CN108727229B - Novel process route for modifying fatty acid type PET reagent precursor - Google Patents
Novel process route for modifying fatty acid type PET reagent precursor Download PDFInfo
- Publication number
- CN108727229B CN108727229B CN201710250117.9A CN201710250117A CN108727229B CN 108727229 B CN108727229 B CN 108727229B CN 201710250117 A CN201710250117 A CN 201710250117A CN 108727229 B CN108727229 B CN 108727229B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- process according
- carried out
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 52
- 230000008569 process Effects 0.000 title claims abstract description 33
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 16
- 239000002243 precursor Substances 0.000 title abstract description 8
- 235000014113 dietary fatty acids Nutrition 0.000 title description 11
- 229930195729 fatty acid Natural products 0.000 title description 11
- 239000000194 fatty acid Substances 0.000 title description 11
- 150000004665 fatty acids Chemical class 0.000 title description 11
- 239000007858 starting material Substances 0.000 claims abstract description 4
- -1 C2-6Alkenyl radical Chemical class 0.000 claims description 108
- 150000001875 compounds Chemical class 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 150000003254 radicals Chemical class 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 150000007530 organic bases Chemical class 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 12
- 239000012312 sodium hydride Substances 0.000 claims description 12
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 238000007239 Wittig reaction Methods 0.000 claims description 8
- 125000003172 aldehyde group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 238000006735 epoxidation reaction Methods 0.000 claims description 7
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 238000005888 cyclopropanation reaction Methods 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 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 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- 239000011388 polymer cement concrete Substances 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 6
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 4
- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 4
- 229960002218 sodium chlorite Drugs 0.000 claims description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 229910052738 indium Inorganic materials 0.000 claims description 3
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 238000007039 two-step reaction Methods 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 4
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 150000004668 long chain fatty acids Chemical class 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 125000001072 heteroaryl group Chemical group 0.000 description 29
- 125000003118 aryl group Chemical group 0.000 description 27
- 125000000753 cycloalkyl group Chemical group 0.000 description 27
- 125000005842 heteroatom Chemical group 0.000 description 27
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 125000000304 alkynyl group Chemical group 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 17
- 125000000217 alkyl group Chemical group 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 125000001188 haloalkyl group Chemical group 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 238000002600 positron emission tomography Methods 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 230000004060 metabolic process Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- DDTRZLZETKPBPQ-YWWFHXEUSA-N 2-[(1S,2R)-2-(5-(18F)fluoranyltridecyl)cyclopropyl]acetic acid Chemical compound CCCCCCCCC([18F])CCCC[C@@H]1C[C@H]1CC(O)=O DDTRZLZETKPBPQ-YWWFHXEUSA-N 0.000 description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 3
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 3
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 3
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 3
- 125000006164 6-membered heteroaryl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229910006069 SO3H Inorganic materials 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Chemical group 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- TZKBVRDEOITLRB-UHFFFAOYSA-N 4-methyl-n-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1h-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2C=C3C=NNC3=NC=2)=C1 TZKBVRDEOITLRB-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- RIMXEJYJXDBLIE-UHFFFAOYSA-N 6-bromohex-1-ene Chemical compound BrCCCCC=C RIMXEJYJXDBLIE-UHFFFAOYSA-N 0.000 description 2
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- GYHFUZHODSMOHU-UHFFFAOYSA-N nonanal Chemical compound CCCCCCCCC=O GYHFUZHODSMOHU-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000005880 oxathiolanyl group Chemical group 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SODPIMGUZLOIPE-UHFFFAOYSA-N (4-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1 SODPIMGUZLOIPE-UHFFFAOYSA-N 0.000 description 1
- ZGDWQQIXRCQCLZ-UHFFFAOYSA-N (4-ethoxynaphthalen-1-yl) hydrogen carbonate Chemical compound C1=CC=C2C(OCC)=CC=C(OC(O)=O)C2=C1 ZGDWQQIXRCQCLZ-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- ZOJKRWXDNYZASL-NSCUHMNNSA-N (e)-4-methoxybut-2-enoic acid Chemical compound COC\C=C\C(O)=O ZOJKRWXDNYZASL-NSCUHMNNSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- FFFIRKXTFQCCKJ-UHFFFAOYSA-M 2,4,6-trimethylbenzoate Chemical compound CC1=CC(C)=C(C([O-])=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-M 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- YURLCYGZYWDCHL-UHFFFAOYSA-N 2-(2,6-dichloro-4-methylphenoxy)acetic acid Chemical compound CC1=CC(Cl)=C(OCC(O)=O)C(Cl)=C1 YURLCYGZYWDCHL-UHFFFAOYSA-N 0.000 description 1
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- UJRMHFPTLFNSTA-UHFFFAOYSA-N 2-chloro-2,2-diphenylacetic acid Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)O)C1=CC=CC=C1 UJRMHFPTLFNSTA-UHFFFAOYSA-N 0.000 description 1
- SHHKMWMIKILKQW-UHFFFAOYSA-N 2-formylbenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1C=O SHHKMWMIKILKQW-UHFFFAOYSA-N 0.000 description 1
- CJNZAXGUTKBIHP-UHFFFAOYSA-M 2-iodobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-M 0.000 description 1
- JWHHNSIZTDYRCL-UHFFFAOYSA-N 2-methylbutan-2-yl 2-phenoxyacetate Chemical compound CCC(C)(C)OC(=O)COC1=CC=CC=C1 JWHHNSIZTDYRCL-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 description 1
- 125000001627 3 membered heterocyclic group Chemical group 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- WAGMYTXJRVPMGW-UHFFFAOYSA-N 4-azidobutanoic acid Chemical compound OC(=O)CCCN=[N+]=[N-] WAGMYTXJRVPMGW-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- KHKJLJHJTQRHSA-UHFFFAOYSA-N 4-methyl-4-nitropentanoic acid Chemical compound [O-][N+](=O)C(C)(C)CCC(O)=O KHKJLJHJTQRHSA-UHFFFAOYSA-N 0.000 description 1
- JOOXCMJARBKPKM-UHFFFAOYSA-M 4-oxopentanoate Chemical compound CC(=O)CCC([O-])=O JOOXCMJARBKPKM-UHFFFAOYSA-M 0.000 description 1
- NNJMFJSKMRYHSR-UHFFFAOYSA-M 4-phenylbenzoate Chemical compound C1=CC(C(=O)[O-])=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-M 0.000 description 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102100031260 Acyl-coenzyme A thioesterase THEM4 Human genes 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 101000638510 Homo sapiens Acyl-coenzyme A thioesterase THEM4 Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000005585 adamantoate group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- FGIVSGPRGVABAB-UHFFFAOYSA-N fluoren-9-ylmethyl hydrogen carbonate Chemical compound C1=CC=C2C(COC(=O)O)C3=CC=CC=C3C2=C1 FGIVSGPRGVABAB-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000005990 isobenzothienyl group Chemical group 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940058352 levulinate Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 1
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
- NYEBKUUITGFJAK-UHFFFAOYSA-N methylsulfanylmethanethioic s-acid Chemical compound CSC(O)=S NYEBKUUITGFJAK-UHFFFAOYSA-N 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 125000005882 oxadiazolinyl group Chemical group 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000005881 triazolinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/41—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrogenolysis or reduction of carboxylic groups or functional derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/24—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran
- C07C67/26—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran with an oxirane ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a novel process route for synthesizing a modified long-chain fatty acid type PET reagent precursor. The route has the characteristics of easily obtained starting materials, simple route, mild reagents, high yield and the like.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a novel process route for modifying a fatty acid type PET reagent precursor.
