CN113200987A - Preparation method of ibrutinib - Google Patents
Preparation method of ibrutinib Download PDFInfo
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- CN113200987A CN113200987A CN202110478246.XA CN202110478246A CN113200987A CN 113200987 A CN113200987 A CN 113200987A CN 202110478246 A CN202110478246 A CN 202110478246A CN 113200987 A CN113200987 A CN 113200987A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a preparation method of ibrutinib and an intermediate thereof, belonging to the field of pharmaceutical chemistry. According to the preparation method, the Ibutotinib can be obtained by taking low-cost logistics as a starting material and carrying out condensation, substitution and suzuki reaction; the method has the advantages of low cost, no use of light delay reaction, high yield, good selectivity, short route, less generation of three wastes, and suitability for industrial scale-up production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and particularly relates to a preparation method of ibrutinib.
Background
Ibrutinib (Ibrutinib), an oral Bruton Tyrosine Kinase (BTK) inhibitor, first marketed in the united states 11 months 2013 for the treatment of Mantle Cell Lymphoma (MCL) that has received prior treatment, recently also approved in succession for the treatment of chronic lymphocytic leukemia that has received prior treatment and Chronic Lymphocytic Leukemia (CLL) carrying a del17p deletion mutation; the chemical structural formula is shown as the following formula G:
at present, a large number of documents report the synthesis technology of the medicine, the related synthesis routes are more, and the purity and the yield of the obtained product are not high.
WO2014022390 reports that 4-amino pyrazolo [3,4-d ] pyrimidine is used as a starting material, an intermediate 3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-4-amine is prepared through iodination, then is sequentially coupled with 4-phenoxyphenylboronic acid through suzuki reaction, is condensed with chiral alcohol through mitsunobu reaction, is subjected to Boc removal protection by hydrochloric acid, forms salt, and finally is subjected to acrylation to obtain ibutinib. The Suzuki reaction of the route uses a catalyst of tetratriphenylphosphine palladium with high dosage, the relative feeding amount of the catalyst is 0.2 equivalent, and the reaction time is up to 24 hours; the mitsunobu reaction step time is long, the yield is low (38%), the total yield of the route is only 9.3%, and the mitsunobu reaction is not suitable for industrialization due to the need of chromatographic purification.
Many reports on preparation of ibrutinib in the prior art are provided, for example, U.S. Pat. nos. US20110039190, US20100254905, US20090050897, US20080058528, US20080108636 and the like, and the methods take 4-phenoxybenzoic acid as a raw material, and gradually add up functional groups through reactions such as acylation, condensation, methyl oxidation, pyrazole cyclization, pyrimidine cyclization, N-alkylation, deprotection, acrylation and the like, so as to finally synthesize a target product. The routes have the defects of long and complicated steps, the used reagents of trimethylsilyldiazomethane and triphenylphosphine are harmful to human and environment, the industrial production is not facilitated, the chiral center is introduced through the mitsunobu reaction, and the optical purity of the product is not good.
Therefore, research on a preparation method of ibrutinib and an intermediate thereof is still needed to obtain a preparation method which is simple and convenient to operate, easy to implement, high in yield, high in purity, low in cost, environment-friendly and suitable for industrial scale-up production.
Disclosure of Invention
Aiming at the technical problems of long reaction route, low yield, poor selectivity caused by a mitsunobu reaction, more generated three wastes and environmental pollution of the preparation method of the ibrutinib and the intermediate thereof, the invention provides the preparation method of the ibrutinib and the intermediate thereof on the one hand, and the preparation method has the characteristics of mild reaction conditions, low cost, high yield, good optical purity, less generated three wastes and suitability for industrial amplification. In another aspect of the invention, the new intermediate compound C of ibrutinib and the application thereof in preparing ibrutinib are provided.
