CN111039932B - High-yield synthesis method of radatinib - Google Patents
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- CN111039932B CN111039932B CN201911282510.1A CN201911282510A CN111039932B CN 111039932 B CN111039932 B CN 111039932B CN 201911282510 A CN201911282510 A CN 201911282510A CN 111039932 B CN111039932 B CN 111039932B
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 12
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims abstract description 10
- WWTGXYAJVXKEKL-UHFFFAOYSA-N 3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)aniline Chemical compound C1=NC(C)=CN1C1=CC(N)=CC(C(F)(F)F)=C1 WWTGXYAJVXKEKL-UHFFFAOYSA-N 0.000 claims abstract description 9
- FGHGVZVGAYQACH-UHFFFAOYSA-N 3-acetamido-4-methylbenzoic acid Chemical compound CC(=O)NC1=CC(C(O)=O)=CC=C1C FGHGVZVGAYQACH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001408 amides Chemical class 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000007259 addition reaction Methods 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000002808 molecular sieve Substances 0.000 claims description 28
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 28
- 239000003054 catalyst Substances 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 9
- 229910017604 nitric acid Inorganic materials 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- FDSJTVJBTDOSNT-UHFFFAOYSA-N 3-acetamido-4-methylbenzoyl chloride Chemical compound C(C)(=O)NC=1C=C(C(=O)Cl)C=CC1C FDSJTVJBTDOSNT-UHFFFAOYSA-N 0.000 claims description 4
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical group [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 3
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 claims description 3
- 239000011609 ammonium molybdate Substances 0.000 claims description 3
- 229940010552 ammonium molybdate Drugs 0.000 claims description 3
- 235000018660 ammonium molybdate Nutrition 0.000 claims description 3
- 229910052750 molybdenum Inorganic materials 0.000 claims description 3
- 239000011733 molybdenum Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- 239000005457 ice water Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- PEQMCOFKBXMGDC-UHFFFAOYSA-N 3-(diaminomethylideneamino)-4-methyl-n-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide Chemical class C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(C(C)=CC=2)N=C(N)N)=CC(C(F)(F)F)=C1 PEQMCOFKBXMGDC-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001119 stannous chloride Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 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
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 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 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a high-yield synthesis method of radatinib, which relates to the technical field of pharmaceutical organic synthesis, and comprises the steps of taking 3-acetamido-4-methylbenzoic acid as a starting material, carrying out amide condensation reaction on the 3- (4-methyl-1H-imidazole-1-yl) -5-trifluoromethylaniline to obtain an intermediate I, carrying out addition reaction on the intermediate I and cyanamide to obtain an intermediate II, and carrying out closed-loop reaction on the intermediate II and dimethylamino-1- (3-pyrazinyl) -2-propylene-1-one to obtain radatinib; the invention simplifies the reaction operation, reduces the cost input, reduces the three-waste generation amount, improves the conversion rate of the initial raw materials and the intermediate, and ensures that the total yield of the prepared radatinib can reach more than 79 percent.
Description
Technical field:
the invention relates to the technical field of organic synthesis of medicines, in particular to a high-yield synthesis method of radatinib.
The background technology is as follows:
radatinib is a TKI-type drug developed in korea-foreign medicine. CML patients approved in 2012 in korea for treatment of other TKI treatment failures have higher potency than imatinib.
The synthesis methods adopted in the past literature are as follows: reacting 3-amino-4-methyl ethyl formate with aqueous solution of cyanamide in the presence of acid to generate 3-guanidino-4-methyl ethyl benzoate, and cyclizing the 3-dimethylamino-1- (3-pyrazinyl) -2-propylene-1-ketone to obtain 4-methyl-3- [ 4- (3-pyrazinyl) amino ] ethyl benzoate. Hydrolyzing the ethyl ester to obtain acid, acylating thionyl chloride, and carrying out amidation condensation on the acid and 3- [ 4-methyl-1H-imidazolyl ] -5-trifluoromethyl aniline in the presence of alkali to obtain a radatinib product. The method has high synthesis cost, the impurities in the product are easy to remove, and the total yield is not high.
The invention comprises the following steps:
the technical problem to be solved by the invention is to provide a high-yield synthesis method of the radatinib, which has the advantages of simplifying the reaction operation, reducing the cost input, reducing the three-waste generation amount, and improving the conversion rate of the initial raw materials and the intermediate, thereby improving the yield of the radatinib product.
