CN116178162A - 一种硝酸酯基转移试剂的绿色快捷制备方法 - Google Patents
一种硝酸酯基转移试剂的绿色快捷制备方法 Download PDFInfo
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- CN116178162A CN116178162A CN202211636307.1A CN202211636307A CN116178162A CN 116178162 A CN116178162 A CN 116178162A CN 202211636307 A CN202211636307 A CN 202211636307A CN 116178162 A CN116178162 A CN 116178162A
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- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 65
- 238000012546 transfer Methods 0.000 title claims abstract description 40
- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical compound [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 229910002651 NO3 Inorganic materials 0.000 claims abstract description 21
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical class CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims abstract description 17
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate group Chemical group [N+](=O)([O-])[O-] NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000005886 esterification reaction Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 25
- 239000007787 solid Substances 0.000 claims description 21
- 238000000967 suction filtration Methods 0.000 claims description 16
- 238000005809 transesterification reaction Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 239000012298 atmosphere Substances 0.000 claims description 12
- -1 nitrate ester Chemical class 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 10
- 239000006227 byproduct Substances 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 239000002253 acid Substances 0.000 abstract description 8
- 230000008901 benefit Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 229910001960 metal nitrate Inorganic materials 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 32
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 238000012512 characterization method Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000012535 impurity Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 6
- 238000006396 nitration reaction Methods 0.000 description 6
