CN115353519A - Method for refining BTK inhibitor intermediate - Google Patents
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Abstract
The invention belongs to the field of medicine synthesis, and particularly provides a novel method for refining a BTK inhibitor intermediate. The technical scheme of the invention can obtain the intermediate compound shown as formula II with high purity and high yield, the reaction is clean and thorough, no raw material is left, the yield can reach 93%, and the purity can reach more than 99.5%. In addition, the technical scheme of the invention avoids using column chromatography for purification, is more simple, convenient and efficient, and has low cost, so that the technical scheme is more suitable for expanding industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly provides a novel method for refining a BTK inhibitor intermediate, wherein IBX is used as an oxidizing agent, and a pulping method is adopted for purification.
Background
Kinases are a class of enzymes that control the transfer of phosphate groups from phosphate donors (such as ATP) to specific substrates. Protein kinases are a large subset of kinases and play a central role in regulating a variety of cellular signals and processes, of which BTK (Bruton's tyrosine kinase) is one. BTK belongs to a member of the TEC cytosolic tyrosine kinase family (TEC family of kinases, TFKs). This family has 5 members in total, besides BTK, lTK, TEC, BMX and TXK.
The BTK structure comprises 5 major domains, namely the PH domain (Pleckstrin homology), the TH domain (Tec homology), the SH3 domain (Src homology 3), the SH2 domain (Src homology 2) and the SH1 domain (Src homology 1), and activation (phosphorylation) of BTK initially occurs in the activation loop in the SH1 domain, and further activation occurs in the SH2 and SH3 domains containing the primary autophosphorylation sites. These SH domains also contain Nuclear Localization Signals (NLS) and Nuclear Export Sequences (NES) required for BTK to shuttle nuclear matter.
BTK is primarily responsible for the transduction and amplification of various intracellular and extracellular signals in B lymphocytes, is a key regulator of B cell development, activation, signaling and survival, and is involved in the regulation of angiogenesis, cell proliferation and apoptosis, and cell motility. The signal receptors upstream of BTK include growth factor and cytokine receptors, G protein-coupled receptors such as chemokine receptors, antigen receptors (especially B cell receptor [ BCR ]), integrins, and the like. BTK in turn activates many major downstream signaling pathways, including the phosphoinositide-3 kinase (P13K) -AKT pathway, phospholipase-C (PLC), and others. An increase in BTK activity was detected in blood cancer cells such as B cell Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). The abnormal activity of BTK often leads to B cell malignancy or autoimmune disease, which makes it a popular target for research and development.
With the continuous optimization and development of BTK inhibitors, the synthesis process of the BTK inhibitors also occupies irreplaceable important position, the BTK inhibitors are pyrrolopyrimidine compounds, wherein the compound of the formula II is a very important intermediate for synthesizing the compounds, the structural formula of the compound is shown as the following formula, and the compound is the basis for synthesizing the BTK inhibitors,
there are many methods for synthesizing the compound of formula II, CN108699062A, CN112812100A, and CN112979656A disclose that tert-butyl lithium is used for reaction to obtain the compound, but the reaction needs to be performed at an ultra-low temperature, i.e., -78 ℃, which undoubtedly increases the difficulty of the production process, and the final product yield is only 41%, besides, the reaction uses column chromatography for purification, and the column chromatography purification requires great cost from the aspects of loss of experimental materials, time and labor, and the like, and the process operation is cumbersome, the efficiency is low, so the column chromatography purification is not suitable for industrial production.
Therefore, more reasonable reaction reagents and conditions are sought, and the method has great significance for large-scale industrial production of the intermediate compound shown in the formula II.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a novel method for refining a BTK inhibitor intermediate, which can obtain an intermediate compound shown as a formula II with high yield and high purity, does not need to use column chromatography for purification, and further improves the efficiency of synthesizing the compound shown as the formula II.
In light of the above objects, the present inventors have attempted to study the reaction steps for producing the intermediate compound of formula II, and have surprisingly found that when the compound of formula I is used as a substrate and IBX (2-iodoxybenzoic acid) is used as an oxidizing agent, a high yield, high purity product, 93% yield, 99.5% purity or more, can be obtained by a beating method, and the use of a column chromatography purification method is avoided.
