CN112430231B - Industrial preparation method of AZD9291 - Google Patents
Industrial preparation method of AZD9291 Download PDFInfo
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- CN112430231B CN112430231B CN202011230392.2A CN202011230392A CN112430231B CN 112430231 B CN112430231 B CN 112430231B CN 202011230392 A CN202011230392 A CN 202011230392A CN 112430231 B CN112430231 B CN 112430231B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 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
- 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 67
- 239000002808 molecular sieve Substances 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003208 petroleum Substances 0.000 claims abstract description 24
- 239000003054 catalyst 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 20
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002149 hierarchical pore Substances 0.000 claims abstract description 10
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 239000002904 solvent Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 19
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 17
- 229910052708 sodium Inorganic materials 0.000 claims description 17
- 239000011734 sodium Substances 0.000 claims description 17
- 235000019353 potassium silicate Nutrition 0.000 claims description 14
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-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 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 claims description 10
- 238000001354 calcination Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001704 evaporation Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 239000005995 Aluminium silicate Substances 0.000 claims description 8
- 235000012211 aluminium silicate Nutrition 0.000 claims description 8
- 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 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 230000032683 aging Effects 0.000 claims description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 150000001875 compounds Chemical class 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
- ICAKDTKJOYSXGC-UHFFFAOYSA-K lanthanum(iii) chloride Chemical compound Cl[La](Cl)Cl ICAKDTKJOYSXGC-UHFFFAOYSA-K 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 238000004537 pulping Methods 0.000 claims description 5
- 238000009718 spray deposition Methods 0.000 claims description 5
- 239000000725 suspension 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
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 229920001296 polysiloxane Polymers 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 239000011148 porous material Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 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
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001308 synthesis method Methods 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
- 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
- 229940125782 compound 2 Drugs 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
- 238000004090 dissolution Methods 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
- 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
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 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
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- 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
- B01J29/08—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the faujasite type, e.g. type X or Y
- B01J29/085—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the faujasite type, e.g. type X or Y containing rare earth elements, titanium, zirconium, hafnium, zinc, cadmium, mercury, gallium, indium, thallium, tin or lead
- B01J29/088—Y-type faujasite
-
- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/0009—Use of binding agents; Moulding; Pressing; Powdering; Granulating; Addition of materials ameliorating the mechanical properties of the product catalyst
- B01J37/0018—Addition of a binding agent or of material, later completely removed among others as result of heat treatment, leaching or washing,(e.g. forming of pores; protective layer, desintegrating by heat)
-
- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/02—Impregnation, coating or precipitation
- B01J37/03—Precipitation; Co-precipitation
- B01J37/036—Precipitation; Co-precipitation to form a gel or a cogel
-
- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/08—Heat treatment
-
- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/08—Heat treatment
- B01J37/10—Heat treatment in the presence of water, e.g. steam
-
- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/30—Ion-exchange
-
- 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
- B01J2229/00—Aspects of molecular sieve catalysts not covered by B01J29/00
- B01J2229/10—After treatment, characterised by the effect to be obtained
- B01J2229/18—After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself
- B01J2229/183—After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself in framework positions
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Thermal Sciences (AREA)
- Dispersion Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
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 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 structural 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 acryloyl chloride has high toxicity and is volatile, so the reaction is carried out at low temperature (-20 ℃), and large-scale production 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 using 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 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 anhydrous sodium sulfate.
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 the present invention, a microporous molecular sieve, a mesoporous molecular sieve and a macroporous molecular sieve are roughly included. 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 Y-type molecular sieve is used as the catalyst, and more preferably a kaolin/Y-type mixed molecular sieve.