The invention provides a preparation method of ibrutinib and an intermediate thereof. An ibutinib intermediate, designated compound C, having the structure shown below:
the preparation method provided by the invention can be used for obtaining a compound C by performing cyclization reaction on a compound A and a compound B, obtaining a compound D by performing condensation reaction on the compound C and formamide, obtaining a compound E by performing substitution reaction on the compound D, obtaining a compound F by performing substitution reaction on the compound E and a compound (01), and obtaining a compound G (ibutinib) by performing Suzuki reaction on the compound F and a compound (02); the specific reaction route is as follows:
in one aspect, the present invention provides a process for the preparation of compound C, comprising: the compound A and the compound B are subjected to condensation reaction in a reaction solvent at the reaction temperature to prepare a compound C,
the reaction solvent is selected from at least one of ethanol, methanol or isopropanol. In some embodiments, the reaction solvent is ethanol, which facilitates the formation and obtaining of the target product.
The molar ratio of the compound B to the compound A can be 1:1.0-1: 3.0. In some embodiments, the molar ratio of compound B to compound a is from 1:1.2 to 1: 2.0.
The reaction temperature of the condensation reaction may be 60 ℃ to 100 ℃. In some embodiments, the condensation reaction has a reaction temperature of 70 ℃ to 90 ℃; or the reaction temperature of the condensation reaction is 78-85 ℃.
The reaction time of the condensation reaction can be 30min-36 h. In some embodiments, the reaction time for the condensation reaction is from 3h to 24 h; or the reaction time of the condensation reaction is 6h-12 h.
In the preparation method of the compound C, a base can be further added, and the base is at least one of triethylamine or N, N-diisopropylethylamine. In some embodiments, the base is triethylamine, which facilitates the reaction.
The preparation method of the compound C optionally carries out post-treatment after the reaction is completed. In some embodiments, the method of preparation of compound C, the post-treatment comprises: stopping the reaction, removing the solvent, adding water, filtering, and drying a filter cake in vacuum to obtain the compound C.
In some embodiments, the method of preparation of compound C, the post-treatment comprises: filtering to obtain a filter cake, and vacuum drying at 60-100 ℃ for 12-24 h.
In some embodiments, a method of making compound C comprises: and (3) reacting the compound A with the compound B in ethanol at 78-85 ℃, refluxing, removing the solvent after the reaction is finished, adding water, filtering, and drying a filter cake in vacuum to obtain a compound C.
The preparation method of the compound C avoids the use of Mitsunobu reaction, so that the target product has good optical purity, the yield is up to more than 95%, the reaction condition is mild, the cost is low, the post-treatment is simple, the generated three wastes are less, and the method is suitable for industrial amplification.
Among them, the compound a may be commercially available or may be prepared by a method referred to in CN 111072518.
Compound B is commercially available or self-made by the method described in CN 109180683.
In some embodiments, a method of making compound D comprises: refluxing the compound C and formamide in a reaction solvent at a reaction temperature to obtain a compound D,
the reaction solvent is at least one of ethanol, methanol or isopropanol. In some embodiments, the reaction solvent is ethanol, which facilitates the obtaining of the product.
The feeding molar ratio of the formamide to the compound C can be 1:1-4: 1. In some embodiments, the molar feed ratio of formamide to compound C is from 2:1 to 3: 1.
In some embodiments, the compound C is a compound D, and the reaction temperature of the cyclization reaction is 60 ℃ to 100 ℃. In some embodiments, the reaction temperature for the cyclization reaction is from 70 ℃ to 90 ℃; or the reaction temperature of the cyclization reaction is 78-85 ℃.
Compound C can be prepared by the methods described previously. In some embodiments, compound C is prepared by the methods described previously and directly participates in the preparation reaction of compound D without work-up.
The preparation method of the compound D is optionally post-treated after the reaction is completed. In some embodiments, after the compound C reaction is complete, a post-treatment is performed, the post-treatment comprising: stopping the reaction, cooling to room temperature, adding water, filtering, and drying a filter cake to obtain a compound D.
In some embodiments, after the compound C reaction is complete, a post-treatment is performed, the post-treatment comprising: stopping reaction, cooling to room temperature, adding water, filtering, dissolving a filter cake by chloroform, concentrating, and purifying by methanol-chloroform gradient silica gel chromatography to obtain a compound D.