To achieve the object of the present invention, the following embodiments are provided:
the compound of the formula I is reacted under the oxidation action of IBX, and is treated by a pulping method to obtain a BTK inhibitor intermediate compound of the formula II, wherein the reaction formula is shown as the following formula:
wherein X is halogen; r 1 Selected from the group consisting of halo, methyl, phenoxy and pyridyloxy, said phenoxy and pyridyloxy being optionally substituted with 1, 2 or 3 halo; n is selected from 1, 2 and 3.
Preferably, the molar ratio of IBX to the compound of formula I is (1-2): 1, more preferably (1.2-1.5): 1, more preferably 1.3.
Preferably, the reaction solvent is selected from the group consisting of DMSO (dimethyl sulfoxide), dichloromethane, chloroform, DMF (N, N-dimethylformamide), DMAC (N, N-dimethylacetamide), acetonitrile, acetone, and a combination of two or more thereof, and more preferably DMSO.
Preferably, the reaction temperature is controlled to be 15 to 35 ℃, more preferably 20 to 30 ℃.
Preferably, the pulping method comprises:
1) After the reaction is finished, quenching the reaction by using a sodium thiosulfate aqueous solution, and then pulping;
2) Filtering after the step 1), adding acetonitrile and an alkaline solution into a filter cake, and pulping for the second time, wherein the alkaline solution is preferably a weakly alkaline solution;
3) Filtering after the step 2) is finished, adding DMSO into the filter cake to dissolve, then adding water dropwise, and pulping for the third time;
4) And 3) filtering after the step 3) is finished, washing a filter cake with water, and drying in vacuum to obtain the compound shown in the formula II.
Preferably, the molar ratio of the sodium thiosulfate in the step 1) to the compound of the formula I is (0.5-1.5): 1, more preferably (0.7-1.2): 1, more preferably 0.9:1.
preferably, the pulping temperature in the step 1) is 15-35 ℃, and more preferably 20-30 ℃; the pulping time is 1-2h.
Preferably, the weakly alkaline solution in step 2) is selected from sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, potassium bicarbonate solution, sodium sulfite solution, potassium sulfite solution, sodium phosphate solution, potassium phosphate solution, disodium hydrogen phosphate solution, dipotassium hydrogen phosphate solution, sodium acetate solution, ammonia water, and a combination of two or more thereof, and more preferably potassium carbonate solution.
Preferably, the solubility of the alkaline solution in step 2) is 3% to 15% by mass, more preferably 6% to 12% by mass, and still more preferably 9% by mass.
Preferably, the pulping temperature in the step 2) is 15-35 ℃, and more preferably 20-30 ℃; the pulping time is 1-2h.
Preferably, the pulping temperature in the step 3) is 35-65 ℃, and more preferably 45-55 ℃; the pulping time is 1-2h.
Further, the invention provides a method for detecting a BTK inhibitor intermediate compound shown as a formula II:
performing high performance liquid chromatography with a chromatographic column using octadecylsilane chemically bonded silica as filler, at 35 deg.C, detection wavelength of 220nm, flow rate of 0.5ml/min, 0.1% phosphoric acid as mobile phase A, and methanol as mobile phase B, and performing gradient elution according to the following Table 1:
TABLE 1
By using the compound of formula II as the intermediate of the BTK inhibitor synthesized as a test sample according to the HPLC detection method provided above, the content of the compound of formula II as the intermediate and the content of each impurity such as impurity a can be detected.
The invention has the beneficial effects that:
compared with the preparation method of the compound disclosed as the intermediate II in the prior art, the technical scheme of the invention can obtain the intermediate compound disclosed as the intermediate II with high purity and high yield, the reaction is clean and thorough, no raw material is left, the yield can reach 93%, and the purity can reach more than 99.5%. In addition, the technical scheme of the invention avoids using column chromatography for purification, is more simple, convenient and efficient, and has low cost, so that the technical scheme is more suitable for expanding industrial production.
Drawings
Figure 1 shows the HPLC mapping of the impurity a compound.
FIG. 2 shows the HPLC chromatogram for the compound of formula II prepared in example 4.
Detailed Description
For better understanding of the technical solutions of the present invention, the technical solutions of the present invention are further described below with reference to specific examples, which are only for assisting understanding of the present invention and should not be construed as specifically limiting the present invention.
According to the preparation method of the present invention, the compounds shown in the following table 2 can be obtained:
specific methods for the preparation of the products of the above table see the examples below, and compounds of formula I may be prepared according to the methods described in CN114409654A, with compounds of formula PL-016 as representative compounds.
