CN114276324A - Preparation method and application of icotinib intermediate - Google Patents
Preparation method and application of icotinib intermediate Download PDFInfo
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- CN114276324A CN114276324A CN202111662343.0A CN202111662343A CN114276324A CN 114276324 A CN114276324 A CN 114276324A CN 202111662343 A CN202111662343 A CN 202111662343A CN 114276324 A CN114276324 A CN 114276324A
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- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 229950007440 icotinib Drugs 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000000047 product Substances 0.000 claims abstract description 62
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 60
- 239000013067 intermediate product Substances 0.000 claims abstract description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229960000583 acetic acid Drugs 0.000 claims abstract description 22
- 239000011259 mixed solution Substances 0.000 claims abstract description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 12
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 11
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- NUWHYWYSMAPBHK-UHFFFAOYSA-N 3,4-dihydroxybenzonitrile Chemical compound OC1=CC=C(C#N)C=C1O NUWHYWYSMAPBHK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 238000001914 filtration Methods 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 238000001035 drying Methods 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- 238000004537 pulping Methods 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical group NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- 238000007865 diluting Methods 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- 238000006479 redox reaction Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims 2
- 239000006185 dispersion Substances 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000000654 additive Substances 0.000 abstract description 3
- 239000003344 environmental pollutant Substances 0.000 abstract description 3
- 231100000719 pollutant Toxicity 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 8
- 239000006227 byproduct Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 6
- 206010020718 hyperplasia Diseases 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- -1 methyl dimethyl acetal Chemical compound 0.000 description 4
- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical compound [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 229910002651 NO3 Inorganic materials 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- NUGGLNMQKCFZJQ-UHFFFAOYSA-N tert-butyl N-(3,4-dihydroxyphenyl)carbamate Chemical compound C(=O)(OC(C)(C)C)NC1=CC(=C(C=C1)O)O NUGGLNMQKCFZJQ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Abstract
The invention provides a preparation method and application of an icotinib intermediate, belonging to the technical field of chemical synthesis and comprising the following steps; (1) adding triethylene glycol into the alkaline mixed solution, and then dropwise adding the mixed solution of paratoluensulfonyl chloride and tetrahydrofuran to obtain a product 1; (2) mixing the product 1, 3, 4-dihydroxy benzonitrile, and then dropwise adding the mixture into a mixed solution of acetonitrile and potassium carbonate to perform cyclization reaction to obtain a product 2; (3) dissolving the product 2 in glacial acetic acid, and then dropwise adding fuming nitric acid and concentrated sulfuric acid to obtain a product 3; (4) dissolving the product 3 in a mixed solution 1 of acetic acid and ethanol, and adding iron powder to generate an Icotinib intermediate product BPI-X04; (5) dissolving the intermediate product BPI-X04 of the Icotinib in toluene, and adding N, N-dimethyl acetal to obtain an intermediate product BPI-X05 of the Icotinib; the process effectively reduces the discharge amount of pollutants, does not add toxic additives such as phosphorus oxychloride and the like, and greatly improves the yield.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method and application of an icotinib intermediate.
Background
Tumor (Tumor) is a new organism formed by that the human body is affected by various carcinogenic factors, and some cells of local tissues on the gene level lose the regulation and control of normal growth of the cells, so that the cells are clonally abnormally proliferated. At present, scientific research generally considers that tumor cells are mostly monoclonal, that is, all tumor cells in a certain tumor are descendants of a mutant cell. Today, medicine divides tumors into two categories, benign and malignant. Malignant tumors are collectively referred to as cancers (cancer). Neoplastic cells have abnormal morphology, metabolism and function and, to varying degrees, lose the ability to differentiate into mature forms. The tumor grows vigorously and has relative autonomy, even if the tumorigenic factors do not exist, the tumor can still grow continuously, and the genetic abnormality of the tumor cell can be transmitted to the daughter cell. Each tumor cell contains alterations in the genome that cause its abnormal growth. Neoplastic hyperplasia is not only discordant with the body, but also harmful. Non-neoplastic hyperplasia is generally polyclonal. The proliferated cells have normal morphology, metabolism and function, can be differentiated and mature, and can restore the structure and function of the original normal tissues to a certain extent. With little non-neoplastic hyperplasia
To the extent, the cause of hyperplasia, once eliminated, does not continue. Non-neoplastic hyperplasia or reactive hyperplasia is one of the cellular turnover required for normal metabolism.
