CN115850224A - 一种修饰长链脂肪酸型pet试剂前体的合成方法及其用途 - Google Patents
一种修饰长链脂肪酸型pet试剂前体的合成方法及其用途 Download PDFInfo
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- CN115850224A CN115850224A CN202310027029.8A CN202310027029A CN115850224A CN 115850224 A CN115850224 A CN 115850224A CN 202310027029 A CN202310027029 A CN 202310027029A CN 115850224 A CN115850224 A CN 115850224A
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- 239000003153 chemical reaction reagent Substances 0.000 title abstract description 34
- 239000002243 precursor Substances 0.000 title abstract description 14
- 150000004668 long chain fatty acids Chemical class 0.000 title abstract description 10
- 238000010189 synthetic method Methods 0.000 title description 3
- -1 triethylsilyl Chemical group 0.000 claims description 93
- 125000000623 heterocyclic group Chemical group 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 34
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 12
- 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 11
- 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 10
- 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 10
- 229940125898 compound 5 Drugs 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 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
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 238000002360 preparation method Methods 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
- 238000006243 chemical reaction Methods 0.000 abstract description 39
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 239000000376 reactant Substances 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
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- 125000001072 heteroaryl group Chemical group 0.000 description 30
- 125000005842 heteroatom Chemical group 0.000 description 29
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- 125000000753 cycloalkyl group Chemical group 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 26
- 238000000034 method Methods 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 18
- 125000000304 alkynyl group Chemical group 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 238000007254 oxidation reaction Methods 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
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- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000002600 positron emission tomography Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 125000001188 haloalkyl group Chemical group 0.000 description 10
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- 230000008569 process Effects 0.000 description 10
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 229940126214 compound 3 Drugs 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
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- 150000004665 fatty acids Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000007800 oxidant agent Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- 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 5