Examples 1-8 preparation of BTK inhibitor intermediate Compounds of formula PL-016
12.0g of the compound of formula I is added into a 250mL reaction flask, 120mL of DMSO is stirred and dissolved, 11.3g of IBX is added under stirring at the temperature of 20-25 ℃, and after the addition is finished, the reaction is carried out for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% alkaline solution, pulping for 1-2h at 20-30 ℃, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after the addition is finished, filtering, washing the filter cake with water, and drying in vacuum to obtain the intermediate compound PL-016.
Wherein, the selected alkaline solution is shown in the following table 3:
TABLE 3
Note: "-" indicates that no impurity A content was detected upon HPLC analysis.
When the product obtained in example 1 is analyzed and detected, the present inventors have found an inevitable impurity, and then the present inventors have separated and studied the impurity, and found that the impurity is a hydrolyzed impurity of the compound of formula PL-016, which has the following structural formula a, and its HPLC chromatogram is shown in fig. 1:
as for the compound of impurity a, which affects the quality of the final BTK inhibitor product with subsequent reactions, the inventors have conducted systematic studies on the cause of the generation of impurity a, and surprisingly found that when a weakly alkaline solution is used as an alkaline solution, potassium carbonate, sodium carbonate, dipotassium hydrogen phosphate, sodium acetate, etc. as shown in table 3 above can effectively avoid the generation of the impurity to obtain a compound of formula PL-016 with high purity, especially when potassium carbonate is used as an alkaline solution in example 4, the generation of impurity a can be completely avoided, and a product with a purity as high as 99.5% can be obtained, the HPLC detection pattern of this example is shown in fig. 2, and the corresponding spectral data of fig. 2 is shown in table 4 below.
TABLE 4
Example 9 preparation of BTK inhibitor intermediate the Compound of formula PL-016
12.0g of the compound of formula I is added into a 250mL reaction flask, 120mL of DMSO is stirred and dissolved, 11.3g of IBX is added under stirring at the temperature of 20-25 ℃, and after the addition is finished, the reaction is carried out for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 15% potassium carbonate solution, pulping at 20-30 ℃ for 1-2h, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after the addition is finished, filtering, washing the filter cake with water, and drying in vacuum to obtain 11.0g of the intermediate PL-016 compound with the yield of 92% and the purity of 99.2%, wherein the impurity A is not detected.
Example 10 preparation of BTK inhibitor intermediate Compounds of formula PL-016
Adding 12.0g of the compound shown in the formula I into a 250mL reaction bottle, stirring and dissolving 120mL of DMSO, adding 11.3g of IBX under stirring at 20-25 ℃, and reacting for 18-24 h at 20-30 ℃ after the addition is finished. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 3% potassium carbonate solution, pulping for 1-2h at 20-30 ℃, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after the addition is finished, filtering, washing the filter cake with water, and drying in vacuum to obtain 10.4g of the intermediate PL-016 compound with the yield of 87% and the purity of 99.0%, wherein the impurity A is not detected.
Example 11 preparation of BTK inhibitor intermediate the Compound of formula PL-016
12.0g of the compound of formula I is added into a 250mL reaction flask, 120mL of DMSO is stirred and dissolved, 11.3g of IBX is added under stirring at the temperature of 20-25 ℃, and after the addition is finished, the reaction is carried out for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 20% potassium carbonate solution, pulping for 1-2h at 20-30 ℃, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after the addition is finished, filtering, washing the filter cake with water, and drying in vacuum to obtain 10.0g of the intermediate PL-016 compound, wherein the yield is 84%, the purity is 98.4%, and 0.7% of impurity A is detected.
Example 12 preparation of BTK inhibitor intermediate Compounds of formula PL-016
12.0g of the compound of formula I and 120mL of dichloromethane are added into a 250mL reaction bottle and stirred to be dissolved, 11.3g of IBX is added under the stirring at the temperature of 20-25 ℃, and after the addition is finished, the reaction is carried out for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping at 20-30 ℃ for 1-2h, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO to dissolve, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 10.5g of the intermediate compound PL-016 with the yield of 88% and the purity of 99.3%, wherein 0.03% of impurity A is detected.
