CN113896716A - Synthesis method of radioisotope carbon-14 double-labeled fulvestrant mesylate - Google Patents
Synthesis method of radioisotope carbon-14 double-labeled fulvestrant mesylate Download PDFInfo
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- CN113896716A CN113896716A CN202111255337.3A CN202111255337A CN113896716A CN 113896716 A CN113896716 A CN 113896716A CN 202111255337 A CN202111255337 A CN 202111255337A CN 113896716 A CN113896716 A CN 113896716A
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- carbon
- methyl
- labeled
- double
- mesylate
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- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 title claims abstract description 60
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 title claims abstract description 50
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 title claims abstract description 22
- 229960002258 fulvestrant Drugs 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title claims description 4
- -1 N- (2- ((2- (dimethylamino) ethyl) methylamino) -5- ((4- (1-methyl-1H-indol-3-yl) -2- [5,6-14C2]Pyrimidinyl) amino) -6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide methanesulfonate Chemical compound 0.000 claims abstract description 95
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 239000000700 radioactive tracer Substances 0.000 claims abstract description 10
- 238000002372 labelling Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000011261 inert gas Substances 0.000 claims description 22
- 239000003960 organic solvent Substances 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 238000004440 column chromatography Methods 0.000 claims description 18
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 16
- 239000011541 reaction mixture Substances 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 claims description 6
- UORVCLMRJXCDCP-XPULMUKRSA-N C([14C]#[14CH])(=O)O Chemical compound C([14C]#[14CH])(=O)O UORVCLMRJXCDCP-XPULMUKRSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 6
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 238000002953 preparative HPLC Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 3
- 101150003085 Pdcl gene Proteins 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 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 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229940035893 uracil Drugs 0.000 claims description 2
- 230000009977 dual effect Effects 0.000 claims 1
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- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 abstract 2
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
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- 150000003839 salts Chemical class 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 239000013076 target substance Substances 0.000 abstract 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 50
- 229910052786 argon Inorganic materials 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
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- 238000001914 filtration Methods 0.000 description 15
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a radioisotope carbon-14 double-labeled formitinib mesylate (N- (2- ((2- (dimethylamino) ethyl) methylamino) -5- ((4- (1-methyl-1H-indol-3-yl) -2- [5,6-14C2]Pyrimidinyl) amino) -6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide methanesulfonate, wherein the asterisk marks the carbon-14 marker site), which provides a viable, safe, economical process for the synthesis of carbon-14 ditag fulvestrant mesylate, characterized in that: carbon-14 double labeling of propiolic acid ([2, 3-)14C2]Propiolic acid) as an isotope raw material, and obtaining carbon-14 double-labeled fulvestrant mesylate through radioactive reactions such as ring closing, hydroxyl chlorination, coupling, substitution, reduction, condensation, salt formation and the like, wherein the specific activity of the marker is 2 times that of a corresponding carbon-14 single marker. The target substance carbon-14 double-labeled Vometinib mesylate can be used as a radioactive tracer, and can meet basic research requirements of radioactive isotope tracer tests and the like related to Vometinib mesylateThe need for high specific activity carbon-14 markers exists.
Description
Technical Field
The invention belongs to the field of radiochemical synthesis, and particularly relates to radioisotope carbon-14 double-labeled brimstinib mesylate (N- (2- ((2- (dimethylamino) ethyl) methylamino) -5- ((4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidine-2-yl) amino) -6- (2,2, 2-trifluoroethoxy) pyridine-3-yl) acrylamide).
Background
The sensitive mutation rate of Epidermal Growth Factor Receptor (EGFR) of non-small cell lung cancer (NSCLC) patients in China is about 50%, and the patients are treated by using first and second generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) conventionally. However, most patients acquire resistance between 9 and 13 months after receiving treatment, wherein about 60% of patients have EGFR T790M mutation, and the occurrence of T790M mutation means that the median survival time of the patients is less than 2 years [ Third-generation inhibition targeting EGFR T790M mutation in advanced non-small cell lung cancer [ J ]. J Hematol Oncol.2016,9(1): 34; analysis of metal nanoparticles at the time of acquired resistance to EGFR-TKI therapy in 155 substrates with EGFR-mutant cells [ J ]. Clin Cancer Res.2013,19(8): 2240-; (iii) a Recent definition of the second and third generation inverse epidemic growth factor receptors [ J ]. Chem biologics.2017, 14(7) e1600372 ].
