CN111116593B - Continuous preparation method of imatinib - Google Patents
Continuous preparation method of imatinib Download PDFInfo
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- CN111116593B CN111116593B CN201911182906.9A CN201911182906A CN111116593B CN 111116593 B CN111116593 B CN 111116593B CN 201911182906 A CN201911182906 A CN 201911182906A CN 111116593 B CN111116593 B CN 111116593B
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Abstract
The invention discloses a continuous and low-cost preparation method of imatinib, and belongs to the technical field of medicine synthesis. The method comprises the following steps: 1) carrying out Mitsunobu reaction on the raw material, DIAD and triphenylphosphine to obtain an intermediate; 2) removing Boc protecting group from the reaction solution, extracting unreacted 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, and feeding for application; 3) step 2) adding dichloromethane into the water phase after extracting the raw materials, adjusting the pH value with sodium hydroxide aqueous solution, separating out an organic phase, drying with anhydrous sodium sulfate, and directly adding triethylamine and acryloyl chloride for acylation reaction; 4) washing, removing impurities and evaporating to remove the solvent to obtain the imatinib. The invention overcomes the defects of large raw material residue, excessive use of the triphenyl phosphine oxide, high cost and the like in the prior art; the preparation method of the imatinib is high in comprehensive yield, low in production cost, environment-friendly and continuous, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of imatinib, and belongs to the technical field of medicine synthesis.
Background
Ibrutinib (Ibrutinib), also known by the chemical name Ibrutinib (R) -1- (3- (4-aMino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyriMidin-1-yl) piperidin-1-yl) prop-2-en-1-one, CAS No.: 936563-96-1, molecular weight 440.5, belonging to small molecule targeting drugs. The drug is an original drug named as a Bruton's Tyrosine Kinase (BTK) inhibitor which is orally developed by Pharmacyclics and Johnson, is used for treating diseases such as Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) and is approved by the Food and Drug Administration (FDA) to be sold on the market in 11-13 days in 2013, has unique and remarkable treatment effects on various diseases, and is rapidly sold internationally and increasingly demanded in recent years. The structural formula is as follows:
for the synthesis of the drug, relevant reports are already made at home and abroad, and the currently mainly adopted route is that intermediate 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine (compound II) is used as a raw material to carry out Mitsunobu reaction with (R, S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine (compound V), and then the Ibrutinib is prepared through deprotection and acylation. As described in US200680056438.5, the route is as follows:
the method has the advantages of mild reaction conditions, high reaction selectivity, less side reactions and the like, but in order to ensure the reaction effect in the Mitsunobu reaction, the added DIAD and triphenylphosphine polymers have large proportion, and the triphenylphosphine polymer is expensive, so that the manufacturing cost is high, and after the acylation reaction, the method of silica gel column chromatography is adopted for purification, which consumes time and labor, and has low production efficiency.
In order to solve the problems, CN106146512A uses triphenylphosphine to replace triphenylphosphine polymer, and the acylation process adopts condensation of acrylic anhydride and a compound VII, and the imatinib is obtained by recrystallization. The route adopts the easily obtained triphenylphosphine without column chromatography, thereby simplifying the process to a certain extent; however, the feeding molar ratio of DIAD and triphenylphosphine is 3 times of that of the compound II, so that the mother liquor is difficult to treat, the product contains more impurities, the quality of the final product can be ensured by carrying out repeated recrystallization, and the steps are complicated.
CN106008525A adopts 1.5-4 times of DIAD and triphenylphosphine to react, and the Imatinib is obtained by reacting with acrylate in the presence of catalyst and activating agent. However, the route also has the problem of large dosage of DIAD and triphenylphosphine, and the final product ibrutinib has more impurities.
CN106083860A provides a 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine: (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine: the DIAD: triphenylphosphine ═ 1: 1: 1: 1, recrystallizing the intermediate formula VII of the obtained imatinib by adopting a methanol ethyl acetate mixed solvent to obtain a high-purity refined product. Although the method has less DIAD and triphenylphosphine feeding amount, the residual quantity of the raw material 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine is large, the post-treatment does not have an effective removal method, the purity can be improved only by recrystallization, and the operation is complicated; therefore, the product yield is low, and the production cost is indirectly increased.