The technical problems to be solved by the invention are realized by adopting the following technical scheme:
a high-yield synthesis method of radatinib uses 3-acetamido-4-methylbenzoic acid as a starting material, and the 3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethyl aniline undergoes an amide condensation reaction to obtain an intermediate I, the intermediate I undergoes an addition reaction with cyanamide to obtain an intermediate II, and the intermediate II undergoes a closed-loop reaction with dimethylamino-1- (3-pyrazinyl) -2-propylene-1-one to obtain radatinib.
The reaction solvent of the amide condensation reaction is methylene dichloride.
The 3-acetamido-4-methylbenzoic acid reacts with thionyl chloride to generate 3-acetamido-4-methylbenzoyl chloride, and then the 3-acetamido-4-methylbenzoyl chloride reacts with 3- (4-methyl-1H-imidazole-1-yl) -5-trifluoromethyl aniline in the presence of triethylamine to generate amide condensation reaction.
The reaction solvent of the addition reaction is an acidic ethanol solution, preferably an ethanol solution of nitric acid.
The nitric acid is dilute nitric acid.
The reaction solvent of the ring-closure reaction is ethanol.
The catalyst of the ring closure reaction is sodium hydroxide.
The invention uses sodium hydroxide as a catalyst of the ring-closure reaction, but the steric hindrance of the intermediate II when reacting with dimethylamino-1- (3-pyrazinyl) -2-propylene-1-ketone is larger, so that the yield of the product radatinib obtained by the ring-closure reaction is lower only under the catalysis of sodium hydroxide, thereby reducing the total yield of the whole synthetic route. Based on the aim of improving the yield of the radatinib, the invention also adds a mesoporous molecular sieve catalyst as a catalyst of the ring-closure reaction to be matched with sodium hydroxide to improve the reactivity of the intermediate II and the dimethylamino-1- (3-pyrazinyl) -2-propylene-1-ketone. Namely:
the catalyst for the ring closure reaction consists of sodium hydroxide and a mesoporous molecular sieve catalyst, and the mass ratio of the sodium hydroxide to the mesoporous molecular sieve catalyst is 5-10:1.
The mesoporous molecular sieve catalyst can be any one of the following:
the mesoporous molecular sieve catalyst consists of an active component and a carrier, wherein the content of the active component accounts for 10-20% of the total weight of the mesoporous molecular sieve catalyst, the carrier is SBA-15 mesoporous molecular sieve, and the active component is molybdenum, and the preparation method comprises the following steps: dissolving ammonium molybdate in water, adding SBA-15 mesoporous molecular sieve, stirring, drying in an oven, and roasting in a muffle furnace to obtain the mesoporous molecular sieve catalyst.
The mesoporous molecular sieve catalyst consists of an active component and a carrier, wherein the content of the active component accounts for 10-20% of the total weight of the mesoporous molecular sieve catalyst, the carrier is SBA-15 mesoporous molecular sieve, the active component is tin, and the preparation method comprises the following steps: and dissolving stannous chloride in absolute ethyl alcohol, adding the SBA-15 mesoporous molecular sieve, stirring, drying in an oven, and roasting in a muffle furnace to obtain the mesoporous molecular sieve catalyst.
The SBA-15 mesoporous molecular sieve is purchased from Talka New energy Co., ltd.
The beneficial effects of the invention are as follows: according to the invention, 3-acetamido-4-methylbenzoic acid is used as a starting material, and the radatinib is prepared through an amide condensation reaction, an addition reaction and a ring closure reaction, so that the raw material is easy to obtain, the cost investment is reduced while the reaction operation is simplified, the three-waste generation amount is reduced, the conversion rate of the starting material and an intermediate is improved, the total yield of the prepared radatinib can reach more than 79%, and the purity reaches more than 99.8%.
The specific embodiment is as follows:
the invention is further described in connection with the following embodiments in order to make the technical means, the creation features, the achievement of the purpose and the effect of the invention easy to understand.
Example 1
(1) Synthesis of 3-acetamido-4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethylphenyl ] benzamide (intermediate I):
100g of 3-acetamido-4-methylbenzoic acid and 100mL of methylene chloride are put into a dry reaction flask, 200mL of thionyl chloride is added under stirring, and then the mixture is heated and refluxed for 4 hours. After the methylene chloride solvent and the excessive chloridized sulfone were distilled off under reduced pressure, 300mL of methylene chloride, 125g of 3- (4-methyl-1H-imidazolyl) -5-trifluoromethylaniline, 108g of triethylamine were added to the residue in the flask in this order, and the mixture was reacted at elevated temperature under reflux for 8 hours. After the reaction, the solvent methylene dichloride is evaporated, the residual liquid is poured into 300mL of water, yellow solid is separated out, the product is obtained by suction filtration and drying, and the yield is 94.7%.
