CN112707846A - Preparation method of dacomitinib key intermediate - Google Patents

Preparation method of dacomitinib key intermediate Download PDF

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CN112707846A
CN112707846A CN201911025220.9A CN201911025220A CN112707846A CN 112707846 A CN112707846 A CN 112707846A CN 201911025220 A CN201911025220 A CN 201911025220A CN 112707846 A CN112707846 A CN 112707846A
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CN112707846B (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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Chengdu D Innovation Pharmaceutical 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
    • C07C257/18—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 having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • 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 dacomitinib key intermediate, which comprises the following steps. The intermediate has the advantages of short synthetic route, mild reaction conditions, short reaction time, simple separation and purification method, low cost because raw material reagents are conventional reagents, high yield of the prepared product, contribution to industrial production and popularization and good application prospect.
Figure DDA0002248424550000011

Description

Preparation method of dacomitinib key intermediate
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of a dacomitinib key intermediate.
Background
Dacotinib (Indonesian name: Dacomitinib) has the following structural formula, is a second-generation, irreversible EGFR Tyrosine Kinase Inhibitor (TKI) developed by Pfizer, USA, and has a mechanism similar to afatinib, and can irreversibly inhibit three different ERBB family molecular members, including EGFR (HER1), HER2 and HER 4. It is possible that a better therapeutic effect is exhibited because proteins of multiple ERBB families can be inhibited. The product is approved by the FDA in the United states and sold on the market in 2018, 9 and 27 months
Figure BDA0002248424530000013
Approved for the treatment of metastatic non-small cell lung cancer (NSCLC) patients carrying an exon 19 deletion or an exon 21L 858R substitution mutation in the EGFR gene.
Figure BDA0002248424530000011
P05-3A is a key intermediate for the synthesis of dacomitinib.
Figure BDA0002248424530000012
However, few methods are reported for synthesizing this intermediate. The preparation methods of other intermediates of dacomitinib have the problems of incomplete reaction, generation of new impurities, long synthesis route, low total yield, complex separation and purification, high cost and the like, and are not beneficial to industrial production and popularization.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of a dacomitinib key intermediate.
The invention provides a preparation method of a dacomitinib intermediate, which comprises the following steps:
Figure BDA0002248424530000021
step 1: reacting a 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 nitrating agent and a dehydrating agent into the compound P05-10A-1A to react to obtain a compound P05-10A-2A;
and 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;
and 4, step 4: dissolving a 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 a compound P05-10A-4A;
and 5: reacting a 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 dacomitinib intermediate.
Further, the air conditioner is provided with a fan,
in the step 1, the molar ratio of the compound P05-10A, the acid-binding agent and the acetylation reagent is (1-5): (1-5): (1-5); the mass-to-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-to-volume ratio of the compound P05-10A-2A to the base 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 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-to-volume ratio of the compound P05-10A-4A to the organic solvent is 1: (1-10) (w/v);
and/or, in the step 6, the molar ratio of the compound P05-4A to the N, N-dimethylformamide dimethyl acetal is (1-5): (1-5); the mass-to-volume ratio of the compound P05-4A to the organic solvent is 1: (1-10) (w/v);
preferably, the first and second electrodes are formed of a metal,
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-to-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-to-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-to-volume ratio of the compound P05-10A-2A to the base is 1:10 (w/v); the mass-to-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 acyl chloride is 15: 12.6; the mass-to-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-to-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-to-volume ratio of the compound P05-4A to the organic solvent is 1:4 (w/v).
Further, the air conditioner is provided with a fan,
in the step 1, the acid-binding agent is pyridine, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine, potassium carbonate or sodium carbonate; the acetylation reagent 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 nitrating 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 aqueous sodium hydroxide solution;
and/or, in the step 4, the reagent for preparing 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 air conditioner is provided with a fan,
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 hours at 0-100 ℃ after the acetylation reagent is dropwise added;
and/or, in the step 2, the adding mode of the nitrating agent is dropwise adding;
and/or in the step 2, the reaction is carried out for 1-5 hours at 0-100 ℃ after the nitrating agent is added dropwise;
and/or in the step 3, the reaction is carried out for 1-5 h at the temperature of 20-80 ℃;
and/or in the step 4, the reaction conditions of dissolving the compound P05-10A-3A and the reagent for preparing acyl chloride 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 h at 20-150 ℃;
and/or in the step 6, the reaction is carried out for 1-5 h at the temperature of 20-150 ℃;
preferably, the first and second electrodes are formed of a metal,
in the step 1, the reaction is carried out for 3 hours at room temperature after the acetylation 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 the step 3, the reaction is carried out for 3.5h at 40 ℃;
and/or in the step 4, the reaction condition of dissolving the compound P05-10A-3A and the reagent for preparing acyl chloride in the organic solvent is heating reflux reaction for 2 hours;
and/or in the step 4, the reaction condition of adding ammonia water for reaction is room temperature reaction for 1 hour;
and/or in the step 5, the reaction is stirred and reacted for 4 hours at the temperature of 50 ℃;
and/or, in the step 6, the reaction is carried out for 3.5h at 70 ℃.