From the above patent methods, in the Mitsunobu reaction of the synthetic route, when the amount of DIAD and TPP is small, a large amount of unreacted 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine remains in the reaction system, resulting in waste of raw materials and lacking of a good removal means at present, and only purification by recrystallization is possible; when the dosage of DIAD and TPP is large, a large amount of three wastes such as triphenylphosphine oxide and the like are generated after the reaction is finished, so that the generation cost is increased sharply, the post-treatment difficulty is increased, the intermediate formula VII also needs to be crystallized for refining, and the process is complicated.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to overcome the defects of large raw material residual quantity, excessive use of triphenyl phosphine oxide, high cost and the like in the prior art; the preparation method of the imatinib is high in comprehensive yield, low in production cost, environment-friendly and continuous, and the obtained imatinib is High Performance Liquid Chromatography (HPLC) with the purity not less than 99%, and is suitable for industrial production.
A continuous, low cost process for the preparation of imatinib comprising the steps of:
1) carrying out Mitsunobu reaction on 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine, DIAD and triphenylphosphine in a solvent dichloromethane to obtain an intermediate compound VI (R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carboxylic acid tert-butyl ester;
the feeding molar ratio of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine to (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine, DIAD and triphenylphosphine is 1: 1-1.5: 0.7-1.5: 0.7-1.5;
2) directly introducing hydrogen chloride gas into the reaction liquid to remove Boc protecting group until the reaction liquid turns turbid after clarification, adding sodium chloride aqueous solution for extraction, adding concentrated hydrochloric acid into the extracted organic phase to extract unreacted 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, wherein the dosage (volume) of the concentrated hydrochloric acid is more than half of the volume of the organic phase, and combining the water phases; adjusting pH with sodium hydroxide solution, extracting 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine with ethyl acetate, evaporating to remove organic phase solvent, adding recrystallization solvent for refining, separating and drying, and feeding the obtained 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine for reuse;
3) step 2) adding dichloromethane into the water phase after extracting the raw materials, adjusting the pH value with sodium hydroxide aqueous solution, separating out an organic phase, drying with anhydrous sodium sulfate, and directly adding triethylamine and acryloyl chloride for acylation reaction;
4) and washing the material liquid after the reaction is finished with a citric acid aqueous solution and a saturated saline solution in sequence, adding silica gel and active carbon, stirring to remove impurities, filtering, and evaporating to remove the solvent to obtain the erlotinib with the HPLC purity of more than or equal to 99%.
The preferred step 1) is to add 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine and (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine, DIAD and triphenylphosphine in a molar ratio of 1: 1.3: 1.3: 1.3.
in step 2), adjusting the pH of the water phase to 1.8-3.5 by using a sodium hydroxide aqueous solution; the recrystallization solvent of the extracted raw material is selected from one or more of methanol, ethanol, isopropanol, acetonitrile or water.
Preferably, the pH of the aqueous phase in the step 2) is adjusted to 2.8; the recrystallization solvent is a mixture of methanol and water, and the volume ratio of the methanol to the water is 2: 3.
adjusting the pH value to 10-11 in the step 3); preferably, the pH is 11.
In the step 4), adding silica gel and activated carbon into the reaction solution according to a mass ratio of 1: 1, the mass is 5-10% of the feeding mass of the 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine.
Experiments show that the reaction liquid after removal of Boc can realize good separation of impurities, a main raw material 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine and an intermediate by using different solvent washing extraction methods under different pH conditions, the recovered main raw material can be directly reused, the obtained intermediate can be directly used for the next reaction without crystallization, reaction impurities are few, purification is not required by using a column chromatography method, and the imatinib with higher quality can be obtained at higher comprehensive yield by using a small amount of silica gel and activated carbon for stirring and impurity removal.
The invention realizes the separation of different materials by utilizing the solubility difference of the ethyl acetate to the main raw material and the intermediate product, and has good separation effect.
Step 2), directly introducing hydrogen chloride gas into the reaction liquid to remove the Boc protective group: the hydrogen chloride gas can make the reaction more complete compared with the hydrogen chloride gas introduced in the same amount of the substance, and more concentrated hydrochloric acid is needed if the same reaction effect is achieved.