Vometinib mesylate (CAS 2130958-55-1; English name: Furmonetinib, Alflutinib, AST 2818; Chinese name: N- (2- ((2- (dimethylamino) ethyl) methylamino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide mesylate, abbreviated as Vometinib and Iflutinib; trade name: Efosa) is a national new class 1 drug [ ZL 105523159, 2016-02-10, independently created by Shanghai Ellis medicine science and technology Limited; ZL107163027,2017-09-15; ZL110606842, 2019-12-24 ]. It acts on EGFR sensitive mutant and EGFR T790M mutant simultaneously, has ideal anti-tumor efficacy, relatively wide therapeutic dose range (40-240 mg) [ Safety, clinical activity, and pharmacokinetics of Alflutinib (AST2818) in patients with advanced NSCLC with EGFR T790M mutation [ J ]. J Thorac Oncol.2020,15(6): 1015-1026); efficiency, safety, and genetic analysis of Furmonetinib (AST2818) in properties with EGFR T790M mutated non-small-cell regulating cancer a phase 2b, multicentre, single-arm, open-label study [ J ] Lancet Resp Med.2021,9(8) 829-; alflutinib (AST2818), primary methylated by CYP3A4, is a potential CYP3A4 indecer [ J ]. Acta Pharmacol Sin.2020,41(10): 1366-. Vortitinib mesylate is subjected to conditional approval of the national drug administration for sale on the market at 3 months 2021, becomes a highly selective and irreversible third-generation epidermal factor receptor tyrosine kinase inhibitor (EGFR-TKI) and is used for treating the disease progression during or after previous treatment by the epidermal factor receptor inhibitor (TKI), and is detected to confirm the existence of local advanced or metastatic non-small cell lung cancer (NSCLC) positive to EGFR T790M mutation [ Deeks, E.D.Furonertinib: First approach. drugs.2021.DOI:10.1007/s 40265-021-; beyond Osimertinib The Development of Third-Generation EGFR Tyrosine primers For Advanced EGFR plus NSCLC [ J ]. JThorac Oncol.2021,16(5): 740-.
With the gradual popularization and application of the fulvestrant mesylate, basic research work related to the medicine is also gradually deepened. Radioisotope carbon-14 labeled fulvestrant mesylate is a necessary radiotracer for the development of the basic study described above. By comprehensively considering the chemical stability, the metabolic stability, the feasibility and the cost of labeling synthesis and the aim of subsequent tracer tests of the Vometinib mesylate, a pyrimidine ring in a Vometinib mesylate molecule is the best labeling unit. The literature reports the chemical structure of carbon-14 labeled sumatrinib mesylate, but the labeling synthesis technical route and process thereof are not disclosed [ Metabolic displacement of the EGFR covalent inhibitor furmontertinib in humans [ J ]. Acta Pharmacol sin.2021(DOI:10.1038/s41401-021-00667-8) ]. It is to be noted that this marker belongs to the carbon-14 single-site marker, whose theoretical maximum specific activity is 62.4mCi/mmol [ Atzrodt J, Allen J: Synthesis of radio labeled Compounds for Clinical students [ M ]// Vogel H G, Maas J, Gebauer A, editor, Drug Discovery and Evaluation: Methods in Clinical pharmacy: Springer Berlin Heidelberg,2011: 105-; for the tracer test with small dosage of the fulvestrant mesylate, no dosage increase and complex system composition, the carbon-14 single-site marker (the specific activity of which is usually about 50mCi/mmol) is difficult to reach the detection limit of a radioactivity measuring instrument, so that the tracer test fails. Therefore, it is highly desirable to improve the specific activity of carbon-14 labeled sumatriib mesylate so as to ensure that the radioactive isotope carbon-14 in a tracer system with a complex composition can be effectively and accurately detected by using a radioactive measuring instrument on the premise of not increasing the dosage of the sumatriib mesylate, so as to ensure the smooth proceeding of a radioactive isotope tracer test.
Disclosure of Invention
According to one aspect of the invention, the invention provides radioisotopic carbon-14 double-labeled fulvatinib mesylate, wherein carbon-14 labeling sites are 5-C and 6-C of a pyrimidine ring in a fulvatinib mesylate molecule, the specific activity of a marker is 2 times that of a corresponding carbon-14 single-site marker, and the theoretical maximum specific activity is 124.8 mCi/mmol. The chemical structure of the target carbon-14 double marker (the star marks the carbon-14 marker site in the figure) is as follows:
according to one aspect of the present invention, the present invention provides a method for synthesizing radioisotope carbon-14 double-labeled sumatriib mesylate, the method comprising the steps of:
s1: under the protection of inert gas at 90-130 ℃, [2,3-14C2]Propiolic acid is reacted with urea in polyphosphoric acid (PPA). After the reaction is finished, the [5,6-14C2]Uracil (2);
s2: under the protection of inert gas and at 90-130 ℃, the intermediate [5,6-14C2]Uracil (2) reacts with phosphorus oxychloride under the catalysis of Diisopropylethylamine (DIPEA). Reaction junctionAfter the reaction, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain 2, 4-dichloro [5,6-14C2]Pyrimidine (3);
s3: under the protection of inert gas and at 70-90 ℃, the intermediate 2, 4-dichloro [5,6-14C2]Pyrimidine (3), N-methylindole and Lewis acid are reacted in an aprotic organic solvent. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4);
s4: under the protection of inert gas and at 90-130 ℃, the intermediate 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4), N2- (2- (dimethylamino) ethyl) -N2-methyl-3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine hydrochloride (SM-1), a base and a palladium catalyst in a mixed solvent of an aprotic organic solvent and water. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5);
s5: under the protection of inert gas and at the temperature of 60-90 ℃, an intermediate N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidine-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5), a metal reducing agent and ammonium chloride are reacted in a mixed solvent of alcohol and water. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment to obtain N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6);
s6: under the protection of inert gas and at the temperature of 0-30 ℃, an intermediate N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6) with propaneReacting acryloyl chloride in an aprotic organic solvent. After the reaction is finished, the reaction mixture is purified by conventional post-treatment, column chromatography and preparative high performance liquid chromatography to obtain carbon-14 double-labeled Vometinib (7, N- (2- ((2- (dimethylamino) ethyl) methylamino) -5- ((4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) amino) -6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide);
s7: under the protection of inert gas and at the temperature of 40-60 ℃, heating carbon-14 double-labeled fulvestrant (7) and methanesulfonic acid in a mixed solvent of a ketone organic solvent and water until the carbon-14 double-labeled fulvestrant and the methanesulfonic acid are completely dissolved, and recrystallizing to obtain the target radioisotope carbon-14 double-labeled fulvestrant.