Background
PET (positron emission tomography) is a relatively advanced clinical examination imaging technique in the field of nuclear medicine. The general method is to mix a certain substance, which is generally necessary in the metabolism of biological life, such as: glucose, proteins, nucleic acids, fatty acids, labelled with short-lived radionuclides (e.g. F)18，C11Etc.) to reflect the metabolic activity of the living body by the accumulation of the substance in metabolism after the injection into the human body, thereby achieving the purpose of diagnosis.
In the basal aerobic metabolism of the myocardium, 70% of ATP is produced by beta-oxidation of fatty acids, and thus fatty acids or modified fatty acids are suitable cardiac positron emission computed tomography reagents. Modified fatty acids have greater diagnostic value due to the fact that the rate of metabolism of unmodified fatty acids is too fast to concentrate more radioactive atoms in the liver or lung than the site of diagnostic interest. [18F]Cardiopet is an innovative PET agent and is currently undergoing clinical phase II research work. It is characterized in that in CH2CO2The cyclopropane ring is introduced at the H group, so that the absorption and enrichment behaviors of the cyclopropane ring are similar to those of fatty acid, but the cyclopropane ring is difficult to perform beta-oxidation, and therefore the cyclopropane ring can be retained in cardiac muscle cells and can be caused by18The decay of F produces positrons that form medically useful images for studying cardiac metabolism and disease diagnosis, particularly coronary heart disease.
The compounds of the formulae (I), (Ia) and (Ib) are [, [2]18F]Precursors of Cardiopet with isotopically irradiated generated K18F is subjected to substitution reaction and hydrolysis reaction, and then purified by semi-preparative chromatography for diagnostic use (reference: US7790142, US 2004253177).
The existing synthetic route of the compound shown in the formula (Ib) is as long as 20 steps, the yield is low, the production process is complex, and therefore, the cost is high, and the industrialization is difficult. And requires the use of a variety of highly toxic, explosive, environmentally unfriendly reagents such as potassium cyanide, diazomethane, pyridinium chlorochromate, and the like:
in summary, the compounds of formulae (I), (Ia) and (Ib) are precursors of modified fatty acid-based PET agents in the second phase of clinical studies. However, the materials used are not suitable for industrial production due to the long synthetic route. In order to realize industrialization at low cost and benefit heart disease patients, it is necessary to design and develop a new process route.
Disclosure of Invention
For improving18F]The precursor compounds of CardioPET, namely the compounds shown as the formula (I), (Ia) and (Ib), have the defects of long process route, low yield, unfriendly reagent industry and the like, the whole process route is redesigned and developed, so that the route is shortened from 20 steps to 11 steps, and the total yield is improved from 1% to more than 5%:
the synthesis method of the invention is adopted to synthesize18F]The precursor compound of CardioPET, namely the compound shown in formula (I), adopts a novel process route, has the yield of more than 5 percent, and has the characteristics of simple operation, low toxicity and risk of used reagents and the like.
Accordingly, in the technical scheme [1] of the present invention, there is provided a process for producing a compound of the formula (I),
wherein,r represents C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl;
x is sulfonyl;
it was prepared using compound 7 as starting material:
wherein Pg represents a protecting group.
In a particular embodiment of this embodiment, R is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, or the like; in a particular embodiment of this embodiment, R is tert-butyl.
In a particular embodiment of this embodiment, X is selected from methylsulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl, and the like; in a particular embodiment of this embodiment, X is methanesulfonyl.
In a particular embodiment of this embodiment, Pg is preferably a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; in a particular embodiment of this aspect, Pg is preferably benzyl.
In technical scheme [2] of the present invention, there is provided a method according to technical scheme [1], which comprises a step of oxidizing compound 7 to compound 8:
in a particular embodiment of this aspect, wherein the oxidation reaction is preferably carried out using an oxidizing agent selected from the group consisting of: sodium chlorite, potassium permanganate, PCC or manganese dioxide.
In technical scheme [3] of the present invention, there is provided the process according to technical scheme [1] or [2], further comprising the step of esterifying compound 8 to obtain compound 9:
in technical scheme [4] of the present invention, there is provided the method according to any one of technical schemes [1] to [3], further comprising a step of deprotecting the compound 9 to obtain a compound 10:
in technical scheme [5] of the present invention, there is provided a process according to any one of technical schemes [1] to [4], further comprising a step of sulfonylating compound 10 to obtain a compound of formula (I):
in technical scheme [6] of the present invention, there is provided a process according to any one of technical schemes [1] to [5], further comprising a step of converting compound 6 into compound 7:
in a particular embodiment of this embodiment, the hydrolysis reaction is preferably carried out under acidic conditions; in a particular embodiment of this embodiment, the hydrolysis reaction is preferably carried out using an acid selected from the group consisting of: hydrochloric acid, perchloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid.