The innovation of the invention is that:
the effect of perfectly separating the main raw material and the intermediate of the imatinib is achieved by accurately controlling the pH value and washing with ethyl acetate;
secondly, the invention adopts a continuous process without crystallization and recrystallization, thereby having simple process and ensuring the purity of the product;
the invention adopts extremely low material proportion, reduces the using amount of auxiliary materials and is environment-friendly; but the recovery and reuse of the unreacted main raw materials have higher comprehensive reuse yield and low cost, and are beneficial to industrial production.
The invention has the beneficial effects that:
1. the feeding proportion of triphenylphosphine and DIAD is small, the purification difficulty of products in the post-treatment process is reduced, the generation of industrial three wastes is reduced, and the method is environment-friendly;
2. multiple solvent replacement steps are avoided in the reaction process, the solvent is convenient to recover and reuse, the energy consumption is saved, and the production efficiency is high;
3. the unreacted raw materials are directly recycled and reused, the comprehensive yield is high, and the production cost is low;
4. the whole reaction is continuously operated, the steps of crystallization, column chromatography and the like are not needed in the intermediate process, repeated recrystallization is not needed, the operation is simple and convenient, and the industrial production is facilitated.
Drawings
FIG. 1 is a process flow diagram of the present invention
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
40ml of methylene chloride was added to a 100ml reaction flask, and (2.875g, 0.0095mol) of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine, (2.479g, 0.0123mol) of(s) -1-tert-butoxycarbonyl-3-hydroxypiperidine, (2.479g, 0.0123mol) of triphenylphosphine were successively added with stirring. A solution of diisopropyl azodicarboxylate in dichloromethane (2.492 g, 0.0123mol of DIAD in 15ml of dichloromethane) was added dropwise at 25 ℃ and the reaction was incubated for 5h after 35 min.
Controlling the temperature to be 0 ℃, introducing HCl gas into the reaction liquid under stirring, continuing for 4 hours, then preserving heat, reacting for 3 hours, adding a sodium chloride aqueous solution for extraction, adding 30ml of concentrated hydrochloric acid into a dichloro phase (an organic phase obtained after extraction) under stirring, separating an aqueous phase after stirring for 30 minutes, combining the two aqueous phases, adjusting the pH value to be 2.8 by using 10% of a sodium hydroxide aqueous solution under stirring, adding 60ml of ethyl acetate, and extracting a compound shown in the formula II. The aqueous phase was washed twice with 60ml of ethyl acetate, 40ml of dichloromethane was added, pH was adjusted to 11 with 10% aqueous sodium hydroxide solution, the dichloromethane phase was separated, and dried by adding 2.0g of anhydrous sodium sulfate to prepare for the next reaction.
And (3) combining ethyl acetate phases, evaporating to remove the solvent, recrystallizing with methanol water (methanol: water is 2: 3), and drying to obtain 0.358g of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine with the HPLC purity of 99.38%.
And (3) taking the reaction liquid obtained in the last step, adding (1.693g, 0.0167mol) triethylamine, controlling the temperature to be-5 ℃, dropwise adding a dichloromethane solution of acryloyl chloride (0.606 g, 0.0066mol of acryloyl chloride is dissolved in 10ml of dichloromethane) while stirring, and finishing dropping for 30 min. And keeping the temperature for reaction for 3 hours. Washed three times with 5% citric acid aqueous solution 60ml each. Adding 0.21g of silica gel and 0.21g of activated carbon, stirring for 3H to remove impurities, filtering, washing with 60ml of saturated saline solution once, drying with 1.0g of anhydrous sodium sulfate, evaporating to remove the solvent to obtain 1.655g of imatinib, wherein the yield is 65.79% based on actual consumption of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, and the HPLC purity is 99.56%.
Example 2:
to a 100ml reaction flask was added 40ml of methylene chloride, and the compound of formula II (containing 0.358g of the compound of formula II recovered in example 1), (1.907g, 0.0095mol) and the compound of formula V (1.989g, 0.0076mol) and the compound of formula III were added successively with stirring (2.875g, 0.0095 mol). Compound IV in dichloromethane (1.533 g, 0.0076mol DIAD in 15ml dichloromethane) was added dropwise at 25 deg.C, and the reaction was incubated for 5h after 35 min.