According to an embodiment of the invention, the base comprises at least one selected from sodium carbonate, sodium bicarbonate, ammonia.
According to an embodiment of the present invention, the lewis acid includes, but is not limited to, aluminum trichloride, ferric trichloride, stannic chloride, zinc chloride; the aprotic organic solvent includes, but is not limited to, at least one of ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether.
According to an embodiment of the present invention, the base includes, but is not limited to, potassium phosphate, potassium carbonate, cesium carbonate; the palladium catalyst includes, but is not limited to, tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (PdCl)2(dppf)), tetrakistriphenylphosphine palladium (Pd (PPh)3)4) (ii) a The aprotic organic solvent includes, but is not limited to, at least one of toluene, dioxane, and ethylene glycol dimethyl ether.
According to an embodiment of the present invention, the metal reducing agent includes, but is not limited to, iron powder, zinc powder; the alcohol solvent includes at least one selected from the group consisting of methanol, ethanol, and t-butanol.
According to an embodiment of the present invention, the aprotic organic solvent includes at least one selected from dichloromethane, chloroform, and toluene.
According to an embodiment of the present invention, in S7, the ketone solvent includes at least one selected from acetone and 2-butanone.
According to one aspect of the present invention, there is provided a carbon-14 containing composite block synthesized by the above synthesis method.
According to one aspect of the invention, the invention provides a tracer application of radioisotope carbon-14 double-labeled fulvestrant mesylate.
Drawings
FIG. 1 chemical structure of carbon-14 double-labeled Vometatinib mesylate
FIG. 2 scheme for the synthesis of carbon-14 ditag fulvestrant mesylate
FIG. 3 intermediate [5,6-14C2]NMR spectrum of uracil (2)
FIG. 4 intermediate 2, 4-dichloro [5,6-14C2]Nuclear magnetic resonance hydrogen spectrum of pyrimidine (3)
FIG. 5 intermediate 3- (2-chloro [5,6-14C2]NMR spectrum of pyrimidin-4-yl) -1-methyl-1H-indole (4)
FIG. 6 intermediate N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Nuclear magnetic resonance hydrogen spectrum of pyrimidine-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5)
FIG. 7 nuclear magnetic resonance hydrogen spectrum of intermediate carbon-14 double-labeled Vometinib (7)
FIG. 8 nuclear magnetic resonance hydrogen spectrogram of target carbon-14 double-labeled formetinib mesylate of the invention
FIG. 9 is an on-line radioactive high performance liquid chromatogram of a target carbon-14 double-labeled fulvestrant mesylate of the invention.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
It should be noted that, the steps one, two, three and four are only for naming each step, and there is no precedence order, and any combination or single use of a single step may be used in actual operation.
It is worth mentioning that the asterisk (#) indicates the carbon-14 marker site. In addition, inert gases in the present invention include, but are not limited to, argon or nitrogen.
The chemical structure of the radioisotope carbon-14 double-labeled brivartinib mesylate is shown in figure 1.
Referring to fig. 2 to 9, in particular, the method for synthesizing the radioisotope carbon-14 double-labeled sumatriib mesylate comprises the following steps:
s1: under the protection of inert gas at 90-130 ℃, [2,3-14C2]Propiolic acid(1)With urea in polyphosphoric acid (PPA).