Icotinib hydrochloride (Kernener) is a quinazoline drug with proprietary intellectual property rights for the treatment of locally advanced or metastatic non-small cell lung cancer that has previously failed at least one chemotherapy regimen.
The published Chinese patent with the application number of CN202010316083.0 discloses a preparation method of an icotinib key intermediate, belonging to the technical field of drug synthesis. The technical scheme of the invention is as follows: tri-triethylene-bis (p-toluenesulfonate) and N-Boc-3, 4-dihydroxyaniline are respectively used as raw materials, and are subjected to crown ether cyclization reaction, halogenation reaction and ammoniation reaction (amidation reaction), quinoline cyclization reaction and chlorination reaction to obtain a key intermediate 4-chloro-quinazolino [6.7-6] -12-crown-4 of icotinib; the synthetic route avoids the need to use strong acid solution in the original route, avoids the operation danger and generates a large amount of acid waste liquid.
In the prior art, a large amount of toxic additives such as phosphorus oxychloride can be added in the production process, the discharge amount of pollutants is large, the pollution to the environment is large, and the yield of the target product is low.
Disclosure of Invention
In view of the above, the invention provides a preparation method and application of an icotinib intermediate, which effectively reduce the discharge amount of pollutants, and the whole preparation process does not add highly toxic additives such as phosphorus oxychloride and the like, and the yield of the icotinib intermediate in the whole process flow is greatly improved to about 80%.
The invention relates to a preparation method of an icotinib intermediate, which comprises the following steps of;
(1) adding triethylene glycol into alkaline mixed liquor, wherein the alkaline mixed liquor is added with tetra
Sodium hydroxide solution with the mass concentration of the tetrahydrofuran being 32-35%, then dropwise adding mixed solution of p-toluenesulfonyl chloride and tetrahydrofuran, carrying out esterification reaction, cooling, filtering and airing after the reaction is finished, and obtaining a product 1, wherein the structural formula of the product 1 is as follows;
(2) mixing the product 1, 3, 4-dihydroxy benzonitrile, and then adding the mixture of acetonitrile and potassium carbonate dropwise
Performing cyclization reaction in the solution, and cooling, filtering and airing after the reaction is finished to obtain a product 2, wherein the structural formula of the product 2 is shown in the specification;
(3) Dissolving the product 2 in glacial acetic acid, then sequentially dropwise adding fuming nitric acid and concentrated sulfuric acid,
reacting at 43-46 ℃ for 2-3h, after the reaction is finished, quenching to zero degree, separating out solid, recrystallizing, filtering and drying to obtain a product 3, wherein the structural formula of the product 3 is as follows;
the reaction equation in this step is;
the step is to oxidize and nitrate the product 2, and the product 2 is provided with a nitro group so as to facilitate the next amination reaction, and because the difficulty is high during the oxidation reaction, the oxidation reaction is carried out by selecting fuming nitric acid and concentrated sulfuric acid mixed acid with strong oxidizability.
(4) Dissolving the product 3 in a mixed solution 1 of acetic acid and ethanol, wherein the acetic acid and the ethanol are contained in the mixed solution 1,
The mass ratio of ethanol is 1: 3-5, adding iron powder, heating and refluxing for oxidation-reduction reaction, wherein the mass ratio of the product 3 to the iron powder is 1: 2-3, diluting the reacted solution with water, adjusting the pH value to 8-9, adding an extracting agent (the extracting agent is dichloromethane) for extraction, collecting an extraction layer, evaporating the extracting agent to obtain a solid, thermally pulping the solid with ethanol, cooling, filtering and drying in vacuum at 62-67 ℃ to obtain an Icotinib intermediate product BPI-X04, wherein the Icotinib intermediate product BPI-X04 has the following structural formula;
nitrate radical with oxidability reacts with iron powder with reducibility under acidic condition, and the addition amount of the iron powder is controlled in the process to avoid the generation of by-products.