The synthesis of the molecular sieve catalyst of the present application is as follows:
step i) adding a sodium metaaluminate solution into water glass at room temperature, stirring and mixing uniformly, then standing and aging at 30-50 ℃, standing for 10-20h to obtain white gel, and taking the white gel as a guiding agent, wherein the mass ratio of sodium metaaluminate to water glass is 1: 1-2;
at room temperature, adding template agent, aluminum sulfate solution, sodium metaaluminate solution and guiding agent gel into water glass, stirring and crystallizing for 12-36 h. After crystallization is finished, cooling, washing, drying and calcining at high temperature to remove the template agent, wherein the ratio of the water glass, the guiding agent, the template agent, the aluminum sulfate solution and the sodium metaaluminate solution is 2-4 g: 6-8 g: 3-4 g: 15-20 mL: 5-10 mL;
step ii) adding the prepared molecular sieve into deionized water to prepare a molecular sieve suspension, adding an ammonium chloride solution and a lanthanum chloride solution with the concentration of 5 weight percent in a water bath at the temperature of 80-100 ℃, controlling the pH value to be 3-5, exchanging for 1-3h, cooling, washing to be neutral, and then roasting; roasting at 400-600 ℃, roasting with 100% water vapor for 2-4h, and repeating the above process for 2-4 times to obtain the ion-modified molecular sieve;
step iii) mixing the ion-modified molecular sieve with kaolin and alumina sol, pulping in a water bath, spray-forming, and calcining at the temperature of 500-600 ℃ to obtain a finished catalyst, wherein the weight ratio of the molecular sieve to the kaolin is 3-5: 1;
the concentration of the aluminum sulfate solution is 25 weight percent, and the concentration of the sodium metaaluminate is 250-300g/l in terms of aluminum oxide.
Wherein the template agent is an organosilicon quaternary ammonium salt surfactant, preferably TPHAC.
Wherein the feeding sequence in the step ii) is an aluminum sulfate solution, a sodium metaaluminate solution, a directing agent gel and a template agent.
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) adding 150g of sodium metaaluminate solution into 200g of water glass at room temperature, stirring and mixing uniformly, then standing and aging at 40 ℃, standing for 15h to obtain white gel, and taking the white gel as a guiding agent;
at room temperature, adding 150mL of aluminum sulfate solution, 60mL of sodium metaaluminate solution, 60g of directing agent gel and 35g of template agent TPHAC into 30g of water glass in sequence, and crystallizing for 24 hours after stirring. After crystallization is finished, cooling, washing and drying the sample, and calcining at high temperature to remove the template agent;
step ii) adding the prepared molecular sieve into deionized water to prepare a molecular sieve suspension, adding an ammonium chloride solution and a lanthanum chloride solution with the concentration of 5 weight percent in a water bath at the temperature of 80 ℃, controlling the pH value to be 3, exchanging for 3 hours, cooling, washing to be neutral, and roasting; roasting at 400 ℃, roasting with 100% water vapor for 2h, and repeating the process for 2 times to obtain the ion-modified molecular sieve;
and step iii) mixing 100g of the ion-modified molecular sieve, 350g of kaolin and a small amount of alumina sol, pulping in a water bath, spray-forming, and calcining at 500 ℃ to obtain the finished catalyst.
Catalyst preparation example 2: preparation of molecular sieve B
Step i) adding 180g of sodium metaaluminate solution into 200g of water glass at room temperature, stirring and mixing uniformly, standing and aging at 40 ℃, standing for 18h to obtain white gel which is used as a guiding agent;
at room temperature, adding 120mL of aluminum sulfate solution, 50mL of sodium metaaluminate solution, 50g of directing agent gel and 40g of template agent TPHAC into 30g of water glass in sequence, and crystallizing for 24 hours after stirring. After crystallization is finished, cooling, washing and drying the sample, and calcining at high temperature to remove the template agent;
step ii) adding the prepared molecular sieve into deionized water to prepare a molecular sieve suspension, adding an ammonium chloride solution and a lanthanum chloride solution with the concentration of 5 weight percent in a water bath at the temperature of 80 ℃, controlling the pH value to be 3, exchanging for 3 hours, cooling, washing to be neutral, and roasting; roasting at 500 ℃, roasting with 100% water vapor for 4h, and repeating the above process for 2 times to obtain the ion-modified molecular sieve;
and step iii) mixing 80g of the ion-modified molecular sieve, 350g of kaolin and a small amount of alumina sol, pulping in a water bath, spray-forming, and calcining at 600 ℃ to obtain the finished catalyst.
