CN114105991A - A kind of preparation method of Ibrutinib intermediate - Google Patents

Abstract

The invention provides a preparation method and application of ibrutinib, wherein the purification step of an intermediate is increased by optimizing the feeding ratio and the reaction conditions, and inorganic base is adopted to replace organic base as an acid-binding agent, so that the content of impurities, especially the content of isomer impurities, in the ibrutinib synthetic intermediate and a final product is remarkably reduced, and the powerful guarantee is provided for guaranteeing the medicine quality and the clinical medication safety.

Description

Preparation method of ibrutinib intermediate

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an ibrutinib intermediate.

Background

Ibutinib (1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl]Piperidin-1-yl radical]-2-propen-1-one, having the structure according to formula (I) is Johnson&A new targeted anticancer drug cooperatively developed by Johnson and pharmacy is approved by the United states Food and Drug Administration (FDA) to be marketed at 11/13/2013 under the trade name of Imbruvica and is used for treating mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma accompanied with 17p deficiency,

Macroglobulinemia, marginal zone lymphoma, chronic graft-versus-host disease.

WO2014022390A discloses a process for the synthesis of ibrutinib which, as shown below, has the following disadvantages: firstly, the prepared 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidine-1-yl ] -1-piperidyl ] tert-butyl formate (35a) has high isomer impurity content, so that the isomer impurity content in the final product ibrutinib prepared by subsequent reaction is high, and the treatment safety and effectiveness are seriously influenced; 2. the (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidine-1-yl ] piperidine (36a) and acryloyl chloride react by using triethylamine as an acid-binding agent, and a single organic solvent (dichloromethane) is adopted to prepare an ibrutinib final product, so that the generated impurities are high in content and difficult to remove, effective control cannot be performed through recrystallization purification and the like, and the quality control standard of a compound medicine cannot be reached.

Disclosure of Invention

One of the purposes of the present invention is to provide a purification method of an ibutinib intermediate compound IV, wherein the purification method comprises the following steps: dissolving the compound IV to be purified in a crystallization solvent at 70-80 ℃, cooling, crystallizing, separating and drying to obtain the compound IV.

In a preferred embodiment of the present invention, the crystallization solvent is selected from any one of methanol, ethanol, isopropanol, acetonitrile, DMF, toluene, xylene, chloroform, ethyl acetate, cyclohexane, DMSO, N-methylpyrrolidone, dioxane, or a combination thereof.

In a preferred embodiment of the present invention, the mass-to-volume ratio of the compound IV to be purified to the crystallization solvent is 1:1 to 10, preferably 1:2 to 5.

In a preferred technical scheme of the invention, the cooling mode is selected from any one of natural cooling and forced cooling or a combination thereof.

In the preferred technical scheme of the invention, the forced cooling adopts a cooling medium to realize forced cooling on the crystallization system.

In a preferred embodiment of the present invention, the cooling medium is selected from any one of condensed water, ice water, ethanol, and ethylene glycol, or a combination thereof.

In the preferred technical scheme of the invention, the crystallization temperature is 0-30 ℃, preferably 5-20 ℃, and more preferably 10-15 ℃.

In a preferred embodiment of the present invention, the crystallization mode is selected from any one of standing crystallization and stirring crystallization or a combination thereof.

In the preferred technical scheme of the invention, the crystallization time is 1-12h, preferably 2-6h, and more preferably 3-5 h.

In the preferable technical scheme of the invention, the separated and collected compound IV solid is dried after being washed, thus obtaining the compound IV.

In a preferred embodiment of the present invention, the washing solvent is selected from any one of methanol, ethanol, isopropanol, acetonitrile, DMF, toluene, xylene, chloroform, ethyl acetate, cyclohexane, DMSO, N-methylpyrrolidone, and water, or a combination thereof.

In a preferred embodiment of the present invention, the drying is selected from any one of vacuum drying, reduced pressure drying, atmospheric drying, spray drying, and boiling drying, or a combination thereof.

In the preferred technical scheme of the invention, the drying temperature is 25-80 ℃, preferably 35-65 ℃, and more preferably 50-70 ℃.

In the preferred technical scheme of the invention, the purity of the compound IV obtained after purification is not less than 99%, preferably not less than 99.3%.