- TZRUKFFDSQQSCK-UHFFFAOYSA-N 2-pent-4-ynoxyoxane Chemical compound C#CCCCOC1CCCCO1 TZRUKFFDSQQSCK-UHFFFAOYSA-N 0.000 description 5
- 238000006677 Appel reaction Methods 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
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- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 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 4
- 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 4
- 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 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 4
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- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- 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 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 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 4
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- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
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- 125000001424 substituent group Chemical group 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical group BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
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- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 3
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- 125000003172 aldehyde group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
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- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
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- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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- 238000005694 sulfonylation reaction Methods 0.000 description 1
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- 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
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 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 group 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
- 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
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[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
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
本申请公开了修饰长链脂肪酸型PET试剂前体的合成方法及其用途,此路线反应及后处理操作简便,反应物易得,使用试剂安全、环保,总体收率可达15%以上。
Description
本申请是中国申请号为2022108670415、发明名称为“一种修饰长链脂肪酸型PET试剂前体的合成方法及其用途”且申请日为2022年7月22日的中国专利申请的分案申请。
技术领域
本申请涉及有机化学合成领域,具体涉及一种修饰脂肪酸型PET试剂前体的新工艺路线。
背景技术
PET(正电子发射型计算机断层显像)是核医学领域比较先进的临床检查影像技术。其大致方法是,将某种物质,一般是生物生命代谢中必须的物质,如:葡萄糖、蛋白质、核酸、脂肪酸,标记上短寿命的放射性核素(如18F,11C等),注入人体后,通过对于该物质在代谢中的聚集,来反映生命代谢活动的情况,从而达到诊断的目的。
心肌的基础有氧代谢中,70%的ATP由脂肪酸的β-氧化产生,因此脂肪酸或者修饰的脂肪酸是合适的心脏正电子发射型计算机断层显像试剂。由于未修饰的脂肪酸的代谢速度过快而将放射性原子更多的富集在肝脏或者肺脏,而非富集在诊断所需部位,修饰的脂肪酸具有更大的诊断学价值。
[18F]CardioPET是一种创新的PET试剂,是一种修饰长链脂肪酸性PET试剂,目前正在进行临床阶段的研究工作。其特点是在CH2CO2H基团处引入环丙烷环,使其吸收和富集行为类似于脂肪酸,但难以进行β-氧化,因此可以滞留在心肌细胞内,进而可以因18F的衰变而产生正电子,形成医学可用的影像,以研究心脏的代谢和疾病诊断,特别是冠心病。
式(I)、(Ia)和(Ib)化合物是[18F]CardioPET的前体,可与经同位素照射产生的K18F发生取代反应、水解反应后,经半制备色谱纯化后用于诊断用途(参考文献:US7790142,US2004253177)。
