CN115701419A - Preparation method and application of irinotecan intermediate - Google Patents
Preparation method and application of irinotecan intermediate Download PDFInfo
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- CN115701419A CN115701419A CN202110880291.8A CN202110880291A CN115701419A CN 115701419 A CN115701419 A CN 115701419A CN 202110880291 A CN202110880291 A CN 202110880291A CN 115701419 A CN115701419 A CN 115701419A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229960004768 irinotecan Drugs 0.000 title claims abstract description 16
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000002253 acid Substances 0.000 claims abstract description 28
- 230000008569 process Effects 0.000 claims abstract description 12
- 238000006396 nitration reaction Methods 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- -1 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene Chemical compound 0.000 claims description 36
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 30
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- 229910017604 nitric acid Inorganic materials 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- CFAZIHISOMCGES-UHFFFAOYSA-N O=C1CCCC2=C1C=CC(F)=C2C Chemical compound O=C1CCCC2=C1C=CC(F)=C2C CFAZIHISOMCGES-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 11
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 239000000758 substrate Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 7
- 230000035484 reaction time Effects 0.000 abstract description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Substances C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 abstract 2
- 239000007788 liquid Substances 0.000 abstract 1
- 239000002699 waste material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 description 3
- 238000013341 scale-up Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 238000004200 deflagration Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 238000005893 bromination reaction Methods 0.000 description 1
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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Abstract
The invention provides a preparation method and application of an irinotecan intermediate. Specifically, 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetralin acid organic solvent solution and mixed acid are subjected to nitration reaction in a microchannel reactor to be converted into 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetralin, and the method has the advantages of high reaction efficiency, small acid consumption, reduction of waste liquid discharge, short reaction time and great improvement of reaction safety. The invention also provides a process for the preparation of irinotecan comprising using this process. The method adopts a brand new design route, the starting materials are easier to obtain, the reaction route is shorter, and compared with the prior art, the total yield of the Isetikang is obviously improved.
Description
Technical Field
The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method and application of an irinotecan intermediate.
Background
Exatecan (irinotecan) is a DNA topoisomerase I (I) inhibitor, a water-soluble camptothecin derivative having the formula:
Irinotecan has excellent antitumor activity.
Trastuzumab (DS-8201) is a new generation of antibody drug conjugates that link the HER2 targeting agent trastuzumab to an exatecan derivative via a protein molecule for targeted delivery of cytotoxic agents into cancer cells, significantly reducing the toxicity of cytotoxic agents to normal cells compared to conventional chemotherapy, 1-15 days 2021-1, and DS-8201 has been officially approved by the Food and Drug Administration (FDA) for locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma patients who have received trastuzumab therapy.
Exatecan (itacetin) compounds and methods for their preparation are disclosed in EP0495432B1, wherein the synthetic route involved is as follows:
the synthesis of the intermediate compound a07 is carried out through decarbonylation, then oxidation and repeated reaction of upper carbonyl, the atom utilization rate is low, and the yield is only 3.69%.
WO1996026181A1 and CN111065621A disclose the compound a07 as a key intermediate for synthesizing the incarnate, and the method for synthesizing the intermediate compound a07 needs to repeatedly carry out ring closing and opening, oxidation and reduction reactions, has long route and complex reaction operation, and is not suitable for industrial scale-up production.
WO2019044946A1 optimizes the synthesis of compound a07, and the reaction route is as follows:
the method has high price of starting raw materials and small market supply amount, and the yield of the first-step bromination reaction is low and is only 30 percent; in the step of reducing the nitro group into amino group, the post-treatment is complex, and the whole reaction route is long, thus being not beneficial to industrial scale-up production.
The research of the inventor finds that the preparation of the compound a07 and the ixitacong by using the 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene as an intermediate has the advantages of shortening the reaction route, simplifying a plurality of post-treatment steps, improving the total yield of the ixitacong and the like. However, no literature has been reported on the preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, and no literature has been reported on the possibility of using 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene as an intermediate for preparing ixitancon.
The conventional nitration reaction is easy to generate explosion, in addition, the by-product (nitro compound or polynitro compound may be explosive/deflagration) of the nitration reaction also has the problem of stability, and secondary decomposition (deflagration) can be generated at a certain temperature, so that great potential safety hazard is always generated in the production.
