reaction is finished, the organic solvent used for dissolving the product is selected from one or more of methanol, ethyl acetate, dichloromethane, acetonitrile, ethanol and acetone.
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| CN201810476691.0A CN108794392B (en) | 2018-05-14 | 2018-05-14 | Method for synthesizing sorafenib by solid-state ball milling |
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| CN201810476691.0A CN108794392B (en) | 2018-05-14 | 2018-05-14 | Method for synthesizing sorafenib by solid-state ball milling |
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| CN107353227A (en) * | 2016-05-09 | 2017-11-17 | 浙江工业大学 | Method for synthesizing biphenyl O-methyl oxime ether compound and biphenyl carbonyl compound under mechanical force promotion |
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