Further, the air conditioner is provided with a fan,
in step 1, after the reaction, the obtained compound P05-10A-1A is purified, the steps are as follows: concentrating to remove organic solvent, pouring into ice water, stirring, filtering, washing filter cake with water, draining, and drying solid at 50 deg.C overnight to obtain the final product;
and/or, in the step 2, after the reaction, purifying the obtained compound P05-10A-2A, 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 compound;
and/or, in step 3, after the reaction, purifying the obtained compound P05-10A-3A by the following steps: adjusting pH to 3 with concentrated hydrochloric acid, separating out solid, filtering, washing filter cake with water, draining, and drying solid at 50 deg.C overnight to obtain the final product;
and/or, in step 4, after the reaction, purifying the obtained compound P05-10A-4A by the following steps: concentrating to remove organic solvent, adding water, precipitating solid, filtering, sequentially washing filter cake with 2N sodium bicarbonate water solution and water, pumping, and drying solid at 50 deg.C overnight to obtain the final product;
and/or, in step 5, after the reaction, purifying the obtained compound P05-4A, wherein the steps are as follows: pouring the reaction solution into ice water, separating out a solid, filtering, washing a filter cake with water, pumping, and drying the solid at 50 ℃ overnight to obtain the compound;
and/or, in step 6, after the reaction, purifying the obtained compound P05-3A, wherein the steps are as follows: adding water into the reaction solution, separating out solid, filtering, draining to obtain crude product, adding ethanol into the crude product, stirring for 1h at 80 ℃, cooling, filtering, draining, and drying the solid overnight at 50 ℃ to obtain the final product.
The invention also provides a method for preparing the dacomitinib by using the dacomitinib intermediate prepared by the preparation method, which comprises the following steps:
Figure BDA0002248424530000051
in the step A: dissolving a compound P05-3A in an organic solvent, introducing hydrogen, and reacting under the action of a catalytic amount of a catalyst to obtain a compound P05-2A;
and B: dissolving piperidine crotonate, alkali and a condensing agent in an organic solvent, reacting, adding a compound P05-2A, and continuously reacting to obtain a compound P05-1A;
and C: dissolving a compound P05-1A and 3-chloro-4-fluoroaniline in an organic solvent, and reacting to obtain the dacomitinib.
Further, the air conditioner is provided with a fan,
in the step A, the introduced hydrogen is excessive hydrogen introduced under normal pressure; the mass-to-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 crotonate to the base to the condensing agent to the compound P05-2A is (1-5): (1-5): (1-5): (1-5); the mass-to-volume ratio of the compound P05-2A to the organic solvent is 1: (1-10) (w/v);
and/or, in step C, the molar ratio of the compound P05-1A to the 3-chloro-4-fluoroaniline is 1: (1-5); the mass-to-volume ratio of the compound P05-1A to the organic solvent is 1: (1-10) (w/v);
preferably, the first and second electrodes are formed of a metal,
in the step A, the introduced hydrogen is excessive hydrogen introduced under normal pressure; the mass-to-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 the piperidine crotonate, the base, the condensing agent and the compound P05-2A is 2.5:4.6:3.4: 2.3; the mass-to-volume ratio of the compound P05-2A to the organic solvent is 1:5 (w/v);
and/or, in step C, the molar ratio of the compound P05-1A to the 3-chloro-4-fluoroaniline is 1: 2; the mass-to-volume ratio of the compound P05-1A to the organic solvent is 1:5 (w/v).