Disclosure of Invention
The invention aims to provide a novel preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene which has the advantages of considering both reaction yield and nitration reaction safety and is suitable for industrial scale-up production, and a preparation method of the compound shown in the formula 07 and the ixitacong, so as to solve the defects in the prior art.
For this reason, the inventors studied the use of a microchannel reactor for the nitration reaction of compound a04 of the formula below to prepare compound 0a 5;
specifically, the present invention provides, in a first aspect, a process for the preparation of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene, said process comprising the steps of:
preparing a reaction solution: dissolving a reaction substrate 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene in an organic solvent; preferably, the organic solvent is one or more of dichloromethane, 1, 2-dichloroethane, chloroform or carbon tetrachloride.
In a preferred embodiment of the present invention, the ratio of the volume (ml) of the organic solvent to the weight (g) of the reaction substrate 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene is 5 to 1, more preferably 8 to 15.
Preparing a mixed acid solution: nitric acid was slowly added to sulfuric acid with stirring.
In one embodiment of the invention, the nitric acid is nitric acid with a mass fraction of not less than 90%, and preferably the nitric acid is nitric acid with a mass fraction of not less than 97%; the sulfuric acid is concentrated sulfuric acid with the mass fraction not less than 70%, and preferably, the sulfuric acid is concentrated sulfuric acid with the mass fraction not less than 98%; further preferably, the weight ratio of the nitric acid to the sulfuric acid is 1.5 to 10, preferably 1; .
In a more specific embodiment of the present invention, the nitric acid is nitric acid with a mass fraction of not less than 97%, the sulfuric acid is concentrated sulfuric acid with a mass fraction of not less than 98%, and the weight ratio of nitric acid to sulfuric acid is 1.5-10, preferably 1.
Further, the prepared reaction liquid and the prepared mixed acid solution are added into a microchannel reactor for nitration reaction, and the flow rate of a feeding pump is controlled to control the reaction residence time and the molar ratio of the mixed acid to the reaction substrate.
In the above method, it is preferable that the molar ratio of nitric acid to the reaction substrate, 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene, is 1 to 1.2. The nitration temperature is 25 to 120 ℃, preferably 30 to 100 ℃.
Further, the reaction residence time of the reaction solution and the mixed acid solution in the microchannel reactor is controlled by controlling the flow rate of the feed pump to be 30 seconds to 180 seconds, preferably 50 seconds to 150 seconds.
Preferably, the method further comprises the steps of introducing the reaction solution into cold water after the reaction is completed at the set temperature, separating an organic layer, concentrating, and further purifying by silica gel column chromatography or recrystallization to obtain a solid, namely the 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene.
In one embodiment of the present invention, the method further comprises, after completion of the reaction at the set temperature, introducing the reaction solution into cold water, standing for separation of layers, separating the organic layers, extracting the aqueous phase with an organic solvent such as dichloromethane, chloroform or carbon tetrachloride, combining the organic layers, washing with a sodium bicarbonate solution and water, and then concentrating, optionally, further purifying the resulting solid by silica gel column chromatography to obtain 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene.
In the above method, preferably, the microchannel reactor is a corning G1 glass reactor system.
The second aspect of the present invention also provides a process for the preparation of irinotecan, comprising the steps of:
(1) Preparing 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene by adopting the method;
(2) Reacting 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene with nitrosoisoamyl ester under basic conditions, then adding acetic acid and acetic anhydride, and starting hydrogenation reduction reaction to obtain a compound represented by formula a 07:
(3) Converting the compound represented by formula a07 to irinotecan.
Further, the base in the step (2) is potassium tert-butoxide, lithium tert-butoxide or sodium tert-butoxide;
the hydrogenation reduction reaction takes Pt/C as a catalyst, and the reaction mixture is reacted in H 2 A reduction reaction carried out under conditions;
preferably, the molar ratio of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene to nitrosoisoamyl ester is 1 to 1.5; the molar ratio of the base to 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene to nitrosoisoamyl ester is 1 to 1.5, preferably, 1.
The conversion of a compound represented by formula a07 to irinotecan can be synthesized by methods known in the art, for example, but not including the documents mentioned in the background of the invention.
The 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene provided by the invention is converted into 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene in a microchannel reactor through nitration reaction, then reacts with isoamyl nitrosoate under alkaline condition, and is subjected to hydrogenation reduction reaction to obtain the compound represented by the formula a07, and the compound a07 is used for preparing the ixitekang.
