CN115197233A - Preparation method of irinotecan and intermediate thereof - Google Patents
Preparation method of irinotecan and intermediate thereof Download PDFInfo
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- CN115197233A CN115197233A CN202110376195.XA CN202110376195A CN115197233A CN 115197233 A CN115197233 A CN 115197233A CN 202110376195 A CN202110376195 A CN 202110376195A CN 115197233 A CN115197233 A CN 115197233A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229960004768 irinotecan Drugs 0.000 title claims abstract description 12
- 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 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 114
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 30
- PVEOYINWKBTPIZ-UHFFFAOYSA-N but-3-enoic acid Chemical compound OC(=O)CC=C PVEOYINWKBTPIZ-UHFFFAOYSA-N 0.000 claims description 26
- DJGXPFQIMLEVPA-UHFFFAOYSA-N 1-bromo-3-fluoro-2-methylbenzene Chemical compound CC1=C(F)C=CC=C1Br DJGXPFQIMLEVPA-UHFFFAOYSA-N 0.000 claims description 17
- 238000006722 reduction reaction Methods 0.000 claims description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 14
- 238000005984 hydrogenation reaction Methods 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 238000007341 Heck reaction Methods 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000006396 nitration reaction Methods 0.000 claims description 7
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 3
- -1 nitrosoisoamyl Chemical group 0.000 claims description 3
- 239000012043 crude product Substances 0.000 abstract description 7
- 238000007867 post-reaction treatment Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 238000013341 scale-up Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 239000008346 aqueous phase Substances 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
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229950009429 exatecan Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 229940049595 antibody-drug conjugate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 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
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 230000006324 decarbonylation Effects 0.000 description 1
- 238000006606 decarbonylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000007492 gastroesophageal junction adenocarcinoma Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Abstract
The invention provides a preparation method of irinotecan and an intermediate thereof, and particularly provides a preparation method of a compound represented by a formula a07 and a preparation method of the irinotecan containing the method. The method provided by the invention adopts a brand-new design route, the starting materials are easier to obtain, the reaction route is shorter, and the total yield is obviously improved compared with the prior art. In addition, the method provided by the invention is adopted to prepare the compound represented by the formula a07, so that the post-reaction treatment can be simplified, and after a plurality of reactions are finished, the crude product can be put into the next reaction only by simple treatment.
Description
Technical Field
The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of irinotecan and an intermediate thereof.
Background
Exatecan (irinotecan), a DNA topoisomerase I inhibitor, is a water-soluble camptothecin derivative of the formula:
irinotecan has excellent antitumor function.
Trastuzumab (DS-8201) is a new generation of antibody drug conjugates, which target delivery of cytotoxic agents to cancer cells by linking trastuzumab, a HER2 targeting agent, to an exatecan derivative via a protein molecule, and which significantly reduce the toxicity of cytotoxic agents to normal cells compared to conventional chemotherapy, i.e., 1/15 days 2021, DS-8201 is 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 ixitacong, and the method for synthesizing the intermediate compound a07 needs to repeatedly carry out ring closing and opening, oxidation and reduction reactions, has a long route and complicated 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 the amino group, the post-treatment is complex, and the whole reaction route is long, which is not beneficial to industrial scale-up production.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a brand-new preparation method of the compound represented by the formula a07, which has the advantages of reaction yield and suitability for industrial scale-up production.
Specifically, the invention provides a preparation method of a compound represented by a formula a07,
the method comprises the following steps:
subjecting 2-bromo-6-fluorotoluene and 3-butenoic acid to Heck reaction, and converting into compounds represented by formulas a01 and a 02:
converting the product of the reaction of 2-bromo-6-fluorotoluene with 3-butenoic acid, the compounds represented by formulae a01 and a02, into the compound represented by formula a03 by a hydrogenation reduction reaction:
converting the compound represented by formula a03 into a compound represented by formula a04 by intramolecular Friedel-Crafts reaction:
preferably, the first and second electrodes are formed of a metal,
converting a compound represented by formula a04 to a compound represented by formula a05 by nitration:
converting a compound represented by formula a05 into a compound represented by formula a 07:
in the above method, preferably, the 2-bromo-6-fluorotoluene and 3-butenoic acid are subjected to Heck reaction to obtain a mixture of products a01 and a02, which can be directly used for the next reduction reaction without separation to be converted into the compound represented by the formula a 03.
Preferably, a mixture of the compounds represented by the formulae a01 and a02 is converted into the compound represented by the formula a03 by Pd/C hydrogenation reduction, and preferably, after the compound represented by the formula a03 obtained by the reaction is concentrated by simple filtration, the obtained crude product can be directly used for intramolecular Friedel-Crafts reaction to convert into the compound represented by the formula a 04.
