CN114276355B - Preparation method of ibrutinib - Google Patents
Preparation method of ibrutinib Download PDFInfo
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- CN114276355B CN114276355B CN202210092683.2A CN202210092683A CN114276355B CN 114276355 B CN114276355 B CN 114276355B CN 202210092683 A CN202210092683 A CN 202210092683A CN 114276355 B CN114276355 B CN 114276355B
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Abstract
The invention relates to a preparation method of ibrutinib, which is characterized in that a compound III, a compound IV, triphenylphosphine and an azo compound are used as raw materials in a micro-channel reactor to prepare an intermediate product under the conditions of the temperature of 20-50 ℃ and the time of 20-200 sAnd carrying out reduction and amidation reactions on the obtained compound II to obtain a target product compound I, wherein the specific synthetic route is as follows. The amount of reaction materials and the reaction temperature and time are strictly controlled in the reaction process, the time required in the whole reaction process is very short, the reaction condition is mild, the content of byproducts is low, the post-treatment is simple, the yield of an intermediate product compound II is high, the yield reaches more than 97 percent, and the purity reaches more than 99 percent; when the obtained intermediate product is used for preparing a target product ibrutinib, the yield and the purity of the target product can be greatly improved, the yield reaches more than 89%, and the purity reaches more than 99%.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of ibrutinib.
Background
Ibrutinib (irutinib, trade name Imbruvica) is the first oral bruton tyrosine kinase inhibitor co-developed by pharmaceuticals and yang pharmaceuticals, a firm grand son company. By 1 month 2015, FDA approved it for the treatment of 4B-cell malignancies, and extensive studies on other B-cell lymphoma indications are still desirable. Ibrutinib exerts its therapeutic effects through an irreversible inhibition mechanism on bruton's tyrosine kinase, which is considered to be the most important breakthrough for the treatment of mantle cell lymphoma to date, and is expected to change chronic lymphocytic leukemia from a death decision to a controllable chronic disease.
The Chinese cultural name of ibrutinib: 1- [3 (R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one having the chemical structure:
currently, the following reaction scheme is mostly adopted in the prior art (e.g., US2008108636 A1):
when the synthesis route is adopted, in the process of a mitsunobu reaction, 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine (compound 2) and 3-hydroxypiperidine-1-tert-butyl formate are subjected to coupling reaction to obtain a compound 3, then the compound 3 is deprotected (namely Boc group removal), and amidation reaction is carried out on the compound 3 and acryloyl chloride to prepare a compound 4, namely ibrutinib. The Boc group in the compound 3 is removed by acid (for example, hydrochloric acid) in the reaction process, which easily causes decomposition of reactants, generates carbon dioxide gas, has a relatively complex product, and has relatively complex post-treatment, increased process cost, relatively low product yield and low purity.
Therefore, it is one of the research hotspots of those skilled in the art to find a preparation method of ibrutinib with high yield and purity.
Disclosure of Invention
The invention aims to provide a preparation method of ibrutinib based on the prior art.
The technical scheme of the invention is as follows:
a preparation method of ibrutinib comprises the following steps,
the method specifically comprises the following steps:
(a) Carrying out chemical reaction on the compound III and the compound IV in a continuous flow microchannel reactor to prepare a compound II, controlling the reaction temperature to be 20-50 ℃ and the reaction time to be 20-200 s;
(b) Under the protection of nitrogen, uniformly mixing the compound II obtained in the step (a), an organic solvent and palladium-carbon, introducing hydrogen to carry out reduction reaction, and concentrating a reaction solution after the reaction is finished to obtain an intermediate; and dissolving the obtained intermediate in an organic solvent, adding triethylamine and acryloyl chloride to perform amidation reaction, washing and drying to prepare the compound I.
In the preparation process of ibrutinib, the compound III and the compound IV are adopted to carry out chemical reaction to prepare the intermediate compound II, so that the defects that the decomposition of a reaction product is easily caused, carbon dioxide gas is easily generated, the product is relatively complex, the post-treatment process is complex, and the yield and the purity of the product are low because the Boc group is removed by adopting acid (for example, hydrochloric acid) in a common intermediate in the prior art are overcome.