Catalyst preparation example 3: preparation of molecular sieve C
Step i) adding 150g of sodium metaaluminate solution into 200g of water glass at room temperature, stirring and mixing uniformly, then standing and aging at 30 ℃, standing for 18h to obtain white gel which is used as a guiding agent;
at room temperature, adding 180mL of aluminum sulfate solution, 60mL of sodium metaaluminate solution, 70g of directing agent gel and 45g of template agent TPHAC into 30g of water glass in sequence, and crystallizing for 24 hours after stirring. After crystallization is finished, cooling, washing and drying the sample, and calcining at high temperature to remove the template agent;
step ii) adding the prepared molecular sieve into deionized water to prepare a molecular sieve suspension, adding an ammonium chloride solution and a lanthanum chloride solution with the concentration of 5 weight percent in a water bath at the temperature of 80 ℃, controlling the pH value to be 3, exchanging for 3 hours, cooling, washing to be neutral, and roasting; roasting at 500 ℃, roasting with 100% water vapor for 3h, and repeating the above process for 3 times to obtain the ion-modified molecular sieve;
and step iii) mixing 100g of the ion-modified molecular sieve, 350g of kaolin and a small amount of alumina sol, pulping in a water bath, spray-forming, and calcining at 600 ℃ to obtain the finished catalyst.
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 ℃, reacting for 4H, drying with 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 (30 g) after dissolving, heating to 55-60 ℃, causing the petroleum ether to reflux, introducing into a reactor after removing water, reacting for 5 hours, evaporating to remove the solvent after the reaction is finished, and drying by sodium sulfate to obtain 444.6g of anhydrous water with the yield of 90.2%.
Example 2
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 5 hours, evaporating to remove the solvent after the reaction is finished, and drying through sodium sulfate to obtain 803.4g of anhydrous water with the yield of 91.3%.
Example 3
Adding 3L of ethanol and 100mL of petroleum ether into a reaction kettle with a reflux water diversion device as solvents, 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 (30 g) after dissolving, heating to 55-60 ℃, refluxing the petroleum ether, removing water, introducing into a reactor, reacting for 5 hours, evaporating to remove the solvents after the reaction is finished, and drying through sodium sulfate to obtain 403.4g of anhydrous water with the yield of 81.5%.
Example 4
Adding 8L of ethanol and 500mL of petroleum ether into a reaction kettle with a reflux water diversion device as solvents, 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 (400 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 5 hours, evaporating to remove the solvents after the reaction is finished, and drying through sodium sulfate to obtain 1955.8g with the yield of 88.9%.
Example 5
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 5 hours, evaporating to remove the solvent after the reaction is finished, and drying through sodium sulfate to obtain 457g of anhydrous yield of 92.3%.
Example 6
10L of ethanol and 500mL of petroleum ether are added into a reaction kettle with a reflux water diversion device as solvents, then N-2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] aniline (2000 g) is added, acrylic acid (400 g) and molecular sieve B (100 g) are added after dissolution, heating is carried out to 55-60 ℃, petroleum ether is refluxed, water is removed, then the mixture is introduced into a reactor for reaction for 5 hours, after the reaction is finished, the solvent is removed by evaporation, and the mixture is dried by sodium sulfate, so 1991g of anhydrous water with the yield of 90.5 percent is obtained.
Example 7
Adding 3L of ethanol and 200mL of petroleum ether into a reaction kettle with a reflux water diversion device as solvents, 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 (30 g) after dissolving, heating to 55-60 ℃, refluxing the petroleum ether, removing water, introducing into a reactor, reacting for 5 hours, evaporating to remove the solvents after the reaction is finished, and drying through sodium sulfate to obtain 438.6g of anhydrous water with the yield of 88.6%.
