TW202330475A - Intermediate, preparing method thereof, and method of preparing drug - Google Patents
Intermediate, preparing method thereof, and method of preparing drug Download PDFInfo
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- TW202330475A TW202330475A TW112101650A TW112101650A TW202330475A TW 202330475 A TW202330475 A TW 202330475A TW 112101650 A TW112101650 A TW 112101650A TW 112101650 A TW112101650 A TW 112101650A TW 202330475 A TW202330475 A TW 202330475A
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- reactant
- reaction
- item
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- 238000000034 method Methods 0.000 title claims description 42
- 239000003814 drug Substances 0.000 title claims description 17
- 229940079593 drug Drugs 0.000 title claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 40
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 38
- 239000000376 reactant Substances 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- 239000003054 catalyst Substances 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- 238000006795 borylation reaction Methods 0.000 claims description 20
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 19
- 229910052763 palladium Inorganic materials 0.000 claims description 15
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims description 14
- 239000000010 aprotic solvent Substances 0.000 claims description 14
- 239000010949 copper Substances 0.000 claims description 13
- 238000003682 fluorination reaction Methods 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- SGCLBIRCSTXTIU-UHFFFAOYSA-N boric acid;2,3-dimethylbutane-2,3-diol Chemical compound OB(O)O.CC(C)(O)C(C)(C)O.CC(C)(O)C(C)(C)O SGCLBIRCSTXTIU-UHFFFAOYSA-N 0.000 claims description 11
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- 229910052802 copper Inorganic materials 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical group [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 3
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- JCIVHYBIFRUGKO-UHFFFAOYSA-N lithium;2,2,6,6-tetramethylpiperidine Chemical compound [Li].CC1(C)CCCC(C)(C)N1 JCIVHYBIFRUGKO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 2
- LTRVAZKHJRYLRJ-UHFFFAOYSA-N lithium;butan-1-olate Chemical group [Li+].CCCC[O-] LTRVAZKHJRYLRJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 76
- 239000000243 solution Substances 0.000 description 54
- 239000012044 organic layer Substances 0.000 description 34
- 238000002360 preparation method Methods 0.000 description 33
- 239000000047 product Substances 0.000 description 14
- -1 second-butyl Chemical group 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 229910052796 boron Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 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 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- GGGVVBGRTWMSPX-QMMMGPOBSA-N (2s)-2-amino-3-(4-borono-2-fluorophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1F GGGVVBGRTWMSPX-QMMMGPOBSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 235000011056 potassium acetate Nutrition 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical group C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- TZEQABAXFGVJED-AWEZNQCLSA-N benzyl (2s)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate Chemical compound C1C(=O)N(C)[C@H](C(C)(C)C)N1C(=O)OCC1=CC=CC=C1 TZEQABAXFGVJED-AWEZNQCLSA-N 0.000 description 2
- 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 description 2
- 239000012025 fluorinating agent Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 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 description 1
- FCFWEOGTZZPCTO-QMMMGPOBSA-N (2s)-3,6-dimethoxy-2-propan-2-yl-2,5-dihydropyrazine Chemical compound COC1=N[C@@H](C(C)C)C(OC)=NC1 FCFWEOGTZZPCTO-QMMMGPOBSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- XMHNLZXYPAULDF-UHFFFAOYSA-N 4-bromo-1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC(Br)=CC=C1CBr XMHNLZXYPAULDF-UHFFFAOYSA-N 0.000 description 1
- IHHHQROJDZQCQH-UHFFFAOYSA-N 4-bromo-1-(bromomethyl)-2-iodobenzene Chemical compound BrCC1=CC=C(Br)C=C1I IHHHQROJDZQCQH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 1
- 238000003461 Miyaura Borylation reaction Methods 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 150000001642 boronic acid derivatives Chemical group 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- CNOXNGAZMFFQSR-UHFFFAOYSA-N lithium;propylazanide Chemical compound [Li+].CCC[NH-] CNOXNGAZMFFQSR-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910001512 metal fluoride Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- HJJLVATZPPJBNG-JTQLQIEISA-N tert-butyl (2s)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate Chemical compound CN1[C@H](C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O HJJLVATZPPJBNG-JTQLQIEISA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
- C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
-
- 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
-
- 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
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Liquid Crystal (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
本揭示內容是關於中間體及其製備方法,以及藉由中間體製備藥物的方法。The present disclosure relates to intermediates and methods for their preparation, as well as methods for the preparation of medicaments from the intermediates.
惡性腫瘤是嚴重危害人類生命和健康的重大疾病,目前已發展出藉由放射治療來醫治罹患惡性腫瘤的病患的方法。舉例來說,硼中子捕獲治療(Boron Neutron Capture Therapy, BNCT)的流程如下:將含硼藥物注射到病患體內,含硼藥物會選擇性累積在腫瘤細胞中,再以中子束照射後,腫瘤細胞內的硼和中子發生核分裂,生成α粒子和鋰離子,藉此精準摧毀腫瘤細胞。在進行BNCT時,可藉由正子斷層造影法(Positron Emission Tomography, PET)確認含硼藥物在病患體內的分布位置及濃度,以確保在進行BNCT時不會損傷正常細胞且可達到預期的治療效果。Malignant tumors are major diseases that seriously endanger human life and health. At present, a method of treating patients suffering from malignant tumors by radiotherapy has been developed. For example, the process of Boron Neutron Capture Therapy (BNCT) is as follows: Boron-containing drugs are injected into the patient's body, and the boron-containing drugs will selectively accumulate in tumor cells, and then irradiated with neutron beams , boron and neutrons in tumor cells undergo nuclear fission to generate alpha particles and lithium ions, thereby precisely destroying tumor cells. During BNCT, the distribution position and concentration of boron-containing drugs in the patient can be confirmed by Positron Emission Tomography (PET), so as to ensure that normal cells will not be damaged and the expected treatment can be achieved during BNCT Effect.
鑑於含硼藥物對於治療惡性腫瘤的重要性,需要開發出新穎的且有效率的製備含硼藥物的方法。In view of the importance of boron-containing drugs for the treatment of malignant tumors, novel and efficient methods for preparing boron-containing drugs need to be developed.
本揭示內容提供一種中間體,其具有如以下式(1)所示的結構: 式(1),其中R 1為-Cl、-Br、-I、三氟磺酸酯基(-OSO 2CF 3)、-B(OH) 2或頻哪醇硼酸酯基(pinacol boronic ester group, ),R 2為-F、- 18F、-Cl、-Br、-I、-SnMe 3、-SnBu 3、-B(OH) 2或頻哪醇硼酸酯基( ),A為手性助劑。 The present disclosure provides an intermediate having a structure as shown in the following formula (1): Formula (1), wherein R 1 is -Cl, -Br, -I, trifluorosulfonate (-OSO 2 CF 3 ), -B(OH) 2 or pinacol boronic ester group, ), R 2 is -F, - 18 F, -Cl, -Br, -I, -SnMe 3 , -SnBu 3 , -B(OH) 2 or pinacol borate group ( ), A is a chiral auxiliary.
在一些實施方式中,A為 或 ,其中A 1為C1-C8的烷基、C7-C10的芳烷基或苯基,A 2為C1-C8的烷基,A 3為C1-C8的烷基。 In some embodiments, A is or , wherein A1 is C1-C8 alkyl, C7-C10 aralkyl or phenyl, A2 is C1-C8 alkyl, and A3 is C1-C8 alkyl.
在一些實施方式中,A為咪唑啉酮手性助劑或雙內醯亞胺醚手性助劑。In some embodiments, A is an imidazolinone chiral auxiliary or a bis-lactimide ether chiral auxiliary.
在一些實施方式中,中間體具有如以下式(2)、式(3)、式(4) 、式(5) 、式(6)、式(7)或式(8)所示的結構: 式(2)、 式(3) 、 式(4) 、 式(5)、 式(6)、 式(7)、或 式(8)。 In some embodiments, the intermediate has a structure as shown in the following formula (2), formula (3), formula (4), formula (5), formula (6), formula (7) or formula (8): Formula (2), formula (3), formula (4), Formula (5), Formula (6), Equation (7), or Formula (8).