In order to better implement the invention, when the intermediate compound II is prepared, a microchannel reactor is adopted for continuous flow type reaction, the materials staying in the microchannel reactor are few, all the reaction materials are fully mixed, the reaction time is short, the reaction time and the reaction temperature can be accurately controlled, the generation of a large amount of byproducts caused by local overheating or prolonged reaction time is avoided, the problems of long reaction time, more byproducts, overhigh reaction temperature, high requirement on equipment, low yield and purity and the like in each reaction step in the prior art are avoided, and under the coordination of other conditions, the preparation method can accurately control the feeding proportion of the reaction materials, greatly shorten the reaction time, has high safety, low cost and simple post-treatment, ensures that the yield of the product compound II is more than 97 percent and the purity is more than 99 percent, and is particularly suitable for industrial large-scale production.
In a preferred embodiment, step (a) comprises the steps of:
(1) Preparation of material a solution: mixing the compound III with a solvent, and uniformly stirring for later use;
(2) Preparation of material B solution: mixing the compound IV with a solvent, and uniformly stirring for later use;
(3) Preparation of stock C solution: mixing triphenylphosphine and a solvent, and uniformly stirring for later use;
(4) Preparation of material D solution: mixing the azo compound with a solvent, and uniformly stirring for later use;
(5) Respectively pumping the material solution A, the material solution B, the material solution C and the material solution D into a microchannel reactor, uniformly mixing, and carrying out chemical reaction at the reaction temperature of 20-50 ℃ for 20-200 s; after the reaction is finished, filtering and concentrating to obtain a compound II.
In the step (5), when the compound II is prepared by using the microchannel reactor, the reaction temperature and the reaction time need to be controlled to improve the yield and the purity of the target product. The reaction temperature has great influence on the yield and the purity of the target compound II, and the reaction temperature is too low to be beneficial to the smooth reaction, so that the yield and the purity of the target compound II are low; too high reaction temperature easily causes a large amount of byproducts in the reaction process, and also reduces the yield and purity of the compound II. For the purposes of the present invention, when the compound II is prepared using a microchannel reactor, the reaction temperature is 20 to 50 ℃ and can be, but is not limited to, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃ or 50 ℃, and in a preferred embodiment, the reaction temperature is 35 ℃.
When the compound II is prepared by using a microchannel reactor, the reaction time is controlled to be 20-200 s, and can be but is not limited to 20s, 30s, 40s, 50s, 60s, 70s, 80s, 90s, 100s, 110s, 120s, 130s, 140s, 150s, 160s, 170s, 180s, 190s or 200s, and in a preferred scheme, the reaction time is 110s.
In the step (5), when the compound II is prepared by adopting the microchannel reactor, the molar ratio of the compound III to the compound IV is controlled by strictly controlling the flow rates of the material A and the material B, so that better yield can be obtained, and the generation of byproducts is reduced. The molar ratio of the compound III to the compound IV has great influence on the yield and purity of the target product, too low is not favorable for smooth reaction, and the yield and purity of the target compound II are low, too high easily causes excessive raw materials and high cost. For the present invention, the molar ratio of compound III to compound IV is 1:1-1.5, which can be, but is not limited to 1:1, 1.1, 1.2, 1.3, 1.4 or 1.
In the step (5), the molar ratio of the compound III to the triphenylphosphine greatly affects the yield and the purity of a target product, the yield and the purity are too low to be favorable for the reaction, the yield and the purity of the target compound II are low, and the raw materials are easily excessive and high in cost due to too high content. For the purposes of the present invention, the molar ratio of compound III to triphenylphosphine is 1:1 to 1.5, and can be, but is not limited to 1:1, 1.1, 1.2, 1.3, 1.4 or 1.5.
In step (5), the azo compound may be, but is not limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate. The molar ratio of the compound III to the azo compound has great influence on the yield and purity of the target product, too low is not favorable for smooth reaction, and the yield and purity of the target compound II are low, too high easily causes excessive raw materials and high cost. For the purposes of the present invention, the molar ratio of compound III to azo compound is 1:1 to 1.5, and can be, but is not limited to 1:1, 1.1, 1.2, 1.3, 1.4 or 1.5.
