WO2023227006A1 - 一类二氘代喜树碱衍生物及制备方法 - Google Patents
一类二氘代喜树碱衍生物及制备方法 Download PDFInfo
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- WO2023227006A1 WO2023227006A1 PCT/CN2023/095927 CN2023095927W WO2023227006A1 WO 2023227006 A1 WO2023227006 A1 WO 2023227006A1 CN 2023095927 W CN2023095927 W CN 2023095927W WO 2023227006 A1 WO2023227006 A1 WO 2023227006A1
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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 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 238000006243 chemical reaction Methods 0.000 claims description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 49
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000003054 catalyst Substances 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 230000035484 reaction time Effects 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
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- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 10
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 5
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- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 4
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- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- 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
- C07D491/02—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 two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Definitions
- the invention belongs to the technical field of pharmaceutical synthesis and relates to dideuterated camptothecin derivatives represented by the general formula Q and their preparation methods, in vitro biological activities and uses. More specifically, it relates to a type of dideuterated camptothecin derivatives with the following structure Camptothecin derivatives Q as well as preparation methods and applications of these compounds in the preparation of drugs and related fields.
- Camptothecin is a classic anti-tumor drug and one of the more widely studied natural anti-tumor drugs besides paclitaxel. Its mechanism is to inhibit the formation of a ternary complex between topoisomerase I (TOP I) and DNA, thereby rapidly inducing tumor cell death. Camptothecin compounds are the only TOPI inhibitors used clinically and have good therapeutic effect on clinically slow-growing solid tumors. Three camptothecin compounds have been approved for cancer treatment.
- Irinotecan first approved by the FDA in 1994, is a first-line treatment for colorectal cancer; topotecan, first approved by the FDA in 1996, is used for the treatment of ovarian cancer; bellotecan was also approved in South Korea in 2005 and is used for for the treatment of small cell lung cancer.
- camptothecin There are several problems with traditional anti-tumor drugs such as camptothecin: 1Poor drugability.
- the special structure of camptothecin results in poor fat solubility and water solubility, and water solubility must be modified.
- 2 Camptothecin compounds have a certain degree of toxicity. If the water-soluble modification is too good, it will cause an instant increase in blood concentration and cause toxic and side effects.
- 3The modification of camptothecin prodrugs needs to consider release efficiency and stability, which are always a contradiction in the design of reasonable prodrugs.
- camptothecin a series of candidate highly toxic compounds such as camptothecin, which were previously undruggable and had severe side effects, have been reused.
- ADC technology can effectively overcome Camptothecin drugs have side effects caused by poor water solubility and insufficient tissue distribution.
- the strong targeting ability of antibodies enables the overall ADC molecules to be concentrated in the target tissue.
- the toxicity of camptothecin compounds is a favorable factor for the therapeutic effect.
- SN-38 is the active metabolite of the marketed anti-tumor drug irinotecan, and its anti-tumor activity is three orders of magnitude stronger than irinotecan.
- IMMU-132 is an ADC drug with SN-38 as the payload.
- Another camptothecin ADC drug, DS-8201a was approved by the FDA in 2019 for metastatic breast cancer that has received at least two anti-HER2 therapies.
- Cathepsin B-activated GGFG tetrapeptide is used as a linker, and a small self-cleaving structure is introduced.
- the drug released is a derivative of ixotecan, Dxd, which currently also has anti-tumor effects in HER2-expressing metastatic colorectal cancer.
- Deuterated drugs go beyond the pure and simple improvement of drug pharmacokinetic parameters and may provide opportunities when faced with problems with metabolism-mediated toxicity, drug interactions, and low bioactivity.
- the wider use of deuterium provides the opportunity to reduce the degree of epimerization and reduce the dose of co-administered enhancer.
- the object of the present invention is to provide a class of dideuterated camptothecin derivatives with a general formula Q structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof.
- Such compounds have inhibitory activity against topoisomerase I.
- Another object of the present invention is to provide a method for preparing the dideuterated camptothecin derivatives described in the general formula Q.
- Another object of the present invention is to provide a class of dideuterated camptothecin derivatives for use in the preparation of medicines and related fields.
- the invention provides a class of dideuterated camptothecin derivatives represented by the general formula Q, their stereoisomers, pharmaceutically acceptable salts or prodrugs:
- R 1 is -H, -CH 3 , -(CH 2 ) n CH 3 , -OCH 3 , -O(CH 2 ) n CH 3 , -F, -Cl, -Br or -I, n represents an integer from 1 to 3;
- R 2 is -H, -OH, -NH 2 , -F, -Cl, -Br, -I, -CH 3 , -OCH 3 , -(CH 2 ) n CH 3 , -(CH 2 ) n Si( CH 3 ) 3 , -(CH 2 ) n NH(CH 3 ) 2 , -O(CH 2 ) n CH 3 , -O(CH 2 ) n NH 2 , -NH(CH 2 ) n NH 2 , -( OCH 2 CH 2 ) n NH 2 or Among them, n represents an integer from 1 to 3; or
- R 1 , R 2 are connected to each other to form -(CH 2 ) p -, -X(CH 2 ) (p-1) -, -(CH 2 ) (p-1) X-, -X(CH 2 ) ( q-1) X-or-(CH 2 ) (q-1) X(CH 2 ) (q-1) , p and q represent integers 2-4, X represents O, NH or S;
- R 4 is -H, -CH 3 , -OCH 3 , -(CH 2 ) n CH 3 , -Si(CH 3 ) 2 C(CH 3 ) 3 , -(CH 2 ) n Si(CH 3 ) 3 , -(CH 2 ) n NHCH(CH 3 ) 2 , -CH 2 NH(CH 2 ) n CH 3 , -CH 2 O(CH 2 ) n CH 3 , -F, -Cl, -Br, -I, Among them, n represents an integer from 1 to 3; or
- R 3 and R 4 are connected to each other to form the structure shown in the following formula:
- R 1 is -H, -CH 3 , -(CH 2 ) n CH 3 , -OCH 3 , -O(CH 2 ) n CH 3 , -F, -Cl, -Br or -I, n represents an integer from 1 to 3;
- R 2 is -H, -OH, -NH 2 , -F, -Cl, -Br, -I, -CH 3 , -OCH 3 , -(CH 2 ) n CH 3 , -(CH 2 ) n Si( CH 3 ) 3 , -(CH 2 ) n NH(CH 3 ) 2 , -O(CH 2 ) n CH 3 , -O(CH 2 ) n NH 2 , -NH(CH 2 ) n NH 2 , -( OCH 2 CH 2 ) n NH 2 or Among them, n represents an integer from 1 to 3; or
- R 1 , R 2 are connected to each other to form -(CH 2 ) p -, -X(CH 2 ) (p-1) -, -(CH 2 ) (p-1) X-, -X(CH 2 ) ( q-1) X-or-(CH 2 ) (q-1) X(CH 2 ) (q-1) -, p represents an integer 2-4, q represents an integer 2-3, ;
- R 4 is -H, -CH 3 , -OCH 3 , -(CH 2 ) n CH 3 , -Si(CH 3 ) 2 C(CH 3 ) 3 , -(CH 2 ) n Si(CH 3 ) 3 , -(CH 2 ) n NHCH(CH 3 ) 2 , -CH 2 NH(CH 2 ) n CH 3 , -CH 2 O(CH 2 ) n CH 3 , -F, -Cl, -Br, -I, Among them, n represents an integer from 1 to 3; or
- R 3 and R 4 are connected to each other to form the structure shown in the following formula:
- R 1 is -H, -F, -Cl, -Br or -I;
- R 2 is -H, -OH, -CH 3 , -(CH 2 ) n CH 3 , or Among them, n represents an integer from 1 to 3; or
- R 1 and R 2 are connected to each other to form -X(CH 2 ) (q-1) X-, q represents an integer 2-3, and X represents O or S;
- R 4 is -H, -CH 3 , -(CH 2 ) n CH 3 , -Si(CH 3 ) 2 C(CH 3 ) 3 , -(CH 2 ) n Si(CH 3 ) 3 , -(CH 2 ) nNHCH (CH 3 ) 2 , Among them, n represents an integer from 1 to 3; or
- R 3 and R 4 are connected to each other to form the structure shown in the following formula:
- R 1 is -H or -F
- R 2 is -H, -OH, -CH 3 , or or
- R 1 and R 2 are connected to each other to form -O(CH 2 ) 2 O-;
- R 4 is -H, -CH 2 CH 3 , -Si(CH 3 ) 2 C(CH 3 ) 3 , -(CH 2 ) 2 Si(CH 3 ) 3 , -(CH 2 ) 2 NHCH(CH 3 ) 2 , or
- R 3 and R 4 are connected to each other to form the structure shown in the following formula:
- R 1 is -H or -F
- R 2 is -H, -OH, or -CH 3 ;
- R 3 is -H
- R 4 is -CH 2 CH 3 , or -(CH 2 ) 2 NHCH(CH 3 ) 2 ; or
- R 3 and R 4 are connected to each other to form the structure shown in the following formula:
- the dideuterated camptothecin derivative is selected from the following compounds:
- the invention provides a method for preparing a class of dideuterated camptothecin derivatives.