It is further preferred that the Heck reaction of 2-bromo-6-fluorotoluene with 3-butenoic acid is carried out in a solvent system comprising tetrakis (triphenylphosphine) palladium and an organic base, such as diisopropylethylamine, preferably the solvent is DMF, tetrahydrofuran, dichloromethane and the like.
More preferably, the molar charge ratio of the Heck reaction of the 2-bromo-6-fluorotoluene and the 3-butenoic acid is 0.8 to 1.2, the amount of the tetrakis (triphenylphosphine) palladium is a catalyst amount, for example, the molar ratio of the tetrakis (triphenylphosphine) palladium to the 2-bromo-6-fluorotoluene is 1 to 55; the molar ratio of the organic base (e.g., diisopropylethylamine) to 2-bromo-6-fluorotoluene is 1 to 2.
Further, the mixture of a01 and a02 may be converted to the compound represented by formula a03 by palladium on carbon catalytic hydrogenation.
Further, the compound represented by the formula a03 is converted into the compound represented by the formula a04 by an intramolecular Friedel-Crafts reaction, preferably, the reaction is carried out in a system containing trifluoroacetic acid and trifluoroacetic anhydride, more preferably, the molar ratio of the compound represented by the formula a03 to the trifluoroacetic anhydride is 1 to 2.5, and the reaction temperature is controlled to be not more than 10 ℃.
In the above method, the compound represented by formula a04 is converted into the compound represented by formula a05 by a nitration reaction, preferably, the molar ratio of the compound represented by formula a04 to fuming nitric acid in the nitration reaction is 0.8 to 1, and further, preferably, the compound represented by formula a04 is first dissolved in concentrated sulfuric acid, the fuming nitric acid and the concentrated sulfuric acid are prepared into mixed acid, the mixed acid is slowly dropped into the concentrated sulfuric acid solution of the compound represented by formula a04 at room temperature, and the reaction is carried out at a temperature not higher than 35 ℃.
Further, in the reaction for converting the compound represented by the formula a05 into the compound represented by the formula a07, preferably, the compound represented by the formula a05 is mixed with isoamyl nitrite and a base and reacted, and then acetic acid, acetic anhydride and Pt/C are added to perform a hydrogenation reaction; preferably, the molar ratio of the compound represented by formula a05 to isoamyl nitrite is 1; wherein the base is potassium tert-butoxide, lithium tert-butoxide or sodium tert-butoxide, preferably the base is potassium tert-butoxide, more preferably the molar ratio of potassium tert-butoxide to the compound represented by formula a05 is 1 to 1.5, preferably 1.
In another aspect of the present invention, there is provided a method for preparing a compound represented by formula a07, comprising:
allowing a compound represented by the formula a05,
conversion to a compound represented by the formula a07
Preferably, the method comprises the steps of: reacting the compound represented by the formula a05 with nitrosoisoamyl under alkaline conditions, then adding acetic acid and acetic anhydride, and then starting hydrogenation reduction reaction to obtain the compound represented by the formula a 07.
Wherein the base 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 in H 2 Reduction reaction under the condition.
Preferably, the molar ratio of the compound represented by formula a05 to isoamyl nitrite is 1; the molar ratio of the base to the compound represented by formula a05 is 1 to 1.5, preferably 1.
The invention also provides a preparation method of the compound represented by the formula a05, wherein the compound represented by the formula a05 is obtained by converting the compound represented by the formula a04 through nitration reaction.
Preferably, in the nitration reaction, the molar ratio of the compound represented by formula a04 to fuming nitric acid is from 0.8 to 1.
Further, the invention also provides a preparation method of the compound represented by the formula a04, wherein the compound represented by the formula a04 is obtained by converting the compound represented by the formula a03 through intramolecular Friedel-Crafts reaction.
Preferably, the Friedel-Crafts reaction is carried out in a system comprising trifluoroacetic acid and trifluoroacetic anhydride, more preferably, the molar ratio of the compound represented by the formula a03 to the trifluoroacetic anhydride is 1 to 2.5, and the reaction temperature is controlled to be not more than 10 ℃.
Further, another aspect of the present invention provides a method for preparing a compound represented by formula a03, wherein the compound represented by formula a03 is obtained by converting a compound represented by formula a01 and/or a02 through a reduction reaction:
further, the invention also provides a preparation method of the compound represented by the formula a01 and/or a02, wherein the compound represented by the formula a01 and/or a02 is obtained by reacting 2-bromo-6-fluorotoluene with 3-butenoic acid and converting. Preferably, the Heck reaction of 2-bromo-6-fluorotoluene with 3-butenoic acid is carried out in a solvent system comprising tetrakis (triphenylphosphine) palladium and an organic base, such as diisopropylethylamine, and more preferably, the solvent is DMF, tetrahydrofuran, dichloromethane, and the like.