本揭示內容提供一種製備中間體的方法,其包括以下操作。在鹼性環境下使第一反應物與第二反應物反應,以得到第一中間體,其中反應溫度為-80°C至0°C。第一反應物具有如以下式(9-1)所示的結構: 式(9-1),R 3為-Cl、-Br、-I或-OSO 2CF 3,R 4為-F、-Cl、-Br、-I、-SnMe 3、-SnBu 3或-B(OH) 2,X為-Br或-I。第二反應物具有如以下式(9-2)或式(9-3)所示的結構: 式(9-2)、 式(9-3),其中A 1為C1-C8的烷基、C7-C10的芳烷基或苯基,A 2為C1-C8的烷基,A 3為C1-C8的烷基。 The present disclosure provides a method for preparing an intermediate, which includes the following operations. reacting the first reactant with the second reactant under a basic environment to obtain the first intermediate, wherein the reaction temperature is from -80°C to 0°C. The first reactant has a structure as shown in the following formula (9-1): Formula (9-1), R 3 is -Cl, -Br, -I or -OSO 2 CF 3 , R 4 is -F, -Cl, -Br, -I, -SnMe 3 , -SnBu 3 or -B (OH) 2 , X is -Br or -I. The second reactant has a structure as shown in the following formula (9-2) or formula (9-3): Formula (9-2), Formula (9-3), wherein A 1 is a C1-C8 alkyl group, a C7-C10 aralkyl group or a phenyl group, A 2 is a C1-C8 alkyl group, and A 3 is a C1-C8 alkyl group.
在一些實施方式中,第二反應物具有如以下式(10)、式(11)或式(12)所示的結構: 式(10)、 式(11)或 式(12)。 In some embodiments, the second reactant has a structure as shown in the following formula (10), formula (11) or formula (12): Formula (10), Equation (11) or Formula (12).
在一些實施方式中,在鹼性環境下使第一反應物與第二反應物反應包括:將第一反應物、第二反應物與有機金屬鹼混合,有機金屬鹼是選自於由二異丙基氨基鋰(Lithium diisopropylamide, LDA)、正丁基鋰(butyllithiu, n-BuLi)、二(三甲基矽基)氨基鋰(Lithium bis(trimethylsilyl)amide, LiHMDS)、2,2,6,6-四甲基呱啶鋰、甲醇鈉、三級丁醇鋰、三級丁醇鈉、三級丁醇鉀及乙醇鈉及所組成之群組。In some embodiments, reacting the first reactant with the second reactant under an alkaline environment comprises: mixing the first reactant, the second reactant, and an organometallic base selected from the group consisting of diiso Lithium diisopropylamide (LDA), n-butyllithium (butyllithiu, n-BuLi), Lithium bis(trimethylsilyl)amide, LiHMDS), 2,2,6, Lithium 6-tetramethylpiperidine, sodium methoxide, lithium tertiary butoxide, sodium tertiary butoxide, potassium tertiary butoxide, sodium ethoxide and groups thereof.
在一些實施方式中,第一反應物具有如以下式(13)或式(14)所示的結構: 式(13)或 式(14)。 In some embodiments, the first reactant has a structure as shown in the following formula (13) or formula (14): Equation (13) or Formula (14).
在一些實施方式中,方法更包括將第一反應物、第二反應物與非質子溶劑混合。In some embodiments, the method further includes mixing the first reactant, the second reactant, and the aprotic solvent.
在一些實施方式中,非質子溶劑是選自於由四氫呋喃(Tetrahydrofuran, THF)、2-甲基四氫呋喃(2-MeTHF)、二甲基甲醯胺(Dimethylformamide, DMF)、二氯甲烷(Dichloromethane, DCM)及二噁烷(Dioxane)所組成之群組。In some embodiments, the aprotic solvent is selected from tetrahydrofuran (Tetrahydrofuran, THF), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (Dimethylformamide, DMF), dichloromethane (Dichloromethane, DCM) and Dioxane (Dioxane) group.
在一些實施方式中,方法更包括:在鈀催化劑存在下,使第一中間體與雙聯頻哪醇硼酸酯(Bis(pinacolato)diboron, (Bpin) 2)反應,得到第二中間體。 In some embodiments, the method further includes: reacting the first intermediate with bis(pinacolato)diboron, (Bpin) 2 ) in the presence of a palladium catalyst to obtain a second intermediate.
在一些實施方式中,方法更包括:將第一中間體、雙聯頻哪醇硼酸酯與非質子溶劑混合。In some embodiments, the method further includes: mixing the first intermediate, bis-pinacol borate, and an aprotic solvent.
本揭示內容提供一種製備藥物的方法,包括以下操作。使前述的中間體與氟化試劑進行氟化反應,生成第一化合物,其中在中間體中,R 1為-Cl、-Br、-I或-OSO 2CF 3, R 2為-Cl、-Br、-I、-SnMe 3、-SnBu 3、-B(OH) 2或 。 The present disclosure provides a method for preparing medicine, including the following operations. The aforementioned intermediate is fluorinated with a fluorinating reagent to generate the first compound, wherein in the intermediate, R 1 is -Cl, -Br, -I or -OSO 2 CF 3 , and R 2 is -Cl, - Br, -I, -SnMe 3 , -SnBu 3 , -B(OH) 2 or .
在一些實施方式中,使中間體與氟化試劑進行氟化反應包括:在銅催化劑存在下,使中間體與K 18F反應。 In some embodiments, fluorinating the intermediate with a fluorinating agent comprises: reacting the intermediate with K 18 F in the presence of a copper catalyst.
在一些實施方式中,方法更包括:使第一化合物與硼化試劑進行硼化反應,生成第二化合物。In some embodiments, the method further includes: performing a borylation reaction of the first compound with a borylation reagent to generate a second compound.
在一些實施方式中,使第一化合物與硼化試劑進行硼化反應包括:在鈀催化劑存在下,使第一化合物與雙聯頻哪醇硼酸酯反應。In some embodiments, performing borylation reaction of the first compound with a borylation reagent comprises: reacting the first compound with bis-pinacol borate in the presence of a palladium catalyst.
在一些實施方式中,方法更包括:水解第二化合物。In some embodiments, the method further includes: hydrolyzing the second compound.
應該理解的是,前述的一般性描述和下列具體說明僅僅是示例性和解釋性的,並旨在提供所要求的本揭示內容的進一步說明。It is to be understood that both the foregoing general description and the following specific description are exemplary and explanatory only and are intended to provide further explanation of the disclosure as claimed.
在本文中,由「一數值至另一數值」表示的範圍,是一種避免在說明書中一一列舉該範圍中的所有數值的概要性表示方式。因此,某一特定數值範圍的記載,涵蓋該數值範圍內的任意數值以及由該數值範圍內的任意數值界定出的較小數值範圍,如同在說明書中明文寫出該任意數值和該較小數值範圍一樣。Herein, a range indicated by "one value to another value" is a general representation which avoids enumerating all values in the range in the specification. Therefore, the description of a specific numerical range covers any numerical value in the numerical range and the smaller numerical range bounded by any numerical value in the numerical range, as if the arbitrary numerical value and the smaller numerical value are expressly written in the specification. same range.
雖然下文中利用一系列的操作或步驟來說明在此揭露之方法,但是這些操作或步驟所示的順序不應被解釋為本揭示內容的限制。例如,某些操作或步驟可以按不同順序進行及/或與其它步驟同時進行。此外,並非必須執行所有繪示的操作、步驟及/或特徵才能實現本揭示內容的實施方式。此外,在此所述的每一個操作或步驟可以包含數個子步驟或動作。Although a series of operations or steps are used to illustrate the methods disclosed herein, the order of these operations or steps should not be construed as a limitation of the present disclosure. For example, certain operations or steps may be performed in a different order and/or concurrently with other steps. In addition, not all illustrated operations, steps and/or features must be performed to implement an implementation of the present disclosure. Furthermore, each operation or step described herein may contain several sub-steps or actions.
本揭示內容提供一種藥物的製備方法。更詳細來說,本揭示內容提供一種 18F標記的2-氟-4-二羥硼基-苯基丙胺酸(2-fluoro-4-borono-phenylalanine, FBPA)的製備方法, 18F標記的FBPA為可應用於硼中子捕獲治療(BNCT)及正子斷層造影法(PET)的含硼藥物。由於 18F的半衰期短於兩小時,故如何在合成藥物的中間體上標記 18F之後,以簡易的流程製得 18F標記的FBPA是相當重要的。本揭示內容提供一種中間體及其製備方法,且能夠以簡易的流程以此中間體製備 18F標記的FBPA,從而有效提升合成 18F標記的FBPA的效率及產率,且 18F標記的FBPA具有良好的比活性(specific activity)。以下將分別描述本揭示內容的各種實施方式。 The present disclosure provides a preparation method of a medicine. In more detail, the present disclosure provides a preparation method of 18 F-labeled 2-fluoro-4-dihydroxyboryl-phenylalanine (2-fluoro-4-borono-phenylalanine, FBPA), 18 F-labeled FBPA is a boron-containing drug that can be used in boron neutron capture therapy (BNCT) and positron tomography (PET). Since the half-life of 18 F is shorter than two hours, it is very important how to prepare 18 F-labeled FBPA in a simple process after labeling 18 F on the intermediate of the synthetic drug. The present disclosure provides an intermediate and its preparation method, and 18 F-labeled FBPA can be prepared from this intermediate in a simple process, thereby effectively improving the efficiency and yield of synthesizing 18 F-labeled FBPA, and 18 F-labeled FBPA Has good specific activity. Various embodiments of the present disclosure will be described respectively below.