For the present invention, compound III, compound IV, triphenylphosphine and azo compounds are mixed with a solvent, respectively, to prepare a material a solution, a material B solution, a material C solution and a material D solution, wherein the selected solvent is tetrahydrofuran, dichloromethane, toluene, dioxane or diethyl ether. In a preferred embodiment, the solvent selected is tetrahydrofuran, dichloromethane or dioxane.
Further, when the microchannel reaction is carried out in the step (5), the flow rate of the solution of the conveyed material A is 8-16 ml/min; the flow rate of the solution of the conveyed material B is 10 to 20ml/min; the flow rate of the solution of the conveyed material C is 15-30 ml/min; the flow rate of the solution of the conveyed material D is 12-24 ml/min.
In the step (b), under the protection of nitrogen, the compound II obtained in the step (a), an organic solvent and palladium-carbon are uniformly mixed, hydrogen is introduced to carry out reduction reaction, and after the reaction is finished, the reaction solution is concentrated to obtain an intermediate. In the preparation of the intermediate, the catalyst is palladium on carbon, preferably 10% palladium on carbon. In the process of reduction reaction, the yield and purity of the product intermediate can be improved by controlling the addition amount of 10 percent palladium carbon. In one embodiment, the mass ratio of compound II to 10% palladium on carbon is 1.2 to 0.5, and can be, but is not limited to, 1.
Further, the time of the reduction reaction is 10 to 20 hours, and may be, but is not limited to, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, or 20 hours. In a preferred embodiment, the time for the reduction reaction is 12 hours.
For the invention, in the step (b), the obtained intermediate is dissolved in an organic solvent, triethylamine and acryloyl chloride are added for amidation reaction, and the compound I is prepared by washing and drying. During the reaction, the molar ratio of the compound II to triethylamine and acryloyl chloride needs to be controlled to control the yield and purity of the target product compound I.
Wherein, the mass ratio of the compound II to the triethylamine is 1.5 to 1, and can be, but is not limited to, 1. The molar ratio of compound II to acryloyl chloride is 1:1-2, and can be, but is not limited to 1:1, 1.2, 1.3, 1.5, 1.8 or 1:2, preferably, the molar ratio of compound II to acryloyl chloride is 1.5.
Further, the time of the amidation reaction is 2 to 6 hours, and may be, but is not limited to, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours. In a preferred embodiment, the time for the amidation reaction is 3 hours.
Further, in the step (b), the selected organic solvent is one or more of methanol, ethanol, dichloromethane or ethyl acetate
By adopting the technical scheme of the invention, the advantages are as follows:
the method utilizes the continuous flow microchannel reactor to synthesize the intermediate product, strictly controls the consumption of reaction materials and the reaction temperature and time in the reaction process, has extremely short time required by the whole reaction process and mild reaction conditions, effectively avoids byproducts generated by overlong reaction time or overhigh reaction temperature, has simple post-treatment, high yield of the intermediate product, high purity and purity of more than 97 percent; the obtained product is used for preparing a target product ibrutinib, so that the yield and the purity of the target product can be greatly improved, the yield reaches more than 89%, and the purity reaches more than 99%.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
(a) Synthesis of Compound II:
(1) Preparation of material a solution: compound III (50g, 165mmol) was added to tetrahydrofuran, diluted to 100ml, stirred well, placed in feed tank A (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen blanket.
(2) Preparation of material B solution: compound IV (38.3 g, 200mmol) was added to tetrahydrofuran, diluted to 125ml, stirred well, placed in feed tank B (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen for further use.
(3) Preparation of stock C solution: triphenylphosphine (55.9g, 213mmol) was added to tetrahydrofuran, diluted to 200ml, stirred well, placed in feed tank C (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve), and kept under nitrogen for further use.
(4) Preparation of material D solution: diethyl azodicarboxylate (37.1g, 213mmol) was added to tetrahydrofuran, diluted to 150ml, stirred well, placed in feed tank D (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen for further use.
(5) Opening a valve at the bottom of the raw material tank, respectively conveying a material solution A in the raw material tank A, a material solution B in the raw material tank B, a material solution C in the raw material tank C and a material solution D in the raw material tank D through a feeding pump, setting the flow rate of the raw material tank A by a counting pump to be 12ml/min, setting the flow rate of the raw material tank B to be 15ml/min, setting the flow rate of the raw material tank C to be 24ml/min and the flow rate of the raw material tank D to be 18ml/min, then preheating the material solution A, the material solution B, the material solution C and the material solution D, setting the temperature of a heat exchanger to be 35 ℃, and keeping the reaction time in a channel to be 110s. After the reaction was completed, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate = 1/1) to obtain 78.09g of compound II, yield 99.3%, purity 99.5%.