- 238000002791 soaking Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910001961 silver nitrate Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 150000001503 aryl iodides Chemical class 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000002823 nitrates Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- ZWWCURLKEXEFQT-UHFFFAOYSA-N dinitrogen pentaoxide Chemical compound [O-][N+](=O)O[N+]([O-])=O ZWWCURLKEXEFQT-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
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- 239000002699 waste material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 150000004798 β-ketoamides Chemical class 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- RODBEKUWCLMBSW-FGZHOGPDSA-M (3r,5r)-7-[1-cyclohexyl-4-(4-fluorophenyl)-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC(C)C1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=CN1C1CCCCC1 RODBEKUWCLMBSW-FGZHOGPDSA-M 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- NHPPIJMARIVBGU-UHFFFAOYSA-N 1-iodonaphthalene Chemical compound C1=CC=C2C(I)=CC=CC2=C1 NHPPIJMARIVBGU-UHFFFAOYSA-N 0.000 description 1
- XOKDXPVXJWTSRM-UHFFFAOYSA-N 4-iodobenzonitrile Chemical compound IC1=CC=C(C#N)C=C1 XOKDXPVXJWTSRM-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- IVGUSVLHAPMUES-UHFFFAOYSA-N C(C)(=O)O.C(C)(=O)O.BrC=1C(=CC=CC1)I Chemical compound C(C)(=O)O.C(C)(=O)O.BrC=1C(=CC=CC1)I IVGUSVLHAPMUES-UHFFFAOYSA-N 0.000 description 1
- IRKJHOQSOGISCP-UHFFFAOYSA-N C(C)(=O)O.C(C)(=O)O.FC1=CC=C(C=C1)I Chemical compound C(C)(=O)O.C(C)(=O)O.FC1=CC=C(C=C1)I IRKJHOQSOGISCP-UHFFFAOYSA-N 0.000 description 1
- JDTYMESADORSJD-UHFFFAOYSA-N C(C)(=O)O.C(C)(=O)O.IC1=CC=C(C=C1)C Chemical compound C(C)(=O)O.C(C)(=O)O.IC1=CC=C(C=C1)C JDTYMESADORSJD-UHFFFAOYSA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- XDEWNEJGNYUDPN-UHFFFAOYSA-N CC(O)=O.CC(O)=O.COC1=CC=C(I)C=C1 Chemical compound CC(O)=O.CC(O)=O.COC1=CC=C(I)C=C1 XDEWNEJGNYUDPN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- NRVCVLFVSDRPOM-UHFFFAOYSA-N [I+].[O-][N+]([O-])=O Chemical compound [I+].[O-][N+]([O-])=O NRVCVLFVSDRPOM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000010306 acid treatment Methods 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- SZQUEWJRBJDHSM-UHFFFAOYSA-N iron(3+);trinitrate;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O SZQUEWJRBJDHSM-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/02—Preparation of esters of nitric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C203/00—Esters of nitric or nitrous acid