(5) Dissolving the intermediate product BPI-X04 of the Icotinib in toluene, and adding N, N-bis
The mass ratio of the methyl dimethyl acetal to the Icotinib intermediate product BPI-X04 to the N, N-dimethyl acetal is 1: 1-1.2. Heating and refluxing, adding methanol after the reaction is finished, stirring and pulping, filtering, and drying to obtain an icotinib intermediate product BPI-X05 (namely the icotinib intermediate product to be prepared in the application), wherein the structural formula of the icotinib intermediate product BPI-X05 is as follows;
n, N-dimethyl acetal is methylating agent, and can methylate alcohol, carboxylic acid, phenol, thiophenol, etc. to synthesize ether, ester, cresol, etc. and can perform formylation reaction of active methylene and other active groups to synthesize heterocyclic compound. The by-products of the process are very small.
A method for preparing an icotinib intermediate based on the above, comprising the following steps; dissolving an icotinib intermediate product BPI-X05 in acetic acid, adding 3-aminophenylacetylene, and carrying out heating reflux reaction, wherein the mass ratio of the icotinib intermediate product BPI-X05 to the 3-aminophenylacetylene is 2-2.5: 1, after the reaction is finished, adding methanol for dispersing, filtering and drying to obtain the Icotinib; the preparation method comprises the steps of dispersing the icotinib into methanol, adding concentrated hydrochloric acid, filtering, pulping with isopropanol, filtering, drying a filter cake, and obtaining the icotinib hydrochloride.
The synthesis route related by the invention avoids the practicability of phosphorus oxychloride, the process is green, the triethylene glycol is taken as a starting point, the key functional group of the icotinib intermediate product is obtained by constructing a closed loop, a substitution reaction and the like, the side reaction in the whole process is small, the byproducts are few, the purity of the product obtained in each step is high, and the yield of the icotinib intermediate is high.
Detailed Description
The present invention will be described in detail with reference to specific embodiments.
Example 1
A preparation method of an icotinib intermediate comprises the following steps;
(1) adding triethylene glycol into alkaline mixed liquor, wherein the alkaline mixed liquor is added with tetra
Adding a sodium hydroxide solution with the mass concentration of the tetrahydrofuran being 32%, then dropwise adding a mixed solution of p-toluenesulfonyl chloride and tetrahydrofuran, carrying out an esterification reaction, and after the reaction is finished, cooling, filtering and airing to obtain a product 1, wherein the structural formula of the product 1 is as follows;
(2) mixing the product 1, 3, 4-dihydroxy benzonitrile, and then adding the mixture of acetonitrile and potassium carbonate dropwise
Performing cyclization reaction in the solution, and cooling, filtering and airing after the reaction is finished to obtain a product 2, wherein the structural formula of the product 2 is shown in the specification;
(3) Dissolving the product 2 in glacial acetic acid, then sequentially dropwise adding fuming nitric acid and concentrated sulfuric acid,
reacting for 2 hours at 43 ℃, after the reaction is finished, quenching to zero degree, separating out solid, and recrystallizing, filtering and drying to obtain a product 3, wherein the structural formula of the product 3 is as follows;
the reaction equation in this step is;
(4) dissolving the product 3 in a mixed solution 1 of acetic acid and ethanol, wherein the acetic acid and the ethanol are contained in the mixed solution 1,
The mass ratio of ethanol is 1: adding iron powder, heating and refluxing for oxidation-reduction reaction, wherein the mass ratio of the product 3 to the iron powder is 1: 2, diluting the reacted solution with water, adjusting the pH value to 8, adding an extracting agent (the extracting agent is dichloromethane) for extraction, collecting an extraction layer, evaporating the extracting agent to obtain a solid, thermally pulping the solid with ethanol, cooling, filtering and drying in vacuum at 62 ℃ to obtain an Icotinib intermediate product BPI-X04, wherein the structural formula of the Icotinib intermediate product BPI-X04 is as follows;
nitrate radical with oxidability reacts with iron powder with reducibility under acidic condition, and the addition amount of the iron powder is controlled in the process to avoid the generation of by-products.