In technical scheme [7] of the present invention, there is provided the method according to any one of technical schemes [1] to [6], further comprising a step of subjecting compound 5 to Wittig reaction to thereby obtain compound 6:
in a particular embodiment of this embodiment, wherein said Wittig reaction is preferably carried out in the presence of an organic base; in a particular embodiment of this embodiment, the organic base is preferably selected from sodium hydride, LDA, potassium tert-butoxide, butyllithium, LiHMDS, NaHMDS, KHMDS or sodium amide; in a particular embodiment of this embodiment, the organic base is preferably sodium hydride.
In technical scheme [8] of the present invention, there is provided the method according to any one of technical schemes [1] to [7], further comprising the step of reducing compound 4 to give compound 5:
in a specific embodiment of this embodiment, the reduction reaction selectively reduces the ester to an aldehyde; in a specific embodiment of this embodiment, the selective reduction is performed using DIBAL-H.
In a specific embodiment of this embodiment, the reduction reaction comprises a two-step reaction of first reducing the ester completely to an alcohol and then oxidizing the alcohol to an aldehyde; in a particular embodiment of this embodiment, the two-step reaction comprises: the first reaction step uses NaBH4Borane-tetrahydrofuran complex, lithium aluminum hydride, DIBAL-H, red aluminum, etc., and the second reaction is carried out using activated manganese dioxide, PCC or dessamidine reagent.
In technical scheme [9] of the present invention, there is provided the method according to any one of technical schemes [1] to [8], further comprising a step of subjecting compound 3 to Wadsworth Emmons cyclopropanation to give compound 4:
in a particular embodiment of this embodiment, said Wadsworth Emmons cyclopropanation is preferably carried out in the presence of an organic base; in a particular embodiment of this embodiment, the organic base is selected from sodium hydride, LDA, potassium tert-butoxide, butyllithium, LiHMDS, NaHMDS, KHMDS, or sodium amide; in a specific embodiment of this embodiment, the organic base is sodium hydride.
In technical scheme [10] of the present invention, there is provided the process according to any one of technical schemes [1] to [9], further comprising a step of epoxidizing a double bond in compound 2 to give compound 3:
in a particular embodiment of this embodiment, the epoxidation is preferably carried out using an agent selected from the group consisting of: mCPBA, hydrogen peroxide, peracetic acid, t-butanol peroxide, or cumene peroxide; in a particular embodiment of this embodiment, the epoxidation is preferably carried out using mCPBA.
In technical scheme [11] of the present invention, there is provided the method according to any one of technical schemes [1] to [10], further comprising a step of protecting a hydroxyl group of compound 1 with a protecting group Pg to obtain compound 2:
in technical solution [12] of the present invention, there is provided the method according to any one of technical solutions [1] to [11], further comprising the step of subjecting the starting materials aldehyde and halide to a nucleophilic addition reaction of a metal organic reagent and aldehyde to obtain compound 1:
wherein R is1Is an aldehyde group, R2Is halogen; or R1Is halogen, R2Is an aldehyde group.
In a particular embodiment of this embodiment, the halogen is preferably Cl or Br; in a specific embodiment of this embodiment, the reaction is preferably carried out in an organic solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether, with magnesium, indium, zinc or lithium as the metal; in a particular embodiment of this embodiment, the reaction is preferably carried out with magnesium as metal in tetrahydrofuran.
In technical solution [13] of the present invention, there is provided the method according to any one of technical solutions [1] to [12], which comprises the steps of:
in technical solution [14] of the present invention, there is provided the method according to any one of technical solutions [1] to [13], which comprises the steps of:
in technical solution [15] of the present invention, there is provided the method according to any one of technical solutions [1] to [14], comprising the steps of:
in technical scheme [16] of the present invention, there is provided compound 7:
wherein Pg represents a protecting group.
In a particular embodiment of this embodiment, Pg is preferably a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; in a particular embodiment of this aspect, Pg is preferably benzyl.
In technical scheme [17] of the present invention, there is provided the use of compound 7 in the preparation of a compound of formula (I).
Detailed Description
Definition of
All terms used herein have the meanings commonly understood by those skilled in the art. Further, the following meanings may be also possible.
“C1-6Alkyl "means a straight or branched chain saturated monovalent alk (en) yl group containing 1 to 6 carbon atoms. In some embodiments, C1-4Alkyl groups are preferred. Typical C1-6Alkyl includes methyl (C)1) Ethyl (C)2) N-propyl (C)3) Isopropyl (C)3) N-butyl (C)4) Tert-butyl (C)4) Sec-butyl (C)4) Isobutyl (C)4) N-pentyl group (C)5) 3-pentyl radical (C)5) Isopentyl group (C)5) Neopentyl (C)5) 3-methyl-2-butyl (C)5) Tert-amyl (C)5) And n-hexyl (C)6) And the like. The term "C1-6Alkyl "also includes heteroalkyl wherein from 1 to 3 nitrogen atoms selected from O, S, N or substituted may be substituted for carbon atoms.
“C2-6Alkenyl "represents a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2-vinylbutyl, 3-hexen-1-yl, and the like. In some embodiments, C2-4Alkenyl groups are preferred. The term "C2-6Alkenyl "also includes heteroalkenyl, wherein from 1 to 3 nitrogen atoms selected from O, S, N or substituted may be substituted for carbon atoms.
“C2-6Alkynyl "refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms containing at least one carbon-carbon triple bond and optionally one or more unsaturated carbon-carbon double bonds. In some embodiments, C2-4Alkynyl groups are preferred. Typical alkynyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, and hexynyl. The term "C2-6Alkynyl also includes heteroalkynyl wherein from 1 to 3 nitrogen atoms selected from O, S, N or substituted may be substituted for a carbon atom.
The term "halogen" as used herein refers to F, Cl, Br and I. Preferably, the halogen in the present invention is selected from Cl, Br and I; more preferably, the halogen in the present invention is selected from Cl or Br.
“C1-6Haloalkyl "means" C "as defined above1-6Alkyl ", which is substituted with one or more halogens. In some embodiments, C1-4Haloalkyl is preferred, more preferably C1-2A haloalkyl group. Exemplary said haloalkyl groups include, but are not limited to: -CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl22,2, 2-trifluoro-1, 1-dimethyl-ethyl, and the like.