- C07C203/02—Esters of nitric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C71/00—Esters of oxyacids of halogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Compounds Of Heavy Metals (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种硝酸酯基转移试剂的制备方法,具体是一种基于芳基非环三价碘骨架的含硝酸酯基官能团的转移试剂的绿色快捷制备方法。该类试剂以取代二乙酸碘苯为起始原料,当量的硝酸为硝酸酯基团的来源,避免了混酸或金属硝酸盐的使用,仅需经过一步反应、重结晶即可得到纯品,故有原料廉价易得、操作简便、安全高效等优点。该硝酸酯基转移试剂具有C2对称性,稳定性好、反应活性高,可以实现多种硝酸酯化反应。
Description
技术领域
本发明涉及一种硝酸酯基转移试剂的绿色快捷制备方法,具体是公开了一种基于芳基非环三价碘骨架的含硝酸酯基官能团的转移试剂的其制备方法,属于有机合成化学领域。
背景技术
硝酸酯类化合物,在石油化工、医药领域、军用领域、含能材料等生产生活中有着广泛的应用。近年来,尤其在医药领域的发展尤为迅速。其作为一氧化氮(NO)最常见的供体,优先在治疗心血管疾病方面受人关注,随着研究的深入,其对免疫、神经系统的疾病也有效果,同时还是表现出优异的抗肿瘤活性。另一方面,将硝酸酯官能团引入现有的药物分子中,可以大大降低药物毒性和毒副作用(Mini Reviews in Medicinal Chemistry,2001,1,57-70)。因此,如何高效地向分子中引入硝酸酯基官能团成为了一项有重要意义的研究课题。
混酸硝化法是制备硝酸酯的传统方法,主要包括浓硝酸-浓硫酸体系、浓硝酸-醋酐体系,其原子经济性和选择性差、产物难分离、环境污染严重,而且对水或酸敏感物质的硝化是不适用的(Journal of the American Pharmaceutical Association,1958,47,368)。除此之外,利用硝酸银、硝酸铈铵、九水合硝酸铁等金属硝酸盐进行硝酸酯的制备主要在实验室内有所应用,但因为不可避免的金属残留、底物范围窄、成本高等问题的限制,实际应用起来难度较高。
五氧化二氮(N2O5),又称硝酐,作为一种新型绿色硝化试剂,与传统混酸硝化法相比,其硝化过程有明显的优点:原子经济性高、热效应低、温度易控制、无废酸处理、产物分离简单、对多官能团反应物硝化选择性高;另一方面,易潮解、熔点低、易升华、易分解,32℃时就会升华并明显分解,47℃时完全分解,需要在-10℃下干燥保存,遇高温或易燃品极易引起燃烧爆炸,这也是限制其发展的根本原因。
因此,发展一种新型绿色高效的硝酸酯化试剂是一个亟待解决的课题。中国专利申请号:202210032363.8公开了新型芳基非环三价碘硝酸酯基转移试剂及其制备方法,该方法以市售的芳基碘化物为初始原料,以硝酸银为硝酸酯基团的来源,经过两步就可以合成相应的非环三价碘硝酸酯基转移试剂,并对该类试剂的反应活性、硝酸酯化反应的适用范围进行了一定的探索。但是该合成方案需要用到硝酸银作为硝酸酯基团的来源,其成本较高,不可避免地也会有痕量银离子难以去除。
综上所述,现有硝酸酯合成方法普遍存在底物适用范围窄、安全性低、后处理过程繁琐、物料浪费严重、选择性差等问题。如何实现硝酸酯类化合物的全过程绿色安全高效合成,为了解决这一问题,避免了混酸或金属硝酸盐的使用,本发明提供了一条绿色高效快捷合成芳基非环三价碘硝酸酯基转移试剂的新方法。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷,提供一种芳基非环三价碘硝酸酯转移试剂的绿色高效快捷合成方法。旨在利用廉价易得的工业原料,开发一种高效、绿色、安全、可大量制备的硝酸酯基转移试剂。同时,基于该三价碘硝酸酯基转移试剂的高反应活性,再次发展了该类试剂在硝酸酯基转移反应中的应用。
本发明的目的可以通过以下技术方案来实现:一种硝酸酯基转移试剂的绿色快捷制备方法,包括的步骤:
以二乙酸碘苯2和硝酸为原料,通过一步法得到硝酸酯基转移试剂1,步骤如下:
其中,R=烷氧基、酰氧基、芳基、烷基、氢、卤素、烷氧羰基、酰基、三氟甲基、氰基、或硝基。
进一步地,所述的方法具体步骤如下:
在室温下,空气氛围中,反应器中依次加入二乙酸碘苯2、溶剂、硝酸,敞口反应0.5-3小时,去除溶剂和副产物乙酸得到黄色粘稠油状物,用二氯甲烷溶解后静置,析出黄色固体,抽滤、干燥即可得到硝酸酯基转移试剂1。
进一步地,所述的溶剂为二氯甲烷、乙腈或乙酸。
进一步地,当溶剂为:二氯甲烷或乙腈时,溶剂的用量为每摩尔二乙酸碘苯2添加溶剂1升;
当溶剂为乙酸时,溶剂的用量为每摩尔二乙酸碘苯2添加溶剂0.5升。
进一步地,所述的二乙酸碘苯2与硝酸的摩尔比为1:2-1:3。
进一步地,所述的硝酸的体积浓度为20%-40%。
进一步地,二氯甲烷溶解黄色粘稠油状物的用量为每摩尔二乙酸碘苯2添加100~500ml。
本发明还提供一种采用如上述方法制得的硝酸酯基转移试剂,结构如下:
其中,R=烷氧基、酰氧基、芳基、烷基、氢、卤素、烷氧羰基、酰基、三氟甲基、氰基、或硝基。
进一步地,所述硝酸酯基转移试剂结构为:
其中,R=3/4-甲氧基、4-乙酰氧基、3/4-苯基、2/3/4-甲基、4-叔丁基、3,5-二甲基、氢、2/3/4-氟、2/3/4-氯、2/3/4-溴、4-甲氧羰基、4-乙酰基、4-三氟甲基、3,5-二三氟甲基、4-氰基或4-硝基。