Further, the molar charge ratio of the Heck reaction of the 2-bromo-6-fluorotoluene and the 3-butenoic acid is 0.8-1.2, the amount of the tetrakis (triphenylphosphine) palladium is a catalyst amount, and the molar ratio of the tetrakis (triphenylphosphine) palladium to the 2-bromo-6-fluorotoluene is 1; the molar ratio of the organic base (e.g., diisopropylethylamine) to 2-bromo-6-fluorotoluene is 1 to 2.
In another aspect of the present invention, there is also provided a process for producing irinotecan, which comprises the step of producing the compound represented by formula a07, and/or the compound represented by formula a05, and/or the compound represented by formula a04, and/or the compound represented by formula a03, and/or the compound represented by formula a02, and/or the compound represented by formula a01, by the aforementioned process of the present invention.
Documents WO2019044946A1, WO1996026181A1, CN111065621A, and EP0495432B1, and the like, the disclosures of which are incorporated herein by reference, disclose methods for preparing irinotecan using a compound represented by formula a 07.
According to the preparation method of the compound represented by the formula a07, the starting materials are easier to obtain, the reaction route is shorter, and compared with the prior art, the total yield is obviously improved.
In addition, the method provided by the invention is adopted to prepare the compound represented by the formula a07, so that the post-reaction treatment can be simplified, and after a plurality of reactions are finished, the crude product can be put into the next reaction by simple treatment: for example, the mixture of the formula a01 and a02 obtained after Heck reaction of 2-bromo-6-fluorotoluene and 3-butenoic acid can be directly used for preparing the compound shown in the formula a03 by hydrogenation reduction without separation, and the compound shown in the formula a03 obtained after hydrogenation reduction can be directly used for the next reaction by simple extraction operation.
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.
Drawings
Fig. 1 shows an HPLC spectrum of the compound represented by formula a07 prepared by the method provided in the present invention, wherein the purity of the compound represented by formula a07 is 98.76%, and peak data thereof is shown in the following table:
detector A220 nm
| Peak number | Retention time | Area of | Height | Degree of separation (USP) | Theoretical plate number (USP) | Area% |
| 1 | 16.497 | 27218 | 2441 | -- | 86593 | 0.442 |
| 2 | 17.358 | 1915 | 187 | 3.357 | 57991 | 0.031 |
| 3 | 18.399 | 3618 | 505 | 4.394 | 156764 | 0.059 |
| 4 | 18.890 | 1045 | 155 | 2.493 | 132703 | 0.017 |
| 3 | 21.305 | 6080602 | 883772 | 12.086 | 196299 | 98.758 |
| 6 | 21.982 | 1108 | 193 | 3.731 | 266889 | 0.018 |
| 7 | 22.940 | 3873 | 572 | 5.278 | 226050 | 0.063 |
| 8 | 24.662 | 16825 | 2435 | 8.919 | 260898 | 0.273 |
| 9 | 25.993 | 5140 | 731 | 6.786 | 272836 | 0.083 |
| 10 | 27.345 | 6525 | 820 | 6.263 | 221190 | 0.106 |
| 11 | 27.483 | 2120 | 351 | 0.332 | 33270 | 0.034 |
| 12 | 47.528 | 7101 | 262 | 29.918 | 66495 | 0.115 |
| In total | 6157090 | 892424 | 100.000 |
。
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 features in the embodiments and examples in the present application may be combined with each other without conflict.
Preparation of the Compounds of example 1, formulae a01 and a02
10.0g of 2-bromo-6-fluorotoluene (52.9 mmol) and 5.5g of 3-butenoic acid (63.5 mmol) were dissolved in 80mL of DMF, and the solution was degassed under reduced pressure and purged with nitrogen. Then, 1.2g of tetrakis (triphenylphosphine) palladium (1.06 mmol) and 11.2g of diisopropylethylamine (87.0 mmol) were added to the solution, and the solution was again replaced with nitrogen. The reaction was stirred at 90 ℃ for 4 hours, then the solvent was removed under vacuum, 150mL of isopropyl acetate, and 150mL of 5% NaOH solution were added to the residue. After stirring at room temperature for 10 minutes, the aqueous phase was separated. The aqueous phase was adjusted to pH =3 with 10% hydrochloric acid solution, extracted twice with 100mL of dichloromethane, and the organic phases were combined and concentrated to dryness under reduced pressure to give 9.6g of a mixture of a01 and a02 (yield: 93%). The crude product was used directly in the next reaction.
Example 2 preparation of Compound of formula a03
9.6g (49.4 mmol) of the crude product obtained in example 1 was dissolved in 120mL of THF, and 0.5g of 10% was added, i.e., pd/C was calculated. At 40 deg.C and 1atm 2 The mixture was stirred vigorously for 6 hours. The reaction was filtered to remove the catalyst and the catalyst was washed with 30mL of THF. The filtrates were combined and concentrated to dryness under reduced pressure to obtain 9.6g of the objective compound (yield: 99%). The crude product was used directly in the next reaction.
Example 3 preparation of Compound of formula a04
9.6g of the crude product of the compound represented by the formula a03 (48.9 mmol) was dissolved in 19mL of trifluoroacetic acid and cooled to 5 ℃ and 20.5g of trifluoroacetic anhydride (97.8 mmol) was slowly added dropwise while controlling the reaction temperature at 10 ℃ or lower. After reacting at 5-10 ℃ for 1 hour, gradually raising the temperature to room temperature and continuing the reaction for 4 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in 120mL of ethyl acetate, washed 3 times with 30mL of 5% NaHCO3 solution, respectively, and the organic phase was concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 8.1g of the objective compound (yield: 93%).
Example 4 preparation of Compound of formula a05
8.1g of the compound represented by the formula a04 (45.5 mmol) was dissolved in 100mL of concentrated sulfuric acid, and 2.9mL of fuming nitric acid (47.8 mmol) and 16mL of concentrated sulfuric acid were mixed to prepare a mixed acid. Slowly dripping the mixed acid into the sulfuric acid solution of the compound represented by the formula a04 at room temperature, and controlling the reaction temperature to be less than or equal to 35 ℃ in the dripping process. After the completion of the dropwise addition, stirring was continued at 35 ℃ for 1 hour. After completion of the reaction, the reaction mixture was poured into 1kg of crushed ice, followed by stirring for 30 minutes. The precipitated solid was collected by filtration. The solid was dried and then purified by silica gel column chromatography to obtain 4.4g of the compound represented by the formula a05 (yield 43%).
Example 5 preparation of Compound of formula a07
5.0g of the compound represented by the formula a05 (22.4 mmol) was dissolved in 75mL of THF and cooled to 10 ℃ followed by addition of 3.4g of isoamyl nitrite (29.0 mmol) and 3.0g of potassium tert-butoxide (26.8 mmol). 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 is at 1atm 2 Stir under ambient 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, the filtrates were combined and concentrated to dryness under reduced pressure. The residue was dissolved in a mixed solvent of 50mL of THF and 50mL of ethyl acetate, 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% and the HPLC spectrum is shown in FIG. 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)
1. A process for the preparation of a compound represented by formula a07,
the method comprises the following steps:
subjecting 2-bromo-6-fluorotoluene to Heck reaction with 3-butenoic acid to convert to a mixture of compounds represented by formulas a01 and a 02:
converting a mixture of the products of the reaction of 2-bromo-6-fluorotoluene with 3-butenoic acid, the compounds represented by formulae a01 and a02, into a compound represented by formula a03 by a hydrogenation reduction reaction:
converting the compound represented by formula a03 into a compound represented by formula a04 by intramolecular Friedel-Crafts reaction:
converting a compound represented by formula a04 to a compound represented by formula a05 by nitration:
converting a compound represented by formula a05 into a compound represented by formula a 07:
2. a process for preparing a compound represented by formula a07, comprising:
allowing a compound represented by the formula a05,
conversion to a compound represented by the formula a07
3. The process according to claim 1 or 2, wherein said converting the compound represented by formula a05 into the compound represented by formula a07 comprises the steps of:
reacting the compound represented by the formula a05 with nitrosoisoamyl under alkaline conditions, then adding acetic acid and acetic anhydride, and then starting hydrogenation reduction reaction to obtain the compound represented by the formula a 07.
4. The process of claim 3, wherein the base is potassium tert-butoxide, lithium tert-butoxide or sodium tert-butoxide.
5. The process of claim 3, wherein the hydrogenation reduction is carried out in the presence of Pd/C as a catalyst and a reaction mixture in the presence of H 2 Reduction reaction under the condition.
6. The method according to claim 2, wherein the compound represented by formula a05 is converted from the compound represented by formula a04 by nitration.
7. The method according to claim 6, wherein the compound represented by formula a04 is obtained by converting the compound represented by formula a03 through an intramolecular Friedel-Crafts reaction.
8. The method according to claim 7, wherein the compound represented by formula a03 is obtained by converting the compound represented by formula a01 and/or a02 through a hydrogenation reduction reaction.
9. The method according to claim 8, wherein the compound represented by formula a01 and/or a02 is obtained by reacting 2-bromo-6-fluorotoluene with 3-butenoic acid.
10. A process for the preparation of irinotecan, which comprises the step of preparing a compound represented by formula a07, and/or a compound represented by formula a05, and/or a compound represented by formula a04, and/or a compound represented by formula a03, and/or a compound represented by formula a02, and/or a compound represented by formula a01 by the process as claimed in any one of claims 1 to 9.
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