本揭示內容提供一種中間體,其具有如以下式(1)所示的結構: 式(1),其中R 1為-Cl、-Br、-I、-OSO 2CF 3、-B(OH) 2或 ,R 2為-F、- 18F、-Cl、-Br、-I、-SnMe 3、-SnBu 3、-B(OH) 2或 ,A為手性助劑(chiral auxiliary)。在一些實施方式中,A為咪唑啉酮(imidazolidinone)手性助劑(亦稱為Seebach手性助劑(Seebach’s chiral auxiliary))或雙內醯亞胺醚(bis-lactim ether)手性助劑(亦稱為Schöllkopf手性助劑 (Schöllkopf’s chiral auxiliary))。在一些實施方式中,A為 或 ,其中A 1為C1-C8的烷基、C7-C10的芳烷基或苯基,A 2為C1-C8的烷基,A 3為C1-C8的烷基。C1-C8的烷基例如為甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基或異戊基。「芳烷基」指至少一氫原子被苯基取代的烷基。C7-C10的芳烷基例如為一氫原子被苯基取代的C1-C4的烷基。在一些實施方式中,A為 、 或 。本揭示內容利用特定結構的手性助劑,開發出用於合成藥物的對掌輔助前驅物,亦即用於製備藥物的中間體。在一些實施方式中,本揭示內容的手性助劑可用於開發 18F標記的FBPA對掌輔助前驅物,亦即用於製備FBPA的中間體,從而以簡易的流程製備FBPA。 The present disclosure provides an intermediate having a structure as shown in the following formula (1): Formula (1), wherein R 1 is -Cl, -Br, -I, -OSO 2 CF 3 , -B(OH) 2 or , R 2 is -F, - 18 F, -Cl, -Br, -I, -SnMe 3 , -SnBu 3 , -B(OH) 2 or , A is a chiral auxiliary. In some embodiments, A is an imidazolidinone chiral auxiliary (also known as Seebach's chiral auxiliary) or a bis-lactim ether chiral auxiliary (Also known as Schöllkopf's chiral auxiliary (Schöllkopf's chiral auxiliary)). In some embodiments, A is or , wherein A1 is C1-C8 alkyl, C7-C10 aralkyl or phenyl, A2 is C1-C8 alkyl, and A3 is C1-C8 alkyl. The C1-C8 alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, second-butyl, isobutyl, tert-butyl, n-pentyl or isopentyl. "Aralkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a phenyl group. The C7-C10 aralkyl group is, for example, a C1-C4 alkyl group in which one hydrogen atom is substituted by a phenyl group. In some embodiments, A is , or . The present disclosure utilizes chiral auxiliaries with specific structures to develop anti-palm auxiliary precursors for the synthesis of drugs, that is, intermediates for the preparation of drugs. In some embodiments, the chiral auxiliaries of the present disclosure can be used to develop 18 F-labeled FBPA on-ancillary precursors, ie, intermediates for the preparation of FBPA, thereby preparing FBPA in a facile procedure.
在一些實施方式中,中間體具有如以下式(2)、式(3)、式(4) 、式(5) 、式(6)、式(7)或式(8)所示的結構: 式(2)、 式(3)、 式(4) 、 式(5)、 式(6)、 式(7)、或 式(8)。上述具有式(2)、式(3) 、式(4) 、式(5) 、式(6)、式(7)或式(8)所示的結構可作為製備 18F標記的FBPA的中間體。 In some embodiments, the intermediate has a structure as shown in the following formula (2), formula (3), formula (4), formula (5), formula (6), formula (7) or formula (8): Formula (2), Formula (3), formula (4), Formula (5), Formula (6), Equation (7), or Formula (8). The above-mentioned structures represented by formula (2), formula (3), formula (4), formula (5), formula (6), formula (7) or formula (8) can be used as intermediates for the preparation of 18 F-labeled FBPA body.
本揭示內容提供一種製備中間體的方法,其包括以下操作。在鹼性環境下使第一反應物與第二反應物反應,以得到第一中間體,其中反應溫度為-80°C至0°C。反應溫度例如為-80、-78、-76、-74、-72、-70、-60、-50、-40、-30、-20、-10或0°C。第一反應物具有如以下式(9-1)所示的結構: 式(9-1),R 3為-Cl、-Br、-I或-OSO 2CF 3,R 4為-F 、-Cl、-Br、-I、-SnMe 3、-SnBu 3或-B(OH) 2,X為-Br或-I。第二反應物具有如以下式(9-2)或式(9-3)所示的結構: 式(9-2)、 式(9-3),其中A 1為C1-C8的烷基、C7-C10的芳烷基或苯基,A 2為C1-C8的烷基,A 3為C1-C8的烷基。因此,第一中間體具有如以下式(9-4)或式(9-5)所示的結構: 式(9-4)、 式(9-5)。在一些實施方式中,第二反應物具有如以下式(10)、式(11)或式(12)所示的結構: 式(10) 、 式(11)或 式(12)。 The present disclosure provides a method for preparing an intermediate, which includes the following operations. reacting the first reactant with the second reactant under a basic environment to obtain the first intermediate, wherein the reaction temperature is from -80°C to 0°C. The reaction temperature is, for example, -80, -78, -76, -74, -72, -70, -60, -50, -40, -30, -20, -10 or 0°C. The first reactant has a structure as shown in the following formula (9-1): Formula (9-1), R 3 is -Cl, -Br, -I or -OSO 2 CF 3 , R 4 is -F, -Cl, -Br, -I, -SnMe 3 , -SnBu 3 or -B (OH) 2 , X is -Br or -I. The second reactant has a structure as shown in the following formula (9-2) or formula (9-3): Formula (9-2), Formula (9-3), wherein A 1 is a C1-C8 alkyl group, a C7-C10 aralkyl group or a phenyl group, A 2 is a C1-C8 alkyl group, and A 3 is a C1-C8 alkyl group. Therefore, the first intermediate has the structure shown in the following formula (9-4) or formula (9-5): Formula (9-4), Formula (9-5). In some embodiments, the second reactant has a structure as shown in the following formula (10), formula (11) or formula (12): formula (10), Equation (11) or Formula (12).
在一些實施方式中,第一反應物具有如以下式(13)或式(14)所示的結構: 式(13)或 式(14)。 In some embodiments, the first reactant has a structure as shown in the following formula (13) or formula (14): Equation (13) or Formula (14).
在一些實施方式中,在鹼性環境下使第一反應物與第二反應物反應包括:將第一反應物、第二反應物與有機金屬鹼混合,有機金屬鹼是選自於由二異丙基氨基鋰(LDA)、正丁基鋰(n-BuLi)、二(三甲基矽基)氨基鋰(LiHMDS)、2,2,6,6-四甲基呱啶鋰、甲醇鈉、三級丁醇鋰、三級丁醇鈉、三級丁醇鉀及乙醇鈉及所組成之群組。In some embodiments, reacting the first reactant with the second reactant under an alkaline environment comprises: mixing the first reactant, the second reactant, and an organometallic base selected from the group consisting of diiso Lithium propylamide (LDA), n-butyllithium (n-BuLi), lithium bis(trimethylsilyl)amide (LiHMDS), lithium 2,2,6,6-tetramethylpiperidine, sodium methoxide, Lithium tertiary butoxide, sodium tertiary butoxide, potassium tertiary butoxide and sodium ethoxide and groups thereof.
在一些實施方式中,製備中間體的方法更包括將第一反應物、第二反應物與非質子溶劑混合。在一些實施方式中,非質子溶劑是選自於由四氫呋喃(THF)、2-甲基四氫呋喃(2-MeTHF)、二甲基甲醯胺(DMF)、二氯甲烷(DCM)及二噁烷(Dioxane)所組成之群組。In some embodiments, the method of preparing the intermediate further includes mixing the first reactant, the second reactant and an aprotic solvent. In some embodiments, the aprotic solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (DMF), dichloromethane (DCM) and dioxane (Dioxane) group.