In some embodiments, compound C is added with formamide in ethanol to perform a reflux reaction at 78-85 ℃, after the reaction is completed, the reaction is stopped, cooled to room temperature, added with water, filtered, and the filter cake is dried to obtain compound D.
The preparation method of the compound D adopts the formamide with low cost as the raw material to prepare the compound D, has high yield, simple operation and less three wastes, avoids the step of a mitsunobu reaction in the prior art and improves the optical selectivity of the product.
In one aspect, a method of making compound E, comprising: the compound D is reacted in a reaction solvent in the presence of a halogenating agent to obtain a compound E,
wherein, X1At least one selected from the group consisting of Cl, Br and I.
The halogenating agent is at least one of bromine, N-chlorosuccinimide, N-iodosuccinimide or N-bromosuccinimide.
In some embodiments, the halogenating agent is bromine, which is beneficial for cost reduction.
The reaction solvent is at least one of DMF, thionyl chloride or a mixed solution of DMF and thionyl chloride.
The compound D can be obtained according to the methods described previously.
The feeding molar ratio of the halogenating agent to the compound D can be 1:1.0-1: 10.0; the feeding molar ratio of the halogenating agent to the compound D can be 1:1.0-1: 4.0; the feeding molar ratio of the halogenating agent to the compound D can be 1:1.0-1: 7.0; alternatively, the molar ratio may be 1:2.0 to 1: 3.0.
The compound D is reacted in a reaction solvent in the presence of a halogenating agent, and the reaction temperature can be 40-100 ℃.
In some embodiments, compound D is reacted in a reaction solvent in the presence of a halogenating agent, which may be at a temperature of 50 ℃ to 80 ℃ to facilitate the reaction. In some embodiments, compound D is reacted in a reaction solvent in the presence of a halogenating agent, which may be at a temperature of 60 ℃ to 70 ℃ to facilitate the reaction.
The compound D is prepared by a method for preparing a compound E, and after the reaction is completed, the compound E is optionally subjected to post-treatment. In some embodiments, the method of making compound E, post-treating comprises: cooling the reaction liquid to room temperature, adding toluene, distilling off the toluene and unreacted brominating agent and solvent under reduced pressure, adding toluene and water, extracting, drying the organic layer, and removing the solvent to obtain the compound E.
The inventors have found that the compound E with high purity can be obtained by the method for preparing the compound E from the compound D by the post-treatment method.
In some embodiments, compound D is reacted with bromine in DMF at 60 ℃ to 70 ℃, after completion of the reaction, the reaction solution is cooled to room temperature, toluene is added, toluene and unreacted brominating agent and solvent are evaporated under reduced pressure, toluene and water are added, extraction is performed, and after drying of the organic layer, the solvent is removed to obtain compound E.
In one aspect, a method of making compound F, comprising: carrying out substitution reaction on the compound E and a compound shown as a formula (01) in a reaction solvent in the presence of alkali to obtain a compound F,
wherein, X is2、X3Each independently is at least one selected from Cl, Br and I; x1As previously described.
The reaction solvent is at least one of tetrahydrofuran, 1, 4-dioxane or 2-methyltetrahydrofuran.
The alkali is at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate water solution, sodium carbonate water solution, potassium carbonate water solution and potassium bicarbonate water solution.
In some embodiments, the temperature of the substitution reaction is from-5 ℃ to 0 ℃.
In some embodiments, the molar ratio of compound (01) to compound E is from 1:1 to 4: 1. In some embodiments, the feed molar ratio of compound (01) to compound E is from 2:1 to 4: 1. In some embodiments, the substitution reaction has a reaction time of 30min to 24 h. In some embodiments, the substitution reaction has a reaction time of 1h to 10 h.
The preparation method of the compound F optionally carries out post-treatment after the reaction is completed. In some embodiments, after the compound F reaction is complete, a post-treatment is performed, the post-treatment comprising: and adding an organic solvent into the reaction solution for extraction, combining organic phases, washing the organic phases, drying, concentrating to remove the solvent to obtain a compound F.