本发明还提供一种如上述方法制得的硝酸酯基转移试剂的应用,将硝酸酯基转移试剂1作为硝酸酯基的转移试剂,进行无金属催化的各类型有机物的硝酸酯化反应。
本发明合成的芳基非环三价碘硝酸酯化合物可以作为硝酸酯基的转移试剂,进行多类有机物的硝酸酯化反应。
与现有技术相比,本发明具有以下有益效果:
本发明提供的芳基非环三价碘硝酸酯基转移试剂,具有C2对称的结构,稳定性好、反应活性高。该类试剂以易得的二乙酸芳基碘(如二乙酸碘苯)为起始原料,以硝酸作为硝酸酯基团的来源,避免了混酸或金属硝酸盐的使用,仅需一步反应、结晶即可以极高收率得到高纯度的产品,避免了柱层析,合成高效。可以克服传统上合成硝酸酯化合物的技术所具有的苛刻的反应条件、使用危险的试剂、繁琐危险的后处理和适用底物有限等缺陷,操作简便安全快捷。另一方面,以二乙酸碘苯和硝酸为原料,大大降低了该试剂的合成成本,在其工业化生产和市场推广中也可以有一定的优势。预期社会效益和经济效益显著。
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
以下实施例中采用的二乙酸芳基碘、乙腈、二氯甲烷都是从商业来源购买,采用的硝酸(浓度为38wt%,密度为1.23g/mL,约7.5mol/L)是由市售硝酸(65-68wt%)加水稀释为原体积的二倍。
实施例1
苯基非环三价碘硝酸酯转移试剂(1a)的制备,按以下反应方程式反应:
具体操作步骤为:
在室温下,空气氛围中,反应瓶中依次加入化合物2a(二乙酸碘苯,322克,1摩尔)、乙腈(1000毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,300毫升,2.2当量),敞口反应1小时,用旋转蒸发仪旋去乙腈和副产物乙酸可得到黄色粘稠油状物,用二氯甲烷(100毫升)混合后静置,析出大量黄色固体,布氏漏斗抽滤、二氯甲烷(200毫升)浸泡出去可溶性杂质,抽滤干燥即可得到硝酸酯基转移试剂化合物1a(黄色固体,263克,96%收率)。
表征数据如下:
1H NMR(400MHz,CDCl3):δ7.91(d,J=8.0Hz,4H),7.64(t,J=7.6Hz,2H),7.48(t,J=8.0Hz,2H);13C{1H}NMR(101MHz,CD3CN):δ135.3,133.8,132.4,125.0;IR(KBr,cm-1):3056,2399,1677,1470,1384,994,732,681;HRMS(ESI,m/z):calcd for C12H10I2NO4 +[M-NO3 -]+:485.8694;found 485.8650;Elemental Analysis:calcd(%)for C12H10I2N2O7:[C]26.30,[H]1.84,[N]5.11,[O]20.44;found[C]25.59,[H]1.93,[N]5.01,[O]20.78.。
实施例2
对氰基苯基非环三价碘硝酸酯转移试剂(1b)的制备,按以下反应方程式反应:
具体操作步骤为:
在室温下,空气氛围中,反应瓶中依次加入化合物2b(二乙酸对氰基碘苯,34.7克,0.1摩尔)、二氯甲烷(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,35毫升,2.6当量),敞口反应1小时,用旋转蒸发仪旋去二氯甲烷和副产物乙酸可得到黄色粘稠油状物,用二氯甲烷(50毫升)混合后静置,析出大量固体,布氏漏斗抽滤、二氯甲烷(20毫升)浸泡出去可溶性杂质,抽滤、干燥即可得到硝酸酯基转移试剂化合物1b(淡黄色固体,28.4克,95%收率)。
表征数据如下:
1H NMR(400MHz,CD3CN):δ8.34-8.10(m,4H),7.87(d,J=7.6Hz,4H);13C{1H}NMR(101MHz,CD3CN):δ135.7,135.2,128.6,116.7;IR(KBr,cm-1):3092,2400,1766,1570,1514,1353,850,735;HRMS(ESI,m/z):calcd for C14H8I2N3O4 +[M-NO3 -]+:535.8599;found535.8602.
实施例3
对甲氧羰基苯基非环三价碘硝酸酯转移试剂(1c)的制备,按以下反应方程式反应:
具体操作步骤为:
在室温下,空气氛围中,反应瓶中依次加入化合物2c(二乙酸对甲氧羰基碘苯,38克,0.1摩尔)、二氯甲烷(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,40毫升,3.0当量),敞口反应1小时,用旋转蒸发仪旋去二氯甲烷和副产物乙酸可得到黄色粘稠油状物,二氯甲烷/正己烷重结晶、抽滤、干燥即可得到硝酸酯基转移试剂化合物1c(淡黄色固体,30.5克,92%收率)。
表征数据如下:
1H NMR(400MHz,CDCl3):δ7.99(d,J=8.0Hz,4H),7.94(d,J=8.4Hz,4H),3.98(s,6H);13C{1H}NMR(101MHz,CDCl3):δ155.2,134.1,133.7,132.5,131.0,53.1;IR(KBr,cm-1):3087,3000,2950,2400,1718,1585,1384,1286,1110,753;HRMS(ESI,m/z):calcd forC16H14I2NO8 +[M-NO3 -]+:601.8803;found 601.8807.