在一些實施方式中,製備中間體的方法更包括在鈀催化劑存在下,使第一中間體與雙聯頻哪醇硼酸酯反應,得到第二中間體。更詳細來說,第一中間體中的R 4會被取代為頻哪醇硼酸酯基,以形成第二中間體。鈀催化劑例如為[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀(Pd(dppf)Cl 2)。在一些實施方式中,製備中間體的方法更包括將第一中間體、雙聯頻哪醇硼酸酯與非質子溶劑混合。非質子溶劑請參前述的實施方式,在此不再贅述。在一些實施方式中,使第一中間體與雙聯頻哪醇硼酸酯反應的溫度為50°C至120°C,例如50、55、60、65、70、75、80、85、90、95、100、105、110、115或120°C。 In some embodiments, the method for preparing the intermediate further includes reacting the first intermediate with bis-pinacol borate in the presence of a palladium catalyst to obtain the second intermediate. In more detail, R4 in the first intermediate will be substituted with a pinacol borate group to form the second intermediate. The palladium catalyst is, for example, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ). In some embodiments, the method for preparing the intermediate further includes mixing the first intermediate, bis-pinacol borate, and an aprotic solvent. For the aprotic solvent, please refer to the aforementioned embodiments, and details will not be repeated here. In some embodiments, the temperature at which the first intermediate is reacted with bis-linked pinacol borate is from 50°C to 120°C, such as 50, 55, 60, 65, 70, 75, 80, 85, 90 , 95, 100, 105, 110, 115 or 120°C.
本揭示內容提供一種製備藥物的方法,其包括:使中間體與氟化試劑進行氟化反應,生成第一化合物,其中在中間體中,R 1為-Cl、-Br、-I或-OSO 2CF 3, R 2為-Cl、-Br、-I、-SnMe 3、-SnBu 3、-B(OH) 2或 。在一些實施方式中,氟化試劑為金屬氟化物,例如為K 18F。在一些實施方式中,中間體與氟化試劑進行氟化反應包括:在銅催化劑存在下,使中間體與K 18F反應。銅催化劑例如為Cu(OTf) 2(py) 4。在一些實施方式中,方法更包括使第一化合物與硼化試劑進行硼化反應,生成第二化合物。硼化試劑例如為雙聯頻哪醇硼酸酯((Bpin) 2)。在一些實施方式中,使第一化合物與硼化試劑進行硼化反應包括:在鈀催化劑存在下,使第一化合物與雙聯頻哪醇硼酸酯反應。在一些實施方式中,方法更包括水解第二化合物。 The present disclosure provides a method for preparing a drug, comprising: fluorinating an intermediate with a fluorinating reagent to generate a first compound, wherein in the intermediate, R is -Cl, -Br, -I or -OSO 2 CF 3 , R 2 is -Cl, -Br, -I, -SnMe 3 , -SnBu 3 , -B(OH) 2 or . In some embodiments, the fluorinating agent is a metal fluoride, such as K 18 F. In some embodiments, the fluorination reaction of the intermediate with a fluorinating reagent comprises: reacting the intermediate with K 18 F in the presence of a copper catalyst. The copper catalyst is, for example, Cu(OTf) 2 (py) 4 . In some embodiments, the method further includes subjecting the first compound to a borylation reagent to form a second compound. The borylation reagent is, for example, bispinacol borate ((Bpin) 2 ). In some embodiments, performing borylation reaction of the first compound with a borylation reagent comprises: reacting the first compound with bis-pinacol borate in the presence of a palladium catalyst. In some embodiments, the method further includes hydrolyzing the second compound.
本揭示內容提供一種製備 18F標記的2-氟-4-二羥硼基-苯基丙胺酸(FBPA)的方法,包括以下操作。使中間體進行氟化反應,生成第一化合物,其中中間體具有如以下式(1)所示的結構: 式(1),R 1為-Cl、-Br、-I或-OSO 2CF 3, R 2為-Cl、-Br、-I、-SnMe 3、-SnBu 3、-B(OH) 2或 ,第一化合物具有如以下式(X)所示的結構: 式(X)。使第一化合物進行硼化反應,生成第二化合物,第二化合物具有如以下式(XI)所示的結構: 式(XI)。水解第二化合物,生成2-氟-4-二羥硼基-苯基丙胺酸,其具有如以下式(XII)所示的結構: 式(XII)。 The present disclosure provides a method for preparing 18 F-labeled 2-fluoro-4-dihydroxyboryl-phenylalanine (FBPA), comprising the following operations. The intermediate is subjected to a fluorination reaction to generate the first compound, wherein the intermediate has a structure as shown in the following formula (1): Formula (1), R 1 is -Cl, -Br, -I or -OSO 2 CF 3 , R 2 is -Cl, -Br, -I, -SnMe 3 , -SnBu 3 , -B(OH) 2 or , the first compound has the structure shown in the following formula (X): Formula (X). Make the first compound carry out borylation reaction, generate the second compound, the second compound has the structure shown in following formula (XI): Formula (XI). Hydrolysis of the second compound produces 2-fluoro-4-dihydroxyboryl-phenylalanine, which has the structure shown in the following formula (XII): Formula (XII).
在一些實施方式中,使中間體進行氟化反應包括:在銅催化劑存在下,使中間體與K 18F反應,從而使芳香環上的R 2被 18F取代,換言之,中間體的芳香環被 18F氟化。上述以銅催化劑催化的氟化反應稱為銅介導之芳香環氟化反應。銅催化劑例如為Cu(OTf) 2(py) 4。在一些實施方式中,氟化反應的溫度為100°C至120°C。溫度例如為100、105、110、115或120°C。在一些實施方式中,氟化反應的反應時間為5分鐘至60分鐘。K 18F與頻哪醇硼酸酯基( )反應性最佳,與-Cl、-Br、-I、-SnMe 3、-SnBu 3或-B(OH) 2等其他基團的反應性次之。在一些實施方式中,K 18F可由以下操作獲得:以加速之質子照射H 2 18O,利用 18O(p,n) 18F反應合成出氟化氫酸(H 18F),再將H 18F通過離子交換管柱使其吸附於管柱內,以與未吸附於管柱的H 2 18O分離。以K 2CO 3水溶液將管柱內的H 18F析出,獲得K 18F。在一些實施方式中,進行氟化反應時,將中間體、K 18F及銅催化劑溶於非質子溶劑中,例如二甲基甲醯胺(DMF)。非質子溶劑的材料請參前述的實施方式,在此不再贅述。 In some embodiments, subjecting the intermediate to fluorination comprises: reacting the intermediate with K 18 F in the presence of a copper catalyst so that R 2 on the aromatic ring is replaced by 18 F, in other words, the aromatic ring of the intermediate Fluorinated by 18 F. The above-mentioned fluorination reaction catalyzed by copper catalyst is called copper-mediated aromatic ring fluorination reaction. The copper catalyst is, for example, Cu(OTf) 2 (py) 4 . In some embodiments, the temperature of the fluorination reaction is from 100°C to 120°C. The temperature is for example 100, 105, 110, 115 or 120°C. In some embodiments, the reaction time of the fluorination reaction is 5 minutes to 60 minutes. K 18 F and pinacol borate group ( ) has the best reactivity, followed by other groups such as -Cl, -Br, -I, -SnMe 3 , -SnBu 3 or -B(OH) 2 . In some embodiments, K 18 F can be obtained by the following operation: irradiating H 2 18 O with accelerated protons, using 18 O(p,n) 18 F to synthesize hydrofluoric acid (H 18 F), and then converting H 18 F It is adsorbed in the column through an ion exchange column to separate from H 2 18 O that is not adsorbed in the column. Precipitate H 18 F in the column with K 2 CO 3 aqueous solution to obtain K 18 F. In some embodiments, during the fluorination reaction, the intermediate, K 18 F and copper catalyst are dissolved in an aprotic solvent, such as dimethylformamide (DMF). For the material of the aprotic solvent, please refer to the foregoing embodiments, and details are not repeated here.
在一些實施方式中,使第一化合物進行硼化反應包括:在鈀催化劑存在下,使第一化合物與雙聯頻哪醇硼酸酯((Bpin) 2)反應,從而使芳香環上的R 1被頻哪醇硼酸酯基取代。上述以鈀催化劑催化的硼化反應稱為宮浦(Miyaura)硼化反應。雙聯頻哪醇硼酸酯與-Br反應性最佳,與-Cl、-I或-OSO 2CF 3等其他基團的反應性次之。鈀催化劑例如為三(二亞苄基丙酮)二鈀(Pd 2(dba) 3),其可以三環己基膦(P(Cy) 3)作為配體。在一些實施方式中,可將Pd 2(dba) 3溶於二噁烷中。鈀催化劑例如為[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀(Pd(dppf)Cl 2)。在一些實施方式中,可將PdCl 2(dppf)溶於醋酸鉀(Potassium acetate, KOAc)中。在一些實施方式中,硼化反應的溫度為70°C至120°C。溫度例如為70、75、80、85、90、95、100、105、110、115或120°C。在一些實施方式中,硼化反應的反應時間為5分鐘至60分鐘。在一些實施方式中,進行硼化反應時,將第一化合物與雙聯頻哪醇硼酸酯溶於非質子溶劑中,例如二甲基亞碸(DMSO)或二噁烷(Dioxane)。非質子溶劑的材料請參前述的實施方式,在此不再贅述。 In some embodiments, the borylation reaction of the first compound comprises: reacting the first compound with bis-pinacol borate ((Bpin) 2 ) in the presence of a palladium catalyst, so that the R on the aromatic ring 1 is substituted with a pinacol borate group. The above-mentioned borylation reaction catalyzed by palladium catalyst is called Miyaura borylation reaction. The bilinked pinacol borate has the best reactivity with -Br, followed by other groups such as -Cl, -I or -OSO 2 CF 3 . The palladium catalyst is, for example, tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), which can use tricyclohexylphosphine (P(Cy) 3 ) as a ligand. In some embodiments, Pd 2 (dba) 3 can be dissolved in dioxane. The palladium catalyst is, for example, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ). In some embodiments, PdCl 2 (dppf) can be dissolved in Potassium acetate (KOAc). In some embodiments, the temperature of the borylation reaction is from 70°C to 120°C. The temperature is for example 70, 75, 80, 85, 90, 95, 100, 105, 110, 115 or 120°C. In some embodiments, the reaction time of the borylation reaction is 5 minutes to 60 minutes. In some embodiments, when carrying out the borylation reaction, the first compound and bis-pinacol borate are dissolved in an aprotic solvent, such as dimethylsulfoxide (DMSO) or dioxane (Dioxane). For the material of the aprotic solvent, please refer to the foregoing embodiments, and details are not repeated here.