Controlling the temperature to be 0 ℃, and introducing HCl gas into the reaction solution for 4 hours under stirring. And keeping the temperature for reaction for 3 hours. Adding sodium chloride aqueous solution for extraction. Adding 30ml of concentrated hydrochloric acid into the dichloro phase while stirring, separating the aqueous phase after stirring for 30min, combining the two aqueous phases, adjusting the pH to 3.1 by using 10% of sodium hydroxide aqueous solution while stirring, adding 60ml of ethyl acetate, and extracting a compound shown in the formula II. The aqueous phase was washed twice with 60ml of ethyl acetate, 40ml of dichloromethane was added, pH was adjusted to 11 with 10% aqueous sodium hydroxide solution, the dichloromethane phase was separated, and dried by adding 2.0g of anhydrous sodium sulfate to prepare for the next reaction.
And (3) combining the ethyl acetate phases, evaporating the solvent, recrystallizing with ethanol water (the ratio of ethanol to water is 1: 2), and drying to obtain a compound shown in the formula II 1.014g with the HPLC purity of 99.15%.
And (3) taking the reaction liquid obtained in the last step, adding (1.037g, 0.010mol) triethylamine, controlling the temperature to be-5 ℃, dropwise adding a dichloromethane solution of acryloyl chloride (0.371 g, 0.0041mol of acryloyl chloride is dissolved in 10ml of dichloromethane) while stirring, and finishing dripping after 30 min. And keeping the temperature for reaction for 3 hours. Washed three times with 5% citric acid aqueous solution 60ml each. Adding 0.20g of silica gel and 0.20g of activated carbon, stirring for 3h to remove impurities, filtering, washing with 60ml of saturated saline solution once, drying with 1.0g of anhydrous sodium sulfate, and evaporating to remove the solvent to obtain 0.994g of the ibrutinib, wherein the actual consumption of the compound shown in the formula II is taken as the standard, the yield is 54.16%, and the HPLC purity is 99.34%.
Example 3:
40ml of methylene chloride was charged into a 100ml reaction flask, and the compound of formula II (containing 1.014g of the compound of formula II recovered in example 2) and the compound of formula V (2.479g, 0.0123mol) and the compound of formula III (3.232g, 0.0123mol) were successively added thereto with stirring (2.875g, 0.0095 mol). A solution of compound IV in dichloromethane (2.492 g, 0.0123mol of DIAD in 15ml of dichloromethane) was added dropwise at controlled temperature of 20 ℃ and the reaction was incubated for 5h after 35 min.
Controlling the temperature to be 0 ℃, and introducing HCl gas into the reaction solution for 4 hours under stirring. And keeping the temperature for reaction for 3 hours. Adding a sodium chloride aqueous solution for extraction, adding 30ml of concentrated hydrochloric acid into the dichloro phase while stirring, stirring for 30min, separating the aqueous phase, combining the two aqueous phases, adjusting the pH value to 2.5 by using 10% of a sodium hydroxide aqueous solution while stirring, adding 60ml of ethyl acetate, and extracting a compound shown in the formula II. The aqueous phase was washed twice with 60ml of ethyl acetate, 40ml of dichloromethane was added, pH was adjusted to 11 with 10% aqueous sodium hydroxide solution, the dichloromethane phase was separated, and dried by adding 2.0g of anhydrous sodium sulfate to prepare for the next reaction.
And (4) combining the ethyl acetate phases, evaporating the solvent, recrystallizing with methanol water (methanol: water is 2: 3), and drying to obtain a compound shown in the formula II, wherein the compound is 0.478g, and the HPLC purity is 99.11%.
The reaction solution obtained in the last step is taken, triethylamine (1.544g, 0.0152mol) is added, a dichloromethane solution of acryloyl chloride (0.552 g, 0.0061mol of acryloyl chloride is dissolved in 10ml of dichloromethane) is added dropwise under stirring at the temperature of minus 5 ℃, and dripping is finished after 30 min. And keeping the temperature for reaction for 3 hours. Washed three times with 5% citric acid aqueous solution 60ml each. Adding 0.19g of silica gel and 0.19g of activated carbon, stirring for 3h to remove impurities, filtering, washing with 60ml of saturated saline solution once, drying with 1.0g of anhydrous sodium sulfate, and evaporating to remove the solvent to obtain 1.538g of ibrutinib, wherein the yield is 64.20% and the HPLC purity is 99.29% based on the actual consumption of the compound shown in the formula II.