“C3-7Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C3-6Cycloalkyl is particularly preferred, more preferably C5-6A cycloalkyl group. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C)3) Cyclopropenyl group (C)3) Cyclobutyl (C)4) Cyclobutenyl radical (C)4) Cyclopentyl (C)5) Cyclopentenyl group (C)5) Cyclohexyl (C)6) Cyclohexenyl (C)6) Cyclohexyldienyl (C)6) Cycloheptyl (C)7) Cycloheptenyl (C)7) Cycloheptadienyl (C)7) Cycloheptatrienyl (C)7) And so on.
"3-7 membered heterocyclyl" means a 3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably a 3-6 membered heterocyclic group which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4-6 membered heterocyclic group which is a 4 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclic group having ring carbon atoms and 1 to 3 ringsA 5 to 6 membered non aromatic ring system of heteroatoms. Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems wherein the aforementioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxacyclopropaneyl, thienylyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulphuryl), and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thiacyclohexyl (thianyl). Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiinyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepane, oxepanyl and thiepane. Exemplary with C6Aryl ring fused 5-membered heterocyclyl (also referred to herein as 5, 6-bicyclic heterocyclyl) includes, but is not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Exemplary with C6Aryl ring fused 6-membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) includes, but is not limited to: fourthlyHydroquinolinyl, tetrahydroisoquinolinyl, and the like.
“C6-10Aryl "refers to a group having a monocyclic or polycyclic (e.g., bicyclic) 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) of 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C)6Aryl "; for example, phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C)10Aryl "; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.
"5-10 membered heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n +2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: a tetrazolyl group. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxacycloheptyl, and thiacycloheptyl trienyl groups. Exemplary 5, 6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisothiafuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indezinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryls include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.
"Sulfonyl" denotes the group R-SO2-, wherein R represents C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl.
"Methanesulfonyl" means the group Me-SO2-。
"P-toluenesulfonyl" denotes the group p-CH3-C6H4-SO2-。
"Trifluoromethanesulfonyl" denotes the group CF3-SO2-。
Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like, as defined herein, are optionally substituted groups.
Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)2Raa、-OP(＝O)2Raa、-P(＝O)(Raa)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)2N(Rbb)2、-OP(＝O)2N(Rbb)2、-P(＝O)(NRbb)2、-OP(＝O)(NRbb)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc) Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2,3, 4 or 5RddSubstituted by groups;
or two geminal hydrogens on a carbon atom are replaced by groups ═ O, ═ S, ═ NN (R)bb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbbOr as NORccSubstitution;
Raaeach is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two RaaThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5RddSubstituted by groups;
Rbbeach independently selected from: hydrogen, -OH, -ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two RbbThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, arylAnd heteroaryl is independently substituted with 0, 1, 2,3, 4 or 5RddSubstituted by groups;
Rcceach is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two RccThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5RddSubstituted by groups;
Rddeach independently selected from: halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)2Ree、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2,3, 4 or 5RggSubstituted by radicals, or two geminal RddSubstituents may combine to form ═ O or ═ S;
Reeis independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5RggSubstituted by groups;
Rffeach is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two RffThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5RggSubstituted by groups;
Rggis independently from each other: halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6Alkyl, -ON (C)1-6Alkyl radical)2、-N(C1-6Alkyl radical)2、-N(C1-6Alkyl radical)3 +X-、-NH(C1-6Alkyl radical)2 +X-、-NH2(C1-6Alkyl radical)+X-、-NH3 +X-、-N(OC1-6Alkyl) (C1-6Alkyl), -N (OH) (C)1-6Alkyl), -NH (OH), -SH, -SC1-6Alkyl, -SS (C)1-6Alkyl), -C (═ O) (C)1-6Alkyl), -CO2H、-CO2(C1-6Alkyl), -OC (═ O) (C)1-6Alkyl), -OCO2(C1-6Alkyl), -C (═ O) NH2、-C(＝O)N(C1-6Alkyl radical)2、-OC(＝O)NH(C1-6Alkyl), -NHC (═ O) (C)1-6Alkyl), -N (C)1-6Alkyl radical)C(＝O)(C1-6Alkyl), -NHCO2(C1-6Alkyl), -NHC (═ O) N (C)1-6Alkyl radical)2、-NHC(＝O)NH(C1-6Alkyl), -NHC (═ O) NH2、-C(＝NH)O(C1-6Alkyl), -OC (═ NH) (C)1-6Alkyl), -OC (═ NH) OC1-6Alkyl, -C (═ NH) N (C)1-6Alkyl radical)2、-C(＝NH)NH(C1-6Alkyl), -C (═ NH) NH2、-OC(＝NH)N(C1-6Alkyl radical)2、-OC(NH)NH(C1-6Alkyl), -OC (NH) NH2、-NHC(NH)N(C1-6Alkyl radical)2、-NHC(＝NH)NH2、-NHSO2(C1-6Alkyl), -SO2N(C1-6Alkyl radical)2、-SO2NH(C1-6Alkyl), -SO2NH2、-SO2C1-6Alkyl, -SO2OC1-6Alkyl, -OSO2C1-6Alkyl, -SOC1-6Alkyl, -Si (C)1-6Alkyl radical)3、-OSi(C1-6Alkyl radical)3、-C(＝S)N(C1-6Alkyl radical)2、C(＝S)NH(C1-6Alkyl), C (═ S) NH2、-C(＝O)S(C1-6Alkyl), -C (═ S) SC1-6Alkyl, -SC (═ S) SC1-6Alkyl, -P (═ O)2(C1-6Alkyl), -P (═ O) (C)1-6Alkyl radical)2、-OP(＝O)(C1-6Alkyl radical)2、-OP(＝O)(OC1-6Alkyl radical)2、C1-6Alkyl radical, C1-6Haloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C7Cycloalkyl radical, C6-C10Aryl radical, C3-C7Heterocyclic group, C5-C10A heteroaryl group; or two geminal RggSubstituents may combine to form ═ O or ═ S; wherein, X-Are counter ions.
Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRbb)Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atomccThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5RddIs substituted by radicals, and wherein Raa、Rbb、RccAnd RddAs described above.
The term "oxidation" as used herein refers to a reaction of introducing oxygen or removing hydrogen in the compound of the present invention. More specifically, it refers to a reaction that converts an aldehyde group to a carboxylic acid group. The oxidation reaction can be accomplished using a variety of oxidizing agents well known in the art, including but not limited to sodium chlorite, potassium permanganate, PCC, and manganese dioxide.
