CN114276355A - Preparation method of ibrutinib - Google Patents
Preparation method of ibrutinib Download PDFInfo
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- CN114276355A CN114276355A CN202210092683.2A CN202210092683A CN114276355A CN 114276355 A CN114276355 A CN 114276355A CN 202210092683 A CN202210092683 A CN 202210092683A CN 114276355 A CN114276355 A CN 114276355A
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Abstract
The invention relates to a preparation method of ibrutinib, which comprises the steps of preparing an intermediate product compound II from a compound III, a compound IV, triphenylphosphine and an azo compound serving as raw materials in a microchannel reactor at the temperature of 20-50 ℃ for 20-200 s, and 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 intermediate product is used for preparing the 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 schemes are mostly used in the prior art (e.g., US2008108636a 1):
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 is removed), and amidation reaction is continuously carried out with 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 on the basis of 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 intermediate compound II is prepared by chemical reaction of the compound III and the compound IV, and the defects that in the prior art, the Boc group of a common intermediate is removed by acid (such as hydrochloric acid), the reaction product is easy to decompose, carbon dioxide gas is easy to generate, the product is relatively miscellaneous, the post-treatment process is complex, and the product yield and purity are low are overcome.
In order to better implement the invention, a microchannel reactor is adopted to carry out continuous flow type reaction when preparing the intermediate compound II, the materials staying in the microchannel reactor are few, the reaction materials are fully mixed, the reaction time is short, can accurately control the reaction time and the reaction temperature, avoid the generation of a large amount of byproducts caused by local overheating or prolonged reaction time, avoid the problems of long reaction time, more byproducts and overhigh reaction temperature in each reaction step in the prior art, the preparation method has the advantages of high requirements on equipment, low yield and purity and the like, and can be used under the coordination of other conditions, the method has the advantages of capability of accurately controlling the feeding proportion of reaction materials, great reduction of reaction time, high safety, low cost, simple post-treatment, high yield of the product compound II (over 97 percent), high purity of over 99 percent, and particular suitability 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 stock 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 purity of the target compound II, and the low reaction temperature is not favorable for smooth reaction, so that the yield and 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 present invention, when the microchannel reactor is used to prepare the compound II, the reaction temperature is 20 to 50 ℃, which may 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 embodiment, the reaction time is 110 s.
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 purposes of the present invention, the molar ratio of compound III to compound IV is 1:1 to 1.5, and may be, but is not limited to, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5, and in a preferred embodiment, the molar ratio of compound III to compound IV is 1: 1.2.
In the step (5), the molar ratio of the compound III to triphenylphosphine has a great influence on the yield and purity of the target product, the yield and purity are too low to facilitate the reaction, the yield and purity of the target compound II are low, and the raw material is easily excessive and the cost is high due to too high purity. For the purposes of the present invention, the molar ratio of compound III to triphenylphosphine is 1:1 to 1.5, and may be, but is not limited to, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5, and in a preferred embodiment, the molar ratio of compound III to compound IV is 1: 1.3.
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 may be, but is not limited to, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, and in a preferred embodiment, the molar ratio of compound III to compound IV is 1: 1.3.
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 for conveying the material A is 8-16 ml/min; the flow rate of the solution for conveying the material B is 10-20 ml/min; the flow rate of the solution for conveying the material C is 15-30 ml/min; the flow rate of the solution for conveying the 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 for 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 the compound II to 10% palladium on carbon is 1: 0.2-0.5, but not limited to 1:0.2, 1:0.3, 1:0.4 or 1:0.5, and in a preferred embodiment, the mass ratio of the compound II to 10% palladium on carbon is 1: 0.3.
Further, the time of the reduction reaction is 10 to 20 hours, but 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 the triethylamine and the acryloyl chloride needs to be controlled to control the yield and the purity of the target product compound I.
The mass ratio of the compound II to the triethylamine is 1: 0.5-1, but not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9 or 1:1, and preferably the mass ratio of the compound II to the triethylamine is 1: 0.9. The molar ratio of the compound II to the acryloyl chloride is 1: 1-2, but the compound II can be, but is not limited to, 1:1, 1:1.2, 1:1.3, 1:1.5, 1:01.8 or 1:2, and preferably the molar ratio of the compound II to the acryloyl chloride is 1: 1.5.
Further, the time of the amidation reaction is 2 to 6 hours, but 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 clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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 (38.3g, 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 (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: 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 110 s. After completion of the reaction, the obtained reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate: 1/1) to obtain compound II 78.09g, yield 99.3%, purity 99.5%.
(b) Synthesis of Compound I:
adding 250ml of methanol and the compound II (25g, 52.5mmol) prepared in the step (a) into a 500ml reaction bottle, stirring to dissolve completely, performing 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 completed, dissolving the obtained intermediate into 250ml of dichloromethane, adding 22.5g of triethylamine and acryloyl chloride (7g, 77.3mmol), and performing 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, 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 for further use.
(2) Preparation of material B solution: compound IV (47.3g, 247.5mmol) was added to dioxane, 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 (43.3g, 165mmol) was added to dioxane, diluted to 188ml, 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 blanket.
(4) Preparation of stock D solution: diisopropyl azodicarboxylate (33.4g, 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 kept under nitrogen blanket.