After the reaction is finished, the [5,6-14C2]Uracils(2)；
S2: under the protection of inert gas and at 90-130 ℃, the intermediate [5,6-14C2]Uracils(2)Reacting with phosphorus oxychloride under the catalysis of Diisopropylethylamine (DIPEA). After the reaction is finished, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain 2, 4-dichloro [5,6-14C2]Pyrimidines(3)；
S3: under the protection of inert gas and at 70-90 ℃, the intermediate 2, 4-dichloro [5,6-14C2]Pyrimidines(3)N-methylindole and Lewis acid in an aprotic organic solvent. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indoles(4)；
S4: under the protection of inert gas and at 90-130 ℃, the intermediate 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4), N2- (2- (dimethylamino) ethyl) -N2-methyl-3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine hydrochloride (SM-1), a base and a palladium catalyst in the aprotic rangeReacting in a mixed solvent of organic solvent and water. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine(5)；
S5: under the protection of inert gas and at the temperature of 60-90 ℃, an intermediate N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidine-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5), a metal reducing agent and ammonium chloride are reacted in a mixed solvent of alcohol and water. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment to obtain N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamines(6)；
S6: under the protection of inert gas and at the temperature of 0-30 ℃, an intermediate N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Reacting pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6) with acryloyl chloride in an aprotic organic solvent. After the reaction is finished, the reaction mixture is purified by conventional post-treatment, column chromatography and preparative high performance liquid chromatography to obtain the carbon-14 double-labeled Vometinib(7，Namely N- (2- ((2- (dimethylamino) ethyl) methylamino) -5- ((4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) amino) -6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide);
s7: under the protection of inert gas and at the temperature of 40-60 ℃, carbon-14 double-labeled Vomettinib(7)Heating the product and methanesulfonic acid in a mixed solvent of a ketone organic solvent and water until the product is completely dissolved, and recrystallizing the product to obtain the target radioisotope carbon-14 double-labeled fulvestrant mesylate.
It is worth mentioning that in S1, the alkali includes, but is not limited to, sodium carbonate, sodium bicarbonate, ammonia water.
In S3, the lewis acid includes aluminum trichloride, ferric trichloride, stannic chloride, zinc chloride; the aprotic organic solvent includes, but is not limited to, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether.
Also noteworthy are, in S4, bases including, but not limited to, potassium phosphate, potassium carbonate, cesium carbonate; the palladium catalyst includes, but is not limited to, tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (PdCl)2(dppf)), tetrakistriphenylphosphine palladium (Pd (PPh)3)4) (ii) a The aprotic organic solvent includes but is not limited to toluene, dioxane, ethylene glycol dimethyl ether.
At S5, the metal reducing agent includes, but is not limited to, iron powder, zinc powder; the alcohol solvent includes but is not limited to methanol, ethanol, tert-butanol.
Preferably, in S6, the aprotic organic solvent includes, but is not limited to, dichloromethane, chloroform, toluene.
Preferably, in S7, the ketone solvent includes, but is not limited to, acetone, 2-butanone.
Example one
Under the protection of argon and at 50 ℃, urea (50mg) and polyphosphoric acid (1.5mL) are stirred and dissolved, and [2,3-14C2]Propiolic acid (1, 80.4. mu. Ci, 750. mu. mol). After the addition, the temperature is raised to 90 ℃, and the reaction is finished after stirring for 16 h. Adding 1mL of water into the reaction solution to quench the reaction, adjusting the pH to about 7 by using ammonia water (28-30 wt%), and stirring for 4h at 5 ℃ to crystallize. Filtering, leaching the obtained solid with 1mL of water and 5mL of methanol in sequence, and drying to obtain solid [5,6-14C2]Uracil (2, 65.2. mu. Ci, 81%).1H NMR(400MHz,DMSO-d6)δ10.87(s,2H),7.38(d,J＝7.6Hz,1H),5.45(d,J＝7.6Hz,1H).ESI-MS(m/z):135,139[M+H]+。
Under the protection of argon, the [5,6-14C2]Uracil (2, 63.2. mu. Ci) and 2 drops of diisopropylethylamine were added to phosphorus oxychloride (3mL) in that order, heated to 90 ℃ and stirred for 2.5 h. The reaction solution was cooled to room temperature, and 15mL of ice water was addedThe reaction was quenched, extracted with dichloromethane (15 mL. times.4), and the organic phases were combined and dried by addition of anhydrous sodium sulfate. Filtering, concentrating and purifying by column chromatography to obtain light yellow solid 2, 4-dichloro [5,6-14C2]Pyrimidine (3, 55.0. mu. Ci, 87%).1H NMR(400MHz,CD3OD)δ8.63(d,J＝5.3Hz,1H),7.58(d,J＝5.3Hz,1H).ESI-MS(m/z):149,151,153[M+H]+,155[M+H+2]+。