The term "reduction" as used herein refers to a reaction of introducing hydrogen or removing oxygen in the compound of the present invention. More specifically, it refers to a reaction of converting an ester group into an aldehyde group. The reduction may be accomplished using a variety of reducing agents well known in the art, including, but not limited to, one-step conversion of DIBAL-H, and first with NaBH4Borane-tetrahydrofuran complex, lithium aluminum hydride, DIBAL-H, red aluminum, etc., followed by two-step conversion with activated manganese dioxide, PCC or dessimutane reagent.
The term "protecting group" as used herein refers to a group that is capable of covalently bonding to a functional group, protecting it from chemical reactions, and being removed after the reaction is complete to recover the functional group. More specifically, the protecting group in the present invention refers to an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen Protecting Groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, t.w.greene and p.g.m.wuts, third edition, John Wiley & Sons, 1999, which is incorporated herein by reference.
Exemplary oxygen protecting groups include, but are not limited to, methyl, t-butyloxycarbonyl (BOC or Boc), methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), Benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), Guaiacolmethyl (GUM), t-butoxymethyl, 4-Pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2, 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl group, 4-methoxytetrahydropyranyl group (MTHP), 4-methoxytetrahydrothiopyranyl group, 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1- [ (2-chloro-4-methyl) phenyl group]-4-methoxypiperidin-4-yl (CTMP), 1, 4-bis
Alk-2-yl, tetrahydrofuryl, tetrahydrothienyl, 2,3,3a,4,5,6,7,7 a-octahydro-7, 8, 8-trimethyl-4, 7-methanobenzofuran (methanobenzofuran) -2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylhydrogenselenyl) ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, benzyl (Bn), P-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p' -dinitrobenzhydryl, 5-dibenzosuberenyl, triphenylmethyl, alpha-naphthyldiphenylmethyl, p-methoxyphenylDiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4 '-bromobenzoyloxyphenyl) diphenylmethyl, 4', 4 "-tris (4, 5-dichlorophthalimidophenyl) methyl, 4 ', 4" -tris (levulinoyloxyphenyl) methyl, 4', 4 "-tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-yl) bis (4 ', 4" -dimethoxyphenyl) methyl, 1-bis (4-methoxyphenyl) -1' -pyrenylmethyl, 9-anthracenyl, 9- (9-phenyl)
Xanthyl, 9- (9-phenyl-10-oxo) anthracenyl, 1, 3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxide, Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, Diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (MPS), formate, benzoylformate, TBacetate, chloroacetate, dichloroacetate, trichloroacetate, Trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-pentanoate (levulinate), 4- (ethylenedithio) valerate (levulinyl dithioacetal), pivalate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4, 6-trimethylbenzoate (miketonate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2, 2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2- (phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphine.
Yl) Ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl EtherAlkenyl carbonate, alkylallyl carbonate, alkyl p-nitrophenyl carbonate, alkylbenzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3, 4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate, 2, 6-dichloro-4-methylphenoxyacetate, alkyl p-nitrobenzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3, 4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-, 2, 6-dichloro-4- (1,1,3, 3-tetramethylbutyl) phenoxyacetate, 2, 4-bis (1, 1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate, o- (methoxyacyl) benzoate, α -naphthoate, nitrate, alkyl N, N' -tetramethylphosphorodiamidite, alkyl N-phenylcarbamate, borate, dimethylphosphinylsulfinyl, alkyl 2, 4-dinitrophenylsulfenate, sulfate, methanesulfonate (methanesulfonate), benzylsulfonate, and tosylate (Ts).
"hydroxy protection" and "deprotection" refer to the reaction of introducing a protecting group to a hydroxy functional group and removing the protecting group to recover the hydroxy functional group, respectively. The reaction conditions for introducing and removing protecting groups are well known to those skilled in the art.
The term "esterification" as used in the present invention refers to a reaction of converting a carboxyl group into an ester group. The esterification reaction may be accomplished using a variety of reagents well known in the art, including but not limited to halogenated hydrocarbons, alcohols, and the like.
The term "sulfonylation" as used herein refers to a reaction that converts a hydroxyl group to a sulfonyloxy group. For example, methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like may effect the reaction.
The term "hydrolysis" as used herein refers to a reaction that deprotects a protected aldehyde group. For example, the reaction is carried out under acidic conditions, wherein the acid used includes, but is not limited to, hydrochloric acid, perchloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid.
The term "Wittig reaction" as used in the present invention refers to a reaction in which a carbonyl group is converted to an olefin with a phosphorus ylide. The conditions under which the Wittig reaction is carried out are well known to those skilled in the art and are preferably carried out in the presence of an organic base. The organic bases include, but are not limited to, sodium hydride, LDA, potassium tert-butoxide, butyllithium, LiHMDS, NaHMDS, KHMDS, and sodium amide.
The term "Wadsworth-Emmons reaction" as used in the present invention refers to a reaction in which ethylene oxide is converted to cyclopropane carboxylic acid ester using phosphorous phosphite ylide. The conditions under which the Wadsworth-Emmons reaction is carried out are well known to the person skilled in the art and are preferably carried out in the presence of an organic base. The organic bases include, but are not limited to, sodium hydride, LDA, potassium tert-butoxide, butyllithium, LiHMDS, NaHMDS, KHMDS, and sodium amide.
The term "nucleophilic addition reaction" as used herein refers to a reaction in which an alkyl halide reacts with a metal to form a metal organic compound, which is then reacted with an aldehyde ketone to form an alcohol. The conditions for carrying out the nucleophilic addition reaction of the metalorganic reagent and the aldehyde are well known to those skilled in the art. Preferably, the grignard reaction of the present invention is carried out in an organic solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether with magnesium, indium, zinc or lithium as a metal.
The term "aldehyde group" as used herein refers to the group-C (O) H.
The term "epoxidation" as used in the present invention refers to the reaction of an olefinic bond to ethylene oxide. The conditions under which the epoxidation reaction is carried out are well known to those skilled in the art. Preferably, the epoxidation according to the invention is carried out using an agent selected from the group consisting of: mCPBA, hydrogen peroxide, peracetic acid, t-butanol peroxide, or cumene hydroperoxide.
