CN112745300A - Method for preparing N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine - Google Patents
Method for preparing N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine Download PDFInfo
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- CN112745300A CN112745300A CN202110082296.6A CN202110082296A CN112745300A CN 112745300 A CN112745300 A CN 112745300A CN 202110082296 A CN202110082296 A CN 202110082296A CN 112745300 A CN112745300 A CN 112745300A
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- 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
- C07D403/02—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 two hetero rings
- C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for preparing N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine, which specifically comprises the following steps: step 1, carrying out an ethylation reaction on 3-nitro-4-methylbenzoic acid serving as an initial raw material to generate a compound 2 in the synthetic route; step 2, the nitro group of the compound 2 is subjected to hydrogenation reduction reaction by palladium carbon to generate a compound 3; step 3, reacting the compound 3 with a nitrilamine aqueous solution, and exchanging bases to obtain a compound 4; step 4, cyclizing the compound 4 and the compound 6 to obtain a compound 7; and step 5, hydrolyzing the compound 7 under the action of alkalinity to generate a compound 8, namely N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine.
Description
Technical Field
The invention relates to a preparation method of an intermediate N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine of a bulk drug nilotinib, and provides a process method which is efficient, environment-friendly, economical, high in yield and suitable for industrial production.
Background
Nilotinib (nilotinib) is a highly selective oral tyrosine kinase inhibitor developed by Nowa pharmaceutical company of Switzerland, the monohydrochloride monohydrate of nilotinib (imatinib mesylate) is approved by FDA in US 10.2007 under the trade name of Tasigna and is clinically used for treating chronic granulocytic leukemia which is ineffective in imatinib mesylate, N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamide is a main intermediate for synthesizing nilotinib, and the original research patent US7169791B2 reports a synthetic route, in which ethyl 3-amino-4-methylbenzoate (3) and mononitrile ammonia are reacted to obtain ethyl 3-guanidino-4-methylbenzoate nitrate (4), and (4) is cyclized with 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one (6) to obtain 4-methyl-propanoic acid 3- [ [4- (3-pyridyl) -2-pyrimidyl ] amino ] ethyl benzoate (7), and obtaining the synthetic route of N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine (8) through hydrolysis.
The method has a plurality of obvious defects, firstly, mononitrile amine crystals are unstable, rhombic, colorless and easy to deliquesce, and are easy to decompose in a heating reaction, so the reaction cannot be completely carried out, the conversion rate is low, the market price of the solid mononitrile amine crystals is very high, the market price of the solid mononitrile amine crystals is greatly different from that of a nitrilamine aqueous solution, the mononitrile amine is 600-700/kg, the price of a 50% nitrilamine aqueous solution is 60-100/kg, and the price is nearly ten times that of the 50% nitrilamine aqueous solution, but the nitrilamine aqueous solution is also unstable after being heated and can be decomposed into urea which does not participate in the reaction, so the reaction cannot be carried out, the method utilizes a ternary azeotropic system of toluene, ethanol and water for reaction, water is continuously separated from the system in the reaction process to avoid the hydrolysis of the nitrilamine into the urea, and the continuous separation of the water from the reaction system can promote the completion of the reaction, the yield can be greatly improved, and the cost is greatly reduced.
Disclosure of Invention
In order to solve the defects in the prior art, the invention discloses a method for preparing N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine, which is realized by adopting the following technical scheme.
A method for preparing N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine specifically comprises the following steps: step 1, carrying out an ethylation reaction on 3-nitro-4-methylbenzoic acid serving as an initial raw material to generate a compound 2 in the synthetic route; step 2, the nitro group of the compound 2 is subjected to hydrogenation reduction reaction by palladium carbon to generate a compound 3; step 3, reacting the compound 3 with a nitrilamine aqueous solution, and exchanging bases to obtain a compound 4; step 4, cyclizing the compound 4 and the compound 6 to obtain a compound 7; and 5, hydrolyzing the compound 7 under the action of alkalinity to generate a compound 8, namely N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine.
As a further improvement of the technology, 3-nitro-4-methylbenzoic acid is selected as the starting material in the step 1.
As a further improvement of the technology, the nitro group of the compound 2 in the step 2 is reduced by catalytic hydrogenation of palladium carbon (w/w: 5-10%) and ammonium formate, and the compound 3 generated by the reaction is directly applied to the step 3 without drying and post-treatment.
As a further improvement of the technology, the nitrilamine used in the step 3 is a nitrilamine aqueous solution, and the mass fraction of the nitrilamine is 30-50%.
As a further improvement of the present technology, the solvent used in step 3 is a mixed solvent, and the mixed solvent is toluene, ethanol and water, wherein V toluene: and V ethanol is 1: 1-2: 1.
As a further improvement of the technology, the compound 4 obtained in the step 3 is obtained by ethanol recrystallization, the temperature for heating and dissolving the compound 4 by ethanol is 50-60 ℃, the crystallization temperature is 0-10 ℃, and the crystallization time is 1-2 hours.
As a further improvement of the technology, in the step 4, the compound 5 and DMF-DMA are directly mixed and heated for condensation reaction without participation of a solvent.
As a further improvement of the technology, the temperature for directly mixing and heating the compound 5 and DMF-DMA in the step 4 is 80-90 ℃.
As a further improvement of the technology, the reaction solvent in the step 5 is n-butyl alcohol with a high boiling point, and the reaction temperature in the step 5) is 90-110 ℃.
The invention has the beneficial effects that:
the invention adopts the technical scheme to provide a method for preparing N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine, makes up the defects of the prior art, and provides a synthetic method of N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine, which has high reaction yield, economy, environmental protection and high efficiency.
Detailed Description
Various aspects of the invention are illustrated below, and the following examples are presented to illustrate specific embodiments of the invention and are not intended to limit the invention.
Preparation of ethyl 3-nitro-4-methylbenzoate (2):
sequentially adding 3-nitro-4-methylbenzoic acid, toluene, ethanol and p-toluenesulfonic acid into a reaction bottle, heating to 78-85 ℃ for reaction for 12-20 hours, concentrating after the reaction is finished, adding water, adjusting the pH value to 8.0-8.5 by saturated sodium carbonate, removing residual p-toluenesulfonic acid, extracting an aqueous layer by ethyl acetate, and concentrating an oil layer to obtain 3-nitro-4-methylbenzoic acid ethyl ester (2).
Preparation of ethyl 3-amino-4-methylbenzoate (3):
adding palladium carbon (5-10%) and ammonium formate into methanol, dissolving ethyl 3-nitro-4-methylbenzoate (2) into the methanol, dripping the methanol solution containing the (2) into a reaction bottle, heating to 55-65 ℃ for reaction till completion, filtering the palladium carbon, concentrating the methanol, adding water, filtering to obtain white solid ethyl 3-amino-4-methylbenzoate (3), and directly applying a wet product to the next step without drying.
Preparation of ethyl 3-guanidino-4-methylbenzoate nitrate (4):
adding 3-amino-4-ethyl methyl benzoate (3) and ethanol into a reaction bottle, adding 30-50% (W/W) of cyanamide aqueous solution under stirring, adding concentrated hydrochloric acid, adding toluene, heating to 78-85 ℃, reacting for 20-24 hours, concentrating the reaction solution after the reaction is finished, adding water, cooling to 0-10 ℃, adding the prepared ammonium nitrate aqueous solution (W/W: 20-40%), stirring at 0-10 ℃ for crystallization for 1-2 hours, filtering, heating ethanol at 50-60 ℃ for complete dissolution, stirring at 0-10 ℃ for crystallization for 1-2 hours, and filtering to obtain 3-guanidino-4-ethyl methyl benzoate nitrate (4).
Preparation of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one (6):
adding 3-acetylpyridine and DMF-DMA into a reactor, reacting for 8-10 hours at 80-90 ℃ under the solvent-free condition, concentrating until dry filtration is carried out, washing with petroleum ether at 60-80 ℃ and drying to obtain the 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one (6).
Preparation of ethyl 4-methyl-3- [ [4- (3-pyridinyl) -2-pyrimidinyl ] amino ] benzoate (7):
adding 3-guanidino-4-methyl ethyl benzoate nitrate (4), 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one (6) and sodium hydroxide into n-butyl alcohol, reacting for 8-9 hours at 90-110 ℃, concentrating the n-butyl alcohol, adding ethyl acetate and water for extraction, drying and concentrating an oil layer, adding petroleum ether for crystallization at room temperature, stirring and washing for 1-2 hours, filtering to obtain 4-methyl-3- [ [4- (3-pyridyl) -2-pyrimidyl ] amino ] ethyl benzoate (7), and directly applying wet products to the next step without treatment.
Preparation of N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine (8):
adding ethyl 4-methyl-3- [ [4- (3-pyridyl) -2-pyrimidyl ] amino ] benzoate (7) into ethanol, adding equal volume of water, adding 2M sodium hydroxide, heating to 40-55 ℃, carrying out hydrolysis reaction for 7-9 hours, concentrating, adjusting the pH value of an aqueous layer to be not higher than 6.5 by using hydrochloric acid, filtering, washing, and drying at 70-80 ℃ for more than 12 hours. To obtain the N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine (8).
Example (b): preparation of ethyl 3-nitro-4-methylbenzoate (2)
Adding 100g of 3-nitro-4-methylbenzoic acid, 1L of toluene, 640ml of ethanol and 209g of p-toluic acid in sequence, heating and refluxing for 16-17 hours after the addition is finished, finishing reaction and concentration, adding 2L of water, adjusting the pH value to be 8.0-8.5 by using saturated sodium carbonate, extracting 1L of ethyl acetate for 3 times respectively, combining, drying by using anhydrous sodium sulfate, and concentrating to obtain 2, 136g, wherein the yield is 136%.
Example (b): preparation of ethyl 3-amino-4-methylbenzoate (3)
10g of palladium carbon (10%) and 140g of ammonium formate are dissolved in 400ml of methanol, 136g of ethyl 3-nitro-4-methylbenzoate (2) is dissolved in 400ml of methanol, the methanol solution of (2) is dropwise added into a reaction bottle at normal temperature, the reaction releases heat until the methanol boils, the dropwise addition is continued, after the dropwise addition is completed, the palladium carbon is filtered after the TLC detection reaction is completed, the methanol is concentrated, 400ml of water is added, and a white solid 156g of ethyl 3-amino-4-methylbenzoate (3) wet product is obtained through filtration, and the product is directly applied to the next step without drying.
Example (b): preparation of ethyl 3-guanidino-4-methylbenzoate nitrate (4)
Adding 156g of 3-amino-4-ethyl methyl benzoate (3) and 1L of ethanol into a reaction bottle, adding 160ml of a 50% (W/W) nitrilamine aqueous solution under stirring, adding 120ml of concentrated hydrochloric acid, adding 1L of toluene, carrying out heating reflux reaction for 22-23 hours, reacting to obtain a concentrated reaction solution, adding 900ml of water, cooling to 5-10 ℃, adding a prepared ammonium nitrate aqueous solution under stirring (W ammonium nitrate/W water is 15g/50g), stirring and crystallizing for 1 hour at 5-10 ℃, filtering, heating with 175-200 ml of ethanol at 50 ℃ until complete dissolution, stirring and crystallizing for 1-2 hours at 0-5 ℃, filtering to obtain 3-guanidino-4-ethyl methyl benzoate nitrate (4), and drying at 60 ℃ to obtain 120 g. The yield thereof was found to be 120% based on (2).
Example (b): preparation of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one (6)
124.7g of 3-acetylpyridine and 147.2ml of DMF-DMA are added into a reactor, the reaction is carried out for 8 hours at 82-84 ℃, the reaction is completed, the reaction is stopped, the concentration is carried out until the reaction is completed, the reaction is carried out, the concentration is carried out until the reaction is dried, petroleum ether is washed, the temperature is 60 ℃, and the drying is carried out, so that 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one (6) is obtained, 135g is obtained, and the.
Example (b): preparation of ethyl 4-methyl-3- [ [4- (3-pyridinyl) -2-pyrimidinyl ] amino ] benzoate (7)
Adding 103.5g of 3-guanidino-4-methyl ethyl benzoate nitrate (4), 68.4g of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one (6) and 16.2g of sodium hydroxide into n-butyl alcohol, carrying out reflux reaction for 8-9 hours, concentrating the n-butyl alcohol, adding 1L of ethyl acetate and water respectively, extracting the water phase twice with 1L of ethyl acetate respectively, combining oil layers, drying the oil layer with anhydrous sodium sulfate, concentrating the ethyl acetate, adding 400ml of petroleum ether, crystallizing, stirring and washing for 1 hour, and filtering to obtain 4-methyl-3- [ [4- (3-pyridyl) -2-pyrimidyl ] amino ] ethyl benzoate (7) and 110g of wet product. The yield was 106% calculated as 4, and the wet product was used in the next step without further treatment.
Example (b): preparation of N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine (8)
Adding 110g of 4-methyl-3- [ [4- (3-pyridyl) -2-pyrimidyl ] amino ] ethyl benzoate (7) into 1L of ethanol, adding equal volume of water, adding 414ml of 2M sodium hydroxide, heating to 45-50 ℃, reacting for 7-8 hours, concentrating, adjusting the pH value of a water layer to be not higher than 6.5 by using 1M hydrochloric acid, filtering, and drying at 80 ℃ for more than 12 hours. To obtain N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine (8), 99g, the yield is 99 percent calculated by 2, and the product is light yellow solid.
While the present invention has been described in conjunction with the above embodiments, the present invention is not limited to the above embodiments but is limited only by the appended claims, and those skilled in the art can easily make modifications and variations thereto without departing from the true spirit and scope of the present invention.
Claims (9)
1. A process for the preparation of N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine characterized in that: the method specifically comprises the following steps:
step 1, carrying out an ethylation reaction on 3-nitro-4-methylbenzoic acid serving as an initial raw material to generate a compound 2 in the synthetic route;
step 2, the nitro group of the compound 2 is subjected to hydrogenation reduction reaction by palladium carbon to generate a compound 3;
step 3, reacting the compound 3 with a nitrilamine aqueous solution, and exchanging bases to obtain a compound 4;
step 4, cyclizing the compound 4 and the compound 6 to obtain a compound 7;
and 5, hydrolyzing the compound 7 under the action of alkalinity to generate a compound 8, namely N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine.
2. The method for preparing N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine according to claim 1, wherein 3-nitro-4-methylbenzoic acid is selected as the starting material in the step 1.
3. The method for preparing N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine according to claim 1, wherein the nitro group of compound 2 in step 2 is reduced by catalytic hydrogenation of palladium on carbon (w/w: 5-10%) and ammonium formate, and compound 3 generated by the reaction is directly applied to step 3 without drying and post-treatment.
4. The method for preparing N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine according to claim 1, wherein the nitrilamine used in the step 3 is an aqueous nitrilamine solution, and the mass fraction of the nitrilamine is 30-50%.
5. The method for preparing N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine according to claim 1, wherein the solvent used in the step 3 is a mixed solvent comprising toluene, ethanol and water, wherein the ratio of toluene: and V ethanol is 1: 1-2: 1.
6. The method for preparing N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine according to claim 1, wherein the compound 4 obtained in the step 3 is obtained by ethanol recrystallization, the temperature for heating and dissolving the compound 4 by ethanol is 50-60 ℃, the crystallization temperature is 0-10 ℃, and the crystallization time is 1-2 hours.
7. The method for preparing N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine according to claim 1, wherein the condensation reaction of compound 5 and DMF-DMA in step 4 is carried out by direct mixing and heating without the participation of solvent.
8. The method for preparing N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine according to claim 1, wherein the temperature for directly mixing and heating the compound 5 and DMF-DMA in the step 4 is 80-90 ℃.
9. The method for preparing N- (5-carboxy-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine according to claim 1, wherein the reaction solvent in the step 5 is N-butanol with high boiling point, and the reaction temperature in the step 5) is 90-110 ℃.
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| US4281000A (en) * | 1979-07-09 | 1981-07-28 | American Cyanamid Company | Substituted pyrazolo (1,5-a)pyrimidines and their use as anxiolytic agents |
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| CN102321073A (en) * | 2011-08-12 | 2012-01-18 | 西安交通大学 | Preparation method of nilotinib |
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