实施例4
对氟苯基非环三价碘硝酸酯转移试剂(1d)的制备,按以下反应方程式反应:
具体操作步骤为:
在室温下,空气氛围中,反应瓶中依次加入化合物2d(二乙酸对氟碘苯,34.1克,0.1摩尔)、乙腈(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,30毫升,2.2当量),敞口反应1小时,用旋转蒸发仪旋去乙腈和副产物乙酸可得到黄色粘稠油状物,用二氯甲烷(50毫升)混合后静置,析出大量固体,布氏漏斗抽滤、二氯甲烷(20毫升)浸泡出去可溶性杂质,抽滤、干燥即可得到硝酸酯基转移试剂化合物1d(淡黄色固体,27.5克,94%收率)。
表征数据如下:
1H NMR(400MHz,CD3CN):δ8.09(brs,4H),7.24(brs,4H);13C{1H}NMR(101MHz,CD3CN):δ165.6(JC-F=254.0Hz),138.2(JC-F=9.4Hz),119.5(JC-F=23.3Hz);IR(KBr,cm-1):3091,2399,1766,1576,1481,1383,1230,822,716;HRMS(ESI,m/z):calcd for C12H8F2I2NO4 +[M-NO3 -]+:521.8505;found 521.8514.
实施例5
邻溴苯基非环三价碘硝酸酯转移试剂(1e)的制备,按以下反应方程式反应:
具体操作步骤为:
在室温下,空气氛围中,反应瓶中依次加入化合物2e(二乙酸邻溴碘苯,40克,0.1摩尔)、二氯甲烷(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,30毫升,2.2当量),敞口反应1小时,用旋转蒸发仪旋去二氯甲烷和副产物乙酸可得到黄色粘稠油状物,用二氯甲烷(50毫升)混合后静置,析出大量固体,布氏漏斗抽滤、二氯甲烷(20毫升)浸泡出去可溶性杂质,抽滤、干燥即可得到硝酸酯基转移试剂化合物1e(淡黄色固体,32.1克,91%收率)。
表征数据如下:
1H NMR(400MHz,CD3CN):δ8.28(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,2H),7.56(t,J=7.6Hz,2H),7.46(t,J=7.6Hz,2H);13C{1H}NMR(101MHz,CD3CN):δ139.4,136.1,134.4,131.2,127.5;IR(KBr,cm-1):3055,2399,1766,1437,1368,1001,745;HRMS(ESI,m/z):calcdfor C12H8Br2I2NO4 +[M-NO3 -]+:641.6904;found641.6911;Elemental Analysis:calcd(%)for C12H8Br2I2N2O7:[C]20.42,[H]1.14,[N]3.97,[O]15.87;found[C]20.24,[H]1.22,[N]3.84,[O]16.18.