在一些實施方式中,水解第二化合物包括:使第二化合物與酸反應。酸例如為氯化氫(HCl)、溴化氫(HBr)、碘化氫(HI)或其組合。酸可打開第二化合物的頻哪醇硼酸酯基( ),使其水解為-B(OH) 2,酸亦可使第二化合物的手性助劑A水解為胺基酸基團。在一些實施方式中,水解的溫度為130°C至170°C。溫度例如為130、140、150、160或170°C。在一些實施方式中,水解的反應時間為5分鐘至60分鐘。 In some embodiments, hydrolyzing the second compound includes reacting the second compound with an acid. The acid is, for example, hydrogen chloride (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), or combinations thereof. The acid can open the pinacol borate group of the second compound ( ) to hydrolyze it into -B(OH) 2 , and the acid can also hydrolyze the chiral auxiliary A of the second compound into an amino acid group. In some embodiments, the temperature of hydrolysis is from 130°C to 170°C. The temperature is for example 130, 140, 150, 160 or 170°C. In some embodiments, the reaction time for hydrolysis is 5 minutes to 60 minutes.
下文將參照實驗例,更具體地描述本揭示內容的特徵。雖然描述了以下實驗例,但是在不逾越本揭示內容範疇之情況下,可適當地改變所用材料、其量及比率、處理細節以及處理流程等等。因此,不應由下文所述之實驗例對本揭示內容作出限制性地解釋。Hereinafter, features of the present disclosure will be described more specifically with reference to experimental examples. Although the following experimental examples are described, the materials used, their amounts and ratios, processing details, processing flow, and the like can be appropriately changed without departing from the scope of the present disclosure. Therefore, the present disclosure should not be limitedly interpreted by the experimental examples described below.
實驗例1:製備具有式(5)及式(2)的中間體Experimental example 1: preparation has the intermediate of formula (5) and formula (2)
首先,製備具有式(5)的中間體,製備流程請參以下反應式。 First, prepare the intermediate with formula (5), please refer to the following reaction formula for the preparation process.
以下將詳細說明製備流程。在100 ml 反應瓶加入具有式(10)的化合物(3.0 g)及THF(40 ml),亦即(S)-2-叔丁基-3-甲基-4-氧代咪唑烷-1-羧酸叔丁酯((S)-tert-butyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate)及THF,°C將溶液攪拌至溶質全溶。在氮氣下將溶液溫度降至-75°C至-70°C。滴加LDA溶液(14.0 ml) 至溶液中,控制溫度為-75°C至-70°C,在LDA溶液中,LDA的濃度為1M,且LDA溶於THF/己烷中。保持溶液溫度為-75°C至-70°C,並攪拌混合液30分鐘。滴加4-溴-1-(溴甲基)-2-碘苯(4-bromo-1-(bromomethyl)-2-iodobenzene) (4.8 g)與THF(5 ml)的混合液至溶液中,控制溶液溫度為-75°C至-70°C。將溶液回溫至室溫(本文中的室溫為約25°C),攪拌溶液16小時。以飽和氯化銨水溶液(50 ml)及二氯甲烷(60 ml)萃取溶液,得到第一有機層及水層,水層再以二氯甲烷(30 ml)萃取兩次,得到第二有機層。合併第一有機層及第二有機層為有機層萃取液,將有機層萃取液以無水硫酸鈉乾燥、過濾再濃縮,得到濃縮液。濃縮液經快速管柱層析(乙酸乙酯(Ethyl ethanoate, EA): 庚烷=1:5)純化得到產物(4.2 g,65%)。產物的核磁共振(Nuclear magnetic resonance, NMR)氫譜( 1H-NMR (400 MHz, CDCl 3))的化學位移(δ)(單位:ppm)為 0.99 (s, 9H)、1.31 (s, 9H)、3.01 (s, 3H)、3.38 (dd, 1H, J = 16.4, 6.8 Hz)、3.52 (dd, 1H, J = 16.4, 3.2 Hz)、4.35 (dd, 1H, J = 6.0, 4.0 Hz)、5.06 (s, 1H)、6.78 (d, 1H, J = 8.4 Hz)、7.35 (dd, 1H, J = 8.4, 2.0 Hz)、7.97 (d, 1H, J = 1.6 Hz)。由NMR氫譜可證明實驗例1可製備出前述本揭示內容具有式(5)的中間體,其結構命名為(2S,5S)-tert-butyl 5-(4-bromo-2-iodobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate。 The preparation process will be described in detail below. Add the compound (3.0 g) and THF (40 ml) having the formula (10) into a 100 ml reaction flask, namely (S)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1- tert-butyl carboxylate ((S)-tert-butyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate) and THF, at °C, stir the solution until the solute is completely dissolved. Lower the solution temperature to -75 °C to -70 °C under nitrogen. LDA solution (14.0 ml) was added dropwise to the solution, and the temperature was controlled at -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF/hexane. Keep the solution temperature at -75°C to -70°C and stir the mixture for 30 min. A mixture of 4-bromo-1-(bromomethyl)-2-iodobenzene (4-bromo-1-(bromomethyl)-2-iodobenzene) (4.8 g) and THF (5 ml) was added dropwise to the solution, Control the solution temperature at -75°C to -70°C. The solution was warmed to room temperature (room temperature here is about 25° C.), and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride (50 ml) and dichloromethane (60 ml) to obtain the first organic layer and the aqueous layer, and the aqueous layer was extracted twice with dichloromethane (30 ml) to obtain the second organic layer . The first organic layer and the second organic layer were combined into an organic layer extract, which was dried over anhydrous sodium sulfate, filtered and then concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (ethyl acetate (EA):heptane=1:5) to obtain the product (4.2 g, 65%). The chemical shift (δ) (unit: ppm) of the product's nuclear magnetic resonance (NMR) hydrogen spectrum ( 1 H-NMR (400 MHz, CDCl 3 )) is 0.99 (s, 9H), 1.31 (s, 9H ), 3.01 (s, 3H), 3.38 (dd, 1H, J = 16.4, 6.8 Hz), 3.52 (dd, 1H, J = 16.4, 3.2 Hz), 4.35 (dd, 1H, J = 6.0, 4.0 Hz) , 5.06 (s, 1H), 6.78 (d, 1H, J = 8.4 Hz), 7.35 (dd, 1H, J = 8.4, 2.0 Hz), 7.97 (d, 1H, J = 1.6 Hz). It can be proved from the NMR hydrogen spectrum that Experimental Example 1 can prepare the intermediate of formula (5) in the foregoing disclosure, and its structure is named as (2S, 5S)-tert-butyl 5-(4-bromo-2-iodobenzyl)- 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.
接下來,以具有式(5)的中間體製備具有式(2)的中間體,製備流程請參以下反應式。 Next, the intermediate of formula (2) is prepared from the intermediate of formula (5). Please refer to the following reaction formula for the preparation process.
