CN112358468A - Industrial synthesis method of AZD9291 - Google Patents
Industrial synthesis method of AZD9291 Download PDFInfo
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- CN112358468A CN112358468A CN202011247889.5A CN202011247889A CN112358468A CN 112358468 A CN112358468 A CN 112358468A CN 202011247889 A CN202011247889 A CN 202011247889A CN 112358468 A CN112358468 A CN 112358468A
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- 229960003278 osimertinib Drugs 0.000 title claims abstract description 13
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 239000002808 molecular sieve Substances 0.000 claims abstract description 49
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 49
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 27
- 239000003208 petroleum Substances 0.000 claims abstract description 23
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims abstract description 22
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 239000002149 hierarchical pore Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000001354 calcination Methods 0.000 claims description 10
- 238000001704 evaporation Methods 0.000 claims description 10
- 235000019353 potassium silicate Nutrition 0.000 claims description 9
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 claims description 9
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 8
- 239000005995 Aluminium silicate Substances 0.000 claims description 7
- 235000012211 aluminium silicate Nutrition 0.000 claims description 7
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- 239000012467 final product Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 229920001296 polysiloxane Polymers 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000011148 porous material Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000006845 Michael addition reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- CSDREXVUYHZDNP-UHFFFAOYSA-N alumanylidynesilicon Chemical compound [Al].[Si] CSDREXVUYHZDNP-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J29/00—Catalysts comprising molecular sieves
- B01J29/04—Catalysts comprising molecular sieves having base-exchange properties, e.g. crystalline zeolites
- B01J29/06—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
- B01J29/40—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11, as exemplified by patent documents US3702886, GB1334243 and US3709979, respectively
-
- B01J35/60—
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B39/00—Compounds having molecular sieve and base-exchange properties, e.g. crystalline zeolites; Their preparation; After-treatment, e.g. ion-exchange or dealumination
- C01B39/02—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof; Direct preparation thereof; Preparation thereof starting from a reaction mixture containing a crystalline zeolite of another type, or from preformed reactants; After-treatment thereof
- C01B39/36—Pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11
- C01B39/38—Type ZSM-5
- C01B39/40—Type ZSM-5 using at least one organic template directing agent
Abstract
A preparation method of AZD9291 comprises the steps of taking N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline and acrylic acid as raw materials, taking an alcohol reagent as a reaction solvent, taking a hierarchical pore ZSM-5 molecular sieve as a catalyst, and taking petroleum ether as a water carrying agent, so that AZD9291 is obtained through reaction.
Description
Technical Field
The invention relates to a preparation method of a bulk drug, in particular to a preparation method of AZD 9291.
Background
AZD9191 (Osimertinib, ocitinib) is a third generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor used for activation of resistance mutant EGFR. The medicine improves the defects of the previous tinib targeted medicine, and obviously reduces the side effects such as diarrhea, rash and the like.
The chemical name of AZD9291 is: n- {2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl } -2-propenamide having the formula:
AZD9291 was developed by astrazen, uk, and its parent patent is WO2013014448 (CN 103702990A), and the following synthetic route is disclosed for the preparation of this compound:
in the preparation of compound X from compound VIII, acryloyl chloride was used for the reaction, although it is described therein, the reaction yield of this step reached 95%. But the acryloyl chloride has high toxicity and is easy to volatilize, so the reaction is carried out at low temperature (-20 ℃), and the large-scale production of the acryloyl chloride is difficult to realize.
In subsequent applications, most of the reaction processes are still adopted, such as CN104817541, CN104910049A, CN106366072A, CN108218839A, CN109134435A, and the like, although the steps of adding acryloyl chloride are not completely the same, the reaction temperature still needs to be controlled, and the reaction raw materials are not environment-friendly.
In CN107216313A, the mixed anhydride solution of acrylic acid is used for the reaction in this step, but it still needs to form acyl chloride, and dioxane solvent is used, which also has high toxicity and low reaction temperature, and the problems in the above patent still can not be solved.
In CN110317197, in this step, molecular sieve was used as catalyst, acrylic acid was used as raw material, and reaction was carried out under microwave heating, although in the examples, the yield was very good, and was mostly above 97%. However, since the reaction requires microwave heating, it is not effective for industrial mass production. According to the experiments of the present applicant, the reaction was difficult to proceed without microwave heating.
Therefore, there is a need for a method for preparing AZD9291 on an industrial scale, while avoiding problems such as environmental protection and reducing production costs.
Disclosure of Invention
In view of the above problems, the present application aims to provide a method for preparing AZD9291 using N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline and acrylic acid as raw materials using a specific molecular sieve as a catalyst, which can obtain a final product in high yield under mild reaction conditions.
In the technical scheme of the application, a specific molecular sieve is selected, and a small amount of water-binding agent is added into a reaction system, so that the technical problem can be solved.
In the embodiment of CN110317197, HY molecular sieve is used as catalyst, because the molecular sieve is microporous molecular sieve, macromolecule can not enter into its micropores effectively, so that the reaction efficiency is greatly reduced, and under the condition of no extra measure, the conversion rate of the reaction is not high. In addition, acrylic acid has much lower reactivity than acryloyl chloride, and the double bond thereof is liable to undergo a reaction Michael addition reaction with an amine in the structure of the raw material to form a by-product, which further lowers the selectivity of the product and finally leads to a decrease in yield. This is also why acryloyl chloride is commonly used in the prior art.
The applicant of the present application has found that the above problems can be effectively avoided if a specific hierarchical pore molecular sieve is used. Meanwhile, if a small amount of water-carrying agent is adopted to carry away water formed during amide formation, the generation of Michael addition can be effectively avoided, the formation of byproducts is reduced, the proceeding of amide reaction is promoted, and the reaction yield is improved.
Specifically, according to the technical scheme, the AZD9291 is obtained by reacting N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (compound 1) and acrylic acid (compound 2) serving as raw materials, an alcohol reagent serving as a reaction solvent, a hierarchical pore molecular sieve serving as a catalyst and petroleum ether serving as a water carrying agent.
The specific reaction steps of the application are that an alcohol solvent and a small amount of petroleum ether are added into a reactor with a reflux water diversion device, then N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline is added, acrylic acid and a molecular sieve are added after the N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline is dissolved, the reaction is carried out for 3-6 hours, after the reaction is finished, the solvent is removed by evaporation, and the final product is obtained by drying through.
Wherein the alcohol reagent can be ethanol, n-propanol, isopropanol, n-butanol, etc.
In this reaction, the weight ratio of molecular sieve catalyst to compounds 1, 2 was 1: (8-15): (1.5-2.5).
In the reaction, the volume-to-weight ratio of the alcohol solvent to the compound 1 is 1:2-8 (l/kg).
In this reaction, the volume-to-weight ratio of petroleum ether to compound 1 was 1:0.3-0.8 (l/kg).
Molecular sieve catalysts are currently widely used in the industrial field due to their excellent catalyst properties. Among the molecular sieves of today, there are roughly included microporous molecular sieves, mesoporous molecular sieves and macroporous molecular sieves. Microporous molecular sieves have a structure of interconnected pores and a large specific surface area, and therefore are widely used as catalysts, adsorbents, and the like. However, as described above, since the pore size of the microporous molecular sieve is small, a macromolecular reactant or product cannot effectively enter or diffuse into or out of the pore channel, thereby resulting in inefficient catalytic reaction and easily causing deactivation of active sites or carbon deposition. Therefore, introduction of mesopores, even macropores, into microporous molecular sieves has been a great deal of research in the industry at present.
The hierarchical pore molecular sieve has micropores, mesopores and macropores, so that macromolecular reactants can effectively enter and exit a pore channel, contact active sites better and can be easily removed from the pore channel after the reaction is finished. It is therefore widely welcomed by the industry.
At present, the synthesis method of the hierarchical pore molecular sieve mainly comprises a demetallization method, a layered molecular sieve pore-enlarging method, a nanoparticle assembly method, a template-assisted synthesis method and the like.
In the present application, a hierarchical pore ZSM-5 type molecular sieve is used as the catalyst.
The synthesis of the molecular sieve catalyst of the present application is as follows:
step i) at room temperature, adding water glass into deionized water, stirring uniformly, then adding a template agent under the stirring condition, stirring until the template agent is completely dissolved, and then adding kaolin as a silica-alumina source;
step ii) slowly adding dilute sulfuric acid into the silica-alumina source to form a gel flocculent structure, reacting under stirring until the system is uniform, then adding a template agent, raising the temperature of the system to 40 ℃, and reacting until the reaction is finished;
and step iii) adding the material obtained in the step ii) into a crystallization kettle, calcining for 18-36 hours at 200 ℃, drying in an oven, calcining in a muffle furnace, and removing the template agent to obtain the finished product ZSM-5 molecular sieve.
In the step 1, the weight ratio of the water glass to the template is 2-4:1, and the weight ratio of the template to the kaolin is 5-7: 1. In the step 2, the weight ratio of the addition amount of the dilute sulfuric acid to the addition amount of the water glass in the step 1 is 1:3-5, and the weight ratio of the addition amount of the template to the addition amount of the template in the step 1 is 1: 15-20.
Wherein the template agent is an organosilicon quaternary ammonium salt surfactant, preferably TPHAC.
The applicant has found that when the hierarchical pore molecular sieve is used as a catalyst, the catalytic performance is excellent, side reactions are less, and the final product can be obtained in a high yield without complicated reaction operations. Meanwhile, the use of a toxic reagent acryloyl chloride is reduced, and the reaction is environment-friendly. Even if the reaction is scaled up to an industrial scale, the reaction impurities do not increase significantly.
Detailed Description
The present invention will be further described with reference to the following examples. In the following examples, various procedures and methods not described in detail are conventional methods well known in the art. It should be understood that: the examples of the present invention are given for the purpose of illustration and not for the purpose of limitation, and therefore, the present invention is susceptible to modification in the form of a method of the present invention.
In the following description, unless otherwise specified, "%" and "part" are both expressed by weight.
Catalyst preparation example 1: preparation of molecular sieve A
Step i) at room temperature, adding 2000g of water glass and 3000g of deionized water into a reaction vessel, uniformly stirring, adding 500g of template agent TPHAC under the stirring condition, stirring until the template agent is completely dissolved, and then adding 100g of kaolin to form a silica-alumina source;
step ii) slowly adding 600g of dilute sulfuric acid with the concentration of 5mol/L into the silica-aluminum source to form a gel flocculent structure, reacting under stirring until the system is uniform, then adding 60g of template agent TPHAC, raising the temperature of the system to 40 ℃, and reacting for 2 hours;
and step iii) adding the material obtained in the step ii) into a crystallization kettle, calcining for 24 hours at 200 ℃, drying in an oven, calcining in a muffle furnace, and removing the template agent to obtain the finished product ZSM-5 molecular sieve.
Catalyst preparation example 2: preparation of molecular sieve B
Step i) at room temperature, adding 2000g of water glass and 3000g of deionized water into a reaction vessel, uniformly stirring, adding 600g of template agent TPHAC under the stirring condition, stirring until the template agent is completely dissolved, and then adding 100g of kaolin to form a silica-alumina source;
step ii) adding 500g of 5mol/L dilute sulfuric acid into the silica-alumina source slowly to form a gel flocculent structure, reacting under stirring until the system is uniform, then adding 70g of template agent TPHAC, raising the temperature of the system to 40 ℃, and reacting for 3 hours;
and step iii) adding the material obtained in the step ii) into a crystallization kettle, calcining for 36 hours at the temperature of 200 ℃, drying in an oven, calcining in a muffle furnace, and removing the template agent to obtain the finished product ZSM-5 molecular sieve.
Catalyst preparation example 3: preparation of molecular sieve C
Step i) at room temperature, adding 3000g of water glass, adding 4500g of deionized water into a reaction vessel, uniformly stirring, adding 1000g of template agent TPHAC under the stirring condition, stirring until the template agent is completely dissolved, and then adding 200g of kaolin to form a silicon-aluminum source;
step ii) slowly adding 800g of dilute sulfuric acid with the concentration of 5mol/L into the silica-alumina source to form a gel flocculent structure, reacting under stirring until the system is uniform, then adding 120g of template agent TPHAC, raising the temperature of the system to 40 ℃, and reacting for 5 hours;
and step iii) adding the material obtained in the step ii) into a crystallization kettle, calcining for 36 hours at the temperature of 200 ℃, drying in an oven, calcining in a muffle furnace, and removing the template agent to obtain the finished product ZSM-5 molecular sieve.
Comparative example 1 (see CN110317194A example 2):
adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (4.45 g, 0.010 mol), adding acrylic acid (0.86 g, 0.012 mol), HY type molecular sieve (0.66 g), isopropanol (32 mL, 7.2 mL/g), heating to 35 ℃ by microwave, reacting for 4H, drying by anhydrous sodium sulfate, and finally performing rotary evaporation to remove the solvent to obtain 4.88g of foamy off-white solid with the yield of 97.9%.
Comparative example 2 (amplified experiment of comparative example 1)
Adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (450 g, 1 mol), acrylic acid (80 g, 0.1 mol), HY type molecular sieve (30 g), isopropanol (3.2L, 7.2 ml/g), heating to 35 ℃ by microwave, reacting for 4H, drying by anhydrous sodium sulfate, and finally removing the solvent by rotary evaporation to obtain 420g of foamy off-white solid with the yield of 84.8%.
Comparative example 3 (in comparative example 1, microwave heating was not used)
Adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (4.45 g, 0.010 mol), adding acrylic acid (0.86 g, 0.012 mol), HY type molecular sieve (0.66 g, 0.003 mol), isopropanol (32 mL, 7.2 mL/g), heating to 35 ℃ by microwave, reacting for 4H, drying by anhydrous sodium sulfate, and finally performing rotary evaporation to remove the solvent to obtain 1.82g of foamed off-white solid with the yield of 36.8%.
As can be seen by comparing the above comparative examples 1-3, the yield of CN101555204A is significantly reduced when the scheme is directly scaled up, and the reaction yield is drastically reduced if the reaction is not promoted by microwave heating.
Example 1
Adding 3L ethanol and 200mL petroleum ether as a solvent into a reaction kettle with a reflux water diversion device, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (450 g), adding acrylic acid (100 g) and molecular sieve A (40 g) after dissolving, heating to 55-60 ℃, refluxing the petroleum ether, removing water, introducing into a reactor, reacting for 6 hours, evaporating to remove the solvent after the reaction is finished, and drying through sodium sulfate to obtain 450.9g of anhydrous water with the yield of 91.1%.
Example 2
Adding 3L ethanol and 200mL petroleum ether as a solvent into a reaction kettle with a reflux water diversion device, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (450 g), adding acrylic acid (100 g) and molecular sieve B (40 g) after dissolving, heating to 55-60 ℃, refluxing the petroleum ether, removing water, introducing into a reactor, reacting for 6 hours, evaporating to remove the solvent after the reaction is finished, and drying through sodium sulfate to obtain 462.3g of anhydrous water with the yield of 93.4%.
Example 3
Adding 3L ethanol and 200mL petroleum ether as a solvent into a reaction kettle with a reflux water diversion device, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (450 g), adding acrylic acid (100 g) and molecular sieve C (40 g) after dissolving, heating to 55-60 ℃, refluxing the petroleum ether, removing water, introducing into a reactor, reacting for 8 hours, evaporating to remove the solvent after the reaction is finished, and drying through sodium sulfate to obtain 471.7g of anhydrous water with the yield of 95.3%.
Example 4
Adding 4L ethanol and 300mL petroleum ether as a solvent into a reaction kettle with a reflux water diversion device, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (800 g), adding acrylic acid (200 g) and molecular sieve A (30 g) after dissolving, heating to 55-60 ℃, causing the petroleum ether to generate reflux, introducing into a reactor after removing water, reacting for 4 hours, evaporating to remove the solvent after the reaction is finished, and drying through sodium sulfate to obtain 793.76g of anhydrous water with the yield of 90.2%.
Example 5
Adding 3L ethanol and 100mL petroleum ether as solvents into a reaction kettle with a reflux water diversion device, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (450 g), adding acrylic acid (100 g) and molecular sieve A (40 g) after dissolving, heating to 55-60 ℃, causing the petroleum ether to generate reflux, introducing into a reactor after removing water, reacting for 5 hours, evaporating to remove the solvents after the reaction is finished, and drying through sodium sulfate to obtain 414.3g of anhydrous water with the yield of 83.7%.
Example 6
Adding 8L ethanol and 400mL petroleum ether into a reaction kettle with a reflux water diversion device as a solvent, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (1500 g), adding acrylic acid (350 g) and molecular sieve A (100 g) after dissolving, heating to 55-60 ℃, refluxing the petroleum ether, removing water, introducing into a reactor, reacting for 6 hours, evaporating to remove the solvent after the reaction is finished, and drying through sodium sulfate to obtain 1445g of anhydrous water with the yield of 87.6%.
Example 7
Adding 8L ethanol and 400mL petroleum ether as a solvent into a reaction kettle with a reflux water diversion device, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (2000 g), adding acrylic acid (4500 g) and molecular sieve C (100 g) after dissolving, heating to 55-60 ℃, refluxing the petroleum ether, removing water, introducing into a reactor, reacting for 6 hours, evaporating to remove the solvent after the reaction is finished, and drying through anhydrous sodium sulfate to obtain 2008.5g with the yield of 91.3%.
Example 8
Adding 8L of ethanol and a solvent into a reaction kettle with a reflux water diversion device, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (2000 g), adding acrylic acid (4500 g) and molecular sieve C (100 g) after dissolving, heating to 55-60 ℃, refluxing petroleum ether, introducing into a reactor after removing water, reacting for 6 hours, evaporating to remove the solvent after the reaction is finished, and drying through anhydrous sodium sulfate to obtain 1610.4g, wherein the yield is 73.2%.
As can be seen from the above examples, it can be seen that by using a hierarchical pore molecular sieve as a catalyst for the synthesis reaction and petroleum ether as a water-carrying agent, the reaction proceeds smoothly without using an additional reaction means, and the final product can be obtained in high yield. Even if the reaction scale is enlarged to the industrial production level, the yield is not reduced obviously. Is obviously superior to the prior art in all aspects.
Simultaneously, this application avoids using acrylyl chloride like this irritability raw materials, has effectively reduced the environmental protection risk.
Claims (9)
1. An industrial synthesis method of AZD9291 comprises the steps of using N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (hereinafter referred to as a compound 1) and acrylic acid (hereinafter referred to as a compound 2) as raw materials, using an alcohol reagent as a reaction solvent, using a hierarchical porous ZSM-5 molecular sieve as a catalyst, and using petroleum ether as a water-carrying agent, thereby obtaining the AZD9291 through reaction
2. The method of claim 1, which comprises the following steps: adding an alcohol solvent and a small amount of petroleum ether into a reactor with a reflux water diversion device, then adding N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline, after dissolving, adding acrylic acid and a molecular sieve, heating to 50-60 ℃, reacting for 3-6 hours, after the reaction is finished, evaporating to remove the solvent, and drying through anhydrous sodium sulfate to obtain a final product.
3. The method of claim 1, wherein the alcohol reagent is ethanol, n-propanol, isopropanol, n-butanol, or the like.
4. The process of claim 1, wherein the weight ratio of molecular sieve to compounds 1, 2 is 1: (8-15): (1.5-2.5).
5. The method of claim 1, wherein the volume to weight ratio of the alcoholic solvent to compound 1 is 1:2-8 (l/kg).
6. The method of claim 1, wherein the volume to weight ratio of petroleum ether to compound 1 is 1:0.3-0.8 (l/kg).
7. The method of claim 1, wherein the hierarchical pore molecular sieve catalyst is synthesized as follows:
step i) at room temperature, adding water glass into deionized water, stirring uniformly, then adding a template agent under the stirring condition, stirring until the template agent is completely dissolved, and then adding kaolin as a silica-alumina source;
step ii) slowly adding dilute sulfuric acid into the silica-alumina source to form a gel flocculent structure, reacting under stirring until the system is uniform, then adding a template agent, raising the temperature of the system to 40 ℃, and reacting until the reaction is finished;
and step iii) adding the material obtained in the step ii) into a crystallization kettle, calcining for 18-36 hours at 200 ℃, drying in an oven, calcining in a muffle furnace, and removing the template agent to obtain the finished product ZSM-5 molecular sieve.
8. The method according to claim 7, wherein in step 1, the weight ratio of the water glass to the template is 2-4:1, the weight ratio of the template to the kaolin is 5-7:1, in step 2, the weight ratio of the addition amount of the dilute sulfuric acid to the addition amount of the water glass in step 1 is 1:3-5, and the weight ratio of the addition amount of the template to the addition amount of the template in step 1 is 1: 15-20.
9. The method of claim 7, wherein the templating agent is a silicone quaternary surfactant, preferably TPHAC.
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| WO2005066156A1 (en) * | 2004-01-12 | 2005-07-21 | Cytopia Research Pty Ltd | Selective kinase inhibitors |
| WO2012158843A2 (en) * | 2011-05-17 | 2012-11-22 | The Regents Of The University Of California | Kinase inhibitors |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN110317194A (en) * | 2019-08-13 | 2019-10-11 | 滨州市鸿源工程有限公司 | A kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005066156A1 (en) * | 2004-01-12 | 2005-07-21 | Cytopia Research Pty Ltd | Selective kinase inhibitors |
| WO2012158843A2 (en) * | 2011-05-17 | 2012-11-22 | The Regents Of The University Of California | Kinase inhibitors |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN110317194A (en) * | 2019-08-13 | 2019-10-11 | 滨州市鸿源工程有限公司 | A kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand |
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