(5) Dissolving the intermediate product BPI-X04 of the Icotinib in toluene, and adding N, N-bis
The mass ratio of the methyl dimethyl acetal to the Icotinib intermediate product BPI-X04 to the N, N-dimethyl acetal is 1: 1, heating and refluxing, adding methanol after the reaction is finished, stirring and pulping, filtering, and drying to obtain an icotinib intermediate product BPI-X05 (namely the icotinib intermediate product to be prepared in the application), wherein the structural formula of the icotinib intermediate product BPI-X05 is as follows;
a method for preparing an icotinib intermediate based on the above, comprising the following steps; dissolving an Icotinib intermediate product BPI-X05 in acetic acid, adding 3-aminophenylacetylene, and carrying out heating reflux reaction, wherein the mass ratio of the Icotinib intermediate product BPI-X05 to the 3-aminophenylacetylene is 2: 1, after the reaction is finished, adding methanol for dispersing, filtering and drying to obtain the Icotinib; the preparation method comprises the steps of dispersing the icotinib into methanol, adding concentrated hydrochloric acid, filtering, pulping with isopropanol, filtering, drying a filter cake, and obtaining the icotinib hydrochloride.
Example 2
A preparation method of an icotinib intermediate comprises the following steps;
(1) adding triethylene glycol into alkaline mixed liquor, wherein the alkaline mixed liquor is added with tetra
Dropwise adding a sodium hydroxide solution with the mass concentration of 33% of tetrahydrofuran, then dropwise adding a mixed solution of p-toluenesulfonyl chloride and tetrahydrofuran, carrying out an esterification reaction, and cooling, filtering and airing after the reaction is finished to obtain a product 1, wherein the structural formula of the product 1 is as follows;
(2) mixing the product 1, 3, 4-dihydroxy benzonitrile, and then adding the mixture of acetonitrile and potassium carbonate dropwise
Performing cyclization reaction in the solution, and cooling, filtering and airing after the reaction is finished to obtain a product 2, wherein the structural formula of the product 2 is shown in the specification;
(3) Dissolving the product 2 in glacial acetic acid, then sequentially dropwise adding fuming nitric acid and concentrated sulfuric acid,
reacting for 2.5 hours at 44 ℃, after the reaction is finished, quenching to zero degree, separating out solid, and recrystallizing, filtering and drying to obtain a product 3, wherein the structural formula of the product 3 is as follows;
the reaction equation in this step is;
the step is to oxidize and nitrate the product 2, and the product 2 is provided with a nitro group so as to facilitate the next amination reaction, and because the difficulty is high during the oxidation reaction, the oxidation reaction is carried out by selecting fuming nitric acid and concentrated sulfuric acid mixed acid with strong oxidizability.
(4) Dissolving the product 3 in a mixed solution 1 of acetic acid and ethanol, wherein the acetic acid and the ethanol are contained in the mixed solution 1,
The mass ratio of ethanol is 1: and 4, adding iron powder, heating and refluxing for oxidation-reduction reaction, wherein the mass ratio of the product 3 to the iron powder is 1: 2.1, diluting the reacted solution with water, adjusting the pH value to 8.5, adding an extracting agent (the extracting agent is dichloromethane) for extraction, collecting an extraction layer, evaporating the extracting agent to obtain a solid, thermally pulping the solid with ethanol, cooling, filtering and drying in vacuum at 62-67 ℃ to obtain an Icotinib intermediate product BPI-X04, wherein the Icotinib intermediate product BPI-X04 has the following structural formula;
nitrate radical with oxidability reacts with iron powder with reducibility under acidic condition, and the addition amount of the iron powder is controlled in the process to avoid the generation of by-products.