- the preparation method includes the following steps:
- the preparation method of the dideuterated camptothecin derivative represented by the general formula Q includes the following steps:
- Compound L-2 is deuterated through a deuterated reducing agent to obtain compound L-3;
- the deuterated reducing agent is selected from sodium deuterated borohydride, potassium deuterated borohydride, deuterated borane or deuterated aluminum tetrahydrogen. Lithium;
- the solvent used is selected from dichloromethane, tetrahydrofuran, methanol or ethanol;
- the molar ratio of the reaction between compound L-2 and the deuterated reducing agent is 1:1.1 ⁇ 2.5, and the reaction temperature is 0°C-40°C, preferably 10-35°C , 20-30°C, reaction time 6-15 hours, preferably 8-14 hours;
- Compound L-5 reacts with a palladium catalyst, a phosphine ligand, a base and an alcohol in a carbon monoxide atmosphere to generate L-6;
- the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate or triethylamine;
- the palladium catalyst is selected from palladium acetate, bistriphenylphosphine palladium dichloride, 1,1-bis(diphenylphosphine)diphenylphosphine palladium dichloride or triphenylphosphine palladium;
- the alcohol is selected from deuterated methanol or deuterium Instead of ethanol;
- the phosphine ligand is selected from 1,3-bis(diphenylphosphine)propane;
- the reaction molar ratio of compound L-5, palladium catalyst, phosphine ligand and base is 1:0.01 ⁇ 0.1:0.01 ⁇ 0.1:1.5 ⁇ 3;
- the solvent
- the deuterated reducing agent is selected from the group consisting of sodium deuterated borohydride, potassium deuterated borohydride, deuterated borane and deuterated lithium aluminum tetrahydrogen;
- the solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, methanol and ethanol, preferably anhydrous solvents of the following solvents: dichloromethane, tetrahydrofuran, methanol and ethanol.
- the molar ratio of the reaction between compound L-2 and the deuterated reducing agent is 1:1.1-2.5.
- reaction temperature of compound L-2 and the deuterated reducing agent is 0°C-40°C, preferably 10-35°C, 20-30°C;
- reaction time of compound L-2 and the deuterated reducing agent is 6-15 hours, preferably 8-14 hours;
- the preparation method of compound L-3 includes the following steps: add compound L-2 to absolute ethanol, cool the system to 0°C, add sodium borodeuteride, stir for 15 minutes, and then raise the temperature. React at room temperature for 12 hours; TLC monitors that the reaction is complete, add hydrochloric acid, extract with dichloromethane, combine the organic phases, wash with saturated sodium bicarbonate, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate the system in vacuum, and purify by column chromatography to obtain Compound L-3;
- the preparation method of compound L-3 includes the following steps: add 21g of compound L-2 to 400 mL of absolute ethanol, and after cooling the system to 0°C, add 14.21g of sodium boron deuteride and stir for 15 minutes, then heated to room temperature and reacted for 12 hours; TLC monitored that the reaction was complete, added 30 mL of 1N hydrochloric acid, extracted with dichloromethane, combined the organic phases, washed with saturated sodium bicarbonate, washed with saturated brine, and dried over anhydrous sodium sulfate. After the system was concentrated in vacuo, compound L-3 was obtained through column chromatography purification.
- the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate and triethylamine
- the palladium catalyst is selected from palladium acetate, bistriphenylphosphine palladium dichloride, 1,1-bis(diphenyl base phosphine) diphenylphosphine palladium dichloride and triphenylphosphine palladium
- the alcohol is selected from deuterated methanol and deuterated ethanol
- the phosphine ligand is selected from 1,3-bis(diphenylphosphine)propane
- the reaction molar ratio of compound L-5 with palladium catalyst, phosphine ligand and base is 1:0.01 ⁇ 0.1:0.01 ⁇ 0.1:1.5 ⁇ 3
- the solvent is selected from N,N-dimethylformamide, and the reaction temperature is between 60 and 120°C, reaction time is 6-48 hours.
- the compound of the present invention has more excellent tumor inhibitory activity, and has more excellent elimination rate and elimination half-life.
- it is used to prepare ADC drugs, if the warhead drug molecules of the resulting ADC drug fall off from the antibody in the body, the fallen warhead drug molecules can be quickly metabolized and Eliminate, from reducing the toxicity of drugs in the body.
- deuteration technology is an important part of modern medical imaging technology. Based on the deuteration on the core of camptothecin, camptothecin and its derivatives can be used in tracer technology for medical research.
- the normal concentration (N) refers to the concentration of the solution expressed by the number of gram equivalents of the solute contained in 1 liter of solution, which is called the normal concentration. , represented by the symbol N. If it is hydrochloric acid, which releases a hydrogen ion, the normal concentration and molar concentration are the same; if it is sulfuric acid, the normal concentration is equal to 0.5 times the molar concentration.
- deuterated position of the deuterated compound of the present invention (for example, compound L3) is well known to those skilled in the art, and can be confirmed, for example, by comparing it with 1 H-NMR data of the corresponding non-deuterated compound.
- the stereoconfiguration of the compound of the present invention (such as compound L3, compound A-3, compound A-9, compound A-11) can be compared with the HPLC retention time or optical rotation of the deuterated compound and the corresponding non-deuterated single isomer. determined by comparison.
- HCT116 cells purchased from ATCC were cultured in DMEM culture medium (purchased from Gibco), added with 10% fetal calf serum and 1% penicillin-streptomycin solution, and placed in a 5% CO 2 , 37°C incubator. Seed 3000 cells per well in a 96-well plate and culture overnight. Add drugs of different concentrations and place them in normal incubators (21% O 2 , 5% CO 2 , 74% N 2 ) for 72 hours. Aspirate 100 ⁇ L of culture medium, add 10 ⁇ L MTT solution (5 mg/mL), and place it in the incubator for 4 hours.
- Compounds with activity designated “A” provide an IC 50 ⁇ 10 nM; compounds designated with activity “B” provide an IC 50 of 10-100 nM; compounds with an activity designated “C” provide an IC 50 of 100-1000 nM; Compounds with activity designated “D” provided IC50s of 1000-10000 nM. Potency (nM); Potency (IC 50 ).
- MDA-MB-468 cells (purchased from ATCC) use L-15 culture medium (purchased from Sigma-Aldrich), NCI-N87 cells (purchased from ATCC) use RPMI-1640 culture medium (purchased from Gibco), HT29 cells (purchased from Gibco) McCoy's 5A culture medium (purchased from Gibco) was used, 10% fetal calf serum and 1% penicillin-streptomycin solution were added, and cultured in a 5% CO 2 , 37°C incubator. Seed 3000 cells per well in a 96-well plate and culture overnight. Add drugs of different concentrations and place them in normal incubators (21% O 2 , 5% CO 2 , 74% N 2 ) for 72 hours.