3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene is dissolved in an organic solvent and then converted into 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene through nitration reaction with mixed acid in a microchannel reactor, so that the using amount of acid is reduced, pollution is reduced, the reaction time is greatly shortened and the energy efficiency is saved by adopting the method disclosed by the invention.
Secondly, the method provided by the invention greatly improves the safety of the reaction and can achieve the aim of pursuing the intrinsic safety of chemical production.
Thirdly, the compound shown as the formula a07 prepared by the method has the advantages of high yield and suitability for industrial production and application, and the compound shown as the formula a07 is used as a key intermediate for preparing the irinotecan, so that the total yield of the preparation of the irinotecan is directly improved, and the production cost is reduced.
Detailed Description
The technical solutions and advantages of the present invention are further explained below with reference to specific embodiments, and it should be noted that the embodiments and features in the embodiments in the present application may be combined with each other without conflict.
Unless otherwise specified, the microchannel reactor apparatus used in the following examples was a corning G1 glass reactor, the nitric acid used was commercially available 97% fuming nitric acid, the concentrated sulfuric acid used was commercially available 98% concentrated sulfuric acid, and the other reagents/starting materials used were commercially available.
Example 1: process for preparing 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene
30.0g of the starting material, 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene, was dissolved in 300mL of methylene chloride to prepare a reaction solution. 13.1g of fuming nitric acid is slowly added into 65.5g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 65 ℃ and the flow rate of the reaction solution was adjusted so that the residence time of the reaction mixture was 140 seconds. And simultaneously adjusting the flow rate of the mixed acid to feed the mixed acid at the flow rate which is equal to the flow rate of the reaction liquid. After the reaction was completed, an organic layer was separated, and an aqueous layer was extracted with 150mL of dichloromethane and combined with the organic layer. The organic phase was washed with 300mL of saturated sodium bicarbonate solution and 300mL of water, and concentrated to dryness under reduced pressure. The obtained solid was purified by silica gel column chromatography to obtain 20.6g of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene as a product in 54.8% yield.
Example 2: process for preparing 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene
30.0g of the starting material, 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene, was dissolved in 270mL1, 2-dichloroethane to prepare a reaction mixture. 12.0g of fuming nitric acid is slowly added into 48.0g of concentrated sulfuric acid to prepare mixed acid solution. The reaction temperature was controlled at 100 ℃ and the flow rate of the reaction solution was adjusted to maintain the reaction time of the materials at 100 seconds. And simultaneously adjusting the flow rate of the mixed acid so that the mixed acid is fed at the flow rate which is equal to the flow rate of the reaction liquid. After the completion of the reaction, 23.3g of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene was obtained in 62.0% yield by the same post-treatment as in example 1.
Example 3: process for preparing 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene
30.0g of the starting material, 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene, was dissolved in 300mL of chloroform to prepare a reaction solution. 12.0g of fuming nitric acid is slowly added into 36.0g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 75 ℃ and the flow rate of the reaction solution was adjusted so that the residence time of the reaction mixture was 120 seconds. And simultaneously adjusting the flow rate of the mixed acid so that the mixed acid is fed at the flow rate which is equal to the flow rate of the reaction liquid. The same post-treatment as in example 1 was carried out to give 21.8g of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene as a product in 58.2% yield.
Example 4: process for the preparation of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene
30.0g of the starting material, 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene, was dissolved in 450mL of chloroform to prepare a reaction solution. 12.5g of fuming nitric acid is slowly added into 37.8g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 60 ℃ and the flow rate of the reaction solution was adjusted so that the residence time of the reaction mixture was 110 seconds. And simultaneously adjusting the flow rate of the mixed acid so that the mixed acid is fed at the flow rate which is equal to the flow rate of the reaction liquid. The same post-treatment as in example 1 was carried out to give 22.7g of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene as a product in a yield of 60.6%.
Example 5: process for the preparation of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene
30.0g of the starting material, 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene, was dissolved in 150mL of chloroform to prepare a reaction solution. 12.0g of fuming nitric acid is slowly added into 72.0g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 75 ℃ and the flow rate of the reaction solution was adjusted so that the residence time of the reaction mixture was 150 seconds. And simultaneously adjusting the flow rate of the mixed acid so that the mixed acid is fed at the flow rate which is equal to the flow rate of the reaction liquid. The same post-treatment as in example 1 was carried out to give 21.0g of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene as a product in a yield of 56%.
Example 6 preparation of Compound of formula a07
5.0g of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene (22.4 mmol) was dissolved in 75mL of THF and cooled to 10 ℃ and then 3.4g of isoamyl nitrite (29.0 mmol) and 3.0g of potassium tert-butoxide (26.8 mmol) were added. After the mixture was stirred at 10 ℃ for 12 hours, 25mL of acetic acid and 25mL of acetic anhydride were added, followed by 0.5g of 5% Pt/C. At normal temperature, the mixture was stirred under an atmosphere of 1atm. H2 for 6 hours. After the reaction was complete, the reaction mixture was filtered to remove the catalyst, the solid was washed with 25mL of THF, and the combined filtrates were concentrated to dryness under reduced pressure. The residue was dissolved in a mixed solvent of 50mL of THF and 50mL of ethyl acetate, and washed twice with 40mL of saturated sodium bicarbonate solution and once with 40mL of saturated brine. The organic phase was concentrated to dryness under reduced pressure. The residue was recrystallized from acetonitrile. 4.4g of a07 as a white solid (total yield: 67%), HPLC:98.7 percent.
The conversion of a compound represented by formula a07 to irinotecan can be synthesized by methods known in the art including, but not limited to, the methods disclosed in EP0495432B 1.
In light of the foregoing description of the preferred embodiments according to the present application, it is to be understood that various changes and modifications may be made without departing from the spirit and scope of the invention. The technical scope of the present application is not limited to the contents of the specification, and must be determined according to the scope of the claims.
Claims (10)
- A process for the preparation of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene comprising the steps of:preparing a reaction solution: dissolving a reaction substrate 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene in an organic solvent;preparing a mixed acid solution: slowly adding nitric acid into sulfuric acid under the condition of stirring;and respectively adding the prepared reaction liquid and the prepared mixed acid solution into a microchannel reactor for nitration reaction, and respectively controlling the reaction residence time and the molar ratio of the mixed acid to a reaction substrate by controlling the flow rate of a feed pump.
- 2. The method of claim 1, wherein the organic solvent is a mixture of one or more of dichloromethane, 1, 2-dichloroethane, or chloroform.
- 3. The process according to any one of claims 1 to 2, wherein the ratio of the volume (ml) of organic solvent to the weight (g) of the reaction substrate 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene is from 5 to 1, preferably from 8 to 15.
- 4. The method according to claim 1, wherein the nitric acid is nitric acid with a mass fraction of not less than 90%, preferably not less than 97%; the sulfuric acid is concentrated sulfuric acid with the mass fraction not less than 70%, and preferably concentrated sulfuric acid with the mass fraction not less than 98%;further preferably, the weight ratio of the nitric acid to the sulfuric acid is 1.5 to 10, preferably 1.
- 5. The method of claim 1, wherein the molar ratio of nitric acid to the reaction substrate 3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene is 1 to 1.2.
- 6. A process according to claim 1, wherein the nitration reaction temperature is between 25 and 120 ℃, preferably between 30 and 100 ℃.
- 7. The method according to claim 1, wherein the reaction residence time of the reaction solution and the mixed acid solution in the microchannel reactor is 30 to 180 seconds, preferably 50 to 150 seconds.
- 8. The method according to any one of claims 1 to 6, further comprising introducing the reaction solution into water after the reaction is completed, separating an organic layer, concentrating, and further purifying by silica gel column chromatography or recrystallization to obtain a solid, i.e., 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene.
- 9. A process for the preparation of irinotecan comprising the steps of:(1) Preparing 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene by the method of any one of claims 1 to 8;(2) Reacting 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene with nitrosoisoamyl ester under basic conditions, then adding acetic acid and acetic anhydride, and then subjecting to a hydrogenation reduction reaction to obtain a compound represented by formula a 07:
(3) Converting the compound represented by formula a07 to irinotecan. - 10. The process of claim 9, wherein the base of step (2) is potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide;the hydrogen isThe reduction reaction is carried out by taking Pt/C as catalyst and reacting mixture in H 2 A reduction reaction carried out under conditions;preferably, the molar ratio of 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene to nitrosoisoamyl ester to isoamyl nitrite is 1; the molar ratio of the base to 1-nitro-3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene to nitrosoisoamyl ester is 1 to 1.5, preferably, 1.
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