(2) Synthesis of 4-methyl-N- [3- (4-methyl-1H-imidazolyl) -5-trifluoromethylphenyl ] -3-guanidinobenzamide salt (intermediate II):
45g of 50% aqueous cyanamide solution, 500mL of ethanol and 200g of intermediate I were put into a reaction flask, and 30% dilute nitric acid 245mL was carefully added with stirring to react for 20 hours at 20 ℃. And after the reaction is finished, 300mL of ice water is added, the mixture is stirred and frozen to-5 ℃, the temperature is kept for 2 hours, the yellow crystalline solid separated out by suction filtration is rinsed with a small amount of ice water, and the product is obtained by drying 210g, wherein the yield is 91.3%.
(3) Synthesis of radatinib:
77g of 3-dimethylamino-1- (3-pyrazinyl) -2-propylene-1-one, 847g of ethanol, 51g of sodium hydroxide and 208g of intermediate II are put into a reaction bottle, heated and refluxed for reaction for 32h. And (3) after the reaction is finished, cooling, freezing and crystallizing. Filtering, washing with water to obtain coarse radatinib product, refining with 5 times volume of ethanol, decolorizing to obtain 212g radatinib product with 92.2% yield and 99.86% purity.
Example 2
(1) Synthesis of 3-acetamido-4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethylphenyl ] benzamide (intermediate I):
100g of 3-acetamido-4-methylbenzoic acid and 100mL of methylene chloride are put into a dry reaction flask, 200mL of thionyl chloride is added under stirring, and then the mixture is heated and refluxed for 4 hours. After the methylene chloride solvent and the excessive chloridized sulfone were distilled off under reduced pressure, 300mL of methylene chloride, 125g of 3- (4-methyl-1H-imidazolyl) -5-trifluoromethylaniline, 108g of triethylamine were added to the residue in the flask in this order, and the mixture was reacted at elevated temperature under reflux for 8 hours. After the reaction is finished, the solvent dichloromethane is evaporated, the residual liquid is poured into 300mL of water, yellow solid is separated out, the product is obtained by suction filtration and drying, and the yield is 93.7%.
(2) Synthesis of 4-methyl-N- [3- (4-methyl-1H-imidazolyl) -5-trifluoromethylphenyl ] -3-guanidinobenzamide salt (intermediate II):
45g of 50% aqueous cyanamide solution, 500mL of ethanol and 200g of intermediate I were put into a reaction flask, and 30% dilute nitric acid 245mL was carefully added with stirring to react for 20 hours at 20 ℃. And after the reaction is finished, 300mL of ice water is added, the mixture is stirred and frozen to-5 ℃, the temperature is kept for 2 hours, the yellow crystalline solid separated out by suction filtration is rinsed with a small amount of ice water, and the product is obtained by drying 211g, and the yield is 91.7%.
(3) Synthesis of radatinib:
dissolving ammonium molybdate in water, adding 5g of SBA-15 mesoporous molecular sieve, stirring for 3h, drying in a 70 ℃ oven for 8h, and roasting in a 400 ℃ muffle furnace for 3h to obtain the mesoporous molecular sieve catalyst with the molybdenum content of 10%.
77g of 3-dimethylamino-1- (3-pyrazinyl) -2-propylene-1-ketone, 847g of ethanol, 51g of sodium hydroxide, 8g of mesoporous molecular sieve catalyst and 208g of intermediate II are put into a reaction bottle, heated and refluxed for reaction for 32h. And after the reaction is finished, filtering while the solution is hot, and cooling, freezing and crystallizing the filtrate. Filtering, washing with water to obtain coarse radatinib product, and refining with 5 times volume of ethanol to decolorize to obtain final radatinib product 221g with 96.1% yield and 99.88% purity.
Example 3
(1) Synthesis of 3-acetamido-4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethylphenyl ] benzamide (intermediate I):
100g of 3-acetamido-4-methylbenzoic acid and 100mL of methylene chloride are put into a dry reaction flask, 200mL of thionyl chloride is added under stirring, and then the mixture is heated and refluxed for 4 hours. After the methylene chloride solvent and the excessive chloridized sulfone were distilled off under reduced pressure, 300mL of methylene chloride, 125g of 3- (4-methyl-1H-imidazolyl) -5-trifluoromethylaniline, 108g of triethylamine were added to the residue in the flask in this order, and the mixture was reacted at elevated temperature under reflux for 8 hours. After the reaction, the solvent methylene dichloride is evaporated, the residual liquid is poured into 300mL of water, yellow solid is separated out, the product is obtained by suction filtration and drying, and the yield is 95.1%.