Example 4:
40ml of methylene chloride was charged into a 100ml reaction flask, and the compound of formula II (containing 0.478g of the compound of formula II recovered in example 3), (2.479g, 0.0123mol) and the compound of formula V (3.232g, 0.0123mol) and the compound of formula III were successively added with stirring (2.875g, 0.0095 mol). A solution of compound IV in dichloromethane (2.492 g, 0.0123mol of DIAD in 15ml of dichloromethane) was added dropwise at controlled temperature of 20 ℃ and the reaction was incubated for 5h after 35 min.
Controlling the temperature to be 5 ℃, and introducing HCl gas into the reaction solution for 4 hours under stirring. And keeping the temperature for reaction for 3 hours. Adding sodium chloride aqueous solution for extraction. Adding 30ml of concentrated hydrochloric acid into the dichloro phase while stirring, separating the aqueous phase after stirring for 30min, combining the two aqueous phases, adjusting the pH to 2.6 by using 10% of sodium hydroxide aqueous solution while stirring, adding 60ml of ethyl acetate, and extracting a compound shown in the formula II. The aqueous phase was washed twice with 60ml of ethyl acetate, 40ml of dichloromethane was added, pH was adjusted to 11 with 10% aqueous sodium hydroxide solution, the dichloromethane phase was separated, and dried by adding 2.0g of anhydrous sodium sulfate to prepare for the next reaction.
And (4) combining the ethyl acetate phases, evaporating the solvent, recrystallizing with methanol water (methanol: water is 2: 3), and drying to obtain the compound shown in the formula II, wherein the compound is 0.491g, and the HPLC purity is 99.35%.
The reaction solution obtained in the previous step is taken, triethylamine (1.543g, 0.0152mol) is added, a dichloromethane solution of acryloyl chloride (0.552 g, 0.0061mol of acryloyl chloride is dissolved in 10ml of dichloromethane) is added dropwise under stirring at the temperature of-5 ℃, and the dropwise addition is completed within 30 min. And keeping the temperature for reaction for 3 hours. Washed three times with 5% citric acid aqueous solution 60ml each. Adding 0.22g of silica gel and 0.22g of activated carbon, stirring for 3h to remove impurities, filtering, washing with 60ml of saturated saline solution once, drying with 1.0g of anhydrous sodium sulfate, and evaporating to remove the solvent to obtain 1.574g of the ibrutinib, wherein the yield is 66.15% and the HPLC purity is 99.18% based on the actual consumption of the compound shown in the formula II.
Example 5:
40ml of methylene chloride was charged into a 100ml reaction flask, and the compound of formula II (containing 0.491g of the compound recovered in example 4) and the compound of formula V (2.864g, 0.0142mol) and the compound of formula III (3.232g, 0.0123mol) were successively added thereto with stirring (2.875g, 0.0095 mol). Compound IV in dichloromethane (3.729 g, 0.0142mol DIAD in 15ml dichloromethane) was added dropwise at controlled temperature of 20 deg.C, and the reaction was incubated for 5h after 35 min.
Controlling the temperature to be 0 ℃, and introducing HCl gas into the reaction solution for 4 hours under stirring. And keeping the temperature for reaction for 3 hours. Adding sodium chloride aqueous solution for extraction. Adding 30ml of concentrated hydrochloric acid into the dichloro phase while stirring, separating the aqueous phase after stirring for 30min, combining the two aqueous phases, adjusting the pH to 3.0 by using 10% of sodium hydroxide aqueous solution while stirring, adding 60ml of ethyl acetate, and extracting a compound shown in the formula II. The aqueous phase was washed twice with 60ml of ethyl acetate, 40ml of dichloromethane was added, pH was adjusted to 11 with 10% aqueous sodium hydroxide solution, the dichloromethane phase was separated, and dried by adding 2.0g of anhydrous sodium sulfate to prepare for the next reaction.
And (3) combining the ethyl acetate phases, evaporating the solvent, recrystallizing with ethanol water (the ratio of ethanol to water is 1: 2), and drying to obtain a compound shown in the formula II, wherein the compound is 0.450g, and the HPLC purity is 98.68%.