中国专利CN108727229B同样公开了式(I)、(Ia)和(Ib)化合物的制备方法。但其所公开的制备方法所制备的[18F]CardioPET的前体收率较低,只有5%左右,因此,探索提高[18F]CardioPET的前体合成收率是必要的。
发明内容
因此,本申请开发了一种合成修饰长链脂肪酸性PET试剂前体的新路线,具体的,本申请采用如下技术方法:
1、一种使用化合物7合成式(I)化合物的方法,其中,式(I)化合物如下所示:
其中,R表示C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;优选地,R选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、环丙基或环戊基等;更优选地,R为叔丁基;
X为磺酰基;优选地,X选自甲磺酰基、对甲苯磺酰基、三氟甲磺酰基等;优选地,X为甲磺酰基;
化合物7如下所示:
其中Pg表示保护基;优选地,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基;最优选地,Pg为苄基。
2、根据项1的方法,其包括将化合物7氧化为化合物8的步骤:
优选地,使用选自以下的氧化剂进行所述氧化反应:亚氯酸钠、高锰酸钾;
优选地,所述氧化反应温度为10-50℃。
3、根据项1或2的方法,其还包括将化合物8酯化,得到化合物9的步骤:
4、根据项1-3中任一项的方法,其还包括将化合物9脱除保护基,得到化合物10的步骤:
5、根据项1-4中任一项的方法,其还包括将化合物10进行磺酰化,得到式(I)化合物的步骤:
6、根据项1-5中任一项的方法,其还包括将化合物6进行环化反应转化为化合物7的步骤:
优选的,使用选自以下环化试剂进行所述环化反应:二碘甲基锌,(碘甲基)三氟硼酸钾,氯碘甲烷和二碘甲烷,优选为二碘甲烷;
优选地,在选自下述试剂中进行环化反应:正己烷、二氯甲烷、四氢呋喃、二氯乙烷、甲苯、乙醚和1,4-二氧六环,优选为四氢呋喃。
7、根据项1-6中任一项的方法,其还包括将化合物5进行脱保护转化为化合物6的步骤:
优选的,使用选自以下的试剂进行所述脱保护基反应:磺酸、对甲苯磺酸、盐酸、氢溴酸、三氟化硼乙醚、醋酸、磷酸或甲酸,进一步优选为对甲苯磺酸。
8、根据项1-7中任一项的方法,其还包括将化合物4进行还原反应转化为化合物5的步骤:
优选地,所述化合物4与还原剂的摩尔比为1:1.0~1:4.0;
优选地,所述还原剂为四氢铝锂。
9、根据项1-8中任一项的方法,其还包括将化合物3进行取代反应转化为化合物4的步骤:
优选地,所述化合物3与2-(4-戊炔氧基)四氢-2H-吡喃进行取代反应,
进一步优选,化合物3与2-(4-戊炔氧基)四氢-2H-吡喃的摩尔比为1:1.0~1:3.0;
优选地,所使用的脱质子试剂选自以下强碱性试剂:NaH、KH、氨基化理或正丁基锂,优选为正丁基锂。
10、根据项1-9中任一项的方法,其还包括将化合物2进行Appel反应转化为化合物3的步骤:
优选的,使用选自以下的卤代试剂进行所述Appel反应:碘甲烷或碘单质,优选为碘单质;
优选地,所述化合物2与卤代试剂的摩尔比为1:1.0~1:2.0。
11、根据项1-10中任一项的方法,其还包括将化合物1经过Brown硼氢化-氧化反应转化为化合物2的步骤:
优选的,使用选自以下试剂进行所述反应:
所述溶剂选自二甘醇二甲醚、四氢呋喃、乙醚或1,4-二氧六环,优选为四氢呋喃;
优选的,所述氧化剂选自间氯过氧苯甲酸、过氧乙酸、过氧化氢、过氧三氟乙酸或过氧苯甲酸,优选为过氧化氢;
优选地,所述化合物1与氧化剂的摩尔比为1:3.0~1:8.0。
12、一种使用化合物1合成式(I)化合物的方法,其包括以下步骤:
式(I)化合物如下所示:
其中,R表示C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基;优选地,R选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、环丙基或环戊基等;更优选地,R为叔丁基;
X为磺酰基;优选地,X选自甲磺酰基、对甲苯磺酰基、三氟甲磺酰基等;优选地,X为甲磺酰基;
13、根据项12的方法,其包括以下步骤:
14、根据项13的方法,其包括以下步骤:
15、化合物7:
其中Pg表示保护基;优选地,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基;最优选地,Pg为苄基。
16、一种使用化合物1合成化合物7的方法,其包括以下步骤:
化合物7如下所示:
其中Pg表示保护基;优选地,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基;最优选地,Pg为苄基。
17、化合物6:
其中Pg表示保护基;优选地,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基;最优选地,Pg为苄基。
18、化合物5:
其中Pg表示保护基;优选地,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基;最优选地,Pg为苄基。
19、化合物4:
其中Pg表示保护基;优选地,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基;最优选地,Pg为苄基。
20、化合物3:
其中Pg表示保护基;优选地,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基;最优选地,Pg为苄基。
21、化合物2:
其中Pg表示保护基;优选地,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基;最优选地,Pg为苄基。
发明效果
本申请经过大量实验尝试,开发了一种合成修饰长链脂肪酸性PET试剂前体的新路线,具有如下优点:
1.本申请的合成路线反应及后处理操作简便,反应物易得,使用试剂环保,现有技术中合成修饰长链脂肪酸性PET试剂前体的方法,如中国专利CN108727229B所公开的,均多次使用到NaH作为反应物,该物质遇水、湿空气放出氢气可爆,危险性较高。申请所提供的新的合成方法中不再使用使用NaH类物质,安全性更好。而目前已有工艺氧化过程中多使用间氯过氧苯甲酸,此物质遇热易分解易爆,有腐蚀性,对环境不友好。申请所提供的新的合成方法更改反应路线后,使用水溶性氧化试剂双氧水进行反应,加更绿色环保的。且本申请新的反应路线使用的反应类型大多数为经典反应,已经过长时间验证,工艺稳定,易于完成。
2.本申请明显提高了修饰长链脂肪酸性PET试剂前体的总收率,相比于现有技术中如中国专利CN108727229B所公开的合成方法,其总收率在5%左右,本申请所提供的合成路线的总收率可达15%以上,收率提高了2倍以上,具有明显的成本优势。
3.本申请的合成方法总体为10步反应,反应过程更加简洁已操作,相比于现有技术中多达20步的合成路线,节省了大量的人力物力成本,具有更好应用前景。
具体实施方式