(5) Dissolving the intermediate product BPI-X04 of the Icotinib in toluene, and adding N, N-bis
The mass ratio of the methyl dimethyl acetal to the Icotinib intermediate product BPI-X04 to the N, N-dimethyl acetal is 1: 1.1, heating and refluxing, adding methanol after the reaction is finished, stirring and pulping, filtering and drying to obtain an icotinib intermediate product BPI-X05, wherein the structural formula of the icotinib intermediate product BPI-X05 is shown in the specification;
a method for preparing an icotinib intermediate based on the above, comprising the following steps; dissolving an icotinib intermediate product BPI-X05 in acetic acid, adding 3-aminophenylacetylene, and carrying out heating reflux reaction, wherein the mass ratio of the icotinib intermediate product BPI-X05 to the 3-aminophenylacetylene is 2.4: 1, after the reaction is finished, adding methanol for dispersing, filtering and drying to obtain the Icotinib; the preparation method comprises the steps of dispersing the icotinib into methanol, adding concentrated hydrochloric acid, filtering, pulping with isopropanol, filtering, drying a filter cake, and obtaining the icotinib hydrochloride.
Example 3
A preparation method of an icotinib intermediate comprises the following steps;
(1) adding triethylene glycol into alkaline mixed liquor, wherein the alkaline mixed liquor is added with tetra
Dropwise adding a sodium hydroxide solution with the mass concentration of 35% of tetrahydrofuran, then dropwise adding a mixed solution of p-toluenesulfonyl chloride and tetrahydrofuran, carrying out esterification reaction, and cooling, filtering and airing after the reaction is finished to obtain a product 1, wherein the structural formula of the product 1 is as follows;
(2) mixing the product 1, 3, 4-dihydroxy benzonitrile, and then adding the mixture of acetonitrile and potassium carbonate dropwise
Performing cyclization reaction in the solution, and cooling, filtering and airing after the reaction is finished to obtain a product 2, wherein the structural formula of the product 2 is shown in the specification;
(3) Dissolving the product 2 in glacial acetic acid, then sequentially dropwise adding fuming nitric acid and concentrated sulfuric acid,
reacting for 3 hours at 46 ℃, after the reaction is finished, quenching to zero degree, separating out solid, and obtaining a product 3 through recrystallization, filtration and drying, wherein the structural formula of the product 3 is as follows;
the reaction equation in this step is;
the step is to oxidize and nitrate the product 2, and the product 2 is provided with a nitro group so as to facilitate the next amination reaction, and because the difficulty is high during the oxidation reaction, the oxidation reaction is carried out by selecting fuming nitric acid and concentrated sulfuric acid mixed acid with strong oxidizability.
(4) Dissolving the product 3 in a mixed solution 1 of acetic acid and ethanol, wherein the acetic acid and the ethanol are contained in the mixed solution 1,
The mass ratio of ethanol is 1: and 5, adding iron powder, heating and refluxing for oxidation-reduction reaction, wherein the mass ratio of the product 3 to the iron powder is 1: 3, diluting the reacted solution with water, adjusting the pH value to 9, adding an extracting agent (the extracting agent is dichloromethane) for extraction, collecting an extraction layer, evaporating the extracting agent to obtain a solid, thermally pulping the solid with ethanol, cooling, filtering and drying in vacuum at 67 ℃ to obtain an Icotinib intermediate product BPI-X04, wherein the structural formula of the Icotinib intermediate product BPI-X04 is as follows;
nitrate radical with oxidability reacts with iron powder with reducibility under acidic condition, and the addition amount of the iron powder is controlled in the process to avoid the generation of by-products.
(5) Dissolving the intermediate product BPI-X04 of the Icotinib in toluene, and adding N, N-bis
The mass ratio of the methyl dimethyl acetal to the Icotinib intermediate product BPI-X04 to the N, N-dimethyl acetal is 1: 1.2. Heating and refluxing, adding methanol after the reaction is finished, stirring and pulping, filtering and drying to obtain an Icotinib intermediate product BPI-X05, wherein the Icotinib intermediate product BPI-X05 has the following structural formula;
a method for preparing an icotinib intermediate based on the above, comprising the following steps; dissolving an icotinib intermediate product BPI-X05 in acetic acid, adding 3-aminophenylacetylene, and carrying out heating reflux reaction, wherein the mass ratio of the icotinib intermediate product BPI-X05 to the 3-aminophenylacetylene is 2.5: 1, after the reaction is finished, adding methanol for dispersing, filtering and drying to obtain the Icotinib; the preparation method comprises the steps of dispersing the icotinib into methanol, adding concentrated hydrochloric acid, filtering, pulping with isopropanol, filtering, drying a filter cake, and obtaining the icotinib hydrochloride.