The reaction solution obtained in the previous step is taken, triethylamine (1.553g, 0.0153mol) is added, a dichloromethane solution of acryloyl chloride (0.556 g, 0.0061mol of acryloyl chloride is dissolved in 10ml of dichloromethane) is added dropwise under stirring at the temperature of minus 5 ℃, and dripping is finished after 30 min. And keeping the temperature for reaction for 3 hours. Washed three times with 5% citric acid aqueous solution 60ml each. Adding 0.21g of silica gel and 0.21g of activated carbon, stirring for 3h to remove impurities, filtering, washing with 60ml of saturated saline solution once, drying with 1.0g of anhydrous sodium sulfate, and evaporating to remove the solvent to obtain 1.560g of the ibrutinib, wherein the actual consumption of the compound shown in the formula II is taken as the standard, the yield is 64.35%, and the HPLC purity is 99.27%.
Example 6:
40ml of methylene chloride was charged into a 100ml reaction flask, and the compound of formula II (containing 0.450g of the recovered compound of formula II of example 4) and the compound of formula V (2.864g, 0.0142mol) and the compound of formula III (3.232g, 0.0123mol) were successively added thereto with stirring (2.875g, 0.0095 mol). Compound IV in dichloromethane (3.729 g, 0.0142mol DIAD in 15ml dichloromethane) was added dropwise at controlled temperature of 20 deg.C, and the reaction was incubated for 5h after 35 min.
Controlling the temperature to be 0 ℃, and introducing HCl gas into the reaction solution for 4 hours under stirring. And keeping the temperature for reaction for 3 hours. Adding sodium chloride aqueous solution for extraction. Adding 30ml of concentrated hydrochloric acid into the dichloro phase while stirring, separating the aqueous phase after stirring for 30min, combining the two aqueous phases, adjusting the pH to 2.7 by using 10% of sodium hydroxide aqueous solution while stirring, adding 60ml of ethyl acetate, and extracting a compound shown in the formula II. The aqueous phase was washed twice with 60ml of ethyl acetate, 40ml of dichloromethane was added, pH was adjusted to 11 with 10% aqueous sodium hydroxide solution, the dichloromethane phase was separated, and dried by adding 2.0g of anhydrous sodium sulfate to prepare for the next reaction.
And (3) combining the ethyl acetate phases, evaporating the solvent, recrystallizing with methanol water (methanol: water is 1: 2), and drying to obtain a compound shown in the formula II, wherein the compound is 0.301g, and the HPLC purity is 99.26%.
The reaction solution obtained in the last step is taken, triethylamine (1.708g, 0.0168mol) is added, the temperature is controlled to be minus 5 ℃, a dichloromethane solution of acryloyl chloride (0.611 g, 0.0067mol of acryloyl chloride is dissolved in 10ml of dichloromethane) is added dropwise under stirring, and the dropwise addition is completed within 30 min. And keeping the temperature for reaction for 3 hours. Washed three times with 5% citric acid aqueous solution 60ml each. Adding 0.20g of silica gel and 0.20g of activated carbon, stirring for 3h to remove impurities, filtering, washing with 60ml of saturated saline solution once, drying with 1.0g of anhydrous sodium sulfate, and evaporating to remove the solvent to obtain 1.725g of the ibrutinib, wherein the actual consumption of the compound shown in the formula II is taken as the standard, the yield is 67.12%, and the HPLC purity is 99.37%.
Example 7:
40ml of methylene chloride was charged into a 100ml reaction flask, and the compound of formula II (containing 0.301g of the recovered compound of formula II of example 4) and the compound of formula V (2.864g, 0.0142mol) and the compound of formula III (3.232g, 0.0123mol) were successively added thereto with stirring (2.875g, 0.0095 mol). Compound IV in dichloromethane (3.729 g, 0.0142mol DIAD in 15ml dichloromethane) was added dropwise at controlled temperature of 20 deg.C, and the reaction was incubated for 5h after 35 min.
Controlling the temperature to be 0 ℃, and introducing HCl gas into the reaction solution for 4 hours under stirring. And keeping the temperature for reaction for 3 hours. Adding sodium chloride aqueous solution for extraction. Adding 30ml of concentrated hydrochloric acid into the dichloro phase while stirring, separating the aqueous phase after stirring for 30min, combining the two aqueous phases, adjusting the pH to 3.0 by using 10% of sodium hydroxide aqueous solution while stirring, adding 60ml of ethyl acetate, and extracting a compound shown in the formula II. The aqueous phase was washed twice with 60ml of ethyl acetate, 40ml of dichloromethane was added, pH was adjusted to 11 with 10% aqueous sodium hydroxide solution, the dichloromethane phase was separated, and dried by adding 2.0g of anhydrous sodium sulfate to prepare for the next reaction.