In a preferred technical scheme of the invention, the content of isomer impurities (formula V) in the compound IV obtained after purification is not more than 0.1%, preferably not more than 0.08%.

Another object of the present invention is to provide a method for preparing the compound IV to be purified, which specifically comprises: 1. preparing a compound III from a compound IIa and a compound IIb in the presence of trialkyl phosphine and an azo reagent, and 2 reacting the compound III prepared in the step 1 with acid to prepare a compound IV.

In a preferred embodiment of the present invention, in step 1, the molar ratio of compound IIa to compound IIb is 1:1 to 10, preferably 1:1 to 5, more preferably 1: 1.5-3.

In a preferred embodiment of the present invention, in step 1, the molar ratio of the compound IIa, the trialkylphosphine and the azo reagent is 1:1-10:1-10, preferably 1:1-3: 1-3.

In a preferred embodiment of the present invention, in step 1, the trialkylphosphine is selected from any one of triphenylphosphine, tri-tert-butylphosphine, tributylphosphine, or a combination thereof.

In a preferred embodiment of the present invention, in step 1, the azo reagent is selected from any one of or a combination of DIED, DEAD, TMAD, DHTD, and DIAD.

In a preferred technical scheme of the invention, in the step 1, the reaction solvent is selected from one of tetrahydrofuran, dichloromethane and acetonitrile.

In a preferred embodiment of the present invention, the reaction temperature in step 1 is 0 to 40 ℃, preferably 5 to 35 ℃, and more preferably 10 to 25 ℃.

In a preferred embodiment of the present invention, the acid in step 2 is selected from any one of hydrochloric acid, hydrochloric acid ethanol, and acetic acid.

In the preferred technical scheme of the invention, the reaction temperature of the step 2 is 5-40 ℃, preferably 10-30 ℃.

In the preferred technical scheme of the invention, the reaction time of the step 2 is 5-25h, preferably 10-20 h.

In the preferred technical scheme of the invention, the compound III is directly subjected to the next reaction without separation.

The invention also aims to provide a preparation method of ibrutinib, which comprises the following steps: and (3) reacting the compound IV with the compound IIc in a solvent in the presence of an inorganic base to prepare the ibrutinib (formula I).

In a preferred technical scheme of the invention, in the method, the purity of the compound IV is not less than 99%, preferably not less than 99.3%.

In a preferred embodiment of the invention, the process is carried out in such a way that the content of isomeric impurities (formula V) in compound IV is not more than 0.1%, preferably not more than 0.08%.

In a preferred embodiment of the present invention, in the method, before the compound IV and the compound IIc are added, the inorganic base is sufficiently dissolved in the solvent.

In a preferred technical scheme of the invention, the solvent for dissolving the inorganic base is water.

In the preferred technical scheme of the invention, the dissolving temperature of the inorganic base is 5-50 ℃, preferably 10-45 ℃, and more preferably 20-30 ℃.

In the preferred technical scheme of the invention, the compound IV and the organic solvent with the mass volume ratio of 1:1-10 are added into the fully dissolved inorganic alkali solution and fully stirred and dissolved at the temperature of-10 ℃ to 20 ℃.

In a preferred embodiment of the present invention, the compound IIc is dissolved in an organic solvent, and then added to the solution containing the compound IV to perform a reaction.

In a preferred embodiment of the present invention, in the method, the inorganic base is selected from one or a combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate.

In a preferred embodiment of the present invention, in the method, the molar ratio of the inorganic base to the compound IV is 1-5:1, preferably 1-2: 1.

In a preferred technical scheme of the invention, in the method, the organic solvent is selected from one or a combination of acetone, DMF, chlorobenzene, xylene, toluene, acetonitrile, ethanol, THF, chloroform, ethyl acetate, cyclohexane, butanone, acetone and petroleum ether.

In the preferred technical scheme of the invention, in the method, the reaction temperature is-10-20 ℃, preferably-5-10 ℃.

In a preferred technical scheme of the invention, in the method, the reaction time is 0.5-5h, preferably 0.5-2 h.

Another object of the present invention is to provide an impurity a compound.

(impurity A)

Another object of the present invention is to provide the use of impurity a as a standard or control.