Under the protection of argon, 2, 4-dichloro [5,6-14C2]Pyrimidine (3, 54.4. mu. Ci) and anhydrous aluminum trichloride (100mg) were added to dry ethylene glycol dimethyl ether (3mL), cooled to 0 ℃ with an ice-salt bath, stirred, slowly added to a solution of N-methylindole (98mg) in dry ethylene glycol dimethyl ether (2mL), heated to 70 ℃ and stirred overnight with incubation. Cooling to room temperature, filtering, rinsing the filter cake with dichloromethane (20mL), adding water 20mL into the filtrate, stirring for layering, extracting the water phase with dichloromethane (20mL × 4), mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying the crude product by column chromatography (SiO)2V (DCM) V (PE) 2: 1-5: 1 to obtain light green solid 3- (2-chloro [5, 6-)14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4,41.4 μ Ci, 76%).1H NMR(400MHz,DMSO-d6)δ8.53(d,J＝5.5Hz,1H),8.49(s,1H),8.43-8.38(m,1H),7.82(d,J＝5.5Hz,1H),7.60-7.54(m,1H),7.34-7.24(m,2H),3.90(s,3H).ESI-MS(m/z):244,246,248[M+H]+,250[M+2+H]+。
Under the protection of argon, 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4, 40.8. mu. Ci), N2- (2- (dimethylamino) ethyl) -N2-methyl-3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine hydrochloride (SM-1,141mg), Pd2(dba)3(17mg), Xantphos (22mg), tripotassium phosphate (322mg), toluene (2.5mL) and water (1.0mL) were added successively to the reaction tube, and the mixture was replaced with argon for 3 times, heated to 90 ℃ and stirred overnight. Cooling to room temperature, adding 10mL of water to the reaction mixture, extracting with ethyl acetate (15 mL. times.4), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and purifying the crude product by column chromatography (SiO)2V (DCM) V (MeOH) 100: 1-20: 1 to obtain yellow solid N2- (2- (dimethylamino) ethylRadical) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5,32.2 μ Ci, 79%).1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.48(s,1H),8.30(s,1H),8.26(d,J＝5.2Hz,1H),7.51(d,J＝7.9Hz,1H),7.23(t,J＝7.4Hz,1H),7.18(d,J＝5.3Hz,1H),7.12–7.00(m,1H),5.76(s,1H),5.06(dd,J＝17.6,8.8Hz,2H),3.86(s,3H),3.73(t,J＝6.6Hz,2H),2.91(s,3H),2.65–2.55(m,2H),2.21(s,6H).ESI-MS(m/z):545,546,549[M+H]+,550[M+H+1]+。
Under the protection of argon, adding N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5, 31.8. mu. Ci), iron powder (168mg), ammonium chloride (88mg), ethanol (5mL) and water (2.5mL) were added to a reaction flask in this order, heated to 60 ℃ and stirred for 3h to complete the reaction. Cooling to room temperature, adding ethyl acetate (10mL) into the reaction solution, stirring thoroughly, filtering with diatomaceous earth, adding saturated sodium bicarbonate solution (10mL) into the filtrate, extracting with ethyl acetate (15 mL. times.4), combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain crude N as black solid2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6), impure, was used directly in the next reaction. ESI-MS (M/z) 515,516,519[ M + H]+,520[M+H+1]+。
Under the protection of argon, the crude product N obtained in the previous step2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6) and dichloromethane (9mL) were added to a reaction flask, cooled to 0 ℃ with an ice-salt bath, and acryloyl chloride (28mg) was added to dichloromethane (3mL) to make a solution, which was added dropwise to the reaction solution using a syringe pump within 30min, and stirred for 30min at 0 ℃ after completion of the addition. Adding saturated carbonic acid to the reaction solutionSodium hydrogen solution (10mL), extraction with ethyl acetate (15 mL. times.4), combining the organic phases, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography of the crude product (SiO)2V (DCM): V (MeOH) ═ 100: 1-40: 1) and preparative high performance liquid chromatography purification (Waters 2545-; the mobile phase composition is methanol/0.1% ammonia water, and the gradient elution is controlled to be 80: 20-100: 0; the flow rate is 10.00 mL/min; target peak retention time 9.8min) to obtain carbon-14 double-labeled Vometinib (7,18.2 mu Ci, HPLC purity)>99%, two-step yield 57%).1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.66(s,1H),8.43(s,1H),8.31-8.19(m,2H),8.11(s,1H),7.51(d,J＝8.1Hz,1H),7.27–7.09(m,3H),6.49(dd,J＝17.0,10.4Hz,1H),6.25(d,J＝17.0Hz,1H),5.77(d,J＝10.1Hz,1H),4.98(dd,J＝18.1,9.1Hz,2H),3.88(s,3H),3.45(t,J＝5.5Hz,2H),3.17(t,J＝6.5Hz,2H),2.86(s,3H),2.59(t,J＝5.6Hz,2H),2.20(s,6H).ESI-MS(m/z):569,570,573[M+H]+,574[M+H+1]+。