(b) Synthesis of Compound I:
adding 250ml of methanol and the compound II (25g, 52.5 mmol) prepared in the step (a) into a 500ml reaction bottle, stirring to completely dissolve, carrying out nitrogen replacement protection, adding 7.5g of 10% palladium carbon, wetting the 10% palladium carbon by using water before adding, keeping the reaction material under hydrogen pressure for reduction reaction for 12 hours, concentrating the reaction liquid to obtain an intermediate after the reaction is finished, dissolving the obtained intermediate into 250ml of dichloromethane, adding 22.5g of triethylamine and acryloyl chloride (7 g,77.3 mmol), and carrying out amidation reaction for 3 hours. After completion of the reaction, the resultant mixture was washed with 300ml of a 5% aqueous citric acid solution and then with 300ml of a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 21.37g of compound I, i.e. ibrutinib, in 92.4% yield and 99.4% purity.
Example 2
(a) Synthesis of Compound II:
(1) Preparation of material a solution: compound III (50g, 165mmol) was added to dioxane, diluted to 100ml, stirred well, placed in feed tank A (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen blanket.
(2) Preparation of material B solution: adding the compound IV (47.3 g, 247.5mmol) into dioxane, diluting to 125ml, stirring uniformly, placing into a feed tank B (the bottom of which is connected with a corresponding feed pipeline of a microchannel reactor through a valve), and keeping under nitrogen protection for later use.
(3) Preparation of stock C solution: triphenylphosphine (43.3g, 165mmol) was added to dioxane, diluted to 188ml, stirred well, placed in feed tank C (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen blanket.
(4) Preparation of stock D solution: diisopropyl azodicarboxylate (33.4 g, 165mmol) was added to dioxane, diluted to 150ml, stirred well, placed in feed tank D (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve), and protected with nitrogen for further use.
(5) The valve at the bottom of the raw material tank is opened, the material A solution in the raw material tank A, the material B solution in the raw material tank B, the material C solution in the raw material tank C and the material D solution in the raw material tank D are respectively conveyed through the feed pump, the flow rate of the raw material tank A is set to be 16ml/min through the counter pump, the flow rate of the raw material tank B is 20ml/min, the flow rate of the raw material tank C is 30ml/min, the flow rate of the raw material tank D is 24ml/min, then the material A solution, the material B solution, the material C solution and the material D solution are preheated, the temperature of the heat exchanger is set to be 50 ℃, and the reaction time in a channel is 20s. After completion of the reaction, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate = 1/1) to obtain 77.22g of compound II, yield 98.2%, purity 99.2%.
(b) Synthesis of Compound I:
adding 250ml of ethanol and the compound II (25g, 52.5 mmol) prepared in the step (a) into a 500ml reaction bottle, stirring to completely dissolve, carrying out nitrogen replacement protection, adding 12.5g of 10% palladium carbon, wetting the 10% palladium carbon by using water before adding, keeping a reaction material under hydrogen pressure for reduction reaction for 12 hours, concentrating a reaction liquid to obtain an intermediate after the reaction is finished, dissolving the obtained intermediate into 250ml of dichloromethane, adding 22.5g of triethylamine and acryloyl chloride (7 g,77.3 mmol), and carrying out amidation reaction for 3 hours. After the reaction was completed, the resultant mixture was washed with 300ml of a 5% aqueous citric acid solution and then with 300ml of a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 20.72g of compound I, i.e. ibrutinib, in 89.6% yield and 99.1% purity.
Example 3
(a) Synthesis of Compound II:
(1) Preparation of material a solution: compound III (50g, 165mmol) was added to methylene chloride, diluted to 100ml, stirred well, placed in feed tank A (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen blanket.
(2) Preparation of material B solution: compound IV (31.6 g, 165mmol) was added to methylene chloride, diluted to 125ml, stirred well, placed in feed tank B (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen blanket.
(3) Preparation of stock C solution: triphenylphosphine (64.9g, 247.5 mmol) was added to dichloromethane, diluted to 188ml, stirred well, placed in feed tank C (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve), and kept under nitrogen for further use.
(4) Preparation of stock D solution: di-tert-butyl azodicarboxylate (57g, 247.5 mmol) is added into dichloromethane, diluted to 150ml, stirred uniformly, placed in a stock tank D (the bottom of which is connected with a corresponding feed pipeline of a microchannel reactor through a valve), and protected by nitrogen for standby.
(5) Opening a valve at the bottom of the raw material tank, respectively conveying a material solution A in the raw material tank A, a material solution B in the raw material tank B, a material solution C in the raw material tank C and a material solution D in the raw material tank D through a feeding pump, setting the flow rate of the raw material tank A to be 8ml/min through a counting pump, setting the flow rate of the raw material tank B to be 10ml/min, setting the flow rate of the raw material tank C to be 15ml/min, setting the flow rate of the raw material tank D to be 12ml/min, then preheating the material solution A, the material solution B, the material solution C and the material solution D, setting the temperature of a heat exchanger to be 20 ℃, and keeping the reaction time in a channel to be 200s. After completion of the reaction, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate = 1/1) to obtain 76.67g of compound II in 97.5% yield and 99.4% purity.
(b) Synthesis of Compound I:
adding 250ml of dichloromethane and the compound II (25g, 52.5 mmol) prepared in the step (a) into a 500ml reaction bottle, stirring to completely dissolve, carrying out nitrogen replacement protection, adding 5g of 10% palladium carbon, wetting the 10% palladium carbon by using water before adding, keeping the reaction material under hydrogen pressure for reduction reaction for 12 hours, concentrating the reaction liquid to obtain an intermediate after the reaction is finished, dissolving the obtained intermediate into 250ml of dichloromethane, adding 22.5g of triethylamine and acryloyl chloride (7 g,77.3 mmol), and carrying out amidation reaction for 3 hours. After the reaction was completed, the resultant mixture was washed with 300ml of a 5% by mass aqueous citric acid solution and then with 300ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 20.77g of compound I, i.e. ibrutinib, in 89.8% yield and 99.2% purity.
Comparative example 1
(a) Synthesis of Compound II:
(1) Preparation of material a solution: compound III (50g, 165mmol) was added to tetrahydrofuran, diluted to 100ml, stirred well, placed in feed tank A (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen blanket.
(2) Preparation of material B solution: adding the compound IV (38.3 g, 200mmol) into tetrahydrofuran, diluting to 125ml, stirring well, placing into a feed tank B (the bottom of which is connected with a corresponding feed pipeline of the microchannel reactor through a valve), and using nitrogen for protection.
(3) Preparation of stock C solution: triphenylphosphine (55.9g, 213mmol) was added to tetrahydrofuran, diluted to 200ml, stirred well, placed in feed tank C (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve), and kept under nitrogen for further use.
(4) Preparation of material D solution: diethyl azodicarboxylate (37.1g, 213mmol) was added to tetrahydrofuran, diluted to 150ml, stirred well, placed in feed tank D (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen for further use.
(5) Opening a valve at the bottom of the raw material tank, respectively conveying a material solution A in the raw material tank A, a material solution B in the raw material tank B, a material solution C in the raw material tank C and a material solution D in the raw material tank D through a feeding pump, setting the flow rate of the raw material tank A by a counting pump to be 12ml/min, setting the flow rate of the raw material tank B to be 15ml/min, setting the flow rate of the raw material tank C to be 24ml/min and the flow rate of the raw material tank D to be 18ml/min, then preheating the material solution A, the material solution B, the material solution C and the material solution D, setting the temperature of a heat exchanger to be 10 ℃, and keeping the reaction time in a channel to be 110s. After completion of the reaction, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate = 1/1) to obtain 62.6g of compound II, yield 79.6%, purity 96.8%.
Comparative example 2
(a) Synthesis of Compound II:
(1) Preparation of material a solution: compound III (50g, 165mmol) is added to tetrahydrofuran, diluted to 100ml, stirred well, placed in feed tank A (the bottom of which is connected to the corresponding feed line of the microchannel reactor via a valve) and protected with nitrogen until needed.
(2) Preparation of material B solution: compound IV (38.3 g, 200mmol) was added to tetrahydrofuran, diluted to 125ml, stirred well, placed in feed tank B (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen for further use.
(3) Preparation of stock C solution: triphenylphosphine (39.3g, 150mmol) was added to tetrahydrofuran, diluted to 200ml, stirred well, placed in feed tank C (bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen for further use.
(4) Preparation of material D solution: diethyl azodicarboxylate (26.1g, 150mmol) was added to tetrahydrofuran, diluted to 150ml, stirred well, placed in feed tank D (bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and kept under nitrogen for further use.
(5) Opening a valve at the bottom of the raw material tank, respectively conveying a material solution A in the raw material tank A, a material solution B in the raw material tank B, a material solution C in the raw material tank C and a material solution D in the raw material tank D through a feeding pump, setting the flow rate of the raw material tank A by a counting pump to be 12ml/min, setting the flow rate of the raw material tank B to be 15ml/min, setting the flow rate of the raw material tank C to be 24ml/min and the flow rate of the raw material tank D to be 18ml/min, then preheating the material solution A, the material solution B, the material solution C and the material solution D, setting the temperature of a heat exchanger to be 10 ℃, and keeping the reaction time in a channel to be 110s. After completion of the reaction, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate = 1/1) to obtain 50.48g of compound II, 64.2% yield, and 95.7% purity.
Comparative example 3
Synthesis of Compound II:
500ml of tetrahydrofuran and compound III (50g, 165mmol) were charged into a reaction flask and stirred uniformly, and triphenylphosphine (55.9 g, 213mmol), compound IV (38.3 g, 200mmol) and diethyl azodicarboxylate (37.1 g, 213mmol) were further added under nitrogen, and the reaction was stirred at 35 ℃ for 12 hours. After the reaction was completed, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate = 1/1) to obtain compound II 71.95g, yield 91.5%, purity 99.2%.
Comparative example 4
Synthesis of Compound I:
250ml of methanol and the compound II (25 g,52.5 mmol) prepared in the step (a) of example 1 were charged into a 500ml reaction flask, stirred to be completely dissolved, protected by nitrogen substitution, 2.5g of 10% palladium on carbon was added, the 10% palladium on carbon was wetted with water before the addition, the reaction mass was kept under hydrogen pressure for reduction reaction for 12 hours, after the reaction was completed, the reaction solution was concentrated to obtain an intermediate, the obtained intermediate was dissolved in 250ml of dichloromethane, and 22.5g of triethylamine and acryloyl chloride (7g, 77.3 mmol) were added for amidation reaction for 3 hours. After completion of the reaction, the resultant mixture was washed with 300ml of a 5% aqueous citric acid solution and then with 300ml of a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 18.64g of compound I, i.e. ibrutinib, in 80.6% yield and 97.2% purity.
Comparative example 5
Synthesis of Compound I:
250ml of methanol and the compound II (25 g,52.5 mmol) prepared in the step (a) of example 1 were charged into a 500ml reaction flask, stirred to be completely dissolved, protected by nitrogen substitution, 7.5g of 10% palladium on carbon was added, the 10% palladium on carbon was wetted with water before the addition, the reaction mass was kept under hydrogen pressure for reduction reaction for 8 hours, after the completion of the reaction, the reaction solution was concentrated to obtain an intermediate, the obtained intermediate was dissolved in 250ml of dichloromethane, and 22.5g of triethylamine and acryloyl chloride (7 g,77.3 mmol) were added to conduct amidation reaction for 3 hours. After completion of the reaction, the resultant mixture was washed with 300ml of a 5% aqueous citric acid solution and then with 300ml of a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 19.63g of compound I, i.e. ibrutinib, in 84.9% yield and 97.2% purity.
Comparative example 6
Synthesis of Compound I:
250ml of methanol and the compound II (25 g,52.5 mmol) prepared in the step (a) of example 1 were charged into a 500ml reaction flask, stirred to be completely dissolved, protected by nitrogen substitution, 7.5g of 10% palladium on carbon was added, the 10% palladium on carbon was wetted with water before the addition, the reaction mass was kept under hydrogen pressure for reduction reaction for 12 hours, after the completion of the reaction, the reaction solution was concentrated to obtain an intermediate, the obtained intermediate was dissolved in 250ml of dichloromethane, and 5g of triethylamine and acryloyl chloride (7g, 77.3mmol) were added for amidation reaction for 3 hours. After completion of the reaction, the resultant mixture was washed with 300ml of a 5% aqueous citric acid solution and then with 300ml of a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 17.67g of compound I, ibrutinib, in 76.4% yield and 96.7% purity.
The above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (13)
1. A preparation method of ibrutinib is characterized in that the synthetic route is as follows,
the method comprises the following steps:
(a) The compound III and the compound IV are subjected to chemical reaction in a continuous flow microchannel reactor to prepare the compound II, and the specific steps are as follows:
(1) Preparation of material a solution: mixing the compound III with a solvent, and uniformly stirring for later use;
(2) Preparation of material B solution: mixing the compound IV with a solvent, and uniformly stirring for later use;
(3) Preparation of stock C solution: mixing triphenylphosphine and a solvent, and uniformly stirring for later use; the molar ratio of the compound III to the triphenylphosphine is 1:1-1.5;
(4) Preparation of material D solution: mixing the azo compound and a solvent, and uniformly stirring for later use; the molar ratio of the compound III to the azo compound is 1:1-1.5; the azo compound is diethyl azodicarboxylate, diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate;
(5) Respectively pumping the material solution A, the material solution B, the material solution C and the material solution D into a microchannel reactor, uniformly mixing, and carrying out chemical reaction at the reaction temperature of 20-50 ℃ for 20-200 s; after the reaction is finished, filtering and concentrating to obtain a compound II;
(b) Under the protection of nitrogen, uniformly mixing the compound II obtained in the step (a), an organic solvent and palladium-carbon, introducing hydrogen to carry out reduction reaction, and concentrating a reaction solution after the reaction is finished to obtain an intermediate; dissolving the obtained intermediate in an organic solvent, adding triethylamine and acryloyl chloride to perform amidation reaction, washing and drying to prepare a compound I;
wherein the palladium carbon is 10% palladium carbon, and the mass ratio of the compound II to the 10% palladium carbon is 1; the time of the reduction reaction is 10 to 20 hours; the mass ratio of the compound II to the triethylamine is 1.5-1.
2. The process for preparing ibrutinib according to claim 1, wherein in step (5), the reaction temperature is 30-40 ℃.
3. The process for preparing ibrutinib according to claim 2, wherein in step (5) the reaction temperature is 35 ℃.
4. The process for preparing ibrutinib according to claim 1, wherein in step (5), the reaction time is 40-160 s.
5. The process for preparing ibrutinib according to claim 4, wherein in step (5), the reaction time is 110s.
6. The process for preparing ibrutinib according to claim 1, wherein in step (5), the molar ratio of compound III to compound IV is 1:1-1.5.
7. The process for preparing ibrutinib according to claim 1, wherein in step (1), (2), (3) or (4), the solvent is tetrahydrofuran, dichloromethane, toluene, dioxane or diethyl ether.
8. The process for preparing ibrutinib according to claim 7, wherein in step (1), (2), (3) or (4), the solvent is tetrahydrofuran, dichloromethane or dioxane.
9. The preparation method of ibrutinib according to claim 1, wherein in step (5), the flow rate of the solution of the conveying material A is 8-16 ml/min; the flow rate of the solution of the conveyed material B is 10 to 20ml/min; the flow rate of the solution of the conveyed material C is 15-30 ml/min; the flow rate of the solution of the conveyed material D is 12-24 ml/min.
10. The process for preparing ibrutinib according to claim 1, wherein in step (b), the mass ratio of compound II to 10% palladium on carbon is 1.
11. The process for preparing ibrutinib according to claim 1, wherein in step (b) the reduction reaction is carried out for 12 hours; the mass ratio of the compound II to triethylamine is 1; the molar ratio of the compound II to the acryloyl chloride is 1:1-2; the time of the amidation reaction is 2 to 6 hours.
12. The process for preparing ibrutinib according to claim 11, wherein in step (b) the molar ratio of compound II to acryloyl chloride is 1.5; the time of the amidation reaction was 3 hours.
13. The preparation method of ibrutinib according to claim 1, wherein in step (b), the organic solvent is one or more of methanol, ethanol, dichloromethane or ethyl acetate.
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