Another object of the present invention is to provide a high purity compound IV or a pharmaceutically acceptable salt thereof, having a purity of not less than 99%, preferably not less than 99.5%, wherein the content of isomer impurity V is not more than 0.1%, preferably not more than 0.08%, more preferably not more than 0.05%.

In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by formula iv is selected from any one of or a combination of p-toluenesulfonate, methanesulfonate, sulfonate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, tartrate, fumarate, maleate, citrate, acetate, formate, benzoate, cinnamate, succinate, malonate and malate.

Another object of the present invention is to provide a high-purity ibrutinib or a pharmaceutically acceptable salt thereof, having a purity of not less than 99%, preferably not less than 99.5%, wherein the content of impurity A is not more than 0.5%, preferably not more than 0.1%, more preferably not more than 0.08%, and the content of impurity G is not more than 0.1%, preferably not more than 0.05%, more preferably not more than 0.02%.

(impurity G)

In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of ibrutinib is selected from any one of its salts such as p-toluenesulfonate, methanesulfonate, sulfonate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, tartrate, fumarate, maleate, citrate, acetate, formate, benzoate, cinnamate, succinate, malonate, malate, or a combination thereof.

Another object of the present invention is to provide the use of the high-purity ibrutinib or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of tumors or immune system diseases.

In a preferred embodiment of the present invention, the tumor is selected from any one of leukemia and lymphoma, or a complication thereof.

In a preferred embodiment of the present invention, the leukemia is selected from any one of acute lymphocytic leukemia, chronic lymphocytic leukemia, and macroglobulinemia, or a complication thereof.

In a preferred embodiment of the present invention, the lymphoma is any one selected from hodgkin lymphoma, non-hodgkin lymphoma, mantle cell lymphoma, small cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma accompanied by 17p deficiency, marginal zone lymphoma, or a complication thereof.

In a preferred embodiment of the present invention, the immune system disease is selected from any one of chronic graft-versus-host disease (cGVHD), systemic lupus erythematosus, rheumatoid arthritis, sjogren's syndrome, scleroderma, myositis, and vasculitis, or a complication thereof.

Another object of the present invention is to provide a pharmaceutical pack, which contains the high purity compound of formula I of the present invention or its pharmaceutically acceptable salt and other pharmaceutical agents.

In a preferred embodiment of the present invention, the other drug is selected from any one of rituximab, vinatock, obinituzumab, ketoconazole, rifampin, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, carbamazepine, rifampin, phenytoin, TGR-1202, venetolax, doxorubicin, prednisone, cyclophosphamide, vincristine, lenalidomide, bortezomib, or a combination thereof.

Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.

Compared with the prior art, the invention has the following beneficial technical effects:

1. the purification step of the intermediate is increased by optimizing the feed ratio and the reaction conditions, and the inorganic base is adopted to replace the organic base as an acid-binding agent, so that the impurity content, especially the content of isomer impurities, in the ibrutinib synthetic intermediate and the final product is remarkably reduced, and the powerful guarantee is provided for guaranteeing the medicine quality and the clinical medication safety.

2. Quickening the reaction process, simple and convenient operation, high product yield and stable process, and can meet the requirement of industrial production.

Drawings

FIG. 1 purity chart of Compound IV of example 1

FIG. 2 purity chart of Compound IV of example 2

FIG. 3 purity chart of Compound IV of example 3

FIG. 4 example 4 purity of Compound IV before purification

FIG. 5 detection of isomer impurities before purification of Compound IV of example 4

FIG. 6 purity of example 5 Compound IV before purification

FIG. 7 detection of isomer impurities before purification of Compound IV of example 5

FIG. 8 purity of example 6 Compound IV before purification

FIG. 9 detection of isomer impurities before purification of Compound IV of example 6

FIG. 10 example 7 Ibutinib purity profile

FIG. 11 example 8 Ibutinib purity map

FIG. 12 example 9 Ibutinib purity map

Detailed Description

The present invention is illustrated by the following examples, which should be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Other insubstantial modifications and adaptations of the present invention can be made without departing from the scope of the present invention.

The detection method involved in the examples:

the detection method of the IV isomer of the compound comprises the following steps: taking a proper amount of the compound IV, adding a solvent (n-hexane-ethanol 50: 50) for ultrasonic dissolution and dilution to prepare a solution containing about 1.0mg in each 1ml as a test solution. Measuring by high performance liquid chromatography (0512 according to the general regulation of 2015 pharmacopoeia of China), using CHIRALPAK AD-H chiral chromatographic column (250mm × 4.6mm × 5um), 0.3% triethylamine n-hexane-ethanol (70:30) as mobile phase, diode array detector, detecting wavelength of 260mm, column temperature of 40 deg.C, and flow rate of 0.6 ml/min. Precisely measuring 10ul of the test solution, injecting into a liquid chromatograph, and recording chromatogram.

② a method for detecting the purity of the compound IV: taking a proper amount of the compound IV, adding a solvent of 40% acetonitrile for dissolving and diluting to prepare a solution containing 0.5mg in each 1ml, and using the solution as a test solution. Measuring by high performance liquid chromatography (China pharmacopoeia 2015 edition general rules 0512). Octadecylsilane bonded silica gel as a filler (Varian Polaris C18, 3um, 4.6X 150 mm); taking a 0.1% TFA deionized water solution as a mobile phase A, and taking an ACN solution of 0.1% TFA as a mobile phase B; linear gradient elution was performed according to the following table; the detection wavelength is 260 mm; the flow rate is 1.5 ml/min; the column temperature was 40 ℃. Precisely measuring 20ul of the test solution, injecting into a liquid chromatograph, and recording the chromatogram.

③ the purity detection method of ibrutinib: taking a proper amount of ibrutinib, adding a solvent of 40% acetonitrile for dissolving and diluting to prepare a solution containing about 0.5mg in each 1ml as a test solution. Measuring by high performance liquid chromatography (China pharmacopoeia 2015 edition general rules 0512). Octadecylsilane bonded silica gel as a filler (Varian Polaris C18, 3um, 4.6X 150 mm); taking a 0.1% TFA deionized water solution as a mobile phase A, and taking an ACN solution of 0.1% TFA as a mobile phase B; linear gradient elution was performed according to the following table; the detection wavelength is 260 mm; the flow rate is 1.5 ml/min; the column temperature was 40 ℃. Precisely measuring 20ul of the test solution, injecting into a liquid chromatograph, and recording the chromatogram.

Comparative example 1 purification of Compound IV

Adding a crude product of a compound IV to be purified into a 2L reaction bottle, adding 900ml of purified water and 300ml of methanol, stirring, adding KOH, adjusting the pH value to 8.5, stirring, cooling to 20 ℃, and crystallizing for 5 hours at the temperature; suction filtration, leaching the filter cake with 500ml water, drying the filter cake in a forced air oven at 55 ℃ to obtain 176.12g of a compound IV final product with the purity of 99.58 percent and the isomer impurity content of 0.27 percent.

EXAMPLE 1 purification of Compound IV

1966.21g of a crude product of a compound IV to be purified (purity: 94.65%, content of isomer impurities: 1.55%) is added into a 50L reaction kettle, 15.7L of absolute ethyl alcohol is added, the mixture is heated and stirred until the system is basically clear by refluxing, the temperature is reduced to 10 ℃, and the mixture is stirred and crystallized for 3 hours at the temperature; and (3) carrying out suction filtration, leaching a filter cake by using 1500ml of absolute ethyl alcohol, drying the filter cake in a forced air oven at 65 ℃ to obtain 1619.86g of a compound IV final product with the purity of 99.83 percent and undetected isomer impurities, wherein a chromatogram map is shown in figure 1.

EXAMPLE 2 purification of Compound IV

393.21g of a crude product of a compound IV to be purified (purity: 97.02%, content of isomer impurities: 1.38%) is added into a 5L reaction bottle, 1.5L of absolute ethyl alcohol is added, heated, stirred and stirred until the system is basically clear after refluxing, cooled to 15 ℃, and stirred and crystallized for 5 hours at the temperature; and (4) carrying out suction filtration, leaching a filter cake by using 300ml of absolute ethyl alcohol, drying the filter cake in a forced air oven at 50 ℃ to obtain 323.86g of a final product of the compound IV, wherein the purity is 99.84%, isomer impurities are not detected, and a chromatogram map is shown in figure 2.

EXAMPLE 3 purification of Compound IV

1777.80g of crude product of compound IV to be purified (purity: 95.99%, content of isomer impurities: 1.71%) is added into a 20L reaction kettle, 10L of absolute ethyl alcohol is added, heated, stirred until the system is refluxed and basically dissolved, cooled to 12 ℃, and stirred at the temperature for crystallization for 3.5 h; and (4) carrying out suction filtration, leaching a filter cake by using 1L of absolute ethyl alcohol, drying the filter cake in a forced air oven at 60 ℃ to obtain 1064.4g of a final product of the compound IV, wherein the purity is 99.89%, isomer impurities are not detected, and a chromatogram is shown in figure 3.

Comparative example 2 preparation of Compound IV

(1) Adding 180.00g of compound IIa, 358.30g of compound IIb, 466.89g of triphenylphosphine and 1800mL of tetrahydrofuran in sequence into a 3L reaction bottle, and stirring at 10 ℃; 359.93g diisopropyl azodicarboxylate (DIAD) was dissolved in 360ml tetrahydrofuran solution, and the tetrahydrofuran solution of DIAD was added dropwise to the reaction solution, with the temperature being controlled not to exceed 25 ℃; after dropping, the mixture was stirred at 15 ℃ for 4 hours.

(2) Concentrating at 50 deg.C to obtain oily substance, maintaining temperature at 20 deg.C, dropwise adding 1L hydrochloric acid, stirring at 20 deg.C for 12 hr, adding 1L water into the reaction solution, stirring 1L dichloromethane at 20 deg.C for 10min, standing for separating liquid, adding 5N sodium hydroxide solution into the water phase to adjust pH to 7, controlling temperature to be no more than 25 deg.C, extracting with 1.5L dichloromethane and 1L dichloromethane respectively, concentrating the organic phase at 40 deg.C to obtain yellow oily substance, adding 900ml ethanol, stirring at 70 deg.C, and dissolving; adjusting the pH value to 3 by using hydrochloric acid and ethanol, slowly cooling to 20 ℃, stirring and crystallizing for 4 hours; suction filtration is carried out, the filter cake is rinsed with 50ml of ethanol and dried in a forced air oven at 55 ℃ to obtain 340.80g of compound IV.

EXAMPLE 4 preparation of Compound IV

(1) Adding 1500.00g of compound IIa, 2985.90g of compound IIb, 3891.50g of triphenylphosphine and 7500mL of tetrahydrofuran in sequence into a 20L reaction kettle, and stirring at 10 ℃; 3000.00g diisopropyl azodicarboxylate (DIAD) was dissolved in 1500ml tetrahydrofuran solution, and the tetrahydrofuran solution of DIAD was added dropwise to the reaction solution, with the temperature being controlled not to exceed 25 ℃; after dropping, the mixture was stirred at 25 ℃ for 2 hours.

(2) Maintaining the temperature at 25 ℃, dropwise adding 5.77L of hydrochloric acid, and stirring for 16h at 25 ℃ after dropwise adding. Adding 10L of water and 10L of dichloromethane into the reaction solution, stirring for 10min at 25 ℃, and standing for liquid separation; adding 5L of water into the organic phase, stirring for 10min, and standing for liquid separation; mixing the water phases, adding 5L dichloromethane, stirring for 10min, standing, and separating; adding 30% sodium hydroxide solution into the water phase to adjust pH to 10, controlling the temperature not to exceed 35 ℃, stirring for 1h at 30 ℃, and separating out solids. Performing suction filtration, leaching a filter cake with 5L of water, adding the obtained solid into a 50L reaction kettle, adding 7.5L of water, and stirring at 30 ℃ for 1 h; suction filtration is carried out, a filter cake is rinsed by 5L of water, and the filter cake is dried in a forced air oven at 60 ℃ to obtain 1966.21g of a crude compound IV (the purity is 94.65%, the content of isomer impurities is 1.55%, and the chromatogram is shown in figures 4-5).

EXAMPLE 5 preparation of Compound IV

(1) 300.00g of compound IIa, 597.17g of compound IIb, 778.28g of triphenylphosphine and 1500mL of tetrahydrofuran are sequentially added into a 5L reaction bottle and stirred at 10 ℃; 600.00g diisopropyl azodicarboxylate (DIAD) was dissolved in 300ml tetrahydrofuran solution, and the solution of DIAD in tetrahydrofuran was added dropwise to the reaction mixture, with the temperature being controlled not to exceed 25 ℃; after dropping, the reaction was stirred at 18 ℃ for 3 h.

(2) Maintaining the temperature at 16 ℃, dropwise adding 1.16L of hydrochloric acid into the reaction solution in the step (1), stirring for 15h at 16 ℃ after dropwise adding, adding 2L of water into the reaction solution, stirring 2L of dichloromethane for 10min at 22 ℃, standing for liquid separation, stirring the organic phase for 10min with 1L of water, standing for liquid separation, combining the water phases, stirring for 10min with 1L of dichloromethane, and standing for liquid separation; adding 30% sodium hydroxide solution into the water phase to adjust the pH to 9.5, controlling the temperature not to exceed 35 ℃, and stirring for 1h at 25 ℃; performing suction filtration, leaching a filter cake with 1L of water, adding the obtained solid into a 5L beaker, adding 1.5L of water, and stirring for 1h at 25 ℃; suction filtration is carried out, a filter cake is rinsed by 1L of water, and the filter cake is dried in a forced air oven at 57 ℃ to obtain the compound IV393.21g (the purity: 97.02%, the content of isomer impurities: 1.38%, and the chromatogram is shown in FIGS. 6-7).

EXAMPLE 6 preparation of Compound IV

(1) 1000.00g of compound IIa, 1658.80g of compound IIb, 2161.90g of triphenylphosphine and 5000mL of tetrahydrofuran are sequentially added into a 5L reaction bottle and stirred at 10 ℃; 1666.60g diisopropyl azodicarboxylate (DIAD) was dissolved in 1000ml tetrahydrofuran solution, and the solution of DIAD in tetrahydrofuran was added dropwise to the reaction solution, with the temperature being controlled not to exceed 25 ℃; after dropping, the mixture was stirred at 15 ℃ for 2.5 hours.

(2) Maintaining the temperature at 15 ℃, dropwise adding 3.83L of hydrochloric acid, stirring at 15 ℃ for 12h after dropwise adding, adding 4L of water into the reaction solution, stirring 4L of dichloromethane at 20 ℃ for 10min, standing for liquid separation, stirring the organic phase with 2L of water for 10min, standing for liquid separation, combining the water phases, stirring with 4L of dichloromethane for 10min, and standing for liquid separation; adding 30% sodium hydroxide solution into the water phase to adjust the pH value to 9, controlling the temperature not to exceed 35 ℃, and stirring for 1h at 20 ℃; performing suction filtration, leaching a filter cake with 3L of water, adding the obtained solid into a 10L reaction bottle, adding 5L of water, and stirring at 20 ℃ for 1 h; suction filtration, leaching the filter cake with 5L water, drying the filter cake in a forced air oven at 55 deg.C to obtain compound IV1777.80g (purity: 95.99%, isomer impurity content: 1.71%, chromatogram shown in FIGS. 8-9).

Comparative example 3 preparation of ibrutinib

Adding 50.00 g of compound IV and 20.00g of DIEA into a 2L reaction bottle, stirring 500ml of tetrahydrofuran at 0 ℃, dissolving 11.70g of IIc into 100ml of tetrahydrofuran, and dropwise adding the tetrahydrofuran solution of IIc into the reaction solution, wherein the temperature is controlled not to exceed 5 ℃; after dropping, the mixture was stirred at 0 ℃ for 1 hour. Pouring the reaction solution into 500ml of 10% citric acid aqueous solution, adding 500ml of ethyl acetate, stirring at 20 ℃ for 10min, and standing for liquid separation; the water phase is back extracted by 250mL ethyl acetate, the combined organic phases are washed by 250mL of 5 percent citric acid aqueous solution, 250mL of saturated sodium chloride aqueous solution is added into the organic phase, the mixture is stirred for 10min, the mixture is kept stand and separated, 20.0g of anhydrous magnesium sulfate is added into the organic phase, the mixture is dried for 1h and filtered, and the filtrate is decompressed and concentrated at 40 ℃ to obtain off-white solid. The solid obtained is added with 400ml of methanol and stirred for 1h at 65 ℃, cooled to 15 ℃ and crystallized for 15h at the temperature. And (3) carrying out suction filtration, and carrying out vacuum drying on the filter cake at 50 ℃ for 12h to obtain 10.30G of ibrutinib, wherein the molar yield is 30%, the purity is 98.97%, the content of the impurity A is 0.28%, and the content of the impurity G is 0.05%.

Example 7 preparation of ibrutinib

195.40g of lithium hydroxide monohydrate and 3L of water are added into a 20L reaction kettle, and the mixture is stirred at the temperature of 20 ℃ until the reaction solution is clear; adding 7.5L of acetone and 1500.00g of purified compound IV, and stirring at-5 ℃; 368.90g of compound IIc is dissolved in 3L of acetone, the acetone solution of the compound IIc is dripped into the reaction solution, and the temperature is controlled not to exceed 5 ℃; after the dripping is finished, stirring the mixture for 0.5h at the temperature of minus 5 ℃. Pouring the reaction solution into 22L of 10% citric acid aqueous solution, adding 22L of ethyl acetate, stirring at 20 ℃ for 10min, and standing for liquid separation; extracting the water phase with 11L ethyl acetate, mixing the organic phases, washing with 11L 5% citric acid water solution, adding 11L saturated sodium chloride water solution into the organic phase, stirring for 10min, standing, and separating; adding 2.00kg of anhydrous magnesium sulfate into the organic phase, drying for 1h, carrying out suction filtration, and concentrating the filtrate at 40 ℃ under reduced pressure to obtain an off-white solid. Adding 9L methanol into the obtained solid, stirring for 1h at 65 ℃, cooling to 15 ℃, and stirring for crystallization for 12h at the temperature. And (3) carrying out suction filtration, and carrying out vacuum drying on the filter cake at 50 ℃ for 12h to obtain 854.9G of ibrutinib, wherein the molar yield is 50%, the purity is 99.95%, neither impurity A nor impurity G is detected, and the chromatogram is shown in FIG. 10.

Example 8 preparation of Ibutotinib

36.48g of lithium hydroxide monohydrate and 560ml of water are added into a 5L reaction bottle and stirred at 25 ℃ until the reaction solution is clear; 1400ml of acetone and 280.00g of purified compound IV are added and stirred at 5 ℃; 68.86g of IIc is dissolved in 560ml of acetone, the acetone solution of IIc is dripped into the reaction solution, and the temperature is controlled not to exceed 5 ℃; after dropping, the mixture was stirred at 5 ℃ for 1 hour. Pouring the reaction solution into 4L of 10% citric acid aqueous solution, adding 4L of ethyl acetate, stirring at 25 ℃ for 10min, and standing for liquid separation; and back-extracting the water phase with 2L of ethyl acetate, combining the organic phases, washing with 2L of 5% citric acid aqueous solution, adding 2L of saturated sodium chloride aqueous solution into the organic phase, stirring for 10min, standing for liquid separation, adding 280.00g of anhydrous magnesium sulfate into the organic phase, drying for 1h, performing suction filtration, and concentrating the filtrate at 45 ℃ under reduced pressure to obtain an off-white solid. Adding 1.68L methanol into the obtained solid, stirring for 1h at 70 ℃, cooling to 20 ℃, and stirring for crystallization for 13h at the temperature. And (3) carrying out suction filtration, and carrying out vacuum drying on the filter cake at 60 ℃ for 8h to obtain 165.05G of ibrutinib, wherein the molar yield is 52%, the purity is 99.9%, the content of impurity A is 0.08%, the content of impurity G is 0.01%, and the chromatogram is shown in figure 11.

Example 9 preparation of ibrutinib

36.48g of lithium hydroxide monohydrate and 560ml of water are added into a 5L reaction bottle and stirred at 24 ℃ until the reaction solution is clear; 1400ml of acetone and 280.00g of purified compound IV are added and stirred at 0 ℃; 68.86g of IIc is dissolved in 560ml of acetone, the acetone solution of IIc is dripped into the reaction solution, and the temperature is controlled not to exceed 5 ℃; after dropping, the mixture was stirred at 0 ℃ for 1 hour. Pouring the reaction solution into 4L of 10% citric acid aqueous solution, adding 4L of ethyl acetate, stirring at 23 ℃ for 10min, and standing for liquid separation; and back-extracting the water phase with 2L of ethyl acetate, combining the organic phases, washing with 2L of 5% citric acid aqueous solution, adding 2L of saturated sodium chloride aqueous solution into the organic phase, stirring for 10min, standing for liquid separation, adding 280.00g of anhydrous magnesium sulfate into the organic phase, drying for 1h, performing suction filtration, and concentrating the filtrate at 40 ℃ under reduced pressure to obtain an off-white solid. Adding 1.68L methanol into the obtained solid, stirring at 66 deg.C for 1.5h, cooling to 16 deg.C, and stirring at the temperature for crystallization for 15 h. Suction filtration is carried out, the filter cake is dried for 10 hours in vacuum at 55 ℃, 172.16G of ibrutinib is obtained, the molar yield is 54.2%, the purity is 99.87%, the content of impurity A is 0.04%, the content of impurity G is 0.05%, and the chromatogram is shown in figure 12.

Claims (10)

Translated fromChinese

1.一种伊布替尼中间体化合物IV的纯化方法，所述纯化方法包括：将待纯化的化合物IV在70-80℃溶于结晶溶剂，降温，结晶，分离，干燥，即得。1. A purification method for ibrutinib intermediate compound IV, the purification method comprising: dissolving the compound IV to be purified in a crystallization solvent at 70-80° C., cooling, crystallizing, separating, and drying, and then obtaining.

2.如权利要求1所述的方法，其特征在于，所述结晶溶剂选自甲醇、乙醇、异丙醇、乙腈、DMF、甲苯、二甲苯、氯仿、乙酸乙酯、环己烷、DMSO、N-甲基吡咯烷酮、二氧六环中的任一种或其组合中的任一种或其组合。2. method as claimed in claim 1 is characterized in that, described crystallization solvent is selected from methanol, ethanol, isopropanol, acetonitrile, DMF, toluene, xylene, chloroform, ethyl acetate, cyclohexane, DMSO, Any one or a combination of N-methylpyrrolidone, dioxane, or a combination thereof.3.如权利要求1或2所述的方法，其特征在于，待纯化的化合物IV与结晶溶剂的质量体积比为1:1-10，优选1:2-5。3. The method of claim 1 or 2, wherein the mass volume ratio of the compound IV to be purified to the crystallization solvent is 1:1-10, preferably 1:2-5.4.如权利要求1-3所述的方法，其特征在于，所述降温方式选自自然冷却降温、强制冷却降温的任一种或其组合。4. The method of claim 1-3, wherein the cooling method is selected from any one of natural cooling and forced cooling, or a combination thereof.5.如权利要求1-4所述的方法，其特征在于，所述强制冷却降温采用冷却介质对结晶体系实现强制降温。5. The method according to claim 1-4, characterized in that, in the forced cooling and cooling, a cooling medium is used to achieve forced cooling of the crystallization system.6.如权利要求1-5所述的方法，其特征在于，所述冷却介质选自冷凝水、冰水、乙醇、乙二醇的任一种或其组合。6. The method of claims 1-5, wherein the cooling medium is selected from any one of condensed water, ice water, ethanol, and ethylene glycol, or a combination thereof.7.如权利要求1-6所述的方法，其特征在于，所述结晶温度为0-30℃，优选为5-20℃，更优选10-15℃。7. The method of claims 1-6, wherein the crystallization temperature is 0-30°C, preferably 5-20°C, more preferably 10-15°C.8.如权利要求1-7所述的方法，其特征在于，所述结晶方式选自静置析晶或搅拌析晶的任一种或其组合。8. The method of claims 1-7, wherein the crystallization mode is selected from any one of standing crystallization or stirring crystallization or a combination thereof.9.如权利要求1-8所述的方法，其特征在于，所述析晶时间为1-12h，优选为2-6h，更优选为3-5h。9. The method of claim 1-8, wherein the crystallization time is 1-12h, preferably 2-6h, more preferably 3-5h.10.如权利要求1-9所述的方法，其特征在于，将分离收集的化合物IV固体经洗涤处理后干燥，即得。10. The method according to claim 1-9, characterized in that, the separated and collected compound IV solids are washed and processed, and then dried to obtain.

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