In some embodiments, compound E is substituted with compound (02) in 2-methyltetrahydrofuran in the presence of aqueous sodium bicarbonate at-5 ℃ to 0 ℃, after the reaction is completed, the reaction solution is added into an organic solvent for extraction, the organic phases are combined, and after the organic phases are washed, dried and concentrated to remove the solvent, compound F is obtained.
The preparation method of the compound F takes the compound E as a reactant, and the compound E and the compound (02) have substitution reaction under the action of alkali, and the compound (02) is acryloyl chloride which is a reagent for acylation, has weaker activity, produces fewer by-products, is easy to control quality, does not need to be protected by the compound E, has high yield, is high in product purity due to the fact that the product is recrystallized by adopting ethanol, produces less waste liquid in a reaction system and after-treatment, is more environment-friendly, and is beneficial to industrial production of the raw materials.
In one aspect, a method of making compound G comprises: the compound F is coupled with 4-phenoxyphenylboronic acid shown as a compound (02) in a reaction solvent in the presence of alkali and a catalyst to obtain a compound G,
wherein, X1、X3As previously described.
The alkali is one of potassium phosphate, potassium carbonate or sodium carbonate.
The catalyst is Pd (PPh)3)4、PdCl2(PPh3)2、PdCl2(PhCN)2、Pd(OAc)2Pd/C or PdCl2(dppf)2. In some embodiments, the catalyst is Pd (PPh)3)4And is beneficial to the smooth proceeding of the reaction.
The reaction solvent is a mixed solvent of 1, 4-dioxane and water or glycol dimethyl ether and water.
The feeding molar ratio of the compound (02) to the compound F is 1:1.0-1: 5.0; the feeding molar ratio of the compound (02) to the compound F is 1:2.0-1: 3.0; the feeding molar ratio of the compound (02) to the compound F is 1:1.5-1: 2.0.
The feeding molar ratio of the catalyst to the compound F is 0.001:1-0.1: 1; the feeding molar ratio of the catalyst to the compound F is 0.005:1-0.05: 1; the molar ratio of the catalyst to compound F charged was 0.01.
The compound F is prepared into the compound G by a method, and after the reaction is completed, the compound G is optionally subjected to post-treatment. In some embodiments, the method of preparing compound G, post-treating comprises: the reaction mixture was partitioned, the organic phase was evaporated to dryness, and the residue was crystallized with ethanol to obtain compound G.
In some embodiments, compound F is in a mixed solvent of 1, 4-dioxane and water, potassium phosphate and Pd (PPh)3)4In the presence of the compound G, the compound G is subjected to coupling reaction with 4-phenoxyphenylboronic acid shown as a compound (02), after the reaction is completed, a reaction solution mixture is layered, an organic phase is evaporated to dryness, and then the residue is crystallized by ethanol to obtain a compound G.
The preparation method of the compound G takes the compound F as a reactant, and the compound F and the compound (02) are subjected to Suzuki reaction under the action of alkali and a catalyst, and the Suzuki reaction and the hydrogen halide elimination reaction are simultaneously carried out, so that the reaction route is shortened, the impurity content in the product is reduced, the total yield is improved, ethanol is adopted for reaction and purification, the product purity is high, less waste liquid is generated in post-treatment, the preparation method is more environment-friendly, and the industrial production is facilitated.
In another aspect of the present invention, there is provided a compound, which has the structure shown in compound C:
the compound D can be quickly and conveniently prepared by cyclization of the compound C and formamide, and the compound E is obtained by substitution, so that the reaction process is simplified, the optical selectivity of the product is improved, the yield is improved, the cost is reduced, and the industrialized production is facilitated.
The preparation method provided by the invention can obtain an intermediate compound C, and the intermediate compound C is further subjected to cyclization, substitution and Suzuki reaction to obtain the ibrutinib, so that the purpose of the invention is achieved.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound A" and "compound represented by formula A" and "formula A" means the same compound.