Carbon-14 double-labeled fulvenib (7,17.8 μ Ci), methanesulfonic acid (16mg), acetone (3mL) and water (0.6mL) were sequentially added to the reaction flask under argon protection, heated to 40 ℃ and stirred until all dissolved. Concentrating the reaction solution under reduced pressure, adding acetone (10mL), stirring, pulping, filtering, and drying to obtain yellow solid carbon-14 double-labeled fulvestrant mesylate (11.0 μ Ci, yield 62%, HPLC chemical purity>99% radiochemical purity>99％)。1H NMR(400MHz,CD3OD)δ8.74(s,1H),8.31-8.23(m,2H),8.14(s,1H),7.45(d,J＝8.3Hz,1H),7.28-7.20(m,2H),7.14(t,J＝7.6Hz,1H),6.52(d,J＝5.5Hz,2H),5.90(t,J＝5.9Hz,1H),5.00(q,J＝8.8Hz,2H),4.85(s,7H),3.89(s,3H),3.77(t,J＝5.4Hz,2H),3.34(t,J＝5.3Hz,2H),2.91(s,6H),2.83(s,3H),2.70(s,3H).ESI-MS(m/z):569,570,573[M+H]+,574[M+H+1]+。
Example two
Under the protection of argon and at 50 ℃, urea (50mg) and polyphosphoric acid (1.5mL) are stirred and dissolved, and [2,3-14C2]Propiolic acid (1, 80.4. mu. Ci, 750. mu. mol). After the addition, the temperature is raised to 110 ℃, and the reaction is finished after stirring for 13 hours. Adding 1 into the reaction solutionQuenching by using mL of water, dropwise adding a saturated aqueous solution of sodium bicarbonate to adjust the pH to about 7, stirring at 5 ℃ for 4 hours to crystallize, filtering, and leaching the solid by using 1mL of water and 5mL of methanol in sequence. Drying to obtain solid [5,6-14C2]Uracil (2, 64.2. mu. Ci, 80%). ESI-MS (M/z) 135,139[ M + H]+。
Under the protection of argon, the [5,6-14C2]Uracil (2, 63.2. mu. Ci) and 2 drops of diisopropylethylamine were added to phosphorus oxychloride (3mL) in that order, heated to 110 ℃ and stirred for 1.5 h. The reaction solution was cooled to room temperature and treated conventionally (same as in example 1) to obtain 2, 4-dichloro [5,6-14C2]Pyrimidine (3, 52.8. mu. Ci, 85%). ESI-MS (M/z) 149,151,153[ M + H]+,155[M+H+2]+。
Under the protection of argon, 2, 4-dichloro [5,6-14C2]Pyrimidine (3, 52.2. mu. Ci) and anhydrous ferric chloride (117mg) were added to dry methyl tert-butyl ether (3mL), cooled to 0 ℃ with an ice-salt bath, stirred, a solution of N-methylindole (94mg) in methyl tert-butyl ether (2mL) was added slowly, heated to 80 ℃ and stirred overnight with incubation. The light green solid 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4,38.1 μ Ci, 73%). ESI-MS (M/z) 244,246,248[ M + H]+,250[M+2+H]+。
Under the protection of argon, 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4, 38.0. mu. Ci), N2- (2- (dimethylamino) ethyl) -N2-methyl-3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine hydrochloride (SM-1,130mg), PdCl2(dppf) (13mg), Xantphos (20mg), potassium carbonate (193mg), toluene (2.5mL) and water (1.0mL) were added to the reaction tube in this order, and the mixture was replaced with argon 3 times, heated to 110 ℃ and stirred overnight. The yellow solid N is obtained by conventional treatment (same as example 1)2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5,28.0 μ Ci, 74%). ESI-MS (M/z) 545,546,549[ M + H]+,550[M+H+1]+。
Under the protection of argon, the reaction kettle is,will N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5, 27.6. mu. Ci), zinc powder (170mg), ammonium chloride (77mg), methanol (5mL) and water (2.5mL) were added to a reaction flask in this order, heated to 75 ℃ and stirred for 3h to complete the reaction. The crude N was obtained as a black solid by conventional treatment (same as example 1)2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6), impure, was used directly in the next reaction. ESI-MS (M/z) 515,516,519[ M + H]+,520[M+H+1]+。
Under the protection of argon, the crude product N obtained in the previous step2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidine-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6) and chloroform (9mL) are added into a reaction bottle, an ice-salt bath is cooled to 0 ℃, acryloyl chloride (19mg) is added into the chloroform (3mL) to prepare a solution, the solution is dripped into the reaction solution within 30min by using a syringe pump, and the solution is stirred for 30min after the completion of the addition and the temperature is kept at 15 ℃. Adding saturated sodium bicarbonate solution (10mL), extracting with ethyl acetate (15 mL. times.4), combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and separating the crude product by column chromatography (SiO)2V (DCM) V (MeOH) 100: 1-40: 1 and preparative high performance liquid chromatography purification (conditions as in example 1) to obtain carbon-14 double-labeled Vometinib (7, 15.0. mu. Ci, HPLC purity)>99%, two-step yield 54%). ESI-MS (M/z) 569,570,573[ M + H]+,574[M+H+1]+。
Under the protection of argon, carbon-14 double-labeled Vometinib (7,15.0 mu Ci), methanesulfonic acid (13mg), 2-butanone (3mL) and water (0.6mL) are sequentially added into a reaction bottle, heated to 50 ℃, and stirred until all the Vometinib is dissolved. Concentrating the reaction solution under reduced pressure, adding 2-butanone (10mL), stirring, pulping, filtering, and oven drying to obtain yellow solid carbon-14 double-labeled fulvestrant mesylate (8.6 μ Ci, yield 57%, HPLC chemical purity>99% radiochemical purity>99％)。ESI-MS(m/z):569,570,573[M+H]+,574[M+H+1]+。