(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 16ml/min, setting the flow rate of the raw material tank B to be 20ml/min, setting the flow rate of the raw material tank C to be 30ml/min and the flow rate of the raw material tank D to be 24ml/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 50 ℃, and keeping the reaction time in a channel to be 20 s. After completion of the reaction, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate: 1/1) to obtain compound II 77.22g, yield 98.2%, purity 99.2%.
(b) Synthesis of Compound I:
adding 250ml of ethanol and the compound II (25g, 52.5mmol) prepared in the step (a) into a 500ml reaction bottle, stirring to dissolve completely, performing nitrogen replacement protection, adding 12.5g 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 completed, dissolving the obtained intermediate into 250ml of dichloromethane, adding 22.5g of triethylamine and acryloyl chloride (7g, 77.3mmol), and performing 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 (31.6g, 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, 247.5mmol) was added to dichloromethane, diluted to 188ml, 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.
(4) Preparation of stock D solution: di-tert-butyl azodicarboxylate (57g, 247.5mmol) was added to dichloromethane, 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 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 200 s. 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, 52.5mmol) prepared in the step (a) into a 500ml reaction bottle, stirring to completely dissolve, performing nitrogen replacement protection, adding 5g of 10% palladium carbon, wetting the 10% palladium carbon by water before adding, keeping the reaction material under hydrogen pressure for reduction reaction for 12 hours, concentrating the reaction liquid after the reaction is completed to obtain an intermediate, dissolving the obtained intermediate in 250ml of dichloromethane, adding 22.5g of triethylamine and acryloyl chloride (7g, 77.3mmol), and performing 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 20.77g of compound I, 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: compound IV (38.3g, 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 (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: 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 110 s. After completion of the reaction, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate: 1/1) to obtain compound II 62.6g, yield 79.6%, purity 96.8%.
Comparative example 2
(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 (38.3g, 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 blanket.
(4) Preparation of stock D solution: diethyl azodicarboxylate (26.1g, 150mmol) 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 110 s. After completion of the reaction, the resulting reaction mixture was filtered, concentrated, and purified by flash chromatography (pentane/ethyl acetate: 1/1) to obtain compound II 50.48g, yield 64.2%, purity 95.7%.
Comparative example 3
Synthesis of Compound II:
500ml of tetrahydrofuran and compound III (50g, 165mmol) were added to a reaction flask and stirred uniformly, and then triphenylphosphine (55.9g, 213mmol), compound IV (38.3g, 200mmol) and diethyl azodicarboxylate (37.1g, 213mmol) were added under nitrogen protection, and the reaction was stirred at 35 ℃ for 12 hours. After completion of the reaction, the obtained 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 (25g, 52.5mmol) prepared in the step (a) of example 1 were added to 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, 77.3mmol) 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 18.64g of compound I, ibrutinib, in 80.6% yield and 97.2% purity.
Comparative example 5
Synthesis of Compound I:
250ml of methanol and the compound II (25g, 52.5mmol) prepared in the step (a) of example 1 were added to 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 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, 77.3mmol) 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 (25g, 52.5mmol) prepared in the step (a) in example 1 were added to 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 reaction was completed, the reaction solution was concentrated to obtain an intermediate, the intermediate was dissolved in 250ml of dichloromethane, and 5g of triethylamine and acryloyl chloride (7g, 77.3mmol) 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 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, but 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 (10)
1. A preparation method of ibrutinib is characterized in that the synthetic route is as follows,
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.
2. The process for preparing ibrutinib according to claim 1, wherein 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 stock 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.
3. The preparation method of ibrutinib according to claim 2, wherein in step (5), the reaction temperature is 30-40 ℃, preferably 35 ℃.
4. The preparation method of ibrutinib according to claim 2, wherein in step (5), the reaction time is 40-160 s, preferably 110 s.
5. The preparation method of ibrutinib according to claim 2, wherein in step (5), the molar ratio of compound III to compound IV is 1: 1-1.5; the molar ratio of the compound III to triphenylphosphine is 1: 1-1.5; 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.
6. The process for preparing ibrutinib according to claim 2, wherein in step (1), (2), (3) or (4), the solvent is tetrahydrofuran, dichloromethane, toluene, dioxane or diethyl ether; tetrahydrofuran, dichloromethane or dioxane are preferred.
7. The preparation method of ibrutinib according to claim 2, 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 for conveying the material B is 10-20 ml/min; the flow rate of the solution for conveying the material C is 15-30 ml/min; the flow rate of the solution for conveying the material D is 12-24 ml/min.
8. The preparation method of ibrutinib according to claim 1, wherein in step (b), the palladium carbon is 10% palladium carbon, and the mass ratio of the compound II to the 10% palladium carbon is 1: 0.2-0.5; preferably 1: 0.3.
9. The preparation method of ibrutinib according to claim 1, wherein in step (b), the time of the reduction reaction is 10-20 hours, preferably 12 hours; the mass ratio of the compound II to triethylamine is 1: 0.5-1, preferably 1: 0.9; the molar ratio of the compound II to acryloyl chloride is 1: 1-2, preferably 1: 1.5; the time for the amidation reaction is 2 to 6 hours, preferably 3 hours.
10. 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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