- human gastric cancer cell NCI-N87, and human colon cancer cell HT29 all have good inhibitory effects, and are better than non-deuterated belotecan, SN-38, and ixotecan, which shows that deuterium atoms replace specific positions of Hydrogen atoms can improve the anti-tumor effect of drugs.
- mice purchased from Beijing Vitong Lever
- mice/group half male and half female
- a single injection of sample (10% DMSO-90% (20% 2-hydroxypropyl- ⁇ -cyclodextrin-physiological saline), diluted according to dose)
- cross sampling points collect plasma before and 5min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h respectively before and after administration
- LC- The MS method was used to detect the sample concentration in plasma and calculate the pharmacokinetic parameters (see Table 3).
- SD rats (Beijing Weitonglihua Experimental Animal Technology Co., Ltd.) were randomly divided into 6 rats/group, half male and half female, and a single injection of sample (10% DMSO-90% (20% 2-hydroxypropyl- ⁇ -cyclodextrin-physiological saline), diluted according to dose), collect plasma before and 5min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h after administration, and detect it by LC-MS method Sample concentration in plasma was used to calculate pharmacokinetic parameters (see Table 4).
- Each incubation system contains phosphate buffer (PBS, pH7.4), liver microsomal protein, sample to be tested (acetonitrile solution) and NADPH. It is incubated in a water bath at 37oC, and the reaction times are 0.5, 5, 15, and 30 respectively. After 60 min, the same volume of ice-cold acetonitrile was added to terminate the reaction (including internal standard). Centrifuge the sample solution, take 100ul of the supernatant, add 100ul of ultrapure water, and detect the remaining content of the original substrate through the LC-MS/MS method. Negative controls were incubated with heat-inactivated liver microsomes of the corresponding species.
- PBS phosphate buffer
- acetonitrile solution sample to be tested
- NADPH acetonitrile solution
Abstract
本发明提供了通式Q所示的一类二氘代喜树碱衍生物及其制备方法,体外的生物活性和用途,属于药物合成技术领域。该类化合物是一类拓扑异构酶I抑制剂,能应用于制备治疗抗肿瘤相关领域各类疾病的药物。
Description
本发明属于药物合成技术领域,涉及通式Q所示的二氘代喜树碱类衍生物及其制备方法,体外的生物活性和用途,更具体的说,涉及具有以下结构的一类二氘代喜树碱衍生物Q以及制备方法和这些化合物用于制备药物及相关领域的应用。
喜树碱(CPT)为一种是经典的抗肿瘤药物,是除紫杉醇之外,研究较广泛的天然抗肿瘤药物之一。其机制是抑制拓扑异构酶I(TOP I)与DNA形成三元复合物,从而快速诱导肿瘤细胞死亡。喜树碱类化合物是临床中应用的唯一的TOP I抑制剂,对临床上生长缓慢的实体瘤有良好的疗。已有三个喜树碱类化合物被批准上市用于肿瘤治疗。伊立替康,FDA首次批准日期1994年,为结直肠癌一线治疗药物;拓扑替康,FDA首次批准日期1996年,用于卵巢癌治疗;贝洛替康也与2005年在韩国被批准,用于小细胞肺癌的治疗。
喜树碱类传统抗肿瘤药物存在几点问题:①成药性差,喜树碱特殊结构导致脂溶性和水溶性都很差,必须进行水溶性改造。②喜树碱化合物具有一定毒性,水溶性改造太好也会导致血药浓度的瞬间上升从而引起毒副反应。③喜树碱前药改造需要考虑释放效率与稳定性,这在合理前药设计上永远是一对矛盾体。
随着药物传递系统和ADC技术的发展,使喜树碱类一系列以前不能成药和副作用大的候选高毒性化合物重新得到了应用。ADC技术可有效地克服
喜树碱类药物的水溶性差、组织分布不足等带来的副作用。抗体的强大靶向能力使得ADC分子整体能集中分布于靶组织,喜树碱类化合物的毒性反而是起到治疗效果的有利因素。
SN-38是已上市抗肿瘤药物伊立替康活性代谢产物,其抗肿瘤活性比伊立替康强三个数量级。IMMU-132以SN-38作为载荷的ADC药物,2020年,FDA批准上市,用于治疗转移性三阴性乳腺癌。另一种喜树碱类ADC药物DS-8201a,2019年,FDA批准上市,用于至少接受过两种抗HER2疗法的转移性乳腺癌。以组织蛋白酶B活化的GGFG四肽作为linker,并引入一小段自裂解结构,释放出来的药物是依喜替康的衍生物Dxd,目前在表达HER2转移性结直肠癌中也有抗肿瘤效果。
氘化药物超越了药物药代动力学参数的纯粹和简单的改善,并且可能在代谢介导的毒性,药物相互作用和低生物活性方面面临问题时提供机会。氘的使用更广泛,提供了降低差向异构化程度,减少共同施用的增强剂剂量的机会。
发明内容
本发明目的是提供一类通式Q结构的二氘代喜树碱衍生物或其可药用盐或其立体异构体或其立体异构体的可药用盐。此类化合物具有抑制拓扑异构酶I的抑制活性。
本发明的另一目的是提供一种通式Q所述二氘代喜树碱类衍生物的制备方法。
本发明的再一目的在于提供一类二氘代喜树碱衍生物用于制备药物及相关领域的应用。
本发明的目的是这样实现的:
本发明提供了一类通式Q所示的二氘代喜树碱衍生物、其立体异构体、药学上可接受的盐或前药:
其中:
R1为-H、-CH3、-(CH2)nCH3、-OCH3、-O(CH2)nCH3、-F、-Cl、-Br或-I,n代表整数1~3;