Example 1
Reaction type
1. Synthesis of Compound 1
Adding magnesium chips and a little iodine into a 1L three-mouth bottle, and replacing and protecting by nitrogen. Then 60 ml of anhydrous THF and a small amount of 6-bromo-1-hexene were added and the temperature was raised to initiate the reaction. After initiation, 162 g of 6-bromo-1-hexene in tetrahydrofuran was slowly added. And after the dropwise addition is finished, stirring is continuously carried out until the reaction is complete.
Then 72 g of nonanal are added, after the reaction is complete the reaction is quenched with dilute hydrochloric acid and extracted with dichloromethane. Organic phase is combined, desolventized and purified by column chromatography. 68 g of compound 1 are obtained as a pale yellow liquid in 77% yield.
1H-NMR(300MHz，CDCl3)δ：0.88(t，3H)，1.28-1.47(m，20H)，2.06(m，2H)，3.58(m，1H)，4.93(dd,1H)，5.00(dd，1H)，5.80(m，1H)。
13C-NMR(100MHz，CDCl3)δ：14.11，22.72，25.23，25.75，29.07，29.37，29.69，29.82，31.96，33.82，37.35，37.57，71.83，114.34，138.92。
2. Synthesis of Compound 2a
10 ml of anhydrous tetrahydrofuran are mixed with 2.65 g of sodium hydride at room temperature, 10 g of compound 1 are then added, and 9.1 g of benzyl bromide are then added. After heating for 2 hours, the reaction was quenched with dilute hydrochloric acid, extracted with 100 ml of dichloromethane and concentrated to give 19.1 g of crude product, which was used directly in the next step.
1H-NMR(400MHz，CDCl3)δ：0.88(t，3H)，1.27～1.56(m，20H)，2.05(m，2H)，3.36(m,1H)，4.49(s，2H)，4.92-5.02(m，2H)，5.81(m，1H)，7.25-7.36(m，5H)。
13C-NMR(100MHz，CDCl3)δ：14.11，22.72，25.23，25.75，29.07，29.37，29.69，29.82，31.96，33.82，37.35，37.57，71.83，114.34，138.92。
3. Synthesis of Compound 3a
Taking 17.1 g of the crude product of the compound 2a, adding 120 ml of dichloromethane and 12.0 g of m-chloroperoxybenzoic acid, and heating for reacting for 2 hours. The reaction solution was quenched with 10% aqueous sodium bicarbonate solution, separated, the aqueous phase was extracted once with 100 ml dichloromethane, the organic phase was concentrated and column chromatography was carried out to give 9.0 g of compound 3a with a total yield of 68% over the two steps.
1H-NMR(400MHz，CDCl3)δ：0.88(t，3H)，1.27-1.56(m，20H)，2.46(d，1H)，2.74(t，1H)，2.90(s，1H)，3.37(m，1H)，4.50(m，2H)，7.27-7.34(m，5H)。
13C-NMR(100MHz，CDCl3)δ：13.79，22.04，24.52，24.65，25.63，28.63，28.96，29.17，31.24，31.86，33.10，38.90，39.32，39.52，39.73，45.92，51.33，69.70，127.01，127.25，127.94，129.15。
MS：332.5m/e，[M+H]+＝332.2，[M+Na]+＝355.2。
4. Synthesis of Compound 4a
72 ml of toluene and 3.0 g of sodium hydride are mixed at room temperature, and 18.3 g of triethyl phosphonoacetate are added dropwise. 9 g of compound 3a are added, the reaction is heated for 2 hours and quenched by the addition of acetic acid. Concentration followed by column chromatography purification gave 6.4g of compound 4a, 59% yield.
1H-NMR(400MHz，CDCl3)δ：0.58-0.61(m，1H)，0.88(t，3H)，1.08(m，1H)，1.06-1.50(m，27H)，3.28(m，1H)，4.04(q，2H)，4.42(s，2H)，7.19-7.27(m，5H)。
5. Synthesis of Compound 5a
10.4 g of compound 4a were mixed with 146 ml of toluene and 20 ml of dichloromethane, cooled with liquid nitrogen, and 33.58 ml of DIBAL-H solution was added and the reaction was continued for 15 minutes. The reaction was quenched with 30 ml of methanol, 150 ml of ethyl acetate was added, and after concentration, column chromatography gave 6 g of compound 5a with a yield of 65.2%.
1H-NMR(400MHz，CDCl3)δ：0.73-0.78(m，1H)，0.88(t，3H)，0.91-0.93(m，1H)，1.13-1.63(m，24H)，3.36(m，1H)，4.49(m，2H)，7.25-7.51(m，5H)，8.98(m，1H)。
13C-NMR(100MHz，CDCl3)δ：14.28，15.03，22.75，22.78，22.79，25.12，25.47，29.40，29.66，29.67，32.00，32.74，33.89，33.92，370.89，76.95，77.38，78.98，114.45，127.53，127.87，128.40，129.64，200.18。
MS：358.5m/e，[M+Na]+＝381.4。
6. Synthesis of Compound 6a
64 g of methoxymethyltriphenylphosphonium chloride and 30 ml of tetrahydrofuran are mixed and then 351 ml of KHMDS solution are added dropwise. Then 22.5 g of compound 5a was added, the reaction was quenched with 7 ml of methanol after stirring for 1 hour, and after concentration, 15 g of compound 6a was isolated by column chromatography with a yield of 62%.
1H-NMR(400MHz，CDCl3)δ：0.27-0.41(m，2H)，0.48-0.56(m，1H)，0.79(t，3H)，0.83-0.90(m，1H)，1.14-1.49(m，22H)，3.27(m，1H)，3.39(s，2H)，3.53(s，1H)，4.41(m，2H)，5.78(m，1H)，6.25(d，1H)，7.17-7.26(m，5H)。
13C-NMR(100MHz，CDCl3)δ：13.23，14.27，17.02，20.41，22.84，25.34，25.52，29.45，29.70，29.76，29.77，30.02，32.05，34.01，34.04，34.15，56.17，70.90，79.20，111.02，106.85，127.52，127.91，128.45，139.35，145.34。
7. Synthesis of Compound 7a
15 g of compound 6a are dissolved in 135 ml of acetone, and 120 ml of 6N hydrochloric acid are then added. After stirring for 2 hours, 300 ml of ethyl acetate was added, and after separation, drying and concentration, 12 g of compound 7a was obtained with a yield of 83%.