以下將詳細說明製備流程。在25 ml 反應瓶加入DMSO (5 ml),以氬氣鼓泡30分鐘。 加入具有式(5)的中間體(580 mg)、雙聯頻哪醇硼酸酯(588 mg)、醋酸鉀(KOAc)(313 mg)及鈀催化劑Pd(dppf)Cl 2(38.5 mg),持續以氬氣鼓泡10 分鐘。在氬氣下加熱溶液,控制溶液溫度為80°C使溶液反應24小時。將溶液溫度降至室溫。以水(15 ml)及二氯甲烷(20 ml)萃取溶液,得到第一有機層及水層,水層再以二氯甲烷(15 ml)萃取兩次,得到第二有機層。合併第一有機層及第二有機層為有機層萃取液,再以水(15 ml)萃取有機層萃取液。將有機層萃取液以無水硫酸鈉乾燥、過濾再濃縮,得到濃縮液。濃縮液經快速管柱層析(EA:庚烷= 1:9)純化得到產物(211 mg,36%)。產物的NMR氫譜( 1H-NMR (400 MHz, CDCl 3))的化學位移(δ)(單位:ppm)為0.93 (s, 9H)、1.36 (s, 6H)、1.37 (s, 6H)、1.40 (s, 9H)、2.77 (s, 3H)、3.69 (dd, 1H, J = 15.0, 2.6 Hz)、3.83 (br, 1H)、4.29 (t, 1H, J = 3.6 Hz)、4.77 (s, 1H)、6.82 (d, 1H, J = 8.4 Hz)、7.37 (dd, 1H, J = 8.4, 2.4 Hz)、7.82 (d, 1H, J = 2.4 Hz) 。由NMR氫譜可證明實驗例1可製備出前述本揭示內容具有式(2)的中間體,其結構命名為(2S,5S)-tert-butyl 5-(4-bromo-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate。 The preparation process will be described in detail below. DMSO (5 ml) was added to a 25 ml reaction vial and bubbled with argon for 30 minutes. The intermediate of formula (5) (580 mg), bis-pinacol borate (588 mg), potassium acetate (KOAc) (313 mg) and palladium catalyst Pd(dppf) Cl (38.5 mg) were added, Continue bubbling with argon for 10 minutes. The solution was heated under argon, and the temperature of the solution was controlled to be 80° C. to allow the solution to react for 24 hours. The temperature of the solution was lowered to room temperature. The solution was extracted with water (15 ml) and dichloromethane (20 ml) to obtain a first organic layer and an aqueous layer, and the aqueous layer was extracted twice with dichloromethane (15 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined into an organic layer extract, and the organic layer extract was extracted with water (15 ml). The organic layer extract was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA:heptane=1:9) to obtain the product (211 mg, 36%). The chemical shifts (δ) (unit: ppm) of the NMR spectrum ( 1 H-NMR (400 MHz, CDCl 3 )) of the product are 0.93 (s, 9H), 1.36 (s, 6H), 1.37 (s, 6H) , 1.40 (s, 9H), 2.77 (s, 3H), 3.69 (dd, 1H, J = 15.0, 2.6 Hz), 3.83 (br, 1H), 4.29 (t, 1H, J = 3.6 Hz), 4.77 ( s, 1H), 6.82 (d, 1H, J = 8.4 Hz), 7.37 (dd, 1H, J = 8.4, 2.4 Hz), 7.82 (d, 1H, J = 2.4 Hz). It can be proved by NMR hydrogen spectrum that Experimental Example 1 can prepare the intermediate of formula (2) in the foregoing disclosure, and its structure is named as (2S,5S)-tert-butyl 5-(4-bromo-2-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.
實驗例2:製備具有式(6)及式(3)的中間體Experimental example 2: preparation has the intermediate of formula (6) and formula (3)
首先,製備具有式(6)的中間體,製備流程請參以下反應式。 First, prepare the intermediate with formula (6), please refer to the following reaction formula for the preparation process.
以下將詳細說明製備流程。在100 ml 反應瓶加入具有式(11)的化合物(3.9 g)及THF(40 ml),亦即(S)-2-叔丁基-3-甲基-4-氧代咪唑烷-1-甲酸苄酯1-甲酸酯((S)-benzyl 2-tert-butyl-3-methyl-4-oxoimidazolidine- 1-carboxylate)及THF,將溶液攪拌至溶質全溶。在氮氣下將溶液溫度降至-75°C至-70°C。滴加LDA溶液(16.2 ml) 至溶液中,控制溫度為-75°C至-70°C,在LDA溶液中,LDA的濃度為1M,且LDA溶於THF/己烷中。保持溶液溫度為-75°C至-70°C,並攪拌混合液30分鐘。滴加4-溴-1-(溴甲基)-2-碘苯(5.6 g)與THF(5 ml)的混合液至溶液中,控制溶液溫度為-75°C至-70°C。將溶液回溫至室溫,攪拌溶液16小時。以飽和氯化銨水溶液(50 ml)及二氯甲烷(60 ml)萃取溶液,得到第一有機層及水層,水層再以二氯甲烷(30 ml)萃取兩次,得到第二有機層。合併第一有機層及第二有機層為有機層萃取液,將有機層萃取液以無水硫酸鈉乾燥、過濾再濃縮,得到濃縮液。濃縮液經快速管柱層析(EA: 庚烷=1:5)純化得到產物(5.5 g,70%)。產物的NMR氫譜( 1H-NMR (400 MHz, CDCl 3))的化學位移(δ)(單位:ppm)為0.98 (s, 9H)、3.00 (s, 3H)、3.32 (dd, 1H, J = 15.6, 6.4 Hz)、3.53 (d, 1H, J = 15.2 Hz)、4.40 (t, 1H, J = 5.2 Hz)、4.89 (d, 1H, J = 12.0 Hz)、5.09 (s, 1H)、5.15 (d, 1H, J = 12.0 Hz)、6.82 (d, 1H, J = 8.4 Hz)、7.21-7.32 (m, 6H)、7.90 (s, 1H)。由NMR氫譜可證明實驗例2可製備出前述本揭示內容具有式(6)的中間體,其結構命名為(2S,5S)-benzyl 5-(4-bromo-2-iodobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate。 The preparation process will be described in detail below. Add the compound (3.9 g) and THF (40 ml) having the formula (11) into a 100 ml reaction flask, that is, (S)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1- Benzyl formate 1-carboxylate ((S)-benzyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate) and THF, the solution was stirred until the solute was completely dissolved. Lower the solution temperature to -75 °C to -70 °C under nitrogen. LDA solution (16.2 ml) was added dropwise to the solution, and the temperature was controlled at -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF/hexane. Keep the solution temperature at -75°C to -70°C and stir the mixture for 30 min. A mixture of 4-bromo-1-(bromomethyl)-2-iodobenzene (5.6 g) and THF (5 ml) was added dropwise to the solution, and the temperature of the solution was controlled from -75°C to -70°C. The solution was warmed to room temperature and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride (50 ml) and dichloromethane (60 ml) to obtain the first organic layer and the aqueous layer, and the aqueous layer was extracted twice with dichloromethane (30 ml) to obtain the second organic layer . The first organic layer and the second organic layer were combined into an organic layer extract, which was dried over anhydrous sodium sulfate, filtered and then concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA:heptane=1:5) to obtain the product (5.5 g, 70%). The chemical shifts (δ) (unit: ppm) of the NMR hydrogen spectrum ( 1 H-NMR (400 MHz, CDCl 3 )) of the product are 0.98 (s, 9H), 3.00 (s, 3H), 3.32 (dd, 1H, J = 15.6, 6.4 Hz), 3.53 (d, 1H, J = 15.2 Hz), 4.40 (t, 1H, J = 5.2 Hz), 4.89 (d, 1H, J = 12.0 Hz), 5.09 (s, 1H) , 5.15 (d, 1H, J = 12.0 Hz), 6.82 (d, 1H, J = 8.4 Hz), 7.21-7.32 (m, 6H), 7.90 (s, 1H). It can be proved by the NMR hydrogen spectrum that Experimental Example 2 can prepare the intermediate of formula (6) in the foregoing disclosure, and its structure is named as (2S, 5S)-benzyl 5-(4-bromo-2-iodobenzyl)-2- tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.
接下來,以具有式(6)的中間體製備具有式(3)的中間體,製備流程請參以下反應式。 Next, the intermediate with formula (3) is prepared from the intermediate with formula (6). Please refer to the following reaction formula for the preparation process.