Example 8
Adding 10L of ethanol and 600mL of 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 (2000 g), adding acrylic acid (450 g) and molecular sieve C (120 g) after dissolving, heating to 55-60 ℃, refluxing the petroleum ether, removing water, introducing into a reactor, reacting for 5 hours, evaporating to remove the solvent after the reaction is finished, and drying by sodium sulfate to obtain 1900g of anhydrous water with the yield of 86.5%.
As can be seen from the above examples, by using a hierarchical pore molecular sieve as a catalyst for the synthesis reaction and petroleum ether as a water-carrying agent, the reaction can proceed 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. A preparation method of AZD9291 comprises the steps of taking a compound 1 and acrylic acid as raw materials, taking an alcohol reagent as a reaction solvent, taking a hierarchical pore Y-shaped molecular sieve as a catalyst, and taking petroleum ether as a water-carrying agent, so as to obtain AZD9291 through reaction;
the preparation method of the hierarchical pore Y-type molecular sieve comprises the following steps:
step i) adding a sodium metaaluminate solution into water glass at room temperature, stirring and mixing uniformly, then standing and aging at 30-50 ℃, standing for 10-20h to obtain white gel, and taking the white gel as a guiding agent, wherein the mass ratio of sodium metaaluminate to water glass is 1: 1-2;
adding a template agent, an aluminum sulfate solution, a sodium metaaluminate solution and a directing agent gel into water glass at room temperature, stirring, crystallizing for 12-36h, cooling, washing, drying and calcining at high temperature to remove the template agent, wherein the ratio of the water glass, the directing agent, the template agent, the aluminum sulfate solution and the sodium metaaluminate solution is 2-4 g: 6-8 g: 3-4 g: 15-20 mL: 5-10 mL;
step ii) adding the prepared molecular sieve into deionized water to prepare a molecular sieve suspension, adding an ammonium chloride solution and a lanthanum chloride solution with the concentration of 5 weight percent in a water bath at the temperature of 80-100 ℃, controlling the pH value to be 3-5, exchanging for 1-3h, cooling, washing to be neutral, and then roasting; roasting at 400-600 ℃, roasting with 100% water vapor for 2-4h, and repeating the above process for 2-4 times to obtain the ion-modified molecular sieve;
and step iii) mixing the ion-modified molecular sieve with kaolin and alumina sol, pulping in a water bath, spray-forming, and calcining at the temperature of 500-600 ℃ to obtain the finished catalyst, wherein the weight ratio of the molecular sieve to the kaolin is 3-5: 1.
2. The preparation method according to claim 1, comprising 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 a compound 1, adding acrylic acid and a molecular sieve after dissolving, heating to 50-60 ℃, reacting for 3-6 hours, evaporating to remove the solvent after the reaction is finished, and drying through anhydrous sodium sulfate to obtain a final product.
3. The process according to claim 1, wherein the alcohol reagent is ethanol, n-propanol, isopropanol or n-butanol.
4. The method of claim 1, wherein the weight ratio of molecular sieve catalyst to compounds 1, 2 is 1: (8-15): (1.5-2.5).
5. The process according to claim 1, wherein the volume/weight ratio of the alcoholic solvent to the compound 1 is 1:2 to 8 in terms of l/kg.
6. The production method according to claim 1, wherein the volume-to-weight ratio of petroleum ether to compound 1 is 1:0.3 to 0.8 in terms of l/kg.
7. The method of claim 1, wherein the templating agent is a silicone quaternary surfactant.
8. The method according to claim 7, wherein the surfactant is TPHAC.
9. The method of claim 7, wherein the step ii) is carried out by sequentially adding aluminum sulfate solution, sodium metaaluminate solution, directing agent gel and template agent.
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