And (4) combining the ethyl acetate phases, evaporating the solvent, recrystallizing with methanol water (methanol: water is 2: 3), and drying to obtain a compound shown in the formula II, wherein the compound is 0.388g, and the HPLC purity is 99.43%.
The reaction solution obtained in the previous step was taken, triethylamine (1.696g, 0.0167mol) was added, a dichloromethane solution of acryloyl chloride (0.607 g, 0.0067mol of acryloyl chloride was dissolved in 10ml of dichloromethane) was added dropwise with stirring at-5 ℃, and the dropwise addition was completed within 30 min. And keeping the temperature for reaction for 3 hours. Washed three times with 5% citric acid aqueous solution 60ml each. Adding 0.23g of silica gel and 0.23g of activated carbon, stirring for 3h to remove impurities, filtering, washing with 60ml of saturated saline solution once, drying with 1.0g of anhydrous sodium sulfate, and evaporating to remove the solvent to obtain 1.667g of the ibrutinib, wherein the actual consumption of the compound shown in the formula II is taken as the standard, the yield is 67.04%, and the HPLC purity is 99.08%.
The applicant states that the present invention is illustrated by the above examples, but the present invention is not limited to the above process steps, i.e. it is not meant to imply that the present invention must rely on the above process steps to be carried out. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.
Claims (6)
1. A continuous preparation method of imatinib is characterized in that: the method comprises the following steps:
1) mitsunobu reaction of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine with (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine, DIAD, triphenylphosphine in the solvent dichloromethane to give the intermediate (R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidine-1-carboxylic acid tert-butyl ester;
the feeding molar ratio of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine to (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine, DIAD and triphenylphosphine is 1: 1-1.5: 0.7-1.5: 0.7-1.5;
2) directly introducing hydrogen chloride gas into the reaction liquid to remove Boc protecting groups until the reaction liquid turns turbid after clarification, adding sodium chloride aqueous solution for extraction, adding concentrated hydrochloric acid into the extracted organic phase to extract unreacted 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, and combining water phases; adjusting pH with sodium hydroxide solution, extracting 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine with ethyl acetate, evaporating to remove organic phase solvent, adding recrystallization solvent for refining, separating and drying, and feeding the obtained 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine for reuse;
3) step 2) adding dichloromethane into the water phase after extracting the raw materials, adjusting the pH value with sodium hydroxide aqueous solution, separating out an organic phase, drying with anhydrous sodium sulfate, and directly adding triethylamine and acryloyl chloride for acylation reaction;
4) and washing the material liquid after the reaction is finished with a citric acid aqueous solution and a saturated saline solution in sequence, adding silica gel and active carbon, stirring to remove impurities, filtering, and evaporating to remove the solvent to obtain the erlotinib with the HPLC purity of more than or equal to 99%.
2. The process for the preparation of imatinib of claim 1, wherein: the feeding molar ratio of the 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine to the (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine, DIAD and triphenylphosphine in the step 1) is 1: 1.3: 1.3: 1.3.
3. the process for the preparation of imatinib of claim 1, wherein: in the step 2), the pH of the water phase is adjusted to 1.8-3.5 by using a sodium hydroxide aqueous solution; the recrystallization solvent of the extracted raw material is selected from one or more of methanol, ethanol, isopropanol, acetonitrile or water.
4. The process for the preparation of imatinib of claim 3, wherein: in the step 2), the pH value of the water phase is adjusted to 2.8; the recrystallization solvent is a mixture of methanol and water, and the volume ratio of the methanol to the water is 2: 3.
5. the process for the preparation of imatinib of claim 1, wherein: adjusting the pH value to 10-11 in the step 3).
6. The process for the preparation of imatinib of claim 1, wherein: in the step 4), the mass ratio of the silica gel and the activated carbon added into the reaction solution is 1: 1, the mass is 5-10% of the feeding mass of the 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine.
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