1H-NMR(400MHz，CDCl3)δ：0.23-0.31(m，2H)，0.43-0.46(m，1H)，0.59-0.62(m，1H)，0.80(t，4H)，1.18-1.52(m，22H)，2.19(m，2H)，3.27(m，1H)，4.41(s，2H)，7.27-7.27(m，5H)，9.71(d，1H)。
3C-NMR(100MHz，CDCl3)δ：11.68，11.85，13.38，14.27，22.83，25.42，25.51，29.45，29.77，29.93，30.02，32.05，34.02，34.10，34.25，39.21，70.88，79.21，102.04，127.34，127.77，127.88，128.42，129.31，202.66。
MS：372.5m/e，[M+Na]+＝395.3。
8. Synthesis of Compound 8a
9 g of compound 7a and 180 ml of dioxane were mixed, 6.7 g of potassium dihydrogen phosphate was added, an aqueous sodium chlorite solution (5.4 g dissolved in 13.5 ml of water) was added dropwise thereto, and after stirring at room temperature for 1 hour, 500 ml of dichloromethane and 80 ml of water were added, followed by liquid separation and concentration of the organic layer to obtain 9 g of compound 8a with a yield of 96%.
1H-NMR(400MHz，CDCl3)δ：0.26(m，2H)，0.48(m，1H)，0.70(d，1H)，0.82(t，3H)，1.19-1.46(m，22H)，2.18(d，2H)，3.29(m，1H)，4.43(s，2H)，7.19-7.27(m，5H)。
MS：388.5m/e，[M+Na]+＝411.4，[M-H]＝387.2。
9. Synthesis of Compound 9b
1 g of compound 8a is mixed with 5 ml of dichloromethane, 0.63 g of DMAP and 0.95 g of tert-butanol are added, ice water is cooled to about 10 ℃, and a solution of 0.638 g of DCC in 5 ml of dichloromethane is added dropwise. After stirring at room temperature for 4 hours, 5 ml of dichloromethane were added, filtered, concentrated and subjected to column chromatography to obtain 0.8g of compound 9 b.
1H-NMR(400MHz，CDCl3)δ：0.21(m，2H)，0.44(m，1H)，0.64(m，1H)，0.81(t，3H)，1.19-1.44(m，31H)，2.03(m，2H)，3.28(m，1H)，4.42(s，2H)，7.19-7.28(m，5H)。
10. Synthesis of Compound 10a
2.6 g of compound 9b and 18 ml of methanol are mixed, 3.9 g of 10% Pd/C is added, hydrogen is introduced for reaction for 4 hours, the mixture is filtered, and the filtrate is desolventized to obtain 1.4 g of light yellow compound 10a liquid, wherein the yield is 67.6%.
1H-NMR(400MHz，CDCl3)δ：0.21(m，2H)，0.45(m，1H)，0.66(m，1H)，0.81(t，3H)，1.21-1.41(m，31H)，1.96-2.12(m，2H)，3.52(m，1H)。
11. Synthesis of Compound of formula (Ib)
1.4 g of compound 10a and 10 ml of dichloromethane were mixed, 3.12 g of pyridine was added, 0.68 g of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 16 hours. After desolventization, column chromatography gave 1.2 g of compound of formula (Ib) in 70.5% yield.
1H-NMR(400MHz，CDCl3)δ：0.29(m，2H)，0.52(m，1H)，0.73(m，1H)，0.88(t，3H)，1.23-45(m，27H)，1.64-1.72(m，4H)，2.11(m，2H)，2.99(s，3H)，4.69(m，1H)。
MS：432.6m/e，[M+Na]+＝455.3。
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (28)
1. A process for the preparation of a compound of formula (I),
wherein R represents C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl;
x is sulfonyl;
it was prepared using compound 7:
wherein Pg represents a protecting group;
the method comprises the step of subjecting compound 3 to Wadsworth-Emmons cyclopropanation reaction to obtain compound 4:
a step of reducing compound 4 to give compound 5:
a step of subjecting compound 5 to Wittig reaction, thereby obtaining compound 6:
step of hydrolyzing compound 6 to compound 7:
step of oxidizing compound 7 to compound 8:
esterification of compound 8 to give compound 9:
a step of deprotecting compound 9 to obtain compound 10:
2. the process according to claim 1, wherein Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl and triethylsilyl.
3. A process according to claim 2, wherein Pg is benzyl.
4. The process according to claim 1, wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl or cyclopentyl;
x is selected from methylsulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl;
the Wadsworth-Emmons cyclopropanation reaction is carried out in the presence of an organic base.
5. The process according to claim 4, wherein R is tert-butyl, X is methylsulfonyl and the organic base is selected from LDA, potassium tert-butoxide, butyllithium, LiHMDS, NaHMDS or KHMDS.
6. The process according to claim 1, wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl or cyclopentyl;
x is selected from methylsulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl;
the Wadsworth-Emmons cyclopropanation is carried out in the presence of sodium hydride or sodium amide.
7. A process according to claim 6, wherein the Wadsworth-Emmons cyclopropanation is carried out in the presence of sodium hydride.
8. The process according to claim 1, wherein the oxidation reaction is carried out using an oxidizing agent selected from the group consisting of: sodium chlorite, potassium permanganate, PCC or manganese dioxide.
9. The process according to claim 1, further comprising the step of sulfonylating compound 10 to provide a compound of formula (I):
10. the process according to claim 1, wherein the hydrolysis reaction is carried out under acidic conditions.
11. The process according to claim 10, wherein the hydrolysis reaction is carried out using an acid selected from the group consisting of: hydrochloric acid, perchloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid.
12. The process according to claim 1, wherein the Wittig reaction is carried out in the presence of an organic base.
13. The process according to claim 12, wherein the organic base is selected from LDA, potassium tert-butoxide, butyllithium, LiHMDS, NaHMDS or KHMDS.
14. The process according to claim 1, wherein the Wittig reaction is carried out in the presence of sodium hydride or sodium amide.
15. The process according to claim 14, wherein the Wittig reaction is carried out in the presence of sodium hydride.
16. The process according to claim 1, wherein the reduction reaction uses DIBAL-H to selectively reduce the ester to the aldehyde.
17. The process according to claim 1, wherein the reduction reaction comprises a two-step reaction of first reducing the ester completely to the alcohol and then oxidizing the alcohol to the aldehyde.