The yields of BPI-X05 for the intermediate products of examples 1 to three icotinib were analytically calculated to be 78.6%, 80.6%, 78.5%, respectively.
The synthesis route related by the invention avoids the practicability of phosphorus oxychloride, the process is green, the triethylene glycol is taken as a starting point, the key functional group of the icotinib intermediate product is obtained by constructing a closed loop, a substitution reaction and the like, the side reaction in the whole process is small, the byproducts are few, the purity of the product obtained in each step is high, and the yield of the icotinib intermediate is high.
Claims (9)
1. A preparation method of an icotinib intermediate is characterized by comprising the following steps;
adding triethylene glycol into the alkaline mixed solution, then dropwise adding the mixed solution of p-toluenesulfonyl chloride and tetrahydrofuran, carrying out esterification reaction, and after the reaction is finished, cooling, filtering and airing to obtain a product 1;
mixing the product 1, 3, 4-dihydroxy benzonitrile, then dropwise adding the mixture into a mixed solution of acetonitrile and potassium carbonate, carrying out cyclization reaction, and after the reaction is finished, cooling, filtering and airing to obtain a product 2;
dissolving the product 2 in glacial acetic acid, then sequentially dropwise adding fuming nitric acid and concentrated sulfuric acid, reacting at 43-46 ℃ for 2-3h, after the reaction is finished, quenching to zero degree, separating out solid, and recrystallizing, filtering and drying to obtain a product 3;
dissolving a product 3 in a mixed solution 1 of acetic acid and ethanol, adding iron powder, heating and refluxing for oxidation-reduction reaction, wherein the mass ratio of the product 3 to the iron powder is 1: 2-3 to form an icotinib intermediate BPI-X04;
dissolving the intermediate product BPI-X04 of the Icotinib in toluene, adding N, N-dimethyl acetal, heating and refluxing, adding methanol after the reaction is finished, stirring and pulping, filtering, and drying to obtain the intermediate product BPI-X05 of the Icotinib.
2. The method according to claim 1, wherein the alkaline mixed solution is a sodium hydroxide solution with a mass concentration of 32-35% to which tetrahydrofuran is added.
3. The method according to claim 1, wherein the mass ratio of acetic acid to ethanol in the mixed solution 1 is 1: 3-5.
4. The preparation method of the icotinib intermediate according to claim 1, wherein the step (4) further comprises the steps of diluting the reacted solution with water, adjusting the pH value to 8-9, adding an extractant for extraction, collecting an extraction layer, evaporating the extractant to dryness to obtain a solid, thermally pulping the solid with ethanol, cooling, filtering, and vacuum-drying to obtain the icotinib intermediate product BPI-X04.
5. The method of claim 4, wherein the extractant is dichloromethane.
6. The method for preparing an icotinib intermediate according to claim 4, wherein the temperature for vacuum drying is 62-67 ℃.
7. The preparation method of the icotinib intermediate, according to claim 1, characterized in that the mass ratio of aldehyde icotinib intermediate product BPI-X04, N-dimethyl in step (5) is 1: 1-1.2.
8. Use of an icotinib intermediate according to any one of claims 1 to 7, comprising the steps of; dissolving an icotinib intermediate product BPI-X05 in acetic acid, adding 3-aminophenylacetylene, heating and refluxing for reaction, adding methanol for dispersion after the reaction is finished, filtering and drying to obtain icotinib; the preparation method comprises the steps of dispersing the icotinib into methanol, adding concentrated hydrochloric acid, filtering, pulping with isopropanol, filtering, drying a filter cake, and obtaining the icotinib hydrochloride.
9. The use of an icotinib intermediate according to claim 8, wherein the mass ratio of the icotinib intermediate product BPI-X05 to 3-aminophenylacetylene is 2-2.5: 1.
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