EXAMPLE III
Under the protection of argon and at 50 ℃, urea (50mg) and polyphosphoric acid (1.5mL) are stirred and dissolved, and [2,3-14C2]Propiolic acid (1, 80.4. mu. Ci, 750. mu. mol). After the addition, the temperature is raised to 130 ℃, and the reaction is stirred for 10 hours until the reaction is finished. Adding 1mL of water into the reaction solution for quenching, dropwise adding 5% sodium carbonate aqueous solution to adjust the pH to about 7, stirring for 4h at 5 ℃ for crystallization, filtering, and leaching the solid with 1mL of water and 5mL of methanol in sequence. Drying to obtain solid [5,6-14C2]Uracil (2, 64.4. mu. Ci, 80%). ESI-MS (M/z) 135,139[ M + H]+。
Under the protection of argon, the [5,6-14C2]Uracil (2, 63.2. mu. Ci) and 2 drops of diisopropylethylamine were added to phosphorus oxychloride (3mL) in that order, heated to 130 ℃ and stirred for 1.5 h. The reaction solution was cooled to room temperature and treated conventionally (same as in example 1) to obtain 2, 4-dichloro [5,6-14C2]Pyrimidine (3, 54.4. mu. Ci, 86%). ESI-MS (M/z) 149,151,153[ M + H]+,155[M+H+2]+。
Under the protection of argon, 2, 4-dichloro [5,6-14C2]Pyrimidine (3, 54.4. mu. Ci) and anhydrous zinc chloride (102mg) were added to dry isopropyl ether (3mL), cooled to 0 ℃ with an ice-salt bath, stirred, a solution of N-methylindole (98mg) in isopropyl ether (2mL) was added slowly, heated to 90 ℃ and stirred overnight with incubation. The light green solid 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4,39.2 μ Ci, 72%). ESI-MS (M/z) 244,246,248[ M + H]+,250[M+2+H]+。
Under the protection of argon, 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4, 39.2. mu. Ci), N2- (2- (dimethylamino) ethyl) -N2-methyl-3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine hydrochloride (SM-1,134mg), Pd (PPh)3)4(21mg), Xantphos (21mg), cesium carbonate (470mg), dioxane (2.5mL) and water (1.0mL) were added to the reaction tube in this order, replaced with argon for 3 times, heated to 130 ℃ and stirredOvernight. The yellow solid N is obtained by conventional treatment (same as example 1)2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5,30.2 μ Ci, 77%). ESI-MS (M/z) 545,546,549[ M + H]+,550[M+H+1]+。
Under the protection of argon, adding N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5, 30.2. mu. Ci.,), iron powder (156mg), ammonium chloride (82mg), t-butanol (5mL) and water (2.5mL) were added in this order to a reaction flask, heated to 90 ℃ and stirred for 2.5h to terminate the reaction. The crude N was obtained as a black solid by conventional treatment (same as example 1)2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6), impure, was used directly in the next reaction. ESI-MS (M/z) 515,516,519[ M + H]+,520[M+H+1]+。
Under the protection of argon, crude product N obtained in the last step2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidine-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6) and toluene (15mL) are added into a reaction bottle, an ice-salt bath is cooled to 0 ℃, acryloyl chloride (26mg) is added into toluene (5mL) to prepare a solution, the solution is dripped into the reaction solution within 30min by using a syringe pump, and the stirring is continued for 30min at the temperature of 30 ℃ after the addition is finished. Adding saturated sodium bicarbonate solution (10mL), extracting with ethyl acetate (15 mL. times.4), combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and separating the crude product by column chromatography (SiO)2V (DCM) V (MeOH) 100: 1-40: 1 and preparative high performance liquid chromatography purification (conditions as in example 1) to obtain carbon-14 double-labeled Vometinib (7, 16.3. mu. Ci, HPLC chemical purity)>99%, two-step yield 55%). ESI-MS (M/z) 569,570,573[ M + H]+,574[M+H+1]+。
Carbon-14 double-labeled fulvenib (7,16.6 μ Ci), methanesulfonic acid (14mg), acetone (3mL) and water (0.6mL) were sequentially added to the reaction flask under argon protection, heated to 60 ℃ and stirred until all dissolved. Concentrating the reaction solution under reduced pressure, adding acetone (10mL), stirring, pulping, filtering, and drying to obtain yellow solid carbon-14 double-labeled fulvestrant mesylate (11.0 mu Ci, yield 66%, HPLC purity>99% radiochemical purity>99％)。ESI-MS(m/z):569,570,573[M+H]+,574[M+H+1]+。
The invention also provides a carbon-14-containing synthetic building block, wherein the carbon-14-containing component can be selected from any one of the embodiments, but is not limited to the embodiments.
Many modifications may be made by one of ordinary skill in the art in light of the above teachings. Therefore, it is intended that the invention not be limited to the particular details of the embodiments disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.
Claims (10)
1. A radioisotope carbon-14 double-labeled sumatriib mesylate is characterized in that: the carbon-14 labeling sites are 5-C and 6-C of a pyrimidine ring in the Vometinib mesylate molecule, and the chemical structures of related targets (the star marks the carbon-14 labeling sites in the figure) are as follows:
2. a method for synthesizing radioisotope carbon-14 double-labeled sumatriib mesylate, the method comprising the steps of:
s1: under the protection of inert gas at 90-130 ℃, [2,3-14C2]Propiolic acid is reacted with urea in polyphosphoric acid (PPA). After the reaction is finished, the [5,6-14C2]Uracil (2);
s2: under the protection of inert gas and at the temperature of 90-130 ℃, the intermediate[5,6-14C2]Uracil (2) reacts with phosphorus oxychloride under the catalysis of Diisopropylethylamine (DIPEA). After the reaction is finished, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain 2, 4-dichloro [5,6-14C2]Pyrimidine (3);
s3: under the protection of inert gas and at 70-90 ℃, the intermediate 2, 4-dichloro [5,6-14C2]Pyrimidine (3), N-methylindole and Lewis acid are reacted in an aprotic organic solvent. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4);
s4: under the protection of inert gas and at 90-130 ℃, the intermediate 3- (2-chloro [5,6-14C2]Pyrimidin-4-yl) -1-methyl-1H-indole (4), N2- (2- (dimethylamino) ethyl) -N2-methyl-3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine hydrochloride (SM-1), a base and a palladium catalyst in a mixed solvent of an aprotic organic solvent and water. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment and column chromatography purification to obtain N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5);
s5: under the protection of inert gas and at the temperature of 60-90 ℃, an intermediate N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidine-2-yl) -3-nitro-6- (2,2, 2-trifluoroethoxy) pyridine-2, 5-diamine (5), a metal reducing agent and ammonium chloride are reacted in a mixed solvent of alcohol and water. After the reaction is finished, the reaction mixture is subjected to conventional post-treatment to obtain N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6);
s6: under the protection of inert gas and at the temperature of 0-30 ℃, an intermediate N2- (2- (dimethylamino) ethyl) -N2-methyl-N5- (4- (1-methyl-1H-indole)-3-yl) [5,6-14C2]Reacting pyrimidin-2-yl) -6- (2,2, 2-trifluoroethoxy) pyridine-2, 3, 5-triamine (6) with acryloyl chloride in an aprotic organic solvent. After the reaction is finished, the reaction mixture is purified by conventional post-treatment, column chromatography and preparative high performance liquid chromatography to obtain carbon-14 double-labeled Vometinib (7, N- (2- ((2- (dimethylamino) ethyl) methylamino) -5- ((4- (1-methyl-1H-indol-3-yl) [5,6-14C2]Pyrimidin-2-yl) amino) -6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide);
s7: under the protection of inert gas and at the temperature of 40-60 ℃, heating carbon-14 double-labeled fulvestrant (7) and methanesulfonic acid in a mixed solvent of a ketone organic solvent and water until the carbon-14 double-labeled fulvestrant and the methanesulfonic acid are completely dissolved, and recrystallizing to obtain the target radioisotope carbon-14 double-labeled fulvestrant.
3. The method of synthesis according to claim 2, characterized in that: in S1, the alkali includes at least one selected from sodium carbonate, sodium bicarbonate, and ammonia water.
4. The method of synthesis according to claim 2, characterized in that: in S3, the lewis acid includes, but is not limited to, aluminum trichloride, ferric trichloride, stannic chloride, zinc chloride; the aprotic organic solvent includes, but is not limited to, at least one of ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether.
5. The method of synthesis according to claim 2, characterized in that: in S4, the base includes, but is not limited to, potassium phosphate, potassium carbonate, cesium carbonate; the palladium catalyst includes, but is not limited to, tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (PdCl)2(dppf)), tetrakistriphenylphosphine palladium (Pd (PPh)3)4) (ii) a The aprotic organic solvent includes, but is not limited to, at least one of toluene, dioxane, and ethylene glycol dimethyl ether.
6. The method of synthesis according to claim 2, characterized in that: at S5, the metal reducing agent includes, but is not limited to, iron powder, zinc powder; the alcohol solvent includes but is not limited to at least one of methanol, ethanol and tertiary butanol.
7. The method of synthesis according to claim 2, characterized in that: in S6, the aprotic organic solvent includes at least one selected from dichloromethane, chloroform, and toluene.
8. The method of synthesis according to claim 2, characterized in that: in S7, the ketone solvent includes at least one selected from acetone and 2-butanone.
9. A radioisotope C-14 dual labeled sumatriib mesylate synthesized by the method of claim 2 wherein the label acts as a radiotracer with a specific activity 2 times higher than that of the corresponding C-14 single site label, primarily for use in basic studies in which high specific activity (specific activity greater than 55mCi/mmol) C-14 labeled sumatriib must be used.
10. A carbon-14-containing synthetic block synthesized according to the synthesis method of any one of claims 2 to 8.
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