18. The method of claim 17, wherein the first reaction step uses NaBH4Borane-tetrahydrofuran complex, lithium aluminum hydride, DIBAL-H,Or red aluminum and the second reaction is carried out using activated manganese dioxide, PCC or dessimutane reagents.
19. The method according to claim 1, further comprising the step of epoxidizing the double bond in compound 2 to give compound 3:
20. the process according to claim 19, wherein the epoxidation is carried out using an agent selected from the group consisting of: mCPBA, hydrogen peroxide, peracetic acid, t-butanol peroxide, or cumene peroxide.
21. The method of claim 20, wherein the epoxidation is performed using mCPBA.
22. The process according to claim 1, further comprising the step of protecting the hydroxyl group of compound 1 with a protecting group Pg to give compound 2:
23. the method according to claim 1, further comprising the step of subjecting the starting materials aldehyde and halide to a nucleophilic addition reaction of a metal organic reagent and aldehyde to obtain compound 1:
wherein R is1Is an aldehyde group, R2Is halogen; or R1Is halogen, R2Is an aldehyde group.
24. The method according to claim 23, wherein the halogen is Cl or Br; the reaction is carried out in tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether organic solvent with magnesium, indium, zinc or lithium as metal.
25. The process according to claim 24, wherein the reaction is carried out with magnesium as metal in tetrahydrofuran.
26. A method according to any one of claims 23 to 25, comprising the steps of:
27. the method according to claim 1, comprising the steps of:
28. the method according to claim 27, comprising the steps of:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710250117.9A CN108727229B (en) | 2017-04-17 | 2017-04-17 | Novel process route for modifying fatty acid type PET reagent precursor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710250117.9A CN108727229B (en) | 2017-04-17 | 2017-04-17 | Novel process route for modifying fatty acid type PET reagent precursor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108727229A CN108727229A (en) | 2018-11-02 |
| CN108727229B true CN108727229B (en) | 2021-07-02 |
Family
ID=63924633
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710250117.9A Active CN108727229B (en) | 2017-04-17 | 2017-04-17 | Novel process route for modifying fatty acid type PET reagent precursor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108727229B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114700006B (en) * | 2022-06-07 | 2023-03-24 | 北京先通国际医药科技股份有限公司 | Production equipment of liquid composition and preparation method and application thereof |
| CN116199658A (en) * | 2022-07-22 | 2023-06-02 | 北京先通国际医药科技股份有限公司 | Synthesis method and application of modified long-chain fatty acid type PET reagent precursor |
| CN115181013B (en) * | 2022-07-22 | 2023-08-08 | 北京先通国际医药科技股份有限公司 | Preparation method and application of key intermediate of modified fatty acid type PET reagent precursor |
| CN116041169A (en) * | 2022-07-29 | 2023-05-02 | 北京先通国际医药科技股份有限公司 | Process route for synthesizing key intermediate of modified fatty acid type PET reagent precursor and application thereof |
| CN115141087B (en) * | 2022-09-06 | 2023-03-24 | 北京先通国际医药科技股份有限公司 | Synthesis method and application of isomers of PET precursor key intermediate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004093650A2 (en) * | 2003-04-17 | 2004-11-04 | The General Hospital Corporation | Method for monitoring blood flow and metabolic uptake in tissue with radiolabeled alkanoic acid |
| US10407378B2 (en) * | 2014-04-21 | 2019-09-10 | Takasago International Corporation | Compound, and flavor and/or fragrance composition containing said compound |
| JP2017043615A (en) * | 2015-08-27 | 2017-03-02 | 塩野義製薬株式会社 | Cyclopropane amino acid unit that improves membrane permeability and/or metabolic stability of cyclic peptide |
-
2017
- 2017-04-17 CN CN201710250117.9A patent/CN108727229B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN108727229A (en) | 2018-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108727229B (en) | Novel process route for modifying fatty acid type PET reagent precursor | |
| CN118515685A (en) | Synthesis of halichondrin | |
| Pasto et al. | Transfer Reactions Involving Boron. IX. Mechanism of Product Formation in the Hydroboration of Vinyl Halides1, 2 | |
| CN112125803B (en) | Preparation of homoallylic alcohol compound, synthetic method and application thereof | |
| CN111328332B (en) | Process for the preparation of bile acids | |
| GB673451A (en) | Process for the production of organic phosphines | |
| DE3783694T2 (en) | METHOD FOR PRODUCING MYOINOSITOL COMBINATIONS. | |
| ES2691077T3 (en) | Process for the preparation of ingenol-3-angelato from 20-desoxi-ingenol | |
| CN115959978B (en) | Synthesis method and application of modified long-chain fatty acid type PET reagent precursor | |
| Pal et al. | Single-pot conversion of an acid to the corresponding 4-chlorobutyl ester | |
| CN116041169A (en) | Process route for synthesizing key intermediate of modified fatty acid type PET reagent precursor and application thereof | |
| Reddy et al. | Stereoselective Total Synthesis of the Natural Oxylipin (6R, 7E, 9R, 10S)-6, 9, 10-Trihydroxyoctadec-7-enoic Acid1 | |
| JPS5949236B2 (en) | 2-Hydroxyethylphosphine | |
| SU393264A1 (en) | METHOD FOR OBTAINING TETRAGALOIDMETHANE ADDUDES WITH ACRYLIC COMPOUNDS | |
| JPWO2003070684A1 (en) | Method for producing chain oligolactic acid ester | |
| CN115181013B (en) | Preparation method and application of key intermediate of modified fatty acid type PET reagent precursor | |
| JPS637170B2 (en) | ||
| SU891632A1 (en) | Method of producing beta-acyloxyketone | |
| KR101088266B1 (en) | Carotinoid intermediate compound, preparing method thereof, and method for preparing carotinoid compound, astaxanthin and astacene using the same | |
| SU1594162A1 (en) | Method of producing 1-substituted cyclopropanes | |
| US4005109A (en) | Preparation of prostaglandin intermediates | |
| CN116217356A (en) | Synthesis method and application of isomer of PET precursor key intermediate | |
| SU1049469A1 (en) | Process for preparing capric acid | |
| Kelly | General preparation of arylacetic acid precursors. A further example of the iron tricarbonyl group as an agent for lateral control and activation in reactivity of cyclohexa-1, 3-dienes | |
| US20040147789A1 (en) | Allyl esters substituted by a difluoromethylene group, their process of synthesis and their use, and a process for functionalizing a double bond |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |