CN112707846B - Preparation method of dacatinib key intermediate - Google Patents

Preparation method of dacatinib key intermediate Download PDF

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CN112707846B
CN112707846B CN201911025220.9A CN201911025220A CN112707846B CN 112707846 B CN112707846 B CN 112707846B CN 201911025220 A CN201911025220 A CN 201911025220A CN 112707846 B CN112707846 B CN 112707846B
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CN112707846A (en
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付清泉
万华
廖健宇
王建
刘双勇
赵茂先
肖萍
张菊华
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Sichuan Inodabo Pharmaceutical Technology Co ltd
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
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    • 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
    • C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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Abstract

The invention provides a preparation method of a key intermediate of dacatinib, which comprises the following steps. The intermediate has the advantages of short synthetic route, mild reaction condition, short reaction time, simple separation and purification method, low cost, high yield of the prepared product, contribution to industrial production and popularization and good application prospect, and raw material reagents are conventional reagents.
Figure DDA0002248424550000011

Description

Preparation method of dacatinib key intermediate
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of a key intermediate of dacatinib.
Background
Dacotinib (English name: dacomitinib) has the following structural formula, and is a second generation irreversible EGFR Tyrosine Kinase Inhibitor (TKI) developed by the American-type pyroxene company (Pfizer), and the action mechanism of the drug is similar to Afatinib, and can irreversibly inhibit three different ERBB family molecular members including EGFR (HER 1), HER2 and HER4. It is possible that a better therapeutic effect is exhibited because a plurality of ERBB family proteins can be inhibited. The product is approved by the American FDA to be marketed in the 9 th and 27 th 2018, and has the trade name of
Figure BDA0002248424530000013
Is approved for the treatment of metastatic non-small cell lung cancer (NSCLC) patients harboring an EGFR gene exon 19 deletion or exon 21 l858r substitution mutation.
Figure BDA0002248424530000011
P05-3A is a key intermediate for the synthesis of dacatinib.
Figure BDA0002248424530000012
However, few methods are reported for synthesizing this intermediate. The preparation method of other intermediates of dacatinib has the problems of incomplete reaction, generation of new impurities, long synthetic route, lower total yield, complex separation and purification, higher cost and the like, and is not beneficial to industrialized production and popularization.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of a key intermediate of dacatinib.
The invention provides a preparation method of a dacatinib intermediate, which comprises the following steps:
Figure BDA0002248424530000021
step 1: reacting the compound P05-10A, an acid binding agent and an acetylation reagent in an organic solvent to obtain a compound P05-10A-1A;
step 2: adding a nitrifying agent and a dehydrating agent into the compound P05-10A-1A for reaction to obtain a compound P05-10A-2A;
step 3: dissolving the compound P05-10A-2A and alkali or acid in an organic solvent for reaction to obtain a compound P05-10A-3A;
step 4: dissolving the compound P05-10A-3A and a reagent for preparing acyl chloride in an organic solvent for reaction, and adding ammonia water for reaction after the reaction to obtain the compound P05-10A-4A;
step 5: reacting the compound P05-10A-4A with a dehydrating agent in an organic solvent to obtain a compound P05-4A;
step 6: and (3) reacting the compound P05-4A with N, N-dimethylformamide dimethyl acetal in an organic solvent to obtain the dacatinib intermediate.
Further, the method comprises the steps of,
in the step 1, the molar ratio of the compound P05-10A, the acid binding agent and the acetylating agent is (1-5): (1-5): (1-5); the mass volume ratio of the compound P05-10A to the organic solvent is 1: (1-10) (w/v);
and/or, in the step 2, the molar ratio of the compound P05-10A-1A to the nitrating agent is (1-5): (1-5); the mass volume ratio of the compound P05-10A-1A to the dehydrating agent is 1: (1-10) (w/v);
and/or in the step 3, the mass-volume ratio of the compound P05-10A-2A to the alkali is 1: (10-20) (w/v); the mass volume ratio of the compound P05-10A-2A to the organic solvent is 1: (1-20) (w/v);
and/or, in the step 4, the mass ratio of the compound P05-10A-3A to the reagent for preparing the acyl chloride is (10-20): (10-20); the mass volume ratio of the compound P05-10A-3A to the organic solvent is 1: (1-20) (w/v); the volume ratio of the organic solvent to the ammonia water is 1 (1-100);
and/or, in the step 5, the molar ratio of the compound P05-10A-4A to the dehydrating agent is 1: (1-5); the mass volume ratio of the compound P05-10A-4A to the organic solvent is 1: (1-10) (w/v);
and/or, in step 6, the molar ratio of the compound P05-4A to the N, N-dimethylformamide dimethyl acetal is (1-5): (1-5); the mass volume ratio of the compound P05-4A to the organic solvent is 1: (1-10) (w/v);
preferably, the method comprises the steps of,
in the step 1, the molar ratio of the compound P05-10A, the acid binding agent and the acetylation reagent is 1:2:1.5; the mass-volume ratio of the compound P05-10A to the organic solvent is 1:5 (w/v);
and/or in the step 2, the molar ratio of the compound P05-10A-1A to the nitrating agent is 1:1; the mass-volume ratio of the compound P05-10A-1A to the dehydrating agent is 1:6 (w/v);
and/or, in the step 3, the mass-volume ratio of the compound P05-10A-2A to the alkali is 1:10 (w/v); the mass-volume ratio of the compound P05-10A-2A to the organic solvent is 1:10 (w/v);
and/or, in the step 4, the mass ratio of the compound P05-10A-3A to the reagent for preparing the acyl chloride is 15:12.6; the mass-volume ratio of the compound P05-10A-3A to the organic solvent is 1:10 (w/v); the volume ratio of the organic solvent to the ammonia water is 1:1;
and/or, in the step 5, the molar ratio of the compound P05-10A-4A to the dehydrating agent is 1:3; the mass-volume ratio of the compound P05-10A-4A to the organic solvent is 1:6 (w/v);
and/or, in step 6, the molar ratio of the compound P05-4A to the N, N-dimethylformamide dimethyl acetal is 2.3:3.5; the mass-volume ratio of the compound P05-4A to the organic solvent is 1:4 (w/v).
Further, the method comprises the steps of,
in the step 1, the acid binding agent is pyridine, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine, potassium carbonate or sodium carbonate; the acetylating agent is acetic anhydride or acetyl chloride; the organic solvent is dichloromethane, tetrahydrofuran, toluene, ethyl acetate or N, N-dimethylformamide;
and/or in the step 2, the nitrifying agent is concentrated nitric acid, fuming nitric acid or potassium nitrate; the dehydrating agent is concentrated sulfuric acid, glacial acetic acid, acetic anhydride or phosphorus pentoxide;
and/or in the step 3, the alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide; or, the acid is hydrochloric acid or sulfuric acid; the organic solvent is methanol, ethanol, tetrahydrofuran, 1, 4-dioxane or acetonitrile; preferably, the base is sodium hydroxide; more preferably, the sodium hydroxide is a 2N sodium hydroxide aqueous solution;
and/or, in the step 4, the reagent for preparing the acyl chloride is thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride; the organic solvent is dichloromethane, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide or acetonitrile;
and/or in the step 5, the dehydrating agent is phosphorus oxychloride, trifluoroacetic anhydride, cyanuric chloride, acetic anhydride, thionyl chloride, phosphorus pentoxide or triphosgene; the organic solvent is dichloromethane, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, acetonitrile or toluene;
and/or in the step 6, the organic solvent is N, N-dimethylformamide, 1, 4-dioxane, tetrahydrofuran, acetonitrile or toluene.
Further, the method comprises the steps of,
in the step 1, the adding mode of the acetylation reagent is dropwise adding;
and/or in the step 1, the reaction is carried out for 1-5 h at the temperature of 0-100 ℃ after the acetylating reagent is added dropwise;
and/or, in the step 2, dropwise adding the nitrifying agent;
and/or in the step 2, the reaction is carried out for 1-5 h at the temperature of 0-100 ℃ after the nitrating agent is added dropwise;
and/or in the step 3, the reaction is carried out for 1-5 hours at the temperature of 20-80 ℃;
and/or, in the step 4, the reaction conditions of the compound P05-10A-3A and the reagent for preparing the acyl chloride dissolved in the organic solvent are heating reflux reaction for 1-5 h;
and/or in the step 4, the reaction condition of adding ammonia water for reaction is 0-60 ℃ for 1-5 h;
and/or in the step 5, stirring and reacting for 1-5 hours at the temperature of 20-150 ℃;
and/or in the step 6, the reaction is carried out for 1-5 hours at the temperature of 20-150 ℃;
preferably, the method comprises the steps of,
in the step 1, the reaction is carried out for 3 hours at room temperature after the acetylating reagent is added dropwise;
and/or in the step 2, the reaction is carried out for 2 hours at room temperature after the nitrating agent is added dropwise;
and/or, in step 3, the reaction is carried out at 40 ℃ for 3.5 hours;
and/or, in the step 4, the reaction conditions of the compound P05-10A-3A and the reagent for preparing the acyl chloride dissolved in the organic solvent are heating reflux reaction for 2 hours;
and/or, in the step 4, the reaction condition of adding ammonia water for reaction is room temperature for reaction for 1h;
and/or, in the step 5, stirring and reacting for 4 hours at 50 ℃;
and/or, in step 6, the reaction is carried out at 70 ℃ for 3.5 hours.
Further, the method comprises the steps of,
in the step 1, after the reaction, the obtained compound P05-10A-1A is purified as follows: concentrating to remove organic solvent, pouring into ice water, stirring, filtering, washing filter cake with water, pumping, and drying solid at 50deg.C overnight to obtain the final product;
and/or, in the step 2, purifying the obtained compound P05-10A-2A after the reaction, wherein the steps are as follows: pouring the reaction solution into cold water, stirring, filtering, washing a filter cake with water, pumping, and drying the solid at 50 ℃ overnight to obtain the catalyst;
and/or, in the step 3, purifying the obtained compound P05-10A-3A after the reaction, wherein the steps are as follows: adjusting pH to 3 with concentrated hydrochloric acid, precipitating solid, filtering, washing filter cake with water, pumping, and drying solid at 50deg.C overnight to obtain the final product;
and/or, in the step 4, purifying the obtained compound P05-10A-4A after the reaction, wherein the steps are as follows: concentrating to remove organic solvent, adding water, precipitating solid, filtering, sequentially washing filter cake with 2N sodium bicarbonate aqueous solution and water, pumping, and drying solid at 50deg.C overnight to obtain the final product;
and/or, in the step 5, purifying the obtained compound P05-4A after the reaction, wherein the steps are as follows: pouring the reaction solution into ice water, precipitating solid, filtering, washing a filter cake with water, pumping, and drying the solid at 50 ℃ overnight to obtain the catalyst;
and/or, in the step 6, purifying the obtained compound P05-3A after the reaction, wherein the steps are as follows: adding water into the reaction solution, separating out solid, filtering, pumping to obtain crude product, adding ethanol into the crude product, stirring at 80 ℃ for 1h, cooling, filtering, pumping, and drying the solid at 50 ℃ overnight to obtain the product.
The invention also provides a method for preparing the dacatinib by using the dacatinib intermediate prepared by the preparation method, which comprises the following steps:
Figure BDA0002248424530000051
in step A: dissolving the compound P05-3A in an organic solvent, introducing hydrogen, and reacting under the action of a catalytic amount of catalyst to obtain a compound P05-2A;
and (B) step (B): dissolving piperidine crotonate, alkali and condensing agent in an organic solvent, reacting, adding a compound P05-2A, and continuing to react to obtain the compound P05-1A;
step C: and (3) dissolving the compound P05-1A and 3-chloro-4-fluoroaniline in an organic solvent, and reacting to obtain the dacatinib.
Further, the method comprises the steps of,
in the step A, the hydrogen is introduced into the reactor at normal pressure; the mass volume ratio of the compound P05-3A to the organic solvent is 1: (1-10) (w/v);
and/or, in the step B, the molar ratio of the piperidine crotonic acid hydrochloride, the alkali, the condensing agent and the compound P05-2A is (1-5): (1-5): (1-5): (1-5); the mass volume ratio of the compound P05-2A to the organic solvent is 1: (1-10) (w/v);
and/or, in the step C, the molar ratio of the compound P05-1A to the 3-chloro-4-fluoroaniline is 1: (1-5); the mass volume ratio of the compound P05-1A to the organic solvent is 1: (1-10) (w/v);
preferably, the method comprises the steps of,
in the step A, the hydrogen is introduced into the reactor at normal pressure; the mass-volume ratio of the compound P05-3A to the organic solvent is 1:5 (w/v);
and/or, in step B, the molar ratio of piperidine crotonate, base, condensing agent and compound P05-2A is 2.5:4.6:3.4:2.3; the mass-volume ratio of the compound P05-2A to the organic solvent is 1:5 (w/v);
and/or, in the step C, the molar ratio of the compound P05-1A to the 3-chloro-4-fluoroaniline is 1:2; the mass-volume ratio of the compound P05-1A to the organic solvent is 1:5 (w/v).
Further, the method comprises the steps of,
in the step A, the organic solvent is methanol, ethanol, acetic acid, acetonitrile, tetrahydrofuran or 1, 4-dioxane; the catalyst is nickel, platinum, palladium or rhodium; preferably, the catalyst is PtO 2 、Pd/C、Pd(OH) 2 Or Raney Ni; more preferably, the catalyst is 5% Pd/C;
and/or, in step B, the base is triethylamine, pyridine, N-diisopropylethylamine, 2, 6-lutidine or N-methylmorpholine; the condensing agent is 1-propyl phosphoric acid cyclic anhydride, diphenyl phosphoryl chloride, diphenyl azide phosphate, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, O-benzotriazole-tetramethyl urea hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinyl phosphate; the organic solvent is dichloromethane, tetrahydrofuran, acetonitrile, N-dimethylformamide or dimethyl sulfoxide;
and/or in the step C, the organic solvent is glacial acetic acid, acetonitrile, toluene, N-dimethylformamide or dimethyl sulfoxide.
Further, the method comprises the steps of,
in the step A, the reaction is carried out for 5-10 hours at 20-100 ℃;
and/or, in the step A, after the reaction, purifying the obtained compound P05-2A, wherein the steps are as follows: filtering with diatomite, concentrating the filtrate to dry, pulping with acetonitrile, filtering, pumping, and drying the solid at 50deg.C overnight to obtain the final product;
and/or, in the step B, the reaction condition of the reaction after dissolving the piperidine crotonate hydrochloride, the alkali and the condensing agent in the organic solvent is that stirring and reacting for 0.5-3 h at room temperature;
and/or, in the step B, the reaction condition of the reaction after the compound P05-2A is added is 0-50 ℃ for 10-15 h;
and/or, in the step B, purifying the obtained compound P05-1A after the reaction, wherein the steps are as follows: pouring the reaction solution into a mixed solution of toluene and 5% sodium hydroxide aqueous solution, stirring, filtering, washing filter cake water and toluene, pumping, and drying the solid at 50 ℃ overnight to obtain the catalyst; the volume ratio of toluene to 5% sodium hydroxide aqueous solution is 1:1;
and/or, in the step C, the reaction is carried out for 20-25 hours at the temperature of 0-50 ℃;
and/or, in the step C, after the reaction, purifying the obtained compound P05, wherein the steps are as follows: adding a mixed solution of isopropanol and 10% sodium hydroxide aqueous solution into the reaction solution, precipitating solids, filtering, pumping to obtain a crude product, pulping with toluene, filtering, and drying the solid at 50 ℃ overnight to obtain the catalyst; the volume ratio of the isopropyl alcohol to the 10% sodium hydroxide aqueous solution is 3:10;
preferably, the method comprises the steps of,
in the step A, the reaction is carried out for 7 hours at 30 ℃;
and/or, in the step B, the reaction condition of the reaction after dissolving the piperidine crotonate hydrochloride, the alkali and the condensing agent in the organic solvent is that stirring and reacting for 0.5h at room temperature;
and/or, in the step B, the reaction condition of the reaction after the compound P05-2A is added is room temperature reaction for 12 hours;
and/or, in the step C, the reaction is carried out for 24 hours at room temperature.
The invention also provides a dacatinib intermediate, and the structural formula of the dacatinib intermediate is shown as a compound P05-10A-2A:
Figure BDA0002248424530000071
in the invention, v/w represents the volume-mass ratio, and the unit is mL/g; w/v represents the mass to volume ratio in g/mL.
In the invention, the room temperature is 25+/-5 ℃ and the overnight time is 12+/-2 hours.
The invention provides a novel preparation method of a key intermediate of dacatinib, which has the advantages of short synthesis route, mild reaction condition, short reaction time, simple separation and purification method, low cost and high yield of the prepared product, is favorable for industrial production and popularization, and has good application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a LCMS spectrum of compound P05-10A-2A.
FIG. 2 is a HNMR pattern of Compound P05-3A.
FIG. 3 is a HNMR pattern of Compound P05.
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
EXAMPLE 1 Synthesis of Dacotinib intermediate (P05-3A)
The synthetic route for the dacatinib intermediate (P05-3A) is shown below:
Figure BDA0002248424530000081
step 1: synthesis of 2-acetamido-4-methoxybenzoic acid (P05-10A-1A)
2-amino-4-methoxybenzoic acid (50 g,0.30 mol), triethylamine (60.7 g,0.60 mol) and methylene chloride (250 ml) were added to the flask, acetyl chloride (35.3 g,0.45 mol) was added dropwise thereto, and after completion of the dropwise reaction, the reaction was allowed to proceed at room temperature for 3 hours, and TLC was monitored for completion. The dichloromethane was concentrated off and the residue was poured into 500ml of ice water, stirred for 1h, filtered, the filter cake was washed with 500ml of water and drained. The solid was collected and dried overnight at 50℃to give 59.8g of a tan solid (P05-10A-1A) in 95.6% yield.
Step 2: synthesis of 2-acetamido-4-methoxy-5-nitrobenzoic acid (P05-10A-2A)
2-acetamido-4-methoxybenzoic acid (20 g,0.096 mol) was dissolved in concentrated sulfuric acid (120 ml), then concentrated nitric acid (6.02 g,0.096 mol) was added dropwise below 20℃and reacted at room temperature for 2h after completion of the dropwise addition, and TLC monitoring was complete. The reaction solution was slowly poured into 250ml of cold water and stirred for 30min. The mixture was filtered, and the filter cake was washed with 500ml of water and drained. The solid was collected and dried overnight at 50℃to give 20.2g of a yellow solid (P05-10A-2A) in 83.2% yield. The LCMS spectrum of P05-10A-2A is shown in FIG. 1.
Step 3: synthesis of 2-amino-4-methoxy-5-nitrobenzoic acid (P05-10A-3A)
2-acetamido-4-methoxy-5-nitrobenzoic acid (50 g,0.20 mol), methanol (500 ml) and 2N aqueous sodium hydroxide solution (500 ml) were added to the reaction flask. The reaction was heated to 40℃for 3.5h and monitored by TLC for completion. Cooling to room temperature, regulating pH to 3 with concentrated hydrochloric acid, and separating out solid. The mixture was filtered, and the filter cake was washed with 500ml of water and drained. The solid was collected and dried overnight at 50℃to give 40.5g of a yellow solid (P05-10A-3A) in 95.5% yield.
Step 4: synthesis of 2-amino-4-methoxy-5-nitrobenzamide (P05-10A-4A)
2-amino-4-methoxy-5-nitrobenzoic acid (15 g,0.0707 mol), thionyl chloride (12.6 g,0.106 mol) and methylene chloride (150 ml) were added to a reaction flask, and the mixture was heated under reflux for 2 hours and cooled to room temperature. The reaction was added dropwise to aqueous ammonia (150 ml), and after completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 1h, followed by completion of the TLC monitoring. The methylene chloride was concentrated and 150ml of water was added to precipitate a solid. The mixture was filtered, and the filter cake was washed with 2N aqueous sodium bicarbonate (150 ml) followed by water (150 ml X2) and drained. The solid was collected and dried overnight at 50℃to give 13.8g of a yellow solid (P05-10A-4A) in 92.7% yield.
Step 5: synthesis of 2-amino-4-methoxy-5-nitrobenzonitrile (P05-4A)
2-amino-4-methoxy-5-nitrobenzamide (25 g,0.12 mol), phosphorus oxychloride (55.2 g,0.36 mol) and acetonitrile (150 ml) were added to a reaction flask, the temperature was raised to 50℃and the reaction was stirred for 4h, and the completion of the reaction was monitored by TLC. The reaction solution was slowly poured into 500ml of ice water, solids were precipitated, filtered, and the cake was washed with 200ml of water and drained. The solid was collected and dried overnight at 50℃to give 20.8g of a yellow solid (P05-4A) in 89.7% yield.
Step 6: synthesis of N' - (2-cyano-5-methoxy-4-nitrophenyl) -N, N-dimethylformamide (P05-3A)
2-amino-4-methoxy-5-nitrobenzonitrile (45 g,0.23 mol), N-dimethylformamide dimethyl acetal (41.7 g,0.35 mol) and N, N-dimethylformamide (180 ml) were added to the reaction flask. The reaction was heated to 70℃for 3.5h and monitored by TLC for completion. Cooling to room temperature, adding 180ml of water into the reaction solution, precipitating solid, filtering, and pumping to obtain a crude product. Ethanol (500 ml) was added to the crude product, stirred at 80℃for 1h, cooled to room temperature, filtered and dried. The solid was collected and dried overnight at 50℃to give 50.6g of a yellow solid (P05-3A) in 87.5% yield. The HNMR pattern of P05-3A is shown in FIG. 2.
Example 2 preparation of Dacotinib
Dacatinib was prepared using the dacatinib intermediate (P05-3A) prepared in example 1. The preparation route of dacatinib is as follows:
Figure BDA0002248424530000091
step A: synthesis of N' - (2-cyano-5-methoxy-4-aminophenyl) -N, N-dimethylformamide (P05-2A)
The dacatinib intermediate N' - (2-cyano-5-methoxy-4-nitrophenyl) -N, N-dimethylformamide (30 g,0.12 mol), 5% Pd/C (3 g) and acetonitrile (150 ml) prepared in example 1 were added to a reaction flask, and hydrogen was introduced at normal pressure to react for 7h at 30℃and TLC monitored for completion. The mixture was filtered through celite, and the filtrate was concentrated to dryness, and then slurried with 60ml of acetonitrile for 1 hour, filtered and dried. The solid was collected and dried overnight at 50℃to give 20g of a yellow solid (P05-2A) in 76.3% yield.
And (B) step (B): (2E) Synthesis of-N- [ 5-cyano-4- [ [ (dimethylamino) methylene ] amino ] -2-methoxyphenyl ] -4- (1-piperidinyl) -2-butenamide (P05-1A)
Acetonitrile (25 ml), piperidine crotonate hydrochloride (5.2 g,0.025 mol), N-diisopropylethylamine (5.9 g,0.046 mol) and 1-propylphosphoric acid cyclic anhydride (11 g,0.034 mol) were added to the reaction flask, and the reaction was stirred at room temperature for 0.5h, followed by addition of N' - (2-cyano-5-methoxy-4-aminophenyl) -N, N-dimethylformamide (5 g,0.023 mol). Then, the reaction was carried out at room temperature for 12 hours, and the reaction was completed by TLC. The reaction solution was poured into toluene (100 ml) and 5% aqueous sodium hydroxide solution (100 ml), stirred for 0.5h, filtered, and the cake was washed with 50ml of water and 50ml of toluene and drained. The solid was collected and dried overnight at 50℃to give 6.1g of an off-white solid (P05-1A) in a yield of 72.8%.
Step C: synthesis of Dacotinib (P05)
In a reaction flask was charged (2E) -N- [ 5-cyano-4- [ [ (dimethylamino) methylene ] amino ] -2-methoxyphenyl ] -4- (1-piperidinyl) -2-butenamide (6 g,0.016 mol), 3-chloro-4-fluoroaniline (4.8 g,0.032 mol) and glacial acetic acid (30 ml), reacted at room temperature for 24h, and TLC monitored the reaction was complete. To the reaction mixture were added isopropanol (30 ml) and 10% aqueous sodium hydroxide solution (100 ml), and a solid was precipitated. Filtering, pumping to obtain crude product, pulping with toluene (60 ml) for 0.5h, filtering, collecting solid, drying at 50deg.C overnight to obtain off-white solid (Daktinib P05) 5.9g, yield 77.3%. The HNMR profile of P05 is shown in FIG. 3.
In summary, the invention provides a novel preparation method of the key intermediate of dacatinib, which has the advantages of short synthesis route, mild reaction condition, short reaction time, simple separation and purification method, conventional raw material reagents, low cost, high yield of the prepared product, great benefit to industrial production and popularization and good application prospect.

Claims (9)

1. A preparation method of a dacatinib intermediate is characterized by comprising the following steps of: it comprises the following steps:
Figure FDA0004015168450000011
step 1: reacting the compound P05-10A, an acid binding agent and an acetylation reagent in an organic solvent to obtain a compound P05-10A-1A;
step 2: adding a nitrifying agent and a dehydrating agent into the compound P05-10A-1A for reaction to obtain a compound P05-10A-2A;
step 3: dissolving the compound P05-10A-2A and alkali or acid in an organic solvent for reaction to obtain a compound P05-10A-3A;
step 4: dissolving the compound P05-10A-3A and a reagent for preparing acyl chloride in an organic solvent for reaction, and adding ammonia water for reaction after the reaction to obtain the compound P05-10A-4A;
step 5: reacting the compound P05-10A-4A with a dehydrating agent in an organic solvent to obtain a compound P05-4A;
step 6: and (3) reacting the compound P05-4A with N, N-dimethylformamide dimethyl acetal in an organic solvent to obtain the dacatinib intermediate.
2. The method of manufacturing according to claim 1, characterized in that:
in the step 1, the molar ratio of the compound P05-10A, the acid binding agent and the acetylating agent is (1-5): (1-5): (1-5); the mass volume ratio of the compound P05-10A to the organic solvent is 1g: (1-10) mL;
and/or, in the step 2, the molar ratio of the compound P05-10A-1A to the nitrating agent is (1-5): (1-5); the mass volume ratio of the compound P05-10A-1A to the dehydrating agent is 1g: (1-10) mL;
and/or in the step 3, the mass-volume ratio of the compound P05-10A-2A to the alkali is 1g: (10-20) mL; the mass volume ratio of the compound P05-10A-2A to the organic solvent is 1g: (1-20) mL;
and/or, in the step 4, the mass ratio of the compound P05-10A-3A to the reagent for preparing the acyl chloride is (10-20): (10-20); the mass volume ratio of the compound P05-10A-3A to the organic solvent is 1g: (1-20) mL; the volume ratio of the organic solvent to the ammonia water is 1 (1-100);
and/or, in the step 5, the molar ratio of the compound P05-10A-4A to the dehydrating agent is 1: (1-5); the mass volume ratio of the compound P05-10A-4A to the organic solvent is 1g: (1-10) mL;
and/or, in step 6, the molar ratio of the compound P05-4A to the N, N-dimethylformamide dimethyl acetal is (1-5): (1-5); the mass volume ratio of the compound P05-4A to the organic solvent is 1g: (1-10) mL.
3. The preparation method according to claim 2, characterized in that:
in the step 1, the molar ratio of the compound P05-10A, the acid binding agent and the acetylation reagent is 1:2:1.5; the mass volume ratio of the compound P05-10A to the organic solvent is 1g to 5mL;
and/or in the step 2, the molar ratio of the compound P05-10A-1A to the nitrating agent is 1:1; the mass volume ratio of the compound P05-10A-1A to the dehydrating agent is 1g to 6mL;
and/or in the step 3, the mass-volume ratio of the compound P05-10A-2A to the alkali is 1g to 10mL; the mass volume ratio of the compound P05-10A-2A to the organic solvent is 1g to 10mL;
and/or, in the step 4, the mass ratio of the compound P05-10A-3A to the reagent for preparing the acyl chloride is 15:12.6; the mass volume ratio of the compound P05-10A-3A to the organic solvent is 1g to 10mL; the volume ratio of the organic solvent to the ammonia water is 1:1;
and/or, in the step 5, the molar ratio of the compound P05-10A-4A to the dehydrating agent is 1:3; the mass volume ratio of the compound P05-10A-4A to the organic solvent is 1g to 6mL;
and/or, in step 6, the molar ratio of the compound P05-4A to the N, N-dimethylformamide dimethyl acetal is 2.3:3.5; the mass volume ratio of the compound P05-4A to the organic solvent is 1g:4mL.
4. The method of manufacturing according to claim 1, characterized in that:
in the step 1, the acid binding agent is pyridine, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine, potassium carbonate or sodium carbonate; the acetylating agent is acetic anhydride or acetyl chloride; the organic solvent is dichloromethane, tetrahydrofuran, toluene, ethyl acetate or N, N-dimethylformamide;
and/or in the step 2, the nitrifying agent is concentrated nitric acid, fuming nitric acid or potassium nitrate; the dehydrating agent is concentrated sulfuric acid, glacial acetic acid, acetic anhydride or phosphorus pentoxide;
and/or in the step 3, the alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide; or, the acid is hydrochloric acid or sulfuric acid; the organic solvent is methanol, ethanol, tetrahydrofuran, 1, 4-dioxane or acetonitrile;
and/or, in the step 4, the reagent for preparing the acyl chloride is thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride; the organic solvent is dichloromethane, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide or acetonitrile;
and/or in the step 5, the dehydrating agent is phosphorus oxychloride, trifluoroacetic anhydride, cyanuric chloride, acetic anhydride, thionyl chloride, phosphorus pentoxide or triphosgene; the organic solvent is dichloromethane, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, acetonitrile or toluene;
and/or in the step 6, the organic solvent is N, N-dimethylformamide, 1, 4-dioxane, tetrahydrofuran, acetonitrile or toluene.
5. The method of manufacturing according to claim 4, wherein: in the step 3, the alkali is sodium hydroxide.
6. The method of manufacturing according to claim 5, wherein: in the step 3, the sodium hydroxide is a sodium hydroxide aqueous solution with the concentration of 2N.
7. The method of manufacturing according to claim 1, characterized in that:
in the step 1, the adding mode of the acetylation reagent is dropwise adding;
and/or in the step 1, the reaction is carried out for 1-5 h at the temperature of 0-100 ℃ after the acetylating reagent is added dropwise;
and/or, in the step 2, dropwise adding the nitrifying agent;
and/or in the step 2, the reaction is carried out for 1-5 h at the temperature of 0-100 ℃ after the nitrating agent is added dropwise;
and/or in the step 3, the reaction is carried out for 1-5 hours at the temperature of 20-80 ℃;
and/or, in the step 4, the reaction conditions of the compound P05-10A-3A and the reagent for preparing the acyl chloride dissolved in the organic solvent are heating reflux reaction for 1-5 h;
and/or in the step 4, the reaction condition of adding ammonia water for reaction is 0-60 ℃ for 1-5 h;
and/or in the step 5, stirring and reacting for 1-5 hours at the temperature of 20-150 ℃;
and/or in the step 6, the reaction is carried out for 1-5 h at 20-150 ℃.
8. The method of manufacturing according to claim 7, wherein:
in the step 1, the reaction is carried out for 3 hours at room temperature after the acetylating reagent is added dropwise;
and/or in the step 2, the reaction is carried out for 2 hours at room temperature after the nitrating agent is added dropwise;
and/or, in step 3, the reaction is carried out at 40 ℃ for 3.5 hours;
and/or, in the step 4, the reaction conditions of the compound P05-10A-3A and the reagent for preparing the acyl chloride dissolved in the organic solvent are heating reflux reaction for 2 hours;
and/or, in the step 4, the reaction condition of adding ammonia water for reaction is room temperature for reaction for 1h;
and/or, in the step 5, stirring and reacting for 4 hours at 50 ℃;
and/or, in step 6, the reaction is carried out at 70 ℃ for 3.5 hours.
9. The method of manufacturing according to claim 1, characterized in that:
in the step 1, after the reaction, the obtained compound P05-10A-1A is purified as follows: concentrating to remove organic solvent, pouring into ice water, stirring, filtering, washing filter cake with water, pumping, and drying solid at 50deg.C overnight to obtain the final product;
and/or, in the step 2, purifying the obtained compound P05-10A-2A after the reaction, wherein the steps are as follows: pouring the reaction solution into cold water, stirring, filtering, washing a filter cake with water, pumping, and drying the solid at 50 ℃ overnight to obtain the catalyst;
and/or, in the step 3, purifying the obtained compound P05-10A-3A after the reaction, wherein the steps are as follows: adjusting pH to 3 with concentrated hydrochloric acid, precipitating solid, filtering, washing filter cake with water, pumping, and drying solid at 50deg.C overnight to obtain the final product;
and/or, in the step 4, purifying the obtained compound P05-10A-4A after the reaction, wherein the steps are as follows: concentrating to remove organic solvent, adding water, precipitating solid, filtering, sequentially washing filter cake with 2N sodium bicarbonate aqueous solution and water, pumping, and drying solid at 50deg.C overnight to obtain the final product;
and/or, in the step 5, purifying the obtained compound P05-4A after the reaction, wherein the steps are as follows: pouring the reaction solution into ice water, precipitating solid, filtering, washing a filter cake with water, pumping, and drying the solid at 50 ℃ overnight to obtain the catalyst;
and/or, in the step 6, purifying the obtained compound P05-3A after the reaction, wherein the steps are as follows: adding water into the reaction solution, separating out solid, filtering, pumping to obtain crude product, adding ethanol into the crude product, stirring at 80 ℃ for 1h, cooling, filtering, pumping, and drying the solid at 50 ℃ overnight to obtain the product.
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