(2) Synthesis of 4-methyl-N- [3- (4-methyl-1H-imidazolyl) -5-trifluoromethylphenyl ] -3-guanidinobenzamide salt (intermediate II):
45g of 50% aqueous cyanamide solution, 500mL of ethanol and 200g of intermediate I were put into a reaction flask, and 30% dilute nitric acid 245mL was carefully added with stirring to react for 20 hours at 20 ℃. And after the reaction is finished, 300mL of ice water is added, the mixture is stirred and frozen to-5 ℃, the temperature is kept for 2 hours, the yellow crystalline solid separated out by suction filtration is rinsed with a small amount of ice water, and the product is obtained by drying, wherein 213g of product is obtained, and the yield is 92.6%.
(3) Synthesis of radatinib:
dissolving stannous chloride in absolute ethyl alcohol, adding 5g of SBA-15 mesoporous molecular sieve, stirring for 3h, drying in a 70 ℃ oven for 8h, and roasting in a 400 ℃ muffle furnace for 3h to obtain the mesoporous molecular sieve catalyst with the tin content of 10%.
77g of 3-dimethylamino-1- (3-pyrazinyl) -2-propylene-1-ketone, 847g of ethanol, 51g of sodium hydroxide, 8g of mesoporous molecular sieve catalyst and 208g of intermediate II are put into a reaction bottle, heated and refluxed for reaction for 32h. And after the reaction is finished, filtering while the solution is hot, and cooling, freezing and crystallizing the filtrate. Filtering, washing with water to obtain coarse radatinib product, and refining with 5 times volume of ethanol to decolorize to obtain 224g radatinib product with 97.4% yield and 99.89% purity.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (6)
1. A high-yield synthesis method of radatinib is characterized by comprising the following steps of: 3-acetamido-4-methylbenzoic acid is used as a starting material, and is subjected to amide condensation reaction with 3- (4-methyl-1H-imidazol-1-yl) -5-trifluoromethyl aniline to obtain an intermediate I, the intermediate I is subjected to addition reaction with cyanamide to obtain an intermediate II, and the intermediate II is subjected to closed-loop reaction with dimethylamino-1- (3-pyrazinyl) -2-propylene-1-one to obtain radatinib;
the catalyst for the ring-closure reaction consists of sodium hydroxide and a mesoporous molecular sieve catalyst, wherein the mass ratio of the sodium hydroxide to the mesoporous molecular sieve catalyst is 5-10:1;
the mesoporous molecular sieve catalyst consists of an active component and a carrier, wherein the content of the active component accounts for 10-20% of the total weight of the mesoporous molecular sieve catalyst, the carrier is SBA-15 mesoporous molecular sieve, and the active component is molybdenum, and the preparation method comprises the following steps: dissolving ammonium molybdate in water, adding SBA-15 mesoporous molecular sieve, stirring, drying in an oven, and roasting in a muffle furnace to obtain the mesoporous molecular sieve catalyst.
2. The high-yield synthesis method of radatinib according to claim 1, characterized in that: the reaction solvent of the amide condensation reaction is methylene dichloride.
3. The high-yield synthesis method of radatinib according to claim 1, characterized in that: the 3-acetamido-4-methylbenzoic acid reacts with thionyl chloride to generate 3-acetamido-4-methylbenzoyl chloride, and then the 3-acetamido-4-methylbenzoyl chloride reacts with 3- (4-methyl-1H-imidazole-1-yl) -5-trifluoromethyl aniline in the presence of triethylamine to generate amide condensation reaction.
4. The high-yield synthesis method of radatinib according to claim 1, characterized in that: the reaction solvent of the addition reaction is ethanol solution of nitric acid.
5. The high-yield synthesis method of radatinib according to claim 4, characterized in that: the nitric acid is dilute nitric acid.
6. The high-yield synthesis method of radatinib according to claim 1, characterized in that: the reaction solvent of the ring-closure reaction is ethanol.
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| CN101155786A (en) * | 2005-08-05 | 2008-04-02 | 一洋药品株式会社 | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
| CN101735197A (en) * | 2009-12-18 | 2010-06-16 | 天津市炜杰科技有限公司 | Method for synthesizing Imatinib |
| EP2626355A1 (en) * | 2012-02-09 | 2013-08-14 | Natco Pharma Limited | Process for the preparation of nilotinib hydrochloride |
| CN109666023A (en) * | 2017-10-17 | 2019-04-23 | 上海复星星泰医药科技有限公司 | A kind of Preparation Method And Their Intermediate of nilotinib |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US9061028B2 (en) * | 2012-02-15 | 2015-06-23 | Natco Pharma Limited | Process for the preparation of Nilotinib |
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Inventor after: Dong Laishan Inventor after: Jia Tao Inventor before: Dong Laishan |