Comparative example 1 preparation of BTK inhibitor intermediate the Compound of formula PL-016
12.0g of the compound of the formula I is added into a 250mL reaction flask, 120mL of DMSO is stirred and dissolved, 17.1g of dess-martin reagent is added under stirring at the temperature of 20-25 ℃, and after the addition is finished, the reaction lasts for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping for 1-2h at 20-30 ℃, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO to dissolve, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 4.5g of the intermediate compound PL-016 with the yield of 38% and the purity of 90.6%, wherein the impurity A is not detected.
Comparative example 2 preparation of intermediate compound of formula PL-016 for BTK inhibitor
12.0g of the compound of the formula I is added into a 250mL reaction bottle, 120mL of DMSO is stirred and dissolved, 9.5g of iodoxybenzene is added at the temperature of 20-25 ℃ under stirring, and after the addition is finished, the reaction is carried out for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping for 1-2h at 20-30 ℃, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after the addition is finished, filtering, washing the filter cake with water, and drying in vacuum to obtain 3.8g of the intermediate PL-016 compound, wherein the yield is 32%, the purity is 91.9%, and the impurity A is not detected.
EXAMPLE 13 preparation of BTK inhibitor intermediate Compounds of formula PL-021
Adding 11.4g of the compound of the formula I into a 250mL reaction bottle, stirring and dissolving 120mL of DMSO, adding 11.3g of IBX under stirring at 20-25 ℃, and reacting for 18-24 h at 20-30 ℃ after the addition is finished. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping at 20-30 ℃ for 1-2h, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 10.1g of the intermediate PL-021 compound, wherein the yield is 89%, and the purity is 99.0%.
EXAMPLE 14 preparation of intermediate compounds of formula PL-029 for BTK inhibitors
Adding 11.9g of the compound shown in the formula I into a 250mL reaction bottle, stirring and dissolving 120mL of DMSO, adding 11.3g of IBX under stirring at 20-25 ℃, and reacting for 18-24 h at 20-30 ℃ after the addition is finished. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping at 20-30 ℃ for 1-2h, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 10.3g of the intermediate PL-029 compound, wherein the yield is 90% and the purity is 99.3%.
Example 15 preparation of BTK inhibitor intermediate the compound of formula PL-037
12.0g of the compound of formula I is added into a 250mL reaction flask, 120mL of DMSO is stirred and dissolved, 11.3g of IBX is added under stirring at the temperature of 20-25 ℃, and after the addition is finished, the reaction is carried out for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping for 1-2h at 20-30 ℃, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 10.5g of the intermediate compound PL-037, wherein the yield is 88% and the purity is 99.1%.
Example 16 preparation of BTK inhibitor intermediate the compound of formula PL-043
12.6g of the compound of formula I is added into a 250mL reaction bottle, 120mL of DMSO is stirred and dissolved, 11.3g of IBX is added at the temperature of 20-25 ℃ under stirring, and after the addition is finished, the reaction lasts for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping at 20-30 ℃ for 1-2h, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 11.4g of the intermediate PL-043 compound, wherein the yield is 91% and the purity is 99.4%.
EXAMPLE 17 preparation of BTK inhibitor intermediate Compounds of formula PL-101
13.4g of the compound of the formula I is added into a 250mL reaction flask, 120mL of DMSO is stirred and dissolved, 11.3g of IBX is added at the temperature of 20-25 ℃ under stirring, and after the addition is finished, the reaction is carried out for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping at 20-30 ℃ for 1-2h, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 12.3g of the intermediate PL-101 compound, wherein the yield is 92% and the purity is 99.5%.
EXAMPLE 18 preparation of BTK inhibitor intermediate Compounds of formula PL-109
Adding 11.5g of the compound of the formula I into a 250mL reaction bottle, stirring and dissolving 120mL of DMSO, adding 11.3g of IBX under stirring at 20-25 ℃, and reacting for 18-24 h at 20-30 ℃ after the addition is finished. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping for 1-2h at 20-30 ℃, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 10.0g of the intermediate PL-109 compound, wherein the yield is 87% and the purity is 99.0%.
EXAMPLE 19 preparation of BTK inhibitor intermediate the compound of formula PL-124
13.4g of the compound of the formula I is added into a 250mL reaction flask, 120mL of DMSO is stirred and dissolved, 11.3g of IBX is added at the temperature of 20-25 ℃ under stirring, and after the addition is finished, the reaction is carried out for 18-24 h at the temperature of 20-30 ℃. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping at 20-30 ℃ for 1-2h, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after adding, filtering, washing the filter cake with water, and drying in vacuum to obtain 12.3g of the intermediate PL-124 compound, wherein the yield is 92% and the purity is 99.5%.