以下对本申请的示范性实施例做出说明,其中包括本申请实施例的各种细节以助于理解,应当将它们认为仅仅是示范性的。因此,本领域普通技术人员应当认识到,可以对这里描述的实施例做出各种改变和修改,而不会背离本申请的范围和精神。同样,为了清楚和简明,以下的描述中省略了对公知功能和结构的描述。
定义
本申请使用的所有术语具有本领域技术人员通常理解的含义。此外,也可以具有如下含义。
式(I)化合物如下所示:
“C1-6烷基”是指含有1至6个碳原子的直链或支链的饱和单价烷(烃)基。在一些实施方案中,C1-4烷基是优选的。典型的C1-6烷基包括甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、异戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)等。术语“C1-6烷基”还包括杂烷基,其中1至3个选自O、S、N或取代的氮原子可以代替碳原子。
“C2-6烯基”表示具有2至6个碳原子和至少一个碳碳双健的直链或支链的烃基团,包括但不限于乙烯基、3-丁烯-1-基、2-乙烯基丁基、3-己烯-1-基等。在一些实施方案中,C2-4烯基是优选的。术语“C2-6烯基”还包括杂烯基,其中1至3个选自O、S、N或取代的氮原子可以代替碳原子。
“C2-6炔基”指的是具有2至6个碳原子的直链或支链的烃基团,其中含有至少有一个碳碳叁键和任选地一个或多个不饱和碳碳双键。在一些实施方案中,C2-4炔基是优选的。典型的炔基包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、戊炔基和己炔基。术语“C2-6炔基”还包括杂炔基,其中1至3个选自O、S、N或取代的氮原子可以代替碳原子。
本申请中使用的术语“卤素”是指F、Cl、Br和I。优选地,本申请中的卤素选自Cl、Br和I;更优选地,本申请中的卤素选自Cl或Br。
“C1-6卤代烷基”是指上述“C1-6烷基”,其被一个或多个卤素取代。在一些实施方案中,C1-4卤代烷基是优选的,更优选C1-2卤代烷基。示例性的所述卤代烷基包括但不限于:-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2,2,2-三氟-1,1-二甲基-乙基,等等。
“C3-7环烷基”是指具有3至7个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中,C3-6环烷基是特别优选的,更优选C5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在环烷基环上,且在这样的情况中,碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于:环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6)、环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7),等等。
“3-7元杂环基”是指具有环碳原子和1至4个环杂原子的3至7元非芳香环系;优选3-6元杂环基,其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系;优选4-6元杂环基,其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系;更优选5-6元杂环基,其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系,其中连接点在环烷基环上,或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在杂环基环上;且在这样的情况下,环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于:氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于:氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于:四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于:二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于:三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于:哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于:哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于:六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于:氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于:二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基,等等。示例性的与C6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于:四氢喹啉基、四氢异喹啉基,等等。
“C6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如,双环)4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中,芳基具有六个环碳原子(“C6芳基”;例如,苯基)。在一些实施方案中,芳基具有十个环碳原子(“C10芳基”;例如,萘基,例如,1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述芳基环上,在这种情况下,碳原子的数目继续表示所述芳基环系统中的碳原子数目。
“5-10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团,其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中,只要化合价允许,连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述杂芳基环上,在这种情况下,碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中,5-6元杂芳基是特别优选的,其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于:吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于:咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于:三唑基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于:四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于:吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于:哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于:三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于:氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于:吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于:萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。
“磺酰基”表示基团R-SO2-,其中R表示C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基。
“甲磺酰基”表示基团Me-SO2-。
“对甲苯磺酰基”表示基团p-CH3-C6H4-SO2-。
“三氟甲磺酰基”表示基团CF3-SO2-。
本申请中使用的术语“醛基”是指基团-C(O)H。
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。
示例性的碳原子上的取代基包括但不局限于:卤素、-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)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
或者在碳原子上的两个偕氢被基团=O、=S、=NN(Rbb)2、=NNRbbC(=O)Raa、=NNRbbC(=O)ORaa、=NNRbbS(=O)2Raa、=NRbb或=NORcc取代;
Raa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者两个Raa基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rbb的每个独立地选自:氢、-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)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者两个Rbb基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rcc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者两个Rcc基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代;
Rdd的每个独立地选自:卤素、-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)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代,或者两个偕Rdd取代基可结合以形成=O或=S;
Ree的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代;
Rff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者两个Rff基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代;
Rgg的每个独立地是:卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6烷基、-ON(C1-6烷基)2、-N(C1-6烷基)2、-N(C1-6烷基)3+X-、-NH(C1-6烷基)2+X-、-NH2(C1-6烷基)+X-、-NH3+X-、-N(OC1-6烷基)(C1-6烷基)、-N(OH)(C1-6烷基)、-NH(OH)、-SH、-SC1-6烷基、-SS(C1-6烷基)、-C(=O)(C1-6烷基)、-CO2H、-CO2(C1-6烷基)、-OC(=O)(C1-6烷基)、-OCO2(C1-6烷基)、-C(=O)NH2、-C(=O)N(C1-6烷基)2、-OC(=O)NH(C1-6烷基)、-NHC(=O)(C1-6烷基)、-N(C1-6烷基)C(=O)(C1-6烷基)、-NHCO2(C1-6烷基)、-NHC(=O)N(C1-6烷基)2、-NHC(=O)NH(C1-6烷基)、-NHC(=O)NH2、-C(=NH)O(C1-6烷基)、-OC(=NH)(C1-6烷基)、-OC(=NH)OC1-6烷基、-C(=NH)N(C1-6烷基)2、-C(=NH)NH(C1-6烷基)、-C(=NH)NH2、-OC(=NH)N(C1-6烷基)2、-OC(NH)NH(C1-6烷基)、-OC(NH)NH2、-NHC(NH)N(C1-6烷基)2、-NHC(=NH)NH2、-NHSO2(C1-6烷基)、-SO2N(C1-6烷基)2、-SO2NH(C1-6烷基)、-SO2NH2、-SO2C1-6烷基、-SO2OC1-6烷基、-OSO2C1-6烷基、-SOC1-6烷基、-Si(C1-6烷基)3、-OSi(C1-6烷基)3、-C(=S)N(C1-6烷基)2、C(=S)NH(C1-6烷基)、C(=S)NH2、-C(=O)S(C1-6烷基)、-C(=S)SC1-6烷基、-SC(=S)SC1-6烷基、-P(=O)2(C1-6烷基)、-P(=O)(C1-6烷基)2、-OP(=O)(C1-6烷基)2、-OP(=O)(OC1-6烷基)2、C1-6烷基、C1-6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、C3-C7杂环基、C5-C10杂芳基;或者两个偕Rgg取代基可结合形成=O或=S;其中,X-为反离子。
示例性的氮原子上取代基包括但不局限于:氢、-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)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,或者连接至氮原子的两个Rcc基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代,且其中Raa、Rbb、Rcc和Rdd如上所述。
本申请中使用的术语“氧化反应”是指在本申请化合物中引入氧或脱去氢的反应。更具体地,是指将醛基转化为羧酸基的反应。氧化反应可以使用多种本领域熟知的氧化剂实现,包括但不限于亚氯酸钠、高锰酸钾、PCC(氯铬酸吡啶盐)和二氧化锰。
优选的,本申请中氧化反应的温度为10-50℃,例如可以为10℃、15℃、20℃、25℃、30℃、35℃、40℃、45℃、50℃。
本申请中使用的术语“保护基”是指能够与官能团共价结合,使其免受化学反应影响,并可以在反应完成后除去以恢复所述官能团的基团。更具体地,本申请中的保护基是指氧保护基(也称为羟基保护基)。氧保护基是本领域众所周知的且包括详细描述于Protecting Groups in Organic Synthesis,T.W.Greene and P.G.M.Wuts,第三版,JohnWiley&Sons,1999中的那些,其在此引入作为参考。
示例性氧保护基包括,但不限于,甲基、叔丁氧羰基(BOC或Boc)、甲氧基甲基(MOM)、甲基硫基甲基(MTM)、叔丁基硫基甲基、(苯基二甲基甲硅烷基)甲氧基甲基(SMOM)、苄基氧基甲基(BOM)、对甲氧基苄基氧基甲基(PMBM)、(4-甲氧基苯氧基)甲基(p-AOM)、愈创木酚甲基(GUM)、叔丁氧基甲基、4-戊烯基氧基甲基(POM)、甲硅烷氧基甲基、2-甲氧基乙氧基甲基(MEM)、2,2,2-三氯乙氧基甲基、二(2-氯乙氧基)甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEMOR)、四氢吡喃基(THP)、3-溴代四氢吡喃基、四氢噻喃基、1-甲氧基环己基、4-甲氧基四氢吡喃基(MTHP)、4-甲氧基四氢噻喃基、4-甲氧基四氢噻喃基S,S-二氧化物、1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基(CTMP)、1,4-二烷-2-基、四氢呋喃基、四氢噻吩基、2,3,3a,4,5,6,7,7a-八氢-7,8,8-三甲基-4,7-甲桥苯并呋喃(methanobenzofuran)-2-基、1-乙氧基乙基、1-(2-氯乙氧基)乙基、1-甲基-1-甲氧基乙基、1-甲基-1-苄基氧基乙基、1-甲基-1-苄基氧基-2-氟乙基、2,2,2-三氯乙基、2-三甲基甲硅烷基乙基、2-(苯基氢硒基)乙基、叔丁基、烯丙基、对氯苯基、对甲氧基苯基、2,4-二硝基苯基、苄基(Bn)、对甲氧基苄基、3,4-二甲氧基苄基、邻硝基苄基、对硝基苄基、对卤代苄基、2,6-二氯苄基、对氰基苄基、对苯基苄基、2-吡啶甲基、4-吡啶甲基、3-甲基-2-吡啶甲基N-氧化物、二苯基甲基、p,p’-二硝基二苯甲基、5-二苯并环庚三烯基、三苯基甲基、α-萘基二苯基甲基、对甲氧基苯基二苯基甲基、二(对甲氧基苯基)苯基甲基、三(对甲氧基苯基)甲基、4-(4′-溴代苯甲酰基氧基苯基)二苯基甲基、4,4′,4″-三(4,5-二氯苯二酰亚氨基苯基)甲基、4,4′,4″-三(乙酰丙酰基氧基苯基)甲基、4,4′,4″-三(苯甲酰基氧基苯基)甲基、3-(咪唑-1-基)二(4′,4″-二甲氧基苯基)甲基、1,1-二(4-甲氧基苯基)-1′-芘基甲基、9-蒽基、9-(9-苯基)吨基、9-(9-苯基-10-氧代)蒽基、1,3-苯并二硫杂噻吩(disulfuran)-2-基、苯并异噻唑基S,S-二氧化物、三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)、三异丙基甲硅烷基(TIPS)、二甲基异丙基甲硅烷基(IPDMS)、二乙基异丙基甲硅烷基(DEIPS)、二甲基己基甲硅烷基、叔丁基二甲基甲硅烷基(TBDMS)、叔丁基二苯基甲硅烷基(TBDPS)、三苄基甲硅烷基、三-对二甲苯基甲硅烷基、三苯基甲硅烷基、二苯基甲基甲硅烷基(DPMS)、叔丁基甲氧基苯基甲硅烷基(TBMPS)、甲酸酯、苯甲酰基甲酸酯、乙酸酯、氯乙酸酯、二氯乙酸酯、三氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、苯氧基乙酸酯、对氯苯氧基乙酸酯、3-苯基丙酸酯、4-戊酮酸酯(乙酰丙酸酯)、4,4-(亚乙基二硫基)戊酸酯(乙酰丙酰基二硫缩醛)、新戊酸酯、金刚酸酯、巴豆酸酯、4-甲氧基巴豆酸酯、苯甲酸酯、对苯基苯甲酸酯、2,4,6-三甲基苯甲酸酯(米酮酸酯)、烷基甲基碳酸酯、9-芴基甲基碳酸酯(Fmoc)、烷基乙基碳酸酯、烷基2,2,2-三氯乙基碳酸酯(Troc)、2-(三甲基甲硅烷基)乙基碳酸酯(TMSEC)、2-(苯基磺酰基)乙基碳酸酯(Psec)、2-(三苯基磷基)乙基碳酸酯(Peoc)、烷基异丁基碳酸酯、烷基乙烯基碳酸酯、烷基烯丙基碳酸酯、烷基对硝基苯基碳酸酯、烷基苄基碳酸酯、烷基对甲氧基苄基碳酸酯、烷基3,4-二甲氧基苄基碳酸酯、烷基邻硝基苄基碳酸酯、烷基对硝基苄基碳酸酯、烷基S-苄基硫代碳酸酯、4-乙氧基-1-萘基碳酸酯、甲基二硫代碳酸酯、2-碘代苯甲酸酯、4-叠氮基丁酸酯、4-硝基-4-甲基戊酸酯、邻-(二溴甲基)苯甲酸酯、2-甲酰基苯磺酸酯、2-(甲基硫基甲氧基)乙基、4-(甲基硫基甲氧基)丁酸酯、2-(甲基硫基甲氧基甲基)苯甲酸酯、2,6-二氯-4-甲基苯氧基乙酸酯、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯、2,4-二(1,1-二甲基丙基)苯氧基乙酸酯、氯二苯基乙酸酯、异丁酸酯、单琥珀酸酯、(E)-2-甲基-2-丁烯酸酯、邻(甲氧基酰基)苯甲酸酯、α-萘甲酸酯、硝酸酯、烷基N,N,N’,N’-四甲基磷酰二胺酯(phosphorodiamidate)、烷基N-苯基氨基甲酸酯、硼酸酯、二甲基膦基亚硫酰基、烷基2,4-二硝基苯基次磺酸酯、硫酸酯、甲烷磺酸酯(甲磺酸酯)、苄基磺酸酯和甲苯磺酸酯(Ts)。
“羟基保护”和“脱保护基”分别指对羟基官能团引入保护基,以及除去保护基以恢复羟基官能团的反应。引入保护基和脱除保护基的反应条件是本领域技术人员所熟知的。本申请中优选的反应试剂为磺酸、对甲苯磺酸、盐酸、氢溴酸、三氟化硼乙醚、醋酸、磷酸或甲酸,更优选的试剂为对甲苯磺酸。
本申请中使用的术语“酯化反应”是指将羧基基转化为酯基的反应。酯化反应可以使用多种本领域熟知的试剂实现,包括但不限于卤化烃、醇等。
本申请中使用的术语“磺酰化”是指将羟基转化为磺酰氧基的反应。举例而言,甲磺酰氯、甲磺酸酐、对甲苯磺酰氯、三氟甲磺酸酐等可以实现所述反应。
本申请中使用的术语“环化反应”是指是有机化合物分子中形成新的碳环或杂环的反应,也称闭环或成环缩合。在形成碳环时,是以形成碳—碳键来完成环合反应的;在形成含有杂原子的环状结构时,它可以是以形成碳—碳键的方式来完成环合反应,也可以是以形成碳—杂原子键(C-N、C-O、C-S键等)来完成环合反应,有时也可以是在两个杂原子之间成键(N-N、N-S键等)来完成环合反应。环化反应可以使用多种本领域熟知的试剂实现,包括但不限于碘甲基锌,(碘甲基)三氟硼酸钾,氯碘甲烷和二碘甲烷,本申请进一步优选的试剂为二碘甲烷;本申请进一步优选在选自下述试剂中进行环化反应:正己烷、二氯甲烷、四氢呋喃、二氯乙烷、甲苯、乙醚和1,4-二氧六环,优选为四氢呋喃。
本申请中使用的术语“还原反应”是指在本申请化合物中引入氢或脱去氧的反应。更具体地,是指将酯基转化为醛基的反应。还原反应可以使用多种本领域熟知的还原剂实现,包括但不限于DIBAL-H的一步转化,和先用NaBH4、硼烷-四氢呋喃络合物、四氢铝锂、DIBAL-H、红铝等,本申请优选的试剂为四氢铝锂,进一步优选的实施方式中,在由化合物4进行还原反应转化为化合物5的过程中,化合物4与还原剂的摩尔比为1:1.0~1:4.0,例如可以为1:1.0、1:1.5、1:2.0、1:2.5、1:3.0、1:3.5、1:4.0。
本申请中使用的术语“取代反应”是指是化合物或有机物分子中任何一个原子或原子团被试剂中同类型的其它原子或原子团所替代的反应。取代反应可以使用多种本领域熟知的试剂实现,本申请优选的实施方式中,所述化合物3与2-(4-戊炔氧基)四氢-2H-吡喃进行取代反应,进一步优选的,化合物3与2-(4-戊炔氧基)四氢-2H-吡喃的摩尔比为1:1.0~1:3.0;例如可以为1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2.0、1:2.1、1:2.2、1:2.3、1:2.4、1:2.5、1:2.6、1:2.7、1:2.8、1:2.9、1:3.0。在本申请一个优选的实施方式中,在取代反应过程中,所使用的脱质子试剂选自以下试剂:碱NaH、KH、氨基化锂或正丁基锂,优选为正丁基锂。
本申请中使用的术语“Appel反应”是指使用四卤化碳和三苯基膦将伯醇和仲醇转化为烷基卤代物。烷基溴代物和烷基碘代物也可分别用四溴化碳或溴,四碘化碳、碘甲烷或碘代替四氯化碳制得。该反应是用于引入卤原子的较温和方法。Appel反应可以使用多种本领域熟知的试剂实现,包括但不限于四溴化碳、溴、碘甲烷或碘单质,本申请优选的卤代试剂为碘单质。在将化合物2进行Appel反应转化为化合物3的过程中,在一种优选的实施方式中国,所述化合物2与卤代试剂的摩尔比为1:1.0~1:2.0,例如可以为1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2.0。
本申请中使用的术语“Brown硼氢化-氧化反应”是指硼烷对烯烃进行协同顺式加成得到有机硼加成产物,然后在碱性条件下氧化得到醇的反应。Brown硼氢化-氧化反应可以使用多种本领域熟知的试剂实现,在一种优选的实施方式中,所述溶剂选自二甘醇二甲醚、四氢呋喃、乙醚或1,4-二氧六环,进一步优选为四氢呋喃,在另一种优选的实施方式中,所述氧化剂选自间氯过氧苯甲酸、过氧乙酸、过氧化氢、过氧三氟乙酸或过氧苯甲酸,进一步优选为过氧化氢。在将化合物1经过硼氢化-氧化反应转化为化合物2的过程中,所述化合物1与氧化剂的摩尔比为1:3.0~1:8.0,例如可以为1:3.0、1:3.5、1:4.0、1:4.5、1:5.0、1:5.5、1:6.0、1:6.5、1:7.0、1:7.5、1:8.0。
实施例
1.由化合物1a合成化合物2a
合成路线为:
具体合成步骤为:将化合物1a(25.0g,86.73mmol)加入500毫升三口瓶中,在氮气氛围下,加入100毫升无水四氢呋喃(THF),0-5℃条件下,滴加硼烷二甲硫醚络合物(13.4g,173.46mmol,1M的THF溶液,滴加完毕后,使反应体系升至室温,然后加热回流反应4小时。将反应体系冷却至0℃,依次加入乙醇30毫升,4M NaOH溶液(30毫升),30%过氧化氢(H2O2)(35毫升)化合物1a溶液室温搅拌2小时,进行氧化反应。向体系中加入100毫升水,100毫升甲基叔丁基醚,萃取、分液;有机相用200毫升饱和氯化铵溶液洗涤,分液;有机相用200毫升饱和氯化钠溶液洗涤,分液;有机相用无水硫酸钠干燥,过滤,有机相减压浓缩,粗产物通过硅胶快速色谱法纯化(洗脱液:环己烷/EtOAc 100/0至10/90),得产物20.0g。收率:75.3%。
1H-NMR(400MHz,CDCl3)δ:0.86(t,3H),1.24~1.58(m,20H),2.98(m,2H),3.38(m,1H),4.62(s,2H),4.76(m,1H),7.28-7.32(m,5H)
2.由化合物2a合成化合物3a
合成路线为:
具体合成步骤为:将化合物2a(18.0g,58.75mmol)和咪唑(8.0g,0.1175mol)和三苯膦(PPh3)(32.6g,0.1243mol)和无水四氢呋喃(THF)(250mL)加入到500毫升的三口瓶中,氮气氛围内0℃条件下加入碘(I2)(31.5g,0.1242mol)化合物2a,加入完毕后升至室温搅拌过夜。反应后用饱和亚硫酸钠溶液淬灭,用乙酸乙酯(2×100毫升)合并的有机溶液用水、盐水洗涤,经无水硫酸钠干燥,过滤并浓缩,得到粘稠油状物,将其通过硅胶柱色谱法(洗脱液:环己烷/EtOAc 100/10至5/95)纯化,得到14.8g化合物3a。收率:81.1%。
1H-NMR(400MHz,CDCl3)δ:0.88(t,3H),1.24~1.85(m,18H),2.92(m,2H)3.40(m,1H),3.64(m,2H),4.52(s,2H),7.30-7.35(m,5H)
3.由化合物3a合成化合物4a
合成路线为:
具体合成步骤为:
2-(4-戊炔氧基)四氢-2H-吡喃(2-(Pent-4-yn-1-yloxy)tetrahydro-2H-pyran,4-戊炔醇OTHP)(15.4g,91.38mmol)和无水四氢呋喃(THF)(200毫升)加入到500毫升的三口瓶中,氮气氛围,-30℃低温下,加入正丁基锂(n-BuLi)(1.6M的己烷溶液57.1ml,91.38mmol)和化合物3a(19.0g,45.66mmol),加完,将溶液升至室温反应6小时。反应结束加入饱和NH4Cl。所得混合物用己烷/EtOAc(1:1)萃取(3×100mL)。合并的萃取物用水洗涤,经硫酸镁干燥并浓缩,留下残余物,通过硅胶色谱法纯化柱层析(正庚烷:乙酸乙酯=100:1~50:1)纯化得到无色油状液体17.8g。收率:88.1%。
1H NMR(400MHz,CDCl3))δ0.88(m,3H),1.26-1.79(m,26H),2.15(m,2H),2.40(m,2H)3.11(p,1H),3.52(m,2H),3.72(m,2H)4.56(m,H)4.63(d,2H),7.30-7.32(m,5H)
4.由化合物4a合成化合物5a
合成路线为:
具体合成步骤为:氩气下,在0℃下,将氢化铝锂(LAH/LiAlH4)(1.88g,49.54mmol)悬浮在200mL无水四氢呋喃(THF)中,将乙醇(4.2g,91.16mmol)滴加到悬浮液中,然后滴加化合物4a(20.0g,45.21mmol)在50毫升无水四氢呋喃(THF)中,添加完成后,将两种溶液混合,将反应混合物升温至室温,然后加热回流1小时。用水和2M NaOH小心地淬灭混合物,将所得的白色铝盐通过烧结玻璃漏斗真空过滤。盐用100毫升热四氢呋喃反复洗涤,合并的滤液用无水硫酸钠干燥,30-40℃减压浓缩。通过硅胶色谱法纯化柱层析(正庚烷:乙酸乙酯=100:1~50:1),得16.5g化合物5a,收率:82.1%。
1H NMR(400MHz,CDCl3))δ0.88(m,3H),1.24-1.78(m,26H),2.15(m,2H),2.20(m,2H)3.21(p,1H),3.43(m,2H),3.72(m,2H)4.58(m,H)4.62(d,2H),5.42-5.46(m,2H),7.26-7.32(m,5H)
5.由化合物5a合成化合物6a
合成路线为:
具体合成步骤为:氮气保护下,将甲醇(MeOH)(150ml.),水5ml加入到500毫升三口瓶中,加入对甲苯磺酸(PTSA)(0.6g,4.0%wt.)和化合物5a(15.0g,33.76mmol),将反应混合物加热至60℃,搅拌保持2小时。然后冷却至室温,用水稀释并加饱和碳酸氢钠溶液调节至pH=8-10,然后用乙酸乙酯(3×100mL)萃取,无水硫酸钠干燥,过滤,30-40℃减压浓缩得到粗品。通过硅胶色谱法纯化柱层析(正庚烷:乙酸乙酯=100:1~50:1)纯化得到9.8g。收率:80.6%。
1H NMR(400MHz,CDCl3))δ0.86(m,3H),1.16-1.45(m,20H),2.15(m,2H),2.20(m,2H)3.21(p,1H),3.58(m,2H),4.24(m,H)4.62(d,2H),5.43-5.46(m,2H),7.28-7.32(m,5H)
6.由化合物6a合成化合物7a
合成路线为:
具体合成步骤为:无水四氢呋喃(THF)(250毫升)为溶剂,加入到500毫升三口瓶中,降温至-30℃,控温依次将二乙基锌(DEZ)溶液(15.4g,124.9mmol.)、二甲醚(DME)(5.8g,124.9mmol)、二碘甲烷(CH2I2)(33.5g,124.9mmol)滴加到无水四氢呋喃中,同时保持反应温度在-25℃和-10℃之间,加入化合物6a(9.0g,24.98mmol),加入完毕后,升至室温,反应结束用饱和氯化铵淬灭,用乙酸乙酯萃取2×100mL、用100毫升水洗涤,分液、干燥、过滤,30-40℃减压浓缩并通过硅胶色谱法纯化柱层析(正庚烷:乙酸乙酯=100:1~40:1)得到产物8.2g。收率:88.0%。
1H-NMR(400MHz,CDCl3)δ:0.23-0.31(m,2H),0.43-0.46(m,1H),0.59-0.62(m,1H),0.88(m,3H),1.18-1.52(m,22H),2.19(m,2H),3.27(m,1H),3.80(m,2H),4.62(m,2H)7.31-7.33(m,5H),9.71(d,1H)
7.由化合物7a合成化合物8a
合成路线为:
具体合成步骤为:化合物7a(8.0g,21.37mmol)加入到500毫升三口瓶中,加入100毫升乙腈(MeCN),将0.22g四甲基哌啶(TEMPO)加入到反应瓶中,然后加入150毫升(0.67M,pH=6.7)磷酸二氢钠/磷酸氢钠缓冲液,升温到30℃,30℃,加入亚氯酸钠(4.38g,48.43mmol,溶解在20ml水中),加入1ml 2.52%次氯酸钠。搅拌2小时后降温至0℃,用饱和亚硫酸钠溶液淬灭,向体系中加入200ml甲基叔丁基醚萃取,分液,有机相用2.0N盐酸调节pH=2-4,有机相水洗,分液,过滤,干燥,有机相30-40℃减压浓缩后得到7.3g化合物8a,收率84.9%。
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),2.21(d,2H),3.29(m,1H),4.63(s,2H),7.26-7.33(m,5H),11.02(s,1H)
8.由化合物8a合成化合物9b
合成路线为:
具体合成步骤为:将化合物8a(7g,18.02mmol)加入到250毫升三口瓶中,将二氯甲烷(35毫升)加入反应瓶中,加入4-二甲氨基吡啶(DMAP)(4.4g)和叔丁醇(tBuOH)(6.7g,90.40mmol),将反应体系降温到到10℃左右,滴加二环己基碳二亚胺(DCC)(4.5g溶于40ml二氯甲烷的溶液)。滴加完毕后升至室温,室温搅拌4h,向体系中加入35ml二氯甲烷,水2ml,搅拌3h,过滤,滤液30-40℃浓缩,通过硅胶色谱法纯化柱层析(正庚烷:乙酸乙酯=100:1~40:1)6.5g化合物9b,收率:84.0%。
1H-NMR(400MHz,CDCl3)δ:0.21(m,2H),0.45(m,1H),0.64(m,1H),0.88(t,3H),1.19-1.44(m,31H),2.03(m,2H),3.28(m,1H),4.62(s,2H),7.28-7.32(m,5H)。
9.由化合物9b合成化合物10b
合成路线为:
具体合成步骤为:将化合物9b(4.0g,9.0mmol)加入到200毫升高压反应釜内,加入甲醇(100ml),10%钯碳(Pd/C)催化剂1.0g,用氢气置换3次体系,控温40-50℃通氢气反应4小时,降至室温后过滤,滤液30-40℃减压浓缩后得到2.9g化合物10b,产率为90.9%。
1H-NMR(400MHz,CDCl3)δ:0.22(m,2H),0.48(m,1H),0.69(m,1H),0.86(t,3H),1.21-1.47(m,31H),1.92-2.14(m,2H),3.42(m,1H),4.82(m,H)
10.式(Ib)化合物的合成
合成路线为:
具体合成步骤为:将化合物10b(2.0g,6.644mmol)加入到100毫升三口瓶中,加入二氯甲烷(30ml),加入吡啶(4.46g),滴加甲磺酰氯(MsCl)(0.97g,8.468mmol),室温搅拌16小时。将反应液减压浓缩脱,通过硅胶色谱法纯化柱层析(正庚烷:乙酸乙酯=100:1~20:1),得产物1.8g,产率为77.8%。
1H-NMR(400MHz,CDCl3)δ:0.26(m,2H),0.55(m,1H),0.74(m,1H),0.88(t,3H),1.22-1.46(m,27H),1.62-1.72(m,4H),2.17(m,2H),3.12(s,3H),4.65(m,1H)。
MS:[M+H]+=433.66,[M+Na]+=455.3
综上所述,此路线总收率为每步收率相乘:
75.3%*81.1%*88.1*82.1%*80.6%*88.0%*84.9%*84.0%*90.9%*77.8%=15.8%。
尽管以上结合对本申请的实施方案进行了描述,但本申请并不局限于上述的具体实施方案和应用领域,上述的具体实施方案仅仅是示意性的、指导性的,而不是限制性的。本领域的普通技术人员在本说明书的启示下和在不脱离本申请权利要求所保护的范围的情况下,还可以做出很多种的形式,这些均属于本申请保护之列。
Claims (10)
2.根据权利要求1所述的化合物5,其中,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基的保护基。
3.根据权利要求2所述的化合物5,其中,Pg为苄基。
5.根据权利要求4所述的用途,其中,R选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、环丙基或环戊基。
6.根据权利要求5所述的用途,其中,R为叔丁基。
7.根据权利要求4所述的用途,其中,X选自甲磺酰基、对甲苯磺酰基、三氟甲磺酰基。
8.根据权利要求7所述的用途,其中,X为甲磺酰基。
9.根据权利要求4所述的用途,其中,Pg为选自苄基、4-甲基苄基、4-甲氧基苄基、叔丁基二甲基硅基、三异丙基硅基、三乙基硅基保护基。
10.根据权利要求9所述的用途,其中,Pg为苄基。
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