Further, the air conditioner is provided with a fan,
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 PtO2、Pd/C、Pd(OH)2Or Raney Ni; more preferably, the catalyst is 5% Pd/C;
and/or, in step B, the base is triethylamine, pyridine, N-diisopropylethylamine, 2, 6-dimethylpyridine or N-methylmorpholine; the condensing agent is 1-propyl phosphoric acid cyclic anhydride, diphenyl phosphoryl chloride, diphenyl azide phosphate, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, O-benzotriazol-tetramethyl urea hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinyl phosphorus hexafluorophosphate; 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 air conditioner is provided with a fan,
in the step A, the reaction is carried out for 5-10 h at 20-100 ℃;
and/or, in step A, after the reaction, purifying the obtained compound P05-2A, wherein the steps are as follows: filtering with diatomaceous earth, concentrating the filtrate to dryness, pulping with acetonitrile, filtering, draining, and drying the solid at 50 deg.C overnight to obtain the final product;
and/or in the step B, dissolving the piperidine crotonate, the alkali and the condensing agent in the organic solvent for reaction under the reaction condition of stirring at room temperature for 0.5-3 h;
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 step B, after the reaction, purifying the obtained compound P05-1A, and the steps are as follows: pouring the reaction solution into a mixed solution of toluene and a 5% sodium hydroxide aqueous solution, stirring, filtering, washing a filter cake with water and toluene, pumping, and drying the solid at 50 ℃ overnight to obtain the catalyst; the volume ratio of the toluene to the 5% sodium hydroxide aqueous solution is 1: 1;
and/or in the step C, the reaction is carried out for 20-25 h at the temperature of 0-50 ℃;
and/or, in step C, after the reaction, the compound P05 obtained is purified by the following steps: adding a mixed solution of isopropanol and a 10% sodium hydroxide aqueous solution into the reaction solution, separating out a solid, filtering, pumping to obtain a crude product, pulping with toluene, filtering, and drying the solid overnight at 50 ℃ to obtain the compound; the volume ratio of the isopropanol to the 10% sodium hydroxide aqueous solution is 3: 10;
preferably, the first and second electrodes are formed of a metal,
in the step A, the reaction is carried out for 7 hours at 30 ℃;
and/or in the step B, the reaction condition of dissolving the piperidine crotonate, the alkali and the condensing agent in the organic solvent for reaction is that stirring reaction is carried out 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 dacomitinib intermediate, wherein the structural formula of the dacomitinib 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 h.
The invention provides a novel preparation method of a dacomitinib key intermediate, the intermediate has the advantages of short synthetic route, mild reaction conditions, short reaction time, simple separation and purification method, low cost because raw material reagents are conventional reagents, high yield of the prepared product, contribution to industrial production and popularization and good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a LCMS spectrum of compound P05-10A-2A.
FIG. 2 is a HNMR map of compound P05-3A.
Figure 3 is a HNMR map of compound P05.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1 Synthesis of Daktinib intermediate (P05-3A)
The synthetic route of the dacomitinib intermediate (P05-3A) is shown as follows:
Figure BDA0002248424530000081
step 1: synthesis of 2-acetamido-4-methoxybenzoic acid (P05-10A-1A)
2-amino-4-methoxybenzoic acid (50g, 0.30mol), triethylamine (60.7g, 0.60mol) and dichloromethane (250ml) were added to a reaction flask, acetyl chloride (35.3g, 0.45mol) was added dropwise, and after the addition, the reaction was carried out at room temperature for 3 hours, and the completion of the reaction was monitored by TLC. The dichloromethane is removed by concentration, the residue is poured into 500ml of ice-water, stirred for 1h, filtered and the filter cake is washed with 500ml of water and drained. The collected solid was dried at 50 ℃ overnight to give 59.8g of a brown yellow 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 (20g, 0.096mol) is dissolved in concentrated sulfuric acid (120ml), concentrated nitric acid (6.02g, 0.096mol) is added dropwise below 20 ℃, reaction is carried out at room temperature for 2h after the addition is finished, and the reaction is monitored by TLC to be complete. The reaction solution was slowly poured into 250ml of cold water, and stirred for 30 min. Filtration and washing of the filter cake with 500ml of water and draining. The collected solid was dried at 50 ℃ overnight 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 figure 1.
And step 3: synthesis of 2-amino-4-methoxy-5-nitrobenzoic acid (P05-10A-3A)
2-acetamido-4-methoxy-5-nitrobenzoic acid (50g, 0.20mol), methanol (500ml) and 2N aqueous sodium hydroxide (500ml) 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, adjusting the pH value to 3 with concentrated hydrochloric acid, and separating out a solid. Filtration and washing of the filter cake with 500ml of water and draining. The collected solid was dried at 50 ℃ overnight to give 40.5g of a yellow solid (P05-10A-3A) in 95.5% yield.
And 4, step 4: synthesis of 2-amino-4-methoxy-5-nitrobenzamide (P05-10A-4A)
2-amino-4-methoxy-5-nitrobenzoic acid (15g, 0.0707mol), thionyl chloride (12.6g, 0.106mol) and dichloromethane (150ml) were added to a reaction flask, heated to reflux for 2h and allowed to cool to room temperature. The reaction solution was added dropwise to ammonia (150ml), and after completion of the addition, the reaction was carried out at room temperature for 1 hour, and the completion of the reaction was monitored by TLC. The dichloromethane was removed by concentration, 150ml of water was added, and a solid precipitated. The mixture was filtered, and the filter cake was washed successively with 2N aqueous sodium bicarbonate (150ml) and water (150ml X2) and drained. The collected solid was dried at 50 ℃ overnight to give 13.8g of a yellow solid (P05-10A-4A) in 92.7% yield.
And 5: synthesis of 2-amino-4-methoxy-5-nitrobenzonitrile (P05-4A)
2-amino-4-methoxy-5-nitrobenzamide (25g, 0.12mol), phosphorus oxychloride (55.2g, 0.36mol) and acetonitrile (150ml) were added to a reaction flask, the temperature was raised to 50 ℃ and the reaction was stirred for 4h, and TLC monitored for completion. The reaction mixture was slowly poured into 500ml of ice water, the solid precipitated, filtered, the filter cake washed with 200ml of water and drained. The collected solid was dried at 50 ℃ overnight 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 (45g, 0.23mol), N-dimethylformamide dimethyl acetal (41.7g, 0.35mol) and N, N-dimethylformamide (180ml) were added to a 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, separating out solid, filtering, and pumping to obtain a crude product. Ethanol (500ml) was added to the crude product, stirred at 80 ℃ for 1h, cooled to room temperature, filtered and drained. The collected solid was dried at 50 ℃ overnight to give 50.6g of a yellow solid (P05-3A) in 87.5% yield. The HNMR map of P05-3A is shown in FIG. 2.
Example 2 preparation of dacomitinib
Dacomitinib was prepared using the dacomitinib intermediate prepared in example 1 (P05-3A). The preparation route of dacomitinib is shown below:
Figure BDA0002248424530000091
step A: synthesis of N' - (2-cyano-5-methoxy-4-aminophenyl) -N, N-dimethylformamide (P05-2A)
The dacomitinib intermediate, N' - (2-cyano-5-methoxy-4-nitrophenyl) -N, N-dimethylformamide (30g, 0.12mol), 5% Pd/C (3g) and acetonitrile (150ml), prepared in example 1 was added to a reaction flask, and reacted at 30 ℃ for 7h with hydrogen gas under normal pressure, followed by TLC to monitor completion of the reaction. The pad is filtered through celite, the filtrate is concentrated to dryness and then slurried with 60ml acetonitrile for 1h, filtered and drained. The collected solid was dried at 50 ℃ overnight to give 20g of a yellow solid (P05-2A) in 76.3% yield.
And B: (2E) synthesis of (E) -N- [ 5-cyano-4- [ [ (dimethylamino) methylene ] amino ] -2-methoxyphenyl ] -4- (1-piperidinyl) -2-butenamide (P05-1A)
Acetonitrile (25ml), piperidine crotonate (5.2g, 0.025mol), N-diisopropylethylamine (5.9g, 0.046mol) and 1-propylphosphoric cyclic anhydride (11g, 0.034mol) were charged to a 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 (5g, 0.023 mol). The reaction was then carried out at room temperature for 12h and TLC monitored for completion. The reaction solution was poured into toluene (100ml) and 5% aqueous sodium hydroxide solution (100ml), stirred for 0.5h, filtered, and the filter cake was washed with 50ml of water and 50ml of toluene and drained. The collected solid was dried at 50 ℃ overnight to give 6.1g of an off-white solid (P05-1A) in a yield of 72.8%.
And C: synthesis of dacomitinib (P05)
A reaction flask was charged with (2E) -N- [ 5-cyano-4- [ [ (dimethylamino) methylene ] amino ] -2-methoxyphenyl ] -4- (1-piperidinyl) -2-butenamide (6g, 0.016mol), 3-chloro-4-fluoroaniline (4.8g, 0.032mol) and glacial acetic acid (30ml), reacted at room temperature for 24h, and TLC monitored for completion of the reaction. To the reaction mixture were added isopropanol (30ml) and 10% aqueous sodium hydroxide (100ml), to precipitate a solid. Filtering, pumping to obtain a crude product, pulping for 0.5h by using toluene (60ml), filtering, collecting solid, and drying at 50 ℃ overnight to obtain 5.9g of off-white solid (dacomitinib P05) with the yield of 77.3%. The HNMR map of P05 is shown in FIG. 3.
In conclusion, the invention provides a novel preparation method of a dacomitinib key intermediate, the intermediate has the advantages of short synthetic route, mild reaction conditions, short reaction time, simple separation and purification method, low cost due to the fact that raw material reagents are conventional reagents, high yield of the prepared product, contribution to industrial production and popularization and good application prospect.

Claims (10)

1. A preparation method of a dacomitinib intermediate is characterized by comprising the following steps: it comprises the following steps:
Figure FDA0002248424520000011
step 1: reacting a 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 nitrating agent and a dehydrating agent into the compound P05-10A-1A to react to obtain a compound P05-10A-2A;
and 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;
and 4, step 4: dissolving a 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 a compound P05-10A-4A;
and 5: reacting a 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 dacomitinib intermediate.
2. The method of claim 1, wherein:
in the step 1, the molar ratio of the compound P05-10A, the acid-binding agent and the acetylation reagent is (1-5): (1-5): (1-5); the mass-to-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-to-volume ratio of the compound P05-10A-2A to the base 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 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-to-volume ratio of the compound P05-10A-4A to the organic solvent is 1: (1-10) (w/v);
and/or, in the step 6, the molar ratio of the compound P05-4A to the N, N-dimethylformamide dimethyl acetal is (1-5): (1-5); the mass-to-volume ratio of the compound P05-4A to the organic solvent is 1: (1-10) (w/v);
preferably, the first and second electrodes are formed of a metal,
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-to-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-to-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-to-volume ratio of the compound P05-10A-2A to the base is 1:10 (w/v); the mass-to-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 acyl chloride is 15: 12.6; the mass-to-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-to-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-to-volume ratio of the compound P05-4A to the organic solvent is 1:4 (w/v).
3. The method of claim 1, wherein:
in the step 1, the acid-binding agent is pyridine, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine, potassium carbonate or sodium carbonate; the acetylation reagent 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 nitrating 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 aqueous sodium hydroxide solution;
and/or, in the step 4, the reagent for preparing 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.
4. The method of claim 1, wherein:
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 hours at 0-100 ℃ after the acetylation reagent is dropwise added;
and/or, in the step 2, the adding mode of the nitrating agent is dropwise adding;
and/or in the step 2, the reaction is carried out for 1-5 hours at 0-100 ℃ after the nitrating agent is added dropwise;
and/or in the step 3, the reaction is carried out for 1-5 h at the temperature of 20-80 ℃;
and/or in the step 4, the reaction conditions of dissolving the compound P05-10A-3A and the reagent for preparing acyl chloride 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 h at 20-150 ℃;
and/or in the step 6, the reaction is carried out for 1-5 h at the temperature of 20-150 ℃;
preferably, the first and second electrodes are formed of a metal,
in the step 1, the reaction is carried out for 3 hours at room temperature after the acetylation 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 the step 3, the reaction is carried out for 3.5h at 40 ℃;
and/or in the step 4, the reaction condition of dissolving the compound P05-10A-3A and the reagent for preparing acyl chloride in the organic solvent is heating reflux reaction for 2 hours;
and/or in the step 4, the reaction condition of adding ammonia water for reaction is room temperature reaction for 1 hour;
and/or in the step 5, the reaction is stirred and reacted for 4 hours at the temperature of 50 ℃;
and/or, in the step 6, the reaction is carried out for 3.5h at 70 ℃.
5. The method of claim 1, wherein:
in step 1, after the reaction, the obtained compound P05-10A-1A is purified, the steps are as follows: concentrating to remove organic solvent, pouring into ice water, stirring, filtering, washing filter cake with water, draining, and drying solid at 50 deg.C overnight to obtain the final product;
and/or, in the step 2, after the reaction, purifying the obtained compound P05-10A-2A, 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 compound;
and/or, in step 3, after the reaction, purifying the obtained compound P05-10A-3A by the following steps: adjusting pH to 3 with concentrated hydrochloric acid, separating out solid, filtering, washing filter cake with water, draining, and drying solid at 50 deg.C overnight to obtain the final product;
and/or, in step 4, after the reaction, purifying the obtained compound P05-10A-4A by the following steps: concentrating to remove organic solvent, adding water, precipitating solid, filtering, sequentially washing filter cake with 2N sodium bicarbonate water solution and water, pumping, and drying solid at 50 deg.C overnight to obtain the final product;
and/or, in step 5, after the reaction, purifying the obtained compound P05-4A, wherein the steps are as follows: pouring the reaction solution into ice water, separating out a solid, filtering, washing a filter cake with water, pumping, and drying the solid at 50 ℃ overnight to obtain the compound;
and/or, in step 6, after the reaction, purifying the obtained compound P05-3A, wherein the steps are as follows: adding water into the reaction solution, separating out solid, filtering, draining to obtain crude product, adding ethanol into the crude product, stirring for 1h at 80 ℃, cooling, filtering, draining, and drying the solid overnight at 50 ℃ to obtain the final product.
6. A method for preparing dacomitinib by using the dacomitinib intermediate prepared by the preparation method of any one of claims 1 to 5, which is characterized by comprising the following steps: it comprises the following steps:
Figure FDA0002248424520000041
in the step A: dissolving a compound P05-3A in an organic solvent, introducing hydrogen, and reacting under the action of a catalytic amount of a catalyst to obtain a compound P05-2A;
and B: dissolving piperidine crotonate, alkali and a condensing agent in an organic solvent, reacting, adding a compound P05-2A, and continuously reacting to obtain a compound P05-1A;
and C: dissolving a compound P05-1A and 3-chloro-4-fluoroaniline in an organic solvent, and reacting to obtain the dacomitinib.
7. The method of claim 6, wherein:
in the step A, the introduced hydrogen is excessive hydrogen introduced under normal pressure; the mass-to-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 crotonate to the base to the condensing agent to the compound P05-2A is (1-5): (1-5): (1-5): (1-5); the mass-to-volume ratio of the compound P05-2A to the organic solvent is 1: (1-10) (w/v);
and/or, in step C, the molar ratio of the compound P05-1A to the 3-chloro-4-fluoroaniline is 1: (1-5); the mass-to-volume ratio of the compound P05-1A to the organic solvent is 1: (1-10) (w/v);
preferably, the first and second electrodes are formed of a metal,
in the step A, the introduced hydrogen is excessive hydrogen introduced under normal pressure; the mass-to-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 the piperidine crotonate, the base, the condensing agent and the compound P05-2A is 2.5:4.6:3.4: 2.3; the mass-to-volume ratio of the compound P05-2A to the organic solvent is 1:5 (w/v);
and/or, in step C, the molar ratio of the compound P05-1A to the 3-chloro-4-fluoroaniline is 1: 2; the mass-to-volume ratio of the compound P05-1A to the organic solvent is 1:5 (w/v).
8. The method of claim 6, wherein:
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 PtO2、Pd/C、Pd(OH)2Or Raney Ni; more preferably, the catalyst is 5% Pd/C;
and/or, in step B, the base is triethylamine, pyridine, N-diisopropylethylamine, 2, 6-dimethylpyridine or N-methylmorpholine; the condensing agent is 1-propyl phosphoric acid cyclic anhydride, diphenyl phosphoryl chloride, diphenyl azide phosphate, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, O-benzotriazol-tetramethyl urea hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinyl phosphorus hexafluorophosphate; 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.
9. The method of claim 6, wherein:
in the step A, the reaction is carried out for 5-10 h at 20-100 ℃;
and/or, in step A, after the reaction, purifying the obtained compound P05-2A, wherein the steps are as follows: filtering with diatomaceous earth, concentrating the filtrate to dryness, pulping with acetonitrile, filtering, draining, and drying the solid at 50 deg.C overnight to obtain the final product;
and/or in the step B, dissolving the piperidine crotonate, the alkali and the condensing agent in the organic solvent for reaction under the reaction condition of stirring at room temperature for 0.5-3 h;
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 step B, after the reaction, purifying the obtained compound P05-1A, and the steps are as follows: pouring the reaction solution into a mixed solution of toluene and a 5% sodium hydroxide aqueous solution, stirring, filtering, washing a filter cake with water and toluene, pumping, and drying the solid at 50 ℃ overnight to obtain the catalyst; the volume ratio of the toluene to the 5% sodium hydroxide aqueous solution is 1: 1;
and/or in the step C, the reaction is carried out for 20-25 h at the temperature of 0-50 ℃;
and/or, in step C, after the reaction, the compound P05 obtained is purified by the following steps: adding a mixed solution of isopropanol and a 10% sodium hydroxide aqueous solution into the reaction solution, separating out a solid, filtering, pumping to obtain a crude product, pulping with toluene, filtering, and drying the solid overnight at 50 ℃ to obtain the compound; the volume ratio of the isopropanol to the 10% sodium hydroxide aqueous solution is 3: 10;
preferably, the first and second electrodes are formed of a metal,
in the step A, the reaction is carried out for 7 hours at 30 ℃;
and/or in the step B, the reaction condition of dissolving the piperidine crotonate, the alkali and the condensing agent in the organic solvent for reaction is that stirring reaction is carried out 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.
10. A dacomitinib intermediate, characterized by: the structural formula of the dacomitinib intermediate is shown as a compound P05-10A-2A:
Figure FDA0002248424520000061
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113277986A (en) * 2021-05-31 2021-08-20 成都伊诺达博医药科技有限公司 Dacotinib impurity and preparation method thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2342503A1 (en) * 1998-08-21 2000-03-02 Parker Hughes Institute Quinazoline derivatives
CN101570516A (en) * 2009-04-14 2009-11-04 重庆威尔德·浩瑞医药化工有限公司 Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline
WO2011112731A2 (en) * 2010-03-10 2011-09-15 Kalypsys, Inc. Heterocyclic inhibitors of histamine receptors for the treatment of disease
WO2012022707A1 (en) * 2010-08-18 2012-02-23 F. Hoffmann-La Roche Ag Substituted heteroaryl spiropyrrolidine mdm2 antagonists
CN105712940A (en) * 2016-02-26 2016-06-29 南京师范大学 Preparation method for Afatinib intermediate 6-nitryl-7-chlorol-4-quinazolinone
CN107573264A (en) * 2017-08-14 2018-01-12 贵州大学 A kind of preparation technology of the sulfonic acid chloride of 3 cyano group, 5 methoxybenzene 1
TW201900633A (en) * 2017-05-25 2019-01-01 美商亞瑞克西斯製藥公司 KRAS covalent inhibitor

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2342503A1 (en) * 1998-08-21 2000-03-02 Parker Hughes Institute Quinazoline derivatives
CN101570516A (en) * 2009-04-14 2009-11-04 重庆威尔德·浩瑞医药化工有限公司 Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline
WO2011112731A2 (en) * 2010-03-10 2011-09-15 Kalypsys, Inc. Heterocyclic inhibitors of histamine receptors for the treatment of disease
WO2012022707A1 (en) * 2010-08-18 2012-02-23 F. Hoffmann-La Roche Ag Substituted heteroaryl spiropyrrolidine mdm2 antagonists
CN105712940A (en) * 2016-02-26 2016-06-29 南京师范大学 Preparation method for Afatinib intermediate 6-nitryl-7-chlorol-4-quinazolinone
TW201900633A (en) * 2017-05-25 2019-01-01 美商亞瑞克西斯製藥公司 KRAS covalent inhibitor
CN107573264A (en) * 2017-08-14 2018-01-12 贵州大学 A kind of preparation technology of the sulfonic acid chloride of 3 cyano group, 5 methoxybenzene 1

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GOLDSTEIN, HENRI ETAL: "4,5-Dinitroanthranilic acid", 《HELVETICA CHIMICA ACTA 》 *
VERNER, ERIK ETAL: "Development of serine protease inhibitors displaying a multicentered short (<2.3 Å) hydrogen bond binding mode: Inhibitors of urokinase-type", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
YU, SHU ETAL: "Early and late stage process development for the manufacture of dacomitinib", 《ACS SYMPOSIUM SERIES》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113277986A (en) * 2021-05-31 2021-08-20 成都伊诺达博医药科技有限公司 Dacotinib impurity and preparation method thereof

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Patentee before: CHENGDU D-INNOVATION PHARMACEUTICAL CO.,LTD.