In the present invention, "optional" or "optionally" means that it may or may not be present; or may not be performed; the phrase "optionally adding a reaction solvent to the crude product obtained in step (C)" means that the reaction solvent may or may not be added to the crude product obtained in step (C).
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol; min represents minutes; h represents an hour; g represents g; ml means ml; DMF for N, N-dimethylformamide, THF for tetrahydrofuran; DCM represents dichloromethane; DIPEA represents N, N-diisopropylethylamine; TEA represents triethylamine; HPLC means high performance liquid chromatography.
In the present invention, the reaction is considered complete when the remaining amount of the raw materials does not exceed 5%, 3%, 2%, 1% or 0.5% of the charged amount in the reaction.
EXAMPLE 1 preparation of Compound C
Adding 0.61kg of compound A, 0.1L of absolute ethyl alcohol and 1.08kg of compound B into a reaction kettle at room temperature, heating to 90 ℃ after the addition is finished, carrying out reflux reaction, stopping the reaction after HPLC (high performance liquid chromatography) results show that raw materials are completely reacted, cooling to room temperature, filtering reaction liquid, and drying a filter cake at 80 ℃ for 14.0h to obtain 1.32kg of solid, wherein the yield is 87.1% and the purity is 99.5%.
Through detection: MS: [ M +1]304.2 nuclear magnetism1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),6.31(m,2H),3.85-3.91(m,2H),3.96(t,1H),3.52-3.56(m,2H),1.87-2.12(m,2H),1.58-1.68(m,2H),1.39(s,9H).
EXAMPLE 2 preparation of Compound C
Adding 0.30kg of the compound A, 50mL of absolute ethyl alcohol and 0.54kg of the compound B into a reaction kettle at room temperature, adding 0.505kg of triethylamine, heating to 90 ℃ after the addition is finished, carrying out reflux reaction, stopping the reaction after HPLC (high performance liquid chromatography) results show that raw materials completely react, cooling to room temperature, filtering reaction liquid, and drying filter cakes at 80 ℃ for 14.0h to obtain the compound C, wherein the total amount of the compound C is 0.69kg, the yield is 91.2%, and the purity is 99.3%.
EXAMPLE 3 preparation of Compound D
Adding 0.43kg of compound C and 5mL of formamide into a reaction bottle at room temperature, heating to 80-85 ℃ after the addition is finished, carrying out reflux reaction, stopping the reaction after HPLC (high performance liquid chromatography) results show that raw materials completely react, cooling to room temperature, adding water, stirring, filtering, dissolving a filter cake by chloroform, concentrating, and purifying by methanol-chloroform gradient silica gel chromatography to obtain 0.29kg of compound D in total, wherein the yield is 64.5%, and the purity is 98.4%.
EXAMPLE 4 preparation of Compound D
Adding 0.86kg of compound C and 8mL of formamide into a reaction bottle at room temperature, heating to 65-75 ℃ after the addition is finished, carrying out reflux reaction, stopping the reaction after HPLC (high performance liquid chromatography) results show that raw materials completely react, cooling to room temperature, adding water, stirring, filtering, dissolving a filter cake by chloroform, concentrating, and purifying by methanol-chloroform gradient silica gel chromatography to obtain 0.68kg of compound D in total, wherein the yield is 75.3%, and the purity is 98.9%.
EXAMPLE 5 preparation of Compound E
Adding 15.9g of compound D, 3 drops of DMF (dimethyl formamide) and 50mL of thionyl chloride into a reaction bottle at room temperature, stirring and reacting for 1 hour at 30 ℃, dropwise adding 10.4g of bromine, raising the temperature of the system to 60-70 ℃ after dropwise adding, stirring and reacting for 3 hours, stopping heating when HPLC (high performance liquid chromatography) results show that raw materials are completely reacted, adding 150mL of toluene into the reaction bottle, stirring, evaporating the toluene, unreacted dimethyl sulfoxide and bromine, adding 100mL of toluene, stirring, adding 150mL of water, separating an organic layer, washing with water for three times, drying with anhydrous sodium sulfate, filtering, and distilling to remove a solvent to obtain 17.5g of compound E in total, wherein the yield is 88.2% and the purity is 95.0%.