R2为-H、-OH、-NH2、-F、-Cl、-Br、-I、-CH3、-OCH3、-(CH2)nCH3、-(CH2)nSi(CH3)3、-(CH2)nNH(CH3)2、-O(CH2)nCH3、-O(CH2)nNH2、-NH(CH2)nNH2、-(OCH2CH2)nNH2或其中,n代表整数1~3;或者
R1、R2彼此连接以形成-(CH2)p-、-X(CH2)(p-1)-、-(CH2)(p-1)X-、-X(CH2)(q-1)X-或-(CH2)(q-1)X(CH2)(q-1),p和q代表整数2-4,X代表O,NH或S;
R3为-H、-CH3、-(CH2)nCH3、-OCH3、-O(CH2)nCH3、-NHCH3、-NH(CH2)nCH3、-(CH2)nSi(CH3)3、-(CH2)nN(CH3)2、-(CH2)nCH=CH2、-NO2、-F、-Cl、-Br或-I,n代表整数1~3;
R4为-H、-CH3、-OCH3、-(CH2)nCH3、-Si(CH3)2C(CH3)3、-(CH2)nSi(CH3)3、-(CH2)nNHCH(CH3)2、-CH2NH(CH2)nCH3、-CH2O(CH2)nCH3、-F、-Cl、-Br、-I、其中,n代表整数1~3;或者
R3和R4彼此连接以形成如下式所示结构:
根据本发明的一个实施方式,在所述通式Q中,
R1为-H、-CH3、-(CH2)nCH3、-OCH3、-O(CH2)nCH3、-F、-Cl、-Br或-I,n代表整数1~3;
R2为-H、-OH、-NH2、-F、-Cl、-Br、-I、-CH3、-OCH3、-(CH2)nCH3、-(CH2)nSi(CH3)3、-(CH2)nNH(CH3)2、-O(CH2)nCH3、-O(CH2)nNH2、-NH(CH2)nNH2、-(OCH2CH2)nNH2或其中,n代表整数1~3;或者
R1、R2彼此连接以形成-(CH2)p-、-X(CH2)(p-1)-、-(CH2)(p-1)X-、-X(CH2)(q-1)X-或-(CH2)(q-1)X(CH2)(q-1)-,p代表整数2-4,q代表整数2-3,X代表O,NH或S;
R3为-H、-CH3、-(CH2)nCH3、-OCH3、-O(CH2)nCH3、-NHCH3、-NH(CH2)nCH3、-(CH2)nSi(CH3)3、-(CH2)nN(CH3)2、-(CH2)nCH=CH2、-NO2、-F、-Cl、-Br或-I,n代表整数1~3;
R4为-H、-CH3、-OCH3、-(CH2)nCH3、-Si(CH3)2C(CH3)3、-(CH2)nSi(CH3)3、-(CH2)nNHCH(CH3)2、-CH2NH(CH2)nCH3、-CH2O(CH2)nCH3、-F、-Cl、-Br、-I、其中,n代表整数1~3;或者
R3和R4彼此连接以形成如下式所示结构:
根据本发明的一个实施方式,在所述通式Q中,
R1为-H、-F、-Cl、-Br或-I;
R2为-H、-OH、-CH3、-(CH2)nCH3、或其中,n代表整数1~3;或者
R1、R2彼此连接以形成-X(CH2)(q-1)X-,q代表整数2-3,X代表O或S;
R3为-H、-(CH2)nN(CH3)2、-(CH2)nCH=CH2、-NO2,n代表整数1~3;
R4为-H、-CH3、-(CH2)nCH3、-Si(CH3)2C(CH3)3、-(CH2)nSi(CH3)3、-(CH2)nNHCH(CH3)2、其中,n代表整数1~3;或者
R3和R4彼此连接以形成如下式所示结构:
根据本发明的一个实施方式,在所述通式Q中,
R1为-H、或-F;
R2为-H、-OH、-CH3、或或者
R1、R2彼此连接以形成-O(CH2)2O-;
R3为-H、-(CH2)N(CH3)2、-CH2CH=CH2、-NO2;
R4为-H、-CH2CH3、-Si(CH3)2C(CH3)3、-(CH2)2Si(CH3)3、-(CH2)2NHCH(CH3)2、或者
R3和R4彼此连接以形成如下式所示结构:
根据本发明的一个实施方式,在所述通式Q中,
R1为-H、或-F;
R2为-H、-OH、或-CH3;
R3为-H;
R4为-CH2CH3、或-(CH2)2NHCH(CH3)2;或者
R3和R4彼此连接以形成如下式所示结构:
根据本发明的一个实施方式,所述二氘代喜树碱衍生物选自以下化合物:
本发明提供一类二氘代喜树碱衍生物的制备方法,该方法制备包括如下步骤:
a)化合物L-1与1-戊烯-3酮、2,2,6,6-四甲基哌啶和锂化试剂反应得到L-2;
b)化合物L-2通过氘代还原剂,实现化合物氘化得到化合物L-3;
c)化合物L-3通过臭氧化反应得到化合物L-4;
d)化合物L-4与2,2,6,6-四甲基哌啶氧化物、碳酸氢钠、溴化钾和次氯酸钠反应得到化合物L-5;
e)化合物L-5在一氧化碳氛围下,与钯催化剂、膦配体、碱和醇的条件下反应生成L-6;
f)化合物L-6与三甲基氯硅烷和碘化钠反应得到L-7;
g)化合物L-7与碱和酯反应得到L-8;
h)化合物L-8在甲苯做溶剂,三氟醋酸条件下脱羧得到L-9;
i)化合物L-9与多取代苯环和催化剂条件下生成化合物Q;在所述多取代苯环中,R1-R4的定义与上文的通式Q中相同。
根据本发明的一个实施方式,所述通式Q所示的二氘代喜树碱类衍生物的制备方法包括如下步骤:
a)化合物L-1与1-戊烯-3酮、2,2,6,6-四甲基哌啶和锂化试剂反应得到L-2,反应温度为-78℃至-10℃,反应时间为2-12小时;锂化试剂选自正丁基锂、异丁基锂或二异丙基氨基锂;所用溶剂选自四氢呋喃、甲基四氢呋喃、乙酸乙酯或石油醚;化合物L-1与1-戊烯-3-酮、2,2,6,6-四甲基哌啶和锂化试剂反应的摩尔比例为1:2~4:2~4:3~5;
b)化合物L-2通过氘代还原剂,实现化合物氘化得到化合物L-3;氘代还原剂选自氘代硼氢化钠、氘代硼氢化钾、氘代硼烷或氘代四氢铝锂;所用溶剂选自二氯甲烷、四氢呋喃、甲醇或乙醇;化合物L-2与氘代还原剂反应的摩尔比例为1:1.1~2.5,反应温度为0℃-40℃,优选10-35℃,20-30℃,反应时间6-15小时,优选8-14小时;
c)化合物L-3通过臭氧化反应得到化合物L-4,所选溶剂选自乙醇、甲醇、四氢呋喃或二氯甲烷,反应温度为-78℃,反应时间为15-30分钟;
d)化合物L-4与2,2,6,6-四甲基哌啶氧化物、碳酸氢钠、溴化钾和次氯酸钠反应得到化合物L-5,其反应的摩尔比例为1:0.01~0.1:0.1~0.5:0.1~0.5:1~5;反应温度于-10℃至10℃;
e)化合物L-5在一氧化碳氛围下,与钯催化剂、膦配体、碱和醇的条件下反应生成L-6;碱选自碳酸钾、碳酸钠、碳酸铯、磷酸钾或三乙胺;钯催化剂选自醋酸钯、双三苯基膦二氯化钯、1,1-双(二苯基膦)二荗铁二氯化钯或三苯基膦钯;醇选自氘代甲醇或氘代乙醇;膦配体选自1,3-双(二苯基膦)丙烷;化合物L-5与钯催化剂、膦配体和碱的反应摩尔比为1:0.01~0.1:0.01~0.1:1.5~3;溶剂选自N,N-二甲基甲酰胺,反应温度于60至120℃,反应时间为6-48小时;
f)化合物L-6与三甲基氯硅烷和碘化钠反应得到L-7;其中,化合物L-6与三甲基氯硅烷和碘化钠反应的摩尔比为1:2~3:2~3;溶剂选自乙腈、四氢呋喃、二氯甲烷或乙酸乙酯,反应时间为12-24小时,反应温度为室温;
g)化合物L-7与碱和酯反应得到L-8,L-7与碱和酯反应的摩尔比例为1:2~4:2~10;反应时间为12-48小时,反应温度为50℃,生成五元环化合物L-8;其中,碱选自碳酸钾、碳酸铯、碳酸钠或乙醇钠;酯选自丙烯酸甲酯、丙烯酸乙酯、丙烯酸叔丁酯或丙烯酸正丁酯,溶剂选自N,N-二甲基甲酰胺或二甲基亚砜;
h)化合物L-8在甲苯做溶剂,三氟醋酸条件下脱羧得到L-9;反应温度于80℃至140℃,反应时间为2-6小时;
i)化合物L-9与多取代苯环和催化剂条件下生成化合物Q;其中L-9与多取代苯环和催化剂反应的摩尔比为1:1:0.2~0.6;反应所采用溶剂选择四氢呋喃、乙醇或甲苯;催化剂选自无水对甲苯磺酸、对甲苯磺酸的吡啶盐、三氯化锑、硫酸或浓盐酸;反应温度于80℃至140℃,反应时间为12-48小时;在所述多取代苯环中,R1-R4的定义与上文的通式Q中相同。