以下將詳細說明製備流程。在25 ml 反應瓶加入DMSO (5 ml),以氬氣鼓泡30分鐘。加入具有式(6)的中間體(500 mg)、雙聯頻哪醇硼酸酯(477 mg)、醋酸鉀(254 mg)及鈀催化劑Pd(dppf)Cl 2(31.3 mg),持續以氬氣鼓泡10 分鐘。在氬氣下加熱溶液,控制溶液溫度為80°C使溶液反應22小時。將溶液溫度降至室溫。以水(15 ml)及二氯甲烷(20 ml)萃取溶液,得到第一有機層及水層,水層再以二氯甲烷(15 ml)萃取兩次,得到第二有機層。合併第一有機層及第二有機層為有機層萃取液,再以水(15 ml)萃取有機層萃取液。將有機層萃取液以無水硫酸鈉乾燥、過濾再濃縮,得到濃縮液。濃縮液經快速管柱層析(EA:庚烷= 1:7)純化得到產物(246 mg,49%)。產物的NMR氫譜( 1H-NMR (400 MHz, CDCl 3))的化學位移(δ)(單位:ppm)為0.88 (s, 9H)、1.37 (s, 12H)、2.78 (s, 3H)、3.64 (d, 1H, J = 12.8 Hz)、3.88 (br, 1H)、4.35 (t, 1H, J = 3.2 Hz)、4.69 (s, 1H)、4.93 (d, 1H, J = 11.6 Hz)、5.20 (d, 1H, J = 12.0 Hz)、6.72 (d, 1H, J = 8.0 Hz)、7.25-7.36 (m, 6H)、7.79 (d, 1H, J = 2.4 Hz)。由NMR氫譜可證明實驗例2可製備出前述本揭示內容具有式(3)的中間體,其結構命名為(2S,5S)-benzyl 5-(4-bromo-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzyl)-2-tert-butyl-3-methyl-4- oxoimidazolidine-1-carboxylate。 The preparation process will be described in detail below. DMSO (5 ml) was added to a 25 ml reaction vial and bubbled with argon for 30 minutes. The intermediate having formula (6) (500 mg), bis-pinacol borate (477 mg), potassium acetate (254 mg) and palladium catalyst Pd(dppf)Cl 2 (31.3 mg) were added, and the reaction was continued under argon Bubble for 10 minutes. The solution was heated under argon, and the temperature of the solution was controlled to be 80° C. to allow the solution to react for 22 hours. The temperature of the solution was lowered to room temperature. The solution was extracted with water (15 ml) and dichloromethane (20 ml) to obtain a first organic layer and an aqueous layer, and the aqueous layer was extracted twice with dichloromethane (15 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined into an organic layer extract, and the organic layer extract was extracted with water (15 ml). The organic layer extract was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA:heptane=1:7) to obtain the product (246 mg, 49%). The chemical shifts (δ) (unit: ppm) of the NMR spectrum ( 1 H-NMR (400 MHz, CDCl 3 )) of the product are 0.88 (s, 9H), 1.37 (s, 12H), 2.78 (s, 3H) , 3.64 (d, 1H, J = 12.8 Hz), 3.88 (br, 1H), 4.35 (t, 1H, J = 3.2 Hz), 4.69 (s, 1H), 4.93 (d, 1H, J = 11.6 Hz) , 5.20 (d, 1H, J = 12.0 Hz), 6.72 (d, 1H, J = 8.0 Hz), 7.25-7.36 (m, 6H), 7.79 (d, 1H, J = 2.4 Hz). It can be proved by the NMR hydrogen spectrum that Experimental Example 2 can prepare the intermediate of formula (3) in the foregoing disclosure, and its structure is named as (2S,5S)-benzyl 5-(4-bromo-2-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.
實驗例3:製備具有式(7)的中間體Experimental example 3: preparation has the intermediate of formula (7)
具有式(7)的中間體的製備流程請參以下反應式。 Please refer to the following reaction formula for the preparation process of the intermediate with formula (7).
以下將詳細說明製備流程。在100 ml 反應瓶加入具有式(10)的化合物(200 mg)及THF(5 ml),亦即(S)-2-叔丁基-3-甲基-4-氧代咪唑烷-1-甲酸苄酯1-甲酸酯及THF,將溶液攪拌至溶質全溶。在氮氣下將溶液溫度降至-75°C至-70°C。滴加LDA溶液(0.94 ml) 至溶液中,控制溫度為-75°C至-70°C,在LDA溶液中,LDA的濃度為1M,且LDA溶於THF/己烷中。保持溶液溫度為-75°C至-70°C,並攪拌混合液30分鐘。滴加4-溴-1-(溴甲基)-2-氟苯(4-bromo-1-(bromomethyl)-2-fluorobenzene)(209 mg)與THF(2 ml)的混合液至溶液中,控制溶液溫度為-75°C至-70°C。將溶液回溫至室溫,攪拌溶液16小時。以飽和氯化銨水溶液(10 ml)及二氯甲烷(15 ml)萃取溶液,得到第一有機層及水層,水層再以二氯甲烷(10 ml)萃取兩次,得到第二有機層。合併第一有機層及第二有機層為有機層萃取液,將有機層萃取液以無水硫酸鈉乾燥、過濾再濃縮,得到濃縮液。濃縮液經快速管柱層析(EA: 庚烷=1:5)純化得到產物(105 mg,30%)。產物的NMR氫譜( 1H-NMR (400 MHz, CDCl 3))的化學位移(δ)(單位:ppm)為0.95 (s, 9H)、1.41 (s, 9H)、2.87 (s, 3H)、3.31 (dd, 1H, J = 15.0, 2.2 Hz)、3.54 (br, 1H)、4.31 (s, 1H)、4.83 (s, 1H)、6.96 (t, 1H, J = 8.2 Hz)、7.13-7.17 (m, 2H)。由NMR氫譜可證明實驗例3可製備出前述本揭示內容具有式(7)的中間體,其結構命名為(2S,5S)-tert-butyl 5-(4-bromo-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate。具有式(7)的中間體可進一步與雙聯頻哪醇硼酸酯反應,將F基取代為頻哪醇硼酸酯基,產物可用於製備FBPA,反應流程可參照實驗例1或實驗例2。 The preparation process will be described in detail below. Add the compound (200 mg) and THF (5 ml) of formula (10) into a 100 ml reaction bottle, namely (S)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1- Benzyl formate 1-formate and THF, the solution was stirred until the solute was completely dissolved. Lower the solution temperature to -75 °C to -70 °C under nitrogen. LDA solution (0.94 ml) was added dropwise to the solution, and the temperature was controlled at -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF/hexane. Keep the solution temperature at -75°C to -70°C and stir the mixture for 30 min. A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (4-bromo-1-(bromomethyl)-2-fluorobenzene) (209 mg) and THF (2 ml) was added dropwise to the solution, Control the solution temperature at -75°C to -70°C. The solution was warmed to room temperature and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride (10 ml) and dichloromethane (15 ml) to obtain the first organic layer and an aqueous layer, and the aqueous layer was extracted twice with dichloromethane (10 ml) to obtain the second organic layer . The first organic layer and the second organic layer were combined into an organic layer extract, which was dried over anhydrous sodium sulfate, filtered and then concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA: heptane=1:5) to obtain the product (105 mg, 30%). The chemical shifts (δ) (unit: ppm) of the NMR spectrum ( 1 H-NMR (400 MHz, CDCl 3 )) of the product are 0.95 (s, 9H), 1.41 (s, 9H), 2.87 (s, 3H) , 3.31 (dd, 1H, J = 15.0, 2.2 Hz), 3.54 (br, 1H), 4.31 (s, 1H), 4.83 (s, 1H), 6.96 (t, 1H, J = 8.2 Hz), 7.13- 7.17 (m, 2H). It can be proved from the NMR hydrogen spectrum that Experimental Example 3 can prepare the intermediate of formula (7) in the foregoing disclosure, and its structure is named as (2S, 5S)-tert-butyl 5-(4-bromo-2-fluorobenzyl)- 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate. The intermediate with formula (7) can be further reacted with double-linked pinacol borate, and the F group is replaced by a pinacol borate group. The product can be used to prepare FBPA. The reaction process can refer to Experimental Example 1 or Experimental Example 2.