EXAMPLE 6 preparation of Compound E
Adding 15.9g of compound D, 3 drops of DMF and 50mL of thionyl chloride into a reaction bottle at room temperature, stirring and reacting for 1 hour at 30 ℃, adding 11.5g of N-bromosuccinimide, raising the temperature of the system to 60-70 ℃, stirring and reacting for 6.5 hours, stopping heating when HPLC (high performance liquid chromatography) results show that the raw materials are completely reacted, adding 150mL of toluene into the reaction bottle, stirring, adding 150mL of water, separating an organic layer, washing with water for three times, drying with anhydrous sodium sulfate, filtering, and distilling to remove the solvent to obtain 17.2g of compound E, wherein the total yield is 86.7 percent and the purity is 97.3 percent.
EXAMPLE 7 preparation of Compound F
Reacting compound E (X)1Br, 15g) was dissolved in tetrahydrofuran (150mL), and 7% aqueous sodium bicarbonate (8.49g) solution (100mL) was added, followed by cooling to-5 ℃ and slow dropwise addition of 3-chloropropionyl chloride (X)2＝X3Cl, 6.42g) in tetrahydrofuran (15mL), the reaction temperature was kept below 0 ℃ after dropping, and the reaction was stirred under nitrogen for 5 hours. The reaction was partitioned, the aqueous phase was extracted with 2-methyltetrahydrofuran (150mL), the organic phases were combined, washed successively with 7% aqueous sodium bicarbonate (150mL) and water (150mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give compound F in a total of 17.2g, 88.3% yield, and 94.2% purity.
EXAMPLE 8 preparation of Compound F
Reacting compound E (X)1Br (20 g) was dissolved in 2-methyltetrahydrofuran (200mL), and 7% aqueous sodium bicarbonate (11.32g) solution (160mL) was added, followed by cooling to-5 ℃ and slow dropwise addition of 3-bromopropionyl bromide (X)2＝X3Br, 14.52g) in 2-methyltetrahydrofuran (20mL), the reaction temperature was kept below 0 ℃ after dropping, and the reaction was stirred under nitrogen for 5 hours. The reaction solution was separated into layers, the aqueous phase was extracted with 2-methyltetrahydrofuran (200mL), the organic phases were combined and successively treated with 7% sodium bicarbonateThe organic phase was washed with water (200mL), dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give compound F, 23.3g in total, 80.1% yield, 93.5% purity.
EXAMPLE 9 preparation of Compound F
Reacting compound E (X)1I, 5g) was dissolved in 2-methyltetrahydrofuran (50mL), 7% aqueous sodium bicarbonate (2.44g) solution (34.8mL) was added, then the temperature was reduced to-5 ℃, and 3-chloropropionyl chloride (X) was slowly added dropwise2＝X3Cl, 1.84g) in 2-methyltetrahydrofuran (5mL), the reaction temperature was kept below 0 ℃ after dropping, and the reaction was stirred under nitrogen for 1 hour. The reaction was partitioned, the aqueous phase was extracted with 2-methyltetrahydrofuran (50mL), the organic phases were combined, washed successively with 7% aqueous sodium bicarbonate (50mL) and water (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in vacuo to give compound F in a total of 5.7g, yield 90.4%, purity 95.5%.
EXAMPLE 10 preparation of Compound F
Reacting compound E (X)1(ii) 5g) was dissolved in 2-methyltetrahydrofuran (50mL), 7% aqueous sodium bicarbonate (2.44g) solution (34.8mL) was added, then the temperature was reduced to-5 ℃, and 3-bromopropionyl bromide (X) was slowly added dropwise2＝X3Br, 3.14g) was added dropwise to the reaction solution, and the reaction temperature was kept at 0 ℃ or lower, and the reaction was stirred under nitrogen for 1 hour. The reaction was partitioned, the aqueous phase was extracted with 2-methyltetrahydrofuran (50mL), the organic phases were combined, washed successively with 7% aqueous sodium bicarbonate (50mL) and water (50mL), dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give compound F in a total of 6.5g, 93.3% yield, and 92.9% purity.
EXAMPLE 11 preparation of Compound G
4g of Compound F (X) are added to the reaction flask at room temperature1＝Br，X3Br), 4-phenoxyphenylboronic acid (2.97g) and potassium phosphate (6.88g) were added to a mixed solvent of 1, 4-dioxane (40mL) and water (16mL)After bubbling with nitrogen gas for 20min, Pd (PPh) was added3)4(107.1g), nitrogen bubbling was continued for 10min, and the reaction was stirred under reflux for 2 h. The reaction mixture was then separated into layers, the organic phase was evaporated to dryness and the residue was crystallized from ethanol to give compound G (ibutinib) in a total of 3.52G, yield 86.0% and purity 97.8%.
EXAMPLE 12 preparation of Compound G
6g of Compound F (X) are added to the reaction flask at room temperature1＝Br，X3(Cl), 4-phenoxyphenylboronic acid (4.96g) and potassium phosphate (11.50g) were added to a mixed solvent of 1, 4-dioxane (60mL) and water (24mL), nitrogen gas was bubbled through the mixture for 30min, and Pd (PPh) was added3)4(178.8g), nitrogen bubbling was continued for 10min, and the reaction was stirred under reflux for 3 h. The reaction mixture was then separated into layers, the organic phase was evaporated to dryness and the residue was crystallized from ethanol to give compound G (ibutinib) in a total of 5.8G, yield 89.2% and purity 98.8%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A preparation method of ibrutinib comprises the following steps:
step 1: carrying out condensation reaction on the compound A and the compound B to obtain a compound C,
step 2: carrying out condensation reaction on the compound C and formamide to prepare a compound D,
and step 3: carrying out substitution reaction on the compound D and a halogenating agent to obtain a compound E
And 4, step 4: carrying out substitution reaction on the compound E and a compound shown as a formula (01) in the presence of alkali to obtain a compound F,
and 5: the compound F and 4-phenoxyphenylboronic acid shown as a compound (02) are subjected to Suzuki reaction in the presence of alkali and a catalyst to obtain a compound ibrutinib,
wherein, X1、X2、X3Each independently selected from at least one of Cl, Br and I.
2. The preparation method of ibrutinib according to claim 1, wherein in step 1 or step 2, the reaction solvent is at least one of ethanol, methanol or isopropanol.
3. The preparation method of ibrutinib according to claim 1, wherein in step 1 or step 2, the reaction temperature is the reflux temperature of the reaction solvent.
4. The preparation method of ibutinib according to claim 1, wherein in step 3, the halogenating agent is at least one of bromine, N-chlorosuccinimide, N-iodosuccinimide or N-bromosuccinimide.
5. The preparation method of ibrutinib according to claim 1, wherein in step 3, the reaction solvent is at least one of DMF, thionyl chloride or a mixed solution of DMF and thionyl chloride.
6. The preparation method of ibrutinib according to claim 1, wherein in step 4, the base is at least one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate and an aqueous solution of potassium bicarbonate.
7. The preparation method of ibrutinib according to claim 1, wherein in step 4, the reaction solvent is at least one of tetrahydrofuran, 1, 4-dioxane or 2-methyltetrahydrofuran.
8. The preparation method of ibrutinib according to claim 1, wherein in step 5, the base is one of potassium phosphate, potassium carbonate or sodium carbonate.
9. The preparation method of ibrutinib according to claim 1, wherein in step 5, the catalyst is Pd (PPh)3)4、PdCl2(PPh3)2、PdCl2(PhCN)2、Pd(OAc)2Pd/C or PdCl2(dppf)2At least one of (1).
10. The preparation method of ibrutinib according to claim 1, wherein in step 5, the reaction solvent is a mixed solvent of 1, 4-dioxane and water or ethylene glycol dimethyl ether and water.
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