根据本发明的一个实施方式,其提供了一种化合物L-3的制备方法,该方法包括以下步骤:
化合物L-2在溶剂I中与氘代还原剂反应,得到化合物L-3,
其中,所述氘代还原剂选自氘代硼氢化钠、氘代硼氢化钾、氘代硼烷和氘代四氢铝锂;
所述溶剂选I选自二氯甲烷、四氢呋喃、甲醇和乙醇,优选下列溶剂的无水溶剂:二氯甲烷、四氢呋喃、甲醇和乙醇。
在本发明的一个技术方案中,化合物L-2与氘代还原剂反应的摩尔比例为1:1.1~2.5。
在本发明的一个技术方案中,化合物L-2与氘代还原剂的反应温度为0℃-40℃,优选10-35℃,20-30℃;
在本发明的一个技术方案中,化合物L-2与氘代还原剂的反应时间6-15小时,优选8-14小时;
在发明的一个技术方案中,化合物L-3的制备方法包括如下步骤:将化合物L-2加入到无水乙醇中,体系降温至0℃后,加入硼氘化钠,搅拌15分钟,再升温至室温反应12小时;TLC监测反应完全,加入盐酸,二氯甲烷萃取,合并有机相,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,体系真空浓缩后,经柱层析纯化得到化合物L-3;
在本发明的一个技术方案中,化合物L-3的制备方法包括如下步骤:将21g化合物L-2加入到400mL无水乙醇,体系降温至0℃后,加入14.21g硼氘化钠,搅拌15分钟,再升温至室温反应12小时;TLC监测反应完全,加入30mL1N盐酸,二氯甲烷萃取,合并有机相,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥。体系真空浓缩后,经柱层析纯化得到化合物L-3。
根据本发明的一个实施方式,其提供了一种化合物L-6的制备方法,该方法包括以下步骤:
e)化合物L-5在一氧化碳氛围下,与钯催化剂、膦配体、碱和醇的条件下反应生成L-6,
其中,所述碱选自碳酸钾、碳酸钠、碳酸铯、磷酸钾和三乙胺;所述钯催化剂选自醋酸钯、双三苯基膦二氯化钯、1,1-双(二苯基膦)二荗铁二氯化钯和三苯基膦钯;所述醇选自氘代甲醇和氘代乙醇;所述膦配体选自1,3-双(二苯基膦)丙烷;化合物L-5与钯催化剂、膦配体和碱的反应摩尔比为1:0.01~0.1:0.01~0.1:1.5~3;溶剂选自N,N-二甲基甲酰胺,反应温度于60至120℃,反应时间为6-48小时。
本发明化合物具有更为优异的肿瘤抑制活性,且具有更为优异的消除速率和消除半衰期。当其用于制备ADC药物时,所得ADC药物如果在体内出现弹头药物分子从抗体上脱落时,脱落的弹头药物分子能够快速地被代谢和
消除,从减少药物的体内毒性。另外,氘代技术是现代医学造影技术的重要部分,基于喜树碱母核上的氘代,可以使喜树碱及其衍生物用于医学研究的示踪技术。
在本发明中,浓度单位“M”指代mol/L:1M=1mol/L;当量浓度(N)是指溶液的浓度用1升溶液中所含溶质的克当量数来表示的叫当量浓度,用符号N表示。如果是盐酸,放出一个氢离子,则当量浓度和摩尔浓度是一样的;如果是硫酸,则当量浓度等于0.5倍的摩尔浓度。
本发明的氘代化合物(例如化合物L3)的氘代位置的确认是本领域技术人员公知的,例如可以通过与相应的非氘代化合物的1H-NMR数据对比进行确认。本发明化合物的立体构型(例如化合物L3、化合物A-3、化合物A-9、化合物A-11)可以将该氘代化合物与相应的非氘代的单一异构体的HPLC保留时间或旋光度进行对比而确定。
本领域技术人员清楚,在下文中,如果未特别说明,所用的材料是本领域公知的,可以通过市场购买得到或者本领域技术人员根据已经公开文献或常规方法即可获得。除非另外说明,本发明的所有反应均在连续的磁力搅拌下,在干燥氮气或氩气气氛下进行,溶剂为干燥溶剂,其中:(i)温度以摄氏度(℃)表示,操作在室温下进行,所述室温一般指15-35℃,优选20-30℃,更优选20-25℃;(ii)溶剂的去除采用旋转蒸发仪减压蒸发,浴温不高于60℃;(iii)反应过程用薄层色谱(TLC)跟踪;(iv)终产物具有满意的氢核磁共振光谱(1H-NMR)和/或质谱(MS)数据。
本发明所含一类二氘代喜树碱衍生物和制备方法在如下实施例中更详细的叙述,但实施例不构成对本发明的限制。
实施例1
1.1制备化合物L-2
将86.4mL2,2,6,6-四甲基哌啶加入到3L三口瓶中,加入1L无水四氢呋喃,体系降温至-78℃,反应15分钟。加入272mL的2.5M正丁基锂的石油醚溶液,反应30分钟。将32g化合物L-1用200mL无水四氢呋喃溶解后,加入体系,反应1小时。将50mL1-戊烯-3-酮用200mL无水四氢呋喃溶解后,加入体系,反应1小时。TLC检测反应完全后,加入640mL4N盐酸,用乙酸乙酯萃取。合并有机相,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥。体系真空浓缩后,经柱层析纯化得到化合物L-2为白色固体21g,收率:49%。ESI-MS m/z:253.68,[M+H]+.
1H NMR(400MHz,CDCl3)δ6.99(s,1H),6.13(dd,J=17.3,10.6Hz,1H),5.29(d,J=7.0Hz,1H),5.26(s,1H),3.99(s,3H),2.73(s,2H),2.04(dt,J=14.8,7.3Hz,1H),1.98–1.87(m,1H),0.91(t,J=7.3Hz,3H)。
实施例2
1.2制备化合物L-3
将21g化合物L-2加入到1L三口瓶中,加入400mL无水乙醇,体系降温至0℃后,加入14.21g硼氘化钠,搅拌15分钟,再升温至室温反应12小时。TLC监测反应完全,加入30mL1N盐酸,二氯甲烷萃取。合并有机相,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥。体系真空浓缩后,经柱层析纯化得到化合物L-3为透明粘稠状液体17g,收率:80%。ESI-MS m/z:259.73,[M+H]+.通过与相应的L-3非氘代化合物的1H-NMR数据对比,确认氘代物纯度为99%以上。
1H NMR(400MHz,CDCl3)δ6.99(s,1H),6.13(dd,J=17.3,10.6Hz,1H),5.29(d,J=7.0Hz,1H),5.26(s,1H),3.99(s,3H),2.73(s,2H),2.04(dt,J=14.8,7.3Hz,1H),1.98–1.87(m,1H),0.91(t,J=7.3Hz,3H)。
实施例3
1.3制备化合物L-4
将2g化合物L-3加入到250mL圆底烧瓶中,加入100mL二氯甲烷,体系降温至-78℃,在此条件下通入臭氧。TLC检测反应完全后,加入0.5mL二甲硫醚,升至室温搅拌30分钟。体系真空浓缩后经柱层析纯化得到化合物L-4为白色固体1.9g,收率:95%。产物无需进一步分离纯化直接用于下一步反应。ESI-MS m/z:261.70,[M+H]+.
1H NMR(400MHz,CDCl3)δ7.15(s,1H),5.19(d,J=4.8Hz,1H),3.96(s,3H),3.21(d,J=4.8Hz,1H),2.64(s,1H),1.80(q,J=7.5Hz,2H),0.92(t,J=7.5Hz,3H)。
实施例4
1.4制备化合物L-5
将12g化合物L-4加入到1L单口瓶中,加入240mL二氯甲烷,搅拌30分钟,体系降温至0℃。加入286mg 2,2,6,6-四甲基哌啶氧化物,616mg碳酸氢钠,654mg溴化钾,18mL水,搅拌15分钟。加入120mL次氯酸钠溶液(>7.5%wt),反应30分钟。TLC监测反应完全,加入12g亚硫酸氢钠,二氯甲烷萃取。合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥。体系真空浓缩后,经柱层析纯化得到化合物L-5为白色固体6.6g,收率:55%。ESI-MS m/z:259.68,[M+H]+.