實驗例4:製備具有式(8)的中間體Experimental example 4: preparation has the intermediate of formula (8)
具有式(8)的中間體的製備流程請參以下反應式。 以下將詳細說明製備流程。在100 ml 反應瓶加入具有式(11)的化合物(200 mg)及THF(5 ml),亦即(S)-2-叔丁基-3-甲基-4-氧代咪唑烷-1-甲酸苄酯1-甲酸酯((S)-benzyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate)及THF,將溶液攪拌至溶質全溶。在氮氣下將溶液溫度降至-75°C至-70°C。滴加LDA溶液(0.83 ml) 至溶液中,控制溫度為-75°C至-70°C,在LDA溶液中,LDA的濃度為1M,且LDA溶於THF/己烷中。保持溶液溫度為-75°C至-70°C,並攪拌混合液30分鐘。滴加4-溴-1-(溴甲基)-2-氟苯(185 mg)與THF(2 ml)的混合液至溶液中,控制溶液溫度為-75°C至-70°C。將溶液回溫至室溫,攪拌溶液16小時。以飽和氯化銨水溶液(10 ml)及二氯甲烷(15 ml)萃取溶液,得到第一有機層及水層,水層再以二氯甲烷(10 ml)萃取兩次,得到第二有機層。合併第一有機層及第二有機層為有機層萃取液,將有機層萃取液以無水硫酸鈉乾燥、過濾再濃縮,得到濃縮液。濃縮液經快速管柱層析(EA: 庚烷=1:4)純化得到產物(77 mg,23%)。產物的NMR氫譜( 1H-NMR (400 MHz, CDCl 3))的化學位移(δ)(單位:ppm)為0.91 (s, 9H)、2.84 (s, 3H)、3.19 (d, 1H, J = 14.0 Hz)、3.65 (dd, 1H, J = 14.0, 3.2 Hz)、4.38 (s, 1H)、4.81 (s, 1H)、4.96 (d, 1H, J = 12.0 Hz)、5.26 (d, 1H, J = 12.0 Hz)、6.96 (t, 1H, J = 8.0 Hz)、7.08-7.14 (m, 2H)、7.35-7.39 (m, 5H)。由NMR氫譜可證明實驗例4可製備出前述本揭示內容具有式(8)的中間體,其結構命名為(2S,5S)-benzyl 5-(4-bromo-2-fluorobenzyl)-2-tert-butyl-3- methyl-4-oxoimidazolidine-1-carboxylate。具有式(8)的中間體可進一步與雙聯頻哪醇硼酸酯反應,將F基取代為頻哪醇硼酸酯基,產物可用於製備FBPA,反應流程可參照實驗例1或實驗例2。 Please refer to the following reaction formula for the preparation process of the intermediate with formula (8). The preparation process will be described in detail below. Add the compound (200 mg) and THF (5 ml) of formula (11) into a 100 ml reaction bottle, namely (S)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1- Benzyl formate 1-carboxylate ((S)-benzyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate) and THF, the solution was stirred until the solute was completely dissolved. Lower the solution temperature to -75 °C to -70 °C under nitrogen. LDA solution (0.83 ml) was added dropwise to the solution, and the temperature was controlled at -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF/hexane. Keep the solution temperature at -75°C to -70°C and stir the mixture for 30 min. A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (185 mg) and THF (2 ml) was added dropwise to the solution, and the temperature of the solution was controlled from -75°C to -70°C. The solution was warmed to room temperature and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride (10 ml) and dichloromethane (15 ml) to obtain the first organic layer and an aqueous layer, and the aqueous layer was extracted twice with dichloromethane (10 ml) to obtain the second organic layer . The first organic layer and the second organic layer were combined into an organic layer extract, which was dried over anhydrous sodium sulfate, filtered and then concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA: heptane=1:4) to obtain the product (77 mg, 23%). The chemical shifts (δ) (unit: ppm) of the NMR hydrogen spectrum ( 1 H-NMR (400 MHz, CDCl 3 )) of the product are 0.91 (s, 9H), 2.84 (s, 3H), 3.19 (d, 1H, J = 14.0 Hz), 3.65 (dd, 1H, J = 14.0, 3.2 Hz), 4.38 (s, 1H), 4.81 (s, 1H), 4.96 (d, 1H, J = 12.0 Hz), 5.26 (d, 1H, J = 12.0 Hz), 6.96 (t, 1H, J = 8.0 Hz), 7.08-7.14 (m, 2H), 7.35-7.39 (m, 5H). It can be proved from the NMR hydrogen spectrum that Experimental Example 4 can prepare the intermediate of formula (8) in the foregoing disclosure, and its structure is named as (2S, 5S)-benzyl 5-(4-bromo-2-fluorobenzyl)-2- tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate. The intermediate with formula (8) can be further reacted with double-linked pinacol borate, and the F group is replaced by a pinacol borate group. The product can be used to prepare FBPA. The reaction process can refer to Experimental Example 1 or Experimental Example 2.
實驗例5:以具有式(2)結構的中間體製備 18F標記的FBPA Experimental Example 5: Preparation of 18 F-labeled FBPA with an intermediate having the structure of formula (2)
製備流程請參以下的反應式。 Please refer to the following reaction formula for the preparation process.
以下將詳細說明製備流程。以具有式(2)結構的中間體作為起始物,在銅催化劑Cu(OTf) 2(py) 4存在下進行氟化反應,使中間體與K 18F反應,從而使芳香環上的頻哪醇硼酸酯基被 18F取代。在氟化反應中,溶劑為二甲基甲醯胺(DMF),K 222為氨基聚醚,反應溫度為110°C,反應時間為20分鐘。接下來進行硼化反應,在鈀催化劑Pd 2(dba) 3存在下,使經氟化的中間體與雙聯頻哪醇硼酸酯((Bpin) 2)反應,從而使芳香環上的-Br被頻哪醇硼酸酯基取代。鈀催化劑Pd 2(dba) 3以P(Cy) 3作為配體。在硼化反應中,Pd 2(dba) 3及(Bpin) 2可溶於二噁烷(Dioxane),溶劑可為醋酸鉀(KOAc)及水,反應溫度為110°C,反應時間為15分鐘。接下來進行水解反應,使中間體與溴化氫(HBr)反應,HBr可將頻哪醇硼酸酯基( )水解為-B(OH) 2,且使手性助劑水解為胺基酸基團。在水解反應中,反應溫度為150°C,反應時間為20分鐘。 The preparation process will be described in detail below. The intermediate with the structure of formula (2) is used as the starting material, and the fluorination reaction is carried out in the presence of the copper catalyst Cu(OTf) 2 (py) 4 , and the intermediate is reacted with K 18 F, so that the frequency on the aromatic ring The nicohol borate group was substituted by18F . In the fluorination reaction, the solvent is dimethylformamide (DMF), K 222 is amino polyether, the reaction temperature is 110°C, and the reaction time is 20 minutes. This is followed by a borylation reaction in which the fluorinated intermediate is reacted with bis-pinacol borate ((Bpin) 2 ) in the presence of a palladium catalyst Pd 2 (dba) 3 , whereby the - Br is substituted with a pinacol borate group. The palladium catalyst Pd 2 (dba) 3 uses P(Cy) 3 as a ligand. In the borylation reaction, Pd 2 (dba) 3 and (Bpin) 2 are soluble in dioxane (Dioxane), the solvent can be potassium acetate (KOAc) and water, the reaction temperature is 110°C, and the reaction time is 15 minutes . Carry out hydrolysis reaction next, make intermediate and hydrogen bromide (HBr) reaction, HBr can be pinacol borate group ( ) is hydrolyzed to -B(OH) 2 , and the chiral auxiliary is hydrolyzed to an amino acid group. In the hydrolysis reaction, the reaction temperature was 150°C and the reaction time was 20 minutes.
實驗例6:以具有式(3)結構的中間體製備 18F標記的FBPA Experimental Example 6: Preparation of 18 F-labeled FBPA with an intermediate having the structure of formula (3)
製備流程請參以下的反應式。 Please refer to the following reaction formula for the preparation process.
以下將詳細說明製備流程。以具有式(3)結構的中間體作為起始物,製備 18F標記的FBPA。實驗例6的反應條件請參照上述實驗例5,實驗例5及實驗例6的差異在於起始物不同,故在此不再贅述實驗例6的反應流程。 The preparation process will be described in detail below. 18 F-labeled FBPA is prepared by using the intermediate having the structure of formula (3) as a starting material. For the reaction conditions of Experimental Example 6, please refer to the above-mentioned Experimental Example 5. The difference between Experimental Example 5 and Experimental Example 6 lies in the different starting materials, so the reaction process of Experimental Example 6 will not be repeated here.
綜上所述,本揭示內容提供一種製備藥物的方法、用於合成藥物的中間體及中間體的製備方法。特別是關於 18F標記的FBPA的製備方法,用於合成FBPA的中間體及中間體的製備方法。本揭示內容的FBPA的製備方法流程簡易,能夠有效提升合成FBPA的效率及產率,並且,FBPA能夠具有良好的比活性。 In summary, the present disclosure provides a method for preparing a drug, an intermediate for synthesizing a drug, and a method for preparing the intermediate. Especially about the preparation method of 18 F-labeled FBPA, the intermediate used in the synthesis of FBPA and the preparation method of the intermediate. The preparation method of FBPA disclosed in the disclosure has a simple process, can effectively improve the efficiency and yield of FBPA synthesis, and FBPA can have good specific activity.
儘管已經參考某些實施方式相當詳細地描述了本揭示內容,但是亦可能有其他實施方式。因此,所附申請專利範圍的精神和範圍不應限於此處包含的實施方式的描述。Although the disclosure has been described in some detail with reference to certain implementations, other implementations are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of the embodiments contained herein.
對於所屬技術領域具有通常知識者來說,顯而易見的是,在不脫離本揭示內容的範圍或精神的情況下,可以對本揭示內容的結構進行各種修改和變化。鑑於前述內容,本揭示內容意圖涵蓋落入所附申請專利範圍內的本揭示內容的修改和變化。It will be apparent to those having ordinary skill in the art that various modifications and changes can be made in the structure of this disclosure without departing from the scope or spirit of the disclosure. In view of the foregoing, the present disclosure is intended to cover modifications and variations of the disclosure which come within the scope of the appended claims.
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