实施例6
间溴苯基非环三价碘硝酸酯转移试剂(1f)的制备,按以下反应方程式反应:
具体操作步骤为:
在室温下,空气氛围中,反应瓶中依次加入化合物2f(二乙酸间溴碘苯,40克,0.1摩尔)、二氯甲烷(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,30毫升,2.2当量),敞口反应1小时,用旋转蒸发仪旋去二氯甲烷和副产物乙酸可得到黄色粘稠油状物,用二氯甲烷(50毫升)混合后静置,析出大量固体,布氏漏斗抽滤、二氯甲烷(20毫升)浸泡出去可溶性杂质,抽滤、干燥即可得到硝酸酯基转移试剂化合物1f(白色固体,34.2克,97%收率)。
表征数据如下:
1H NMR(400MHz,CD3CN):δ8.11(s,2H),8.04-7.85(m,2H),7.75(d,J=8.4Hz,2H),7.40(t,J=8.4Hz,2H);13C{1H}NMR(101MHz,CD3CN):δ137.0,136.8,133.8,133.7,124.7,124.4;IR(KBr,cm-1):3158,3072,2398,1765,1557,1452,1378,1306,1286,773,710;HRMS(ESI,m/z):calcd for C12H8Br2I2NO4 +[M-NO3 -]+:641.6904;found 641.6902.。
实施例7
对甲基苯基非环三价碘硝酸酯转移试剂(1g)的制备,按以下反应方程式反应:
具体操作步骤为:
在室温下,空气氛围中,反应瓶中依次加入化合物2g(二乙酸对甲基碘苯,33.6克,0.1摩尔)、乙腈(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,27毫升,2.02当量),敞口反应1小时,用旋转蒸发仪旋去乙腈和副产物乙酸可得到黄色粘稠油状物,用二氯甲烷(50毫升)混合后静置,析出大量固体,布氏漏斗抽滤、二氯甲烷(20毫升)浸泡出去可溶性杂质,抽滤、干燥即可得到硝酸酯基转移试剂化合物1g(淡黄色固体,27.4克,95%收率)。
表征数据如下:
1H NMR(400MHz,CD3CN):δ7.87(d,J=8.0Hz,4H),7.27(d,J=8.0Hz,4H),2.42(s,6H);13C{1H}NMR(101MHz,CD3CN):δ145.2,135.4,132.9,121.9,21.6;HRMS(ESI,m/z):calcdfor C14H14I2NO4 +[M-NO3 -]+:513.9007;found 513.9014.
实施例8
对苯基非环三价碘硝酸酯转移试剂(1h)的制备,按以下反应方程式反应:
具体操作步骤为:
在冰水浴下,空气氛围中,反应瓶中依次加入化合物2h(二乙酸对苯基碘苯,39.8克,0.1摩尔)、乙腈(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,27毫升,2.02当量),敞口反应10分钟,静置挥发去除乙腈和乙酸,二氯甲烷(50毫升)浸泡出去可溶性杂质,抽滤、干燥即可得到硝酸酯基转移试剂化合物1h(淡黄色固体,29.4克,84%收率)。
表征数据如下:
1H NMR(400MHz,CD3CN):δ8.06(d,J=8.4Hz,4H),7.64(d,J=8.4Hz,4H),7.54(s,4H),7.43(d,J=5.2Hz,6H);13C{1H}NMR(101MHz,CD3CN):δ146.1,139.6,135.8,130.6,130.1,129.8,128.3,123.7;HRMS(ESI,m/z):calcd for C24H18I2NO4 +[M-NO3 -]+:637.9320;found 637.9326.
实施例9
1-萘基非环三价碘硝酸酯转移试剂(1i)的制备,按以下反应方程式反应:
具体操作步骤为:
在冰水浴下,空气氛围中,反应瓶中依次加入化合物2i(二乙酸1-萘基碘,37.2克,0.1摩尔)、乙腈(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,27毫升,2.02当量),敞口反应10分钟,静置挥发去除乙腈和乙酸,二氯甲烷(50毫升)浸泡出去可溶性杂质,抽滤、干燥即可得到硝酸酯基转移试剂化合物1i(亮黄色固体,24.3克,74%收率)。
表征数据如下:
1H NMR(400MHz,CD3CN):δ8.15(d,J=7.2Hz,2H),8.07(d,J=8.4Hz,2H),7.95(d,J=8.0Hz,2H),7.87(d,J=8.0Hz,2H),7.66-7.60(m,2H),7.62-7.54(m,2H),7.25(t,J=7.6Hz,2H);13C{1H}NMR(101MHz,CD3CN):δ138.7,135.14,135.12,132.7,130.2,129.7,129.0,128.1,128.0;HRMS(ESI,m/z):calcd for C20H14I2NO4 +[M-NO3 -]+:585.9007;found585.9013.
实施例10
对甲氧基苯基非环三价碘硝酸酯转移试剂(1j)的制备,按以下反应方程式反应:
具体操作步骤为:
在冰水浴下,空气氛围中,反应瓶中依次加入化合物1j(二乙酸对甲氧基碘苯,35.2克,0.1摩尔)、乙腈(200毫升)和硝酸(浓度为38wt%,密度为1.23g/mL,37毫升,2.02当量),敞口反应10分钟,静置挥发去除乙腈和乙酸,二氯甲烷(50毫升)浸泡出去可溶性杂质,抽滤、干燥即可得到硝酸酯基转移试剂化合物1j(亮黄色固体,19.8克,65%收率)。
表征数据如下:
1H NMR(400MHz,CD3CN):δ8.06(d,J=8.4Hz,4H),7.04(d,J=8.4Hz,4H),3.87(s,6H);13C{1H}NMR(101MHz,CD3CN):δ139.2,138.2,137.9,117.6,56.6;HRMS(ESI,m/z):calcdfor C14H14I2NO6 +[M-NO3 -]+:545.8905;found 545.8908.
试验例1:β-酮酰胺的硝酸酯化
具体操作步骤为:依次将硝酸酯转移试剂1a(60.3毫克,0.55毫摩尔)、CH2Cl2(2毫升)和β-酮酰胺S1a(61.9毫克,0.2毫摩尔)加入反应管,室温下搅拌反应1分钟,TLC检测反应结束后,用石油醚/乙酸乙酯作为洗脱剂,采用硅胶(200-300目)进行柱色谱纯化得到双硝酸酯化产物S1b(白色固体,51.9毫克,70%收率)。
表征如下:
1H NMR(400MHz,CDCl3):δ7.79(d,J=7.6Hz,1H),7.69(t,J=7.6Hz,1H),7.52(d,J=7.6Hz,1H),7.43(t,J=7.6Hz,1H),6.12(s,1H),4.31(d,J=17.2Hz,1H),3.27(d,J=16.8Hz,1H),2.07(s,3H),1.98(s,5H),1.66(d,J=2.8Hz,7H).
试验例2:合成β-硝酸酯化的羰基化合物
具体操作步骤为:依次将硝酸酯转移试剂1a(2.56克,5.1毫摩尔)、Zn(OTf)2(36毫克,0.1毫摩尔)、CH2Cl2(20毫升)和环丙醇硅醚S2a(2.56克,10毫摩尔)加入反应管,室温下搅拌反应5分钟,TLC检测反应结束后,用石油醚/乙酸乙酯作为洗脱剂,采用硅胶(200-300目)进行柱色谱纯化得到硝酸酯化产物S2b(白色固体,1.57克,64%收率)。
表征如下:
1H NMR(400MHz,CDCl3):δ8.45(s,1H),8.01(d,J=8.8Hz,1H),7.97(d,J=8.0Hz,1H),7.91(t,J=9.2Hz,2H),7.61(dt,J=21.6,7.2Hz,2H),4.98(t,J=6.4Hz,2H),3.55(t,J=6.4Hz,2H);13C{1H}NMR(101MHz,CDCl3):δ195.5,136.0,133.5,132.5,130.2,129.8,129.1,128.9,128.0,127.2,123.6,68.2,35.6;HRMS(ESI,m/z):calcd for C13H12NO4 +[M+H]+:246.0761;found 246.0755.
试验例3:伊索克酸衍生物的硝酸酯化
具体操作步骤为:依次将硝酸酯转移试剂1a(60.3毫克,0.55毫摩尔)、Zn(OTf)2(3.6毫克,0.01毫摩尔)、CH2Cl2(2毫升)和伊索克酸衍生物S3a(90.5毫克,0.2毫摩尔)加入反应管,室温下搅拌反应5分钟,TLC检测反应结束后,用石油醚/乙酸乙酯作为洗脱剂,采用硅胶(200-300目)进行柱色谱纯化得到硝酸酯化产物S3b(无色油状物,70.4毫克,80%收率)。
表征如下:
1H NMR(400MHz,CDCl3):δ8.11(s,1H),7.88(d,J=7.6Hz,1H),7.56(t,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),7.42(d,J=8.8Hz,1H),7.36(d,J=7.6Hz,1H),7.03(d,J=8.4Hz,1H),5.19(s,2H),4.68(t,J=6.4Hz,2H),4.10(t,J=5.6Hz,2H),3.63(s,2H),2.80(t,J=6.0Hz,2H),2.46(t,J=6.4Hz,2H),1.70-1.57(m,4H);13C{1H}NMR(101MHz,CDCl3):δ205.7,191.0,171.6,160.6,140.5,136.5,135.7,133.0,132.5,129.6,129.4,128.0,127.9,125.2,121.2,73.8,67.6,64.6,42.6,40.4,39.2,28.0,19.9;HRMS(ESI,m/z):calcdfor C23H23O6 +[M-NO2 -]+:395.1489;found395.1492.
试验例4:β-酮酯的硝酸酯化
具体操作步骤为:依次将硝酸酯转移试剂1a(60.3毫克,0.55毫摩尔)、CH2Cl2(2毫升)和β-酮酯S4a(62.1毫克,0.2毫摩尔)加入反应管,室温下搅拌反应1分钟,TLC检测反应结束后,用石油醚/乙酸乙酯作为洗脱剂,采用硅胶(200-300目)进行柱色谱纯化得到双硝酸酯化产物S4b(白色固体,74.3毫克,99%收率)。
表征如下:
1H NMR(400MHz,CDCl3):δ7.82(d,J=7.6Hz,1H),7.70(t,J=7.0,1H),7.51(d,J=7.6Hz,1H),7.45(t,J=7.6Hz,1H),4.21(d,J=18.0Hz,1H),3.40(d,J=17.6Hz,1H),2.15(s,3H),2.06(d,J=2.8Hz,6H),1.62(t,J=2.8Hz,6H).
对比例
以专利申请CN 202210032363.8的两步法(以双氯芳基碘和硝酸银为原料)制备相同的硝酸酯基转移试剂作为对比例,与本发明一步法(以二乙酸碘苯和硝酸为原料)制得的硝酸酯基转移试剂进行比较,收率结果如下:
从上表可以看出,制备相同的产品,本发明方法收率一般更高,而且本发明避免了金属硝酸盐的使用,仅需一步反应、结晶即可以极高收率得到高纯度的产品,更适合工业化生产。
Claims (10)
2.根据权利要求1所述的制备方法,其特征在于,所述的方法具体步骤如下:
在室温下,空气氛围中,反应器中依次加入二乙酸碘苯2、溶剂、硝酸,敞口反应0.5-3小时,去除溶剂和副产物乙酸得到黄色粘稠油状物,用二氯甲烷溶解后静置,析出黄色固体,抽滤、干燥即可得到硝酸酯基转移试剂1。
3.根据权利要求2所述的制备方法,其特征在于,所述的溶剂为二氯甲烷、乙腈或乙酸。
4.根据权利要求3所述的制备方法,其特征在于,当溶剂为:二氯甲烷或乙腈时,溶剂的用量为每摩尔二乙酸碘苯2添加溶剂1升;
当溶剂为乙酸时,溶剂的用量为每摩尔二乙酸碘苯2添加溶剂0.5升。
5.根据权利要求2所述的制备方法,其特征在于,所述的二乙酸碘苯2与硝酸的摩尔比为1:2-1:3。
6.根据权利要求2所述的制备方法,其特征在于,所述的硝酸的体积浓度为20%-40%。
7.根据权利要求2所述的制备方法,其特征在于,二氯甲烷溶解黄色粘稠油状物的用量为每摩尔二乙酸碘苯2添加100~500ml。
10.一种如权利要求8所述方法制得的硝酸酯基转移试剂的应用,其特征在于,将硝酸酯基转移试剂1作为硝酸酯基的转移试剂,进行无金属催化的各类型有机物的硝酸酯化反应。
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