1H NMR(400MHz,CDCl3)δ7.20(s,1H),4.00(s,3H),3.64(s,1H),1.79(q,J=7.4Hz,2H),0.97(t,J=7.4Hz,3H)。
实施例5
1.5制备化合物L-6
一氧化碳氛围下,将3g化合物L-5加入到100mL三口瓶中,加入286mg1,3-双(二苯基膦)丙烷,2.4g碳酸钾,129mg醋酸钯,15mLN,N-二甲基甲酰胺,30mL氘代甲醇,体系升温至65℃反应12小时。TLC监测反应完全,加入20mL1N盐酸,乙酸乙酯萃取。合并有机相,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥。体系真空浓缩后,经柱层析纯化得到化合物L-6为白色固体1.33g,收率:40%。ESI-MS m/z:286.29,[M+H]+.
1H NMR(400MHz,CDCl3)δ7.98(d,J=2.0Hz,1H),4.09(d,J=2.0Hz,3H),3.71(d,J=2.6Hz,1H),1.88–1.75(m,2H),0.96(td,J=7.3,1.9Hz,3H)。
实施例6
1.6制备化合物L-7
将1g化合物L-6加入到50mL双口瓶中,加入1.05g碘化钠,10mL乙腈,体系降温至0℃,搅拌30分钟。加入0.89mL三甲基氯硅烷,体系升温至室温反应12小时。TLC监测反应完全,加入40mL水,1mL饱和亚硫酸氢钠溶液,搅拌1小时。二氯甲烷萃取,无水硫酸钠干燥。体系真空浓缩后,经柱层析纯化得到化合物L-7为白色固体800mg,收率:84%。ESI-MS m/z:272.27,[M+H]+.
1H NMR(400MHz,CDCl3)δ10.03(s,1H),7.32(s,1H),3.90(s,1H),1.81(dd,J=14.5,7.2Hz,2H),0.99(t,J=7.4Hz,3H)。
实施例7
1.7制备化合物L-8
将620mg化合物L-7加入到25mL双口瓶中,加入1.48g碳酸铯,8mL二甲亚砜,1.67mL丙烯酸叔丁酯,体系升温至50℃反应12小时。TLC监测反应完全,加入1mL浓盐酸,加入40mL水,二氯甲烷萃取,无水硫酸钠干燥。体系真空浓缩后,经柱层析纯化得到化合物L-8为淡褐色固体468mg,收率:55%。ESI-MS m/z:365.38,[M+H]+。
实施例8
1.8制备化合物L-9
将200mg化合物L-8加入到10mL单口瓶中,加入5mL甲苯,0.5mL三氟醋酸,体系升温至110℃反应2小时。TLC监测,体系真空浓缩后,经柱层析纯化得到化合物L-9为橙色固体140mg,收率:98%。ESI-MS m/z:265.26,[M+H]+。
实施例9
1.9制备化合物(A-9)
将140mg化合物L-9加入到10mL单口瓶中,加入89mg 1-(2-氨基-5-羟基苯基)丙-1-酮,2.5mL甲苯,2.5mL醋酸,41mg对甲苯磺酸吡啶盐。体系升温
至110℃反应18小时。TLC监测反应完全,体系真空浓缩后,经柱层析纯化(IH 4.6*100mm,5um手性柱,30%甲醇/正己烷)得到第二个异构体的吸收峰即为化合物A-9为淡黄色固体80mg,收率:37%。ESI-MS m/z:394.42,[M+H]+.
1H NMR(500MHz,DMSO-d6)δ0.88(t,J=7.25Hz,3H),1.32(t,J=7.5Hz,3H),1.85(m,2H),3.11(q,J=7.5Hz,2H),5.26(s,2H),6.48(s,1H),7.23(s,1H),7.41(d,J=10.0Hz,2H),8.01(d,J=10.0Hz,1H),10.3(s,1H)。
实施例10
2.1制备化合物(A-3)
将140mg化合物L-9加入到10mL单口瓶中,加入180mg(3-(2-氨基苯基)-3-氧代丙基)(异丙基)氨基甲酸苄酯,2.5mL甲苯,2.5mL醋酸,41mg对甲苯磺酸吡啶盐。体系升温至110℃反应18小时。TLC监测反应完全,体系真空浓缩后,经柱层析纯化得到中间体化合物L-10为金黄色固体240mg,收率:80%。
将240mg中间体化合物L-10加入到25mL单口瓶中,加入105mL醋酸,10%钯碳105mg。将体系置换为氢气,于室温反应24小时。TLC监测反应完全,体系真空浓缩后,经柱层析纯化(IH 4.6*100mm,5um手性柱,30%甲醇/正己烷)得到第二个异构体的吸收峰即为化合物A-3为金黄色固体71mg,收率:39%。ESI-MS m/z:435.52,[M+H]+.
1H NMR(400MHz,DMSO)δ9.23(s,2H),8.45(d,J=8.4Hz,1H),8.21(d,J=8.4Hz,1H),7.90(t,J=7.5Hz,1H),7.79(t,J=7.5Hz,1H),7.36(s,1H),5.43(s,2H),3.63(d,J=8.5Hz,2H),3.42–3.34(m,1H),3.21(s,2H),1.95–1.81(m,2H),1.28(d,J=6.2Hz,6H),0.88(t,J=7.0Hz,3H)。
实施例11
3.1制备化合物(A-11)
将300mg化合物L-9加入到25mL单口瓶中,加入266mg N-(8-氨基-6-氟-5-甲基-1-氧代-1,2,3,4-四氢萘-2-基)乙酰胺,9mL甲苯,770mL邻甲酚,133mg对甲苯磺酸吡啶盐。体系升温至110℃反应18小时。TLC监测反应完全,体系真空浓缩后,经柱层析纯化得到中间体化合物L-11为黄绿色固体443mg,收率:81%。
将443mg中间体化合物L-11加入到25mL单口瓶中,加入7mL纯净水,2.2mL甲磺酸,置换体系为氮气氛围。体系升温至85℃反应10小时。TLC监测反应完全,体系真空浓缩后,经柱层析纯化(手性柱CHIRALPAK IK-3,250mm×4.6mm,3μm,流动相A=乙醇(含0.1%二乙胺),流动相B=正己烷(含0.1%二乙胺))得到第一个异构体的吸收峰即为化合物A-11为黄绿色固体141mg,收率:35%。ESI-MS m/z:437.47,[M+H]+.