Example 20 preparation of BTK inhibitor intermediate the compound of formula PL-208
Adding 13.1g of the compound of the formula I into a 250mL reaction bottle, stirring and dissolving 120mL of DMSO, adding 11.3g of IBX under stirring at 20-25 ℃, and reacting for 18-24 h at 20-30 ℃ after the addition is finished. After the reaction is finished, preparing 4.56g of sodium thiosulfate and 144mL of water into a solution, adding the solution into a reaction bottle to quench the reaction, pulping the solution at the temperature of between 20 and 30 ℃ for 1 to 2 hours, filtering the solution, and washing a filter cake by using water; adding the filter cake into a reaction bottle, adding 30mL of acetonitrile and 120mL of 9% potassium carbonate solution, pulping for 1-2h at 20-30 ℃, filtering, and washing the filter cake with water; adding the filter cake into a reaction bottle, adding 72mL of DMSO for dissolving, dropwise adding 180mL of water, pulping at 45-55 ℃ for 1-2h after the addition is finished, filtering, washing the filter cake with water, and drying in vacuum to obtain 11.7g of intermediate PL-208 compound, wherein the yield is 90% and the purity is 99.2%.
Claims (10)
1. A refining method for preparing a BTK inhibitor intermediate compound shown as a formula (II) is characterized in that a compound shown as a formula (I) is subjected to a reaction under the oxidation action of IBX and is treated by a pulping method to obtain the BTK inhibitor intermediate compound shown as a formula:
wherein X is halogen; r is 1 Selected from the group consisting of halo, methyl, phenoxy and pyridyloxy, said phenoxy and pyridyloxy being optionally substituted with 1, 2 or 3 halo; n is selected from 1, 2 and 3.
2. The preparation method according to claim 1, wherein the molar ratio of IBX to the compound of formula (I) is (1-2): 1, more preferably (1.2-1.5): 1, more preferably 1.3.
3. The method according to claim 1, wherein the reaction solvent is selected from the group consisting of DMSO, dichloromethane, chloroform, DMF, DMAC, acetonitrile, acetone and a combination of two or more thereof, and further preferably is DMSO.
4. The process according to claim 1, wherein the reaction temperature is controlled to 15 to 35 ℃, more preferably 20 to 30 ℃.
5. The production method according to claim 1, the beating method comprising:
1) After the reaction is finished, quenching the reaction by using a sodium thiosulfate aqueous solution, and then pulping;
2) Filtering after the step 1), adding acetonitrile and an alkaline solution into a filter cake, and pulping for the second time, wherein the alkaline solution is preferably a weakly alkaline solution;
3) Filtering after the step 2) is finished, adding DMSO into the filter cake to dissolve, then adding water dropwise, and pulping for the third time;
4) And 3) filtering after the step 3) is finished, washing a filter cake with water, and drying in vacuum to obtain the compound shown in the formula (II).
6. The preparation method of claim 5, wherein the molar ratio of the sodium thiosulfate in the step 1) to the compound of the formula (I) is (0.5-1.5): 1, more preferably (0.6-1.2): 1, more preferably 0.9; the pulping temperature in the step 1) is 15-35 ℃, and more preferably 20-30 ℃; the pulping time in the step 1) is 1-2h.
7. The method according to claim 5, wherein the weakly alkaline solution in step 2) is selected from the group consisting of sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, potassium bicarbonate solution, sodium sulfite solution, potassium sulfite solution, sodium phosphate solution, potassium phosphate solution, disodium hydrogen phosphate solution, dipotassium hydrogen phosphate solution, sodium acetate solution, ammonia water, and a combination of two or more thereof, and preferably potassium carbonate solution.
8. The preparation method according to claim 5, wherein the solubility of the alkaline solution in step 2) is 3% to 15% by mass, more preferably 6% to 12% by mass, and still more preferably 9% by mass.
9. The preparation method according to claim 5, wherein the beating temperature in the step 2) is 15-35 ℃, more preferably 20-30 ℃; the pulping time in the step 2) is 1-2h.
10. The preparation method according to claim 5, wherein the beating temperature in the step 3) is 35-65 ℃, more preferably 45-55 ℃; the pulping time in the step 3) is 1-2h.
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