1H NMR(400MHz,D2O)δ7.20–7.06(m,2H),5.42–5.14(m,5H),3.30(dd,J=18.1,4.0Hz,1H),3.06–2.91(m,1H),2.69(s,2H),2.62–2.47(m,1H),2.18(s,3H),1.80(q,J=7.3Hz,2H),0.79(t,J=7.4Hz,3H)。
生物活性试验
实验例1:HCT-116细胞抑制活性测试
HCT116细胞(购自ATCC)使用DMEM培养液(购自Gibco),添加10%胎牛血清和1%青霉素-链霉素溶液,放置于5%CO2、37℃培养箱中培养。以每孔3000个细胞,种于96孔板,培养过夜。加入不同浓度的药物,分别放入正常培养箱(21%O2,5%CO2,74%N2),培养72h。吸去100μL培养液,加入10μL MTT溶液(5mg/mL),放入培养箱培养4小时,加入50μL三联液(10%SDS,5%异丁醇,0.012mol/L HCl),置于培养箱中过夜。在540nm波长下测定OD值,计算得药物对肿瘤细胞生长的半数抑制浓度IC50(n=3)。结果如下表1:
活性指定为“A”的化合物提供的IC50≤10nM;活性指定为“B”的化合物提供的IC50为10-100nM;活性指定为“C”的化合物提供的IC50为100-1000nM;
活性指定为“D”的化合物提供的IC50为1000-10000nM。效价(nM);效能(IC50)。
表1
实验数据表明,本发明化合物A-3、A-9和A-11具有良好的HCT-116细胞抑制活性。
实验例2、MDA-MB-468等细胞抑制活性的测定
MDA-MB-468细胞(购自ATCC)使用L-15培养液(购自Sigma-Aldrich),NCI-N87细胞(购自ATCC)使用RPMI-1640培养液(购自Gibco),HT29细胞(购自ATCC)使用McCoy’s 5A培养液(购自Gibco),均添加10%胎牛血清和1%青霉素-链霉素溶液,放置于5%CO2、37℃培养箱中培养。以每孔3000个细胞,种于96孔板,培养过夜。加入不同浓度的药物,分别放入正常培养箱(21%O2,5%CO2,74%N2),培养72h。吸去100μL培养液,加入10μL MTT溶液(5mg/mL),放入培养箱培养4小时,加入50μL三联液(10%SDS,5%异丁醇,0.012mol/L HCl),置于培养箱中过夜。在540nm波长下测定OD值,计算得药物对肿瘤细胞生长的半数抑制浓度IC50(n=3)。结果如下表2:
表2
实验数据表明,化合物A-3、A-9、A11对乳腺癌细胞MDA-MB-468
、人胃癌细胞NCI-N87、人结肠癌细胞HT29均具有良好的抑制效果,且优于非氘代的贝洛替康、SN-38和依喜替康,这表明,氘原子替代特定位置的氢原子,可以提高药物的抗肿瘤效果。
实验例3:药物代谢动力学实验-小鼠
实验目的:评估本发明化合物在小鼠中的代谢动力学特征。
取Balb/c小鼠(购自北京维通利华),以12只/组,雌雄各半,随机分组,单次注射样品(10%DMSO-90%(20%2-羟丙基-β-环糊精-生理盐水),根据剂量稀释),交叉采点,分别于给药前和给药后5min,30min,1h,2h,4h,6h,8h,10h,24h采集血浆,用LC-MS方法检测血浆中样品浓度,计算药物代谢动力学参数(见表3)。
表3本发明化合物在小鼠体内的药代动力学特征
实验结果表明,本发明化合物具有较短的体内半衰期和较快的体内清除率,具有更好的体内安全性。
实验例4、药物代谢动力学实验-大鼠
实验目的:评估本发明化合物在大鼠中的代谢动力学特征。
取SD大鼠(北京维通利华实验动物技术有限公司),以6只/组,雌雄各半,随机分组,单次注射样品(10%DMSO-90%(20%2-羟丙基-β-环糊精-生理盐水),根据剂量稀释),分别于给药前和给药后5min,30min,1h,2h,4h,6h,8h,10h,24h采集血浆,用LC-MS方法检测血浆中样品浓度,计算药物代谢动力学参数(见表4)。
表4本发明化合物在SD大鼠体内的药代动力学特征
实验结果表明,本发明化合物具有较短的体内半衰期和较快的体内清除率,因此其具有良好的体内安全性,且优于其相应的非氘代化合物。
实验例5、体外肝微粒体稳定性评价
每个孵育体系包含磷酸缓冲液(PBS,pH7.4)、肝微粒体蛋白、待测样品(乙睛溶液)和NADPH,采用水浴37oC条件下进行孵育,分别在反应0.5,5,15,30和60min后加入同体积冰冷乙睛终止反应(含内标品)。样品溶液离心,取100ul上清液,加入100ul超纯水,通过LC-MS/MS方法检测底物原形的剩余含量。阴性对照采用相应种属的热失活肝微粒体进行孵育。
实验结果表明本发明化合物具有优良的体外肝微粒体稳定性,且优于其对应的非氘代化合物。
实施例6、体外血浆稳定性
取398μL血浆,预热至37℃共孵育15分钟。2μL样品溶液加入血浆中配置样品终浓度为5μM。上述溶液于37℃共孵育,分别于0,15,30,60和120分钟取50μL溶液加入450μL冰的乙腈(含内标品)。溶液涡旋10分钟后,离心,通过LC-MS/MS方法检测底物原形的剩余含量。
实验例7.大鼠重复给药毒性实验
观察SD大鼠连续静脉给药7天,药物对机体可能产生的毒性反应及其严重程度,对该化合物的啮齿类动物毒性进行初步评估。取SD大鼠(北京维通利华实验动物技术有限公司),以6只/组,雌雄各半,随机分组,注射样品(制剂为:10%DMSO-90%(20%2-羟丙基-β-环糊精-生理盐水),根据剂量稀释)每日1次,连续7天。每两天进行体重和摄食量监测,并观察动物状态。末次给药后24h取血样测试血液学、血液生化及凝血指标。
实验结果表明,本申请化合物A-3、A-9,A-11具有更优的安全性。
Claims (10)
- 一类通式Q所示的二氘代喜树碱衍生物、其立体异构体、药学上可接受的盐或前药:
其中:R1为-H、-CH3、-(CH2)nCH3、-OCH3、-O(CH2)nCH3、-F、-Cl、-Br或-I,n代表整数1~3;R2为-H、-OH、-NH2、-F、-Cl、-Br、-I、-CH3、-OCH3、-(CH2)nCH3、-(CH2)nSi(CH3)3、-(CH2)nNH(CH3)2、-O(CH2)nCH3、-O(CH2)nNH2、-NH(CH2)nNH2、-(OCH2CH2)nNH2或其中,n代表整数1~3;或者R1、R2彼此连接以形成-(CH2)p-、-X(CH2)(p-1)-、-(CH2)(p-1)X-、-X(CH2)(q-1)X-或-(CH2)(q-1)X(CH2)(q-1),p和q代表整数2-4,X代表O,NH或S;R3为-H、-CH3、-(CH2)nCH3、-OCH3、-O(CH2)nCH3、-NHCH3、-NH(CH2)nCH3、-(CH2)nSi(CH3)3、-(CH2)nN(CH3)2、-(CH2)nCH=CH2、-NO2、-F、-Cl、-Br或-I,n代表整数1~3;R4为-H、-CH3、-OCH3、-(CH2)nCH3、-Si(CH3)2C(CH3)3、-(CH2)nSi(CH3)3、-(CH2)nNHCH(CH3)2、-CH2NH(CH2)nCH3、-CH2O(CH2)nCH3、-F、-Cl、-Br、-I、其中,n代表整数1~3;或者R3和R4彼此连接以形成如下式所示结构:
- 根据权利要求1所述的二氘代喜树碱衍生物、其立体异构体、药学上可接受的盐或前药:
其中:R1为-H、-CH3、-(CH2)nCH3、-OCH3、-O(CH2)nCH3、-F、-Cl、-Br或-I,n代表整数1~3;R2为-H、-OH、-NH2、-F、-Cl、-Br、-I、-CH3、-OCH3、-(CH2)nCH3、-(CH2)nSi(CH3)3、-(CH2)nNH(CH3)2、-O(CH2)nCH3、-O(CH2)nNH2、-NH(CH2)nNH2、-(OCH2CH2)nNH2或其中,n代表整数1~3;或者R1、R2彼此连接以形成-(CH2)p-、-X(CH2)(p-1)-、-(CH2)(p-1)X-、-X(CH2)(q-1)X-或-(CH2)(q-1)X(CH2)(q-1)-,p代表整数2-4,q代表整数2-3,X代表O,NH或S;R3为-H、-CH3、-(CH2)nCH3、-OCH3、-O(CH2)nCH3、-NHCH3、-NH(CH2)nCH3、-(CH2)nSi(CH3)3、-(CH2)nN(CH3)2、-(CH2)nCH=CH2、-NO2、-F、-Cl、-Br或-I,n代表整数1~3;R4为-H、-CH3、-OCH3、-(CH2)nCH3、-Si(CH3)2C(CH3)3、-(CH2)nSi(CH3)3、-(CH2)nNHCH(CH3)2、-CH2NH(CH2)nCH3、-CH2O(CH2)nCH3、-F、-Cl、-Br、 -I、其中,n代表整数1~3;或者R3和R4彼此连接以形成如下式所示结构:
- 根据权利要求1所述的二氘代喜树碱衍生物、其立体异构体、药学上可接受的盐或前药:
其中:R1为-H、-F、-Cl、-Br或-I;R2为-H、-OH、-CH3、-(CH2)nCH3、或其中,n代表整数1~3;或者R1、R2彼此连接以形成-X(CH2)(q-1)X-,q代表整数2-3,X代表O或S;R3为-H、-(CH2)nN(CH3)2、-(CH2)nCH=CH2、-NO2,n代表整数1~3;R4为-H、-CH3、-(CH2)nCH3、-Si(CH3)2C(CH3)3、-(CH2)nSi(CH3)3、-(CH2)nNHCH(CH3)2、其中,n代表整数1~3;或者R3和R4彼此连接以形成如下式所示结构:
- 根据权利要求1所述的二氘代喜树碱衍生物、其立体异构体、药学上可接受的盐或前药:
其中:R1为-H、或-F;R2为-H、-OH、-CH3、或或者R1、R2彼此连接以形成-O(CH2)2O-;R3为-H、-(CH2)N(CH3)2、-CH2CH=CH2、-NO2;R4为-H、-CH2CH3、-Si(CH3)2C(CH3)3、-(CH2)2Si(CH3)3、-(CH2)2NHCH(CH3)2、或者R3和R4彼此连接以形成如下式所示结构:
- 根据权利要求1所述的二氘代喜树碱衍生物、其立体异构体、药学上可接受的盐或前药:
其中:R1为-H、或-F;R2为-H、-OH、或-CH3;R3为-H;R4为-CH2CH3、或-(CH2)2NHCH(CH3)2;或者R3和R4彼此连接以形成如下式所示结构:
- 如权利要求1所述的二氘代喜树碱衍生物、其立体异构体、药学上可接受的盐或前药,所述二氘代喜树碱衍生物选自以下化合物:
- 一种权利要求1所述通式Q所示的二氘代喜树碱类衍生物的制备方法,其特征在于,该方法包括如下步骤:
a)化合物L-1与1-戊烯-3酮、2,2,6,6-四甲基哌啶和锂化试剂反应得到L-2;b)化合物L-2通过氘代还原剂,实现化合物氘化得到化合物L-3;c)化合物L-3通过臭氧化反应得到化合物L-4;d)化合物L-4与2,2,6,6-四甲基哌啶氧化物、碳酸氢钠、溴化钾和次氯酸钠反应得到化合物L-5;e)化合物L-5在一氧化碳氛围下,与钯催化剂、膦配体、碱和醇的条件下反应生成L-6;f)化合物L-6与三甲基氯硅烷和碘化钠反应得到L-7;g)化合物L-7与碱和酯反应得到L-8;h)化合物L-8在甲苯做溶剂,三氟醋酸条件下脱羧得到L-9;i)化合物L-9与多取代苯环和催化剂条件下生成化合物Q;在所述多取代苯环中,R1-R4的定义与权利要求1中相同。 - 根据权利要求7所述的制备方法,其特征在于,该方法包括如下步骤:
a)化合物L-1与1-戊烯-3酮、2,2,6,6-四甲基哌啶和锂化试剂反应得到L-2,反应温度为-78℃至-10℃,反应时间为2-12小时;锂化试剂选自正丁基锂、异丁基锂或二异丙基氨基锂;所用溶剂选自四氢呋喃、甲基四氢呋喃、乙酸乙酯或石油醚;化合物L-1与1-戊烯-3-酮、2,2,6,6-四甲基哌啶和锂化试剂反应的摩尔比例为1:2~4:2~4:3~5;b)化合物L-2通过氘代还原剂,实现化合物氘化得到化合物L-3;氘代还原剂选自氘代硼氢化钠、氘代硼氢化钾、氘代硼烷或氘代四氢铝锂;所用溶剂选自二氯甲烷、四氢呋喃、甲醇或乙醇;化合物L-2与氘代还原剂反应 的摩尔比例为1:1.1~2.5,反应温度为0℃-40℃,优选10-35℃,20-30℃,反应时间6-15小时,优选8-14小时;c)化合物L-3通过臭氧化反应得到化合物L-4,所选溶剂选自乙醇、甲醇、四氢呋喃或二氯甲烷,反应温度为-78℃,反应时间为15-30分钟;d)化合物L-4与2,2,6,6-四甲基哌啶氧化物、碳酸氢钠、溴化钾和次氯酸钠反应得到化合物L-5,其反应的摩尔比例为1:0.01~0.1:0.1~0.5:0.1~0.5:1~5;反应温度于-10℃至10℃;e)化合物L-5在一氧化碳氛围下,与钯催化剂、膦配体、碱和醇的条件下反应生成L-6;碱选自碳酸钾、碳酸钠、碳酸铯、磷酸钾或三乙胺;钯催化剂选自醋酸钯、双三苯基膦二氯化钯、1,1-双(二苯基膦)二荗铁二氯化钯或三苯基膦钯;醇选自氘代甲醇或氘代乙醇;膦配体选自1,3-双(二苯基膦)丙烷;化合物L-5与钯催化剂、膦配体和碱的反应摩尔比为1:0.01~0.1:0.01~0.1:1.5~3;溶剂选自N,N-二甲基甲酰胺,反应温度于60至120℃,反应时间为6-48小时;f)化合物L-6与三甲基氯硅烷和碘化钠反应得到L-7;其中,化合物L-6与三甲基氯硅烷和碘化钠反应的摩尔比为1:2~3:2~3;溶剂选自乙腈、四氢呋喃、二氯甲烷或乙酸乙酯,反应时间为12-24小时,反应温度为室温;g)化合物L-7与碱和酯反应得到L-8,L-7与碱和酯反应的摩尔比例为1:2~4:2~10;反应时间为12-48小时,反应温度为50℃,生成五元环化合物L-8;其中,碱选自碳酸钾、碳酸铯、碳酸钠或乙醇钠;酯选自丙烯酸甲酯、丙烯酸乙酯、丙烯酸叔丁酯或丙烯酸正丁酯,溶剂选自N,N-二甲基甲酰胺或二甲基亚砜;h)化合物L-8在甲苯做溶剂,三氟醋酸条件下脱羧得到L-9;反应温度于80℃至140℃,反应时间为2-6小时;i)化合物L-9与多取代苯环和催化剂条件下生成化合物Q;其中L-9与多取代苯环和催化剂反应的摩尔比为1:1:0.2~0.6;反应所采用溶剂选择四氢呋喃、乙醇或甲苯;催化剂选自无水对甲苯磺酸、对甲苯磺酸的吡啶盐、三氯化锑、硫酸或浓盐酸;反应温度于80℃至140℃,反应时间为12-48小时;在所述多取代苯环中,R1-R4的定义与权利要求1中相同。 - 一种化合物L-3的制备方法,该方法包括以下步骤:
化合物L-2在溶剂I中与氘代还原剂反应,得到化合物L-3,其中,所述氘代还原剂选自氘代硼氢化钠、氘代硼氢化钾、氘代硼烷和氘代四氢铝锂;所述溶剂选I选自二氯甲烷、四氢呋喃、甲醇和乙醇;化合物L-2与氘代还原剂反应的摩尔比例为1:1.1~2.5;反应温度为0℃-40℃;反应时间为6-15小时。 - 一种化合物L-6的制备方法,该方法包括以下步骤:
e)化合物L-5在一氧化碳氛围下,与钯催化剂、膦配体、碱和醇的条件下反应生成L-6,其中,所述碱选自碳酸钾、碳酸钠、碳酸铯、磷酸钾和三乙胺;所述钯催化剂选自醋酸钯、双三苯基膦二氯化钯、1,1-双(二苯基膦)二荗铁二氯化钯和三苯基膦钯;所述醇选自氘代甲醇和氘代乙醇;所述膦配体选自1,3-双(二苯基膦)丙烷;化合物L-5与钯催化剂、膦配体和碱的反应摩尔比为1:0.01~0.1:0.01~0.1:1.5~3;溶剂选自N,N-二甲基甲酰胺,反应温度于60至120℃,反应时间为6-48小时。
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