CN112375040B - 一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 - Google Patents
一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 Download PDFInfo
- Publication number
- CN112375040B CN112375040B CN202011362322.2A CN202011362322A CN112375040B CN 112375040 B CN112375040 B CN 112375040B CN 202011362322 A CN202011362322 A CN 202011362322A CN 112375040 B CN112375040 B CN 112375040B
- Authority
- CN
- China
- Prior art keywords
- alcohol
- isoalloxazine
- chloride
- alcohol dehydrogenase
- trifluoromethyl
- 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 45
- -1 nitrogen-containing heterocyclic compound Chemical class 0.000 title claims abstract description 45
- 239000000126 substance Substances 0.000 title claims abstract description 18
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims abstract description 76
- 108010021809 Alcohol dehydrogenase Proteins 0.000 claims abstract description 58
- 102000007698 Alcohol dehydrogenase Human genes 0.000 claims abstract description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000005515 coenzyme Substances 0.000 claims abstract description 20
- 150000001412 amines Chemical class 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 57
- 229920002554 vinyl polymer Polymers 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 210000004185 liver Anatomy 0.000 claims description 38
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 claims description 12
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 12
- 150000002211 flavins Chemical class 0.000 claims description 11
- XPFVYQJUAUNWIW-UHFFFAOYSA-N furfuryl alcohol Chemical compound OCC1=CC=CO1 XPFVYQJUAUNWIW-UHFFFAOYSA-N 0.000 claims description 11
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 8
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 claims description 6
- OOCCDEMITAIZTP-UHFFFAOYSA-N allylic benzylic alcohol Natural products OCC=CC1=CC=CC=C1 OOCCDEMITAIZTP-UHFFFAOYSA-N 0.000 claims description 6
- VSSAZBXXNIABDN-UHFFFAOYSA-N cyclohexylmethanol Chemical compound OCC1CCCCC1 VSSAZBXXNIABDN-UHFFFAOYSA-N 0.000 claims description 6
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 claims description 4
- FVXBTPGZQMNAEZ-UHFFFAOYSA-N 3-amino-2-methylpropan-1-ol Chemical compound NCC(C)CO FVXBTPGZQMNAEZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 4
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
- 108020000290 Mannitol dehydrogenase Proteins 0.000 claims description 2
- XJLXINKUBYWONI-NNYOXOHSSA-O NADP(+) Chemical group NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-O 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical compound C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 239000012062 aqueous buffer Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 35
- 239000007800 oxidant agent Substances 0.000 abstract description 22
- 230000001590 oxidative effect Effects 0.000 abstract description 20
- 102000004190 Enzymes Human genes 0.000 abstract description 10
- 108090000790 Enzymes Proteins 0.000 abstract description 10
- 230000003197 catalytic effect Effects 0.000 abstract description 6
- 230000008929 regeneration Effects 0.000 abstract description 6
- 238000011069 regeneration method Methods 0.000 abstract description 6
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 4
- 238000010276 construction Methods 0.000 abstract description 3
- 238000010523 cascade reaction Methods 0.000 abstract description 2
- 231100000481 chemical toxicant Toxicity 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 34
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 34
- 229950006238 nadide Drugs 0.000 description 33
- 239000000047 product Substances 0.000 description 25
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 22
- 239000008057 potassium phosphate buffer Substances 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 16
- 238000004445 quantitative analysis Methods 0.000 description 16
- 238000001228 spectrum Methods 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 230000001172 regenerating effect Effects 0.000 description 14
- 230000008878 coupling Effects 0.000 description 12
- 238000010168 coupling process Methods 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 7
- 235000019445 benzyl alcohol Nutrition 0.000 description 7
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 7
- 230000005311 nuclear magnetism Effects 0.000 description 7
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- BKMMTJMQCTUHRP-UHFFFAOYSA-N 2-aminopropan-1-ol Chemical compound CC(N)CO BKMMTJMQCTUHRP-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 4
- DWYHDSLIWMUSOO-UHFFFAOYSA-N 2-phenyl-1h-benzimidazole Chemical compound C1=CC=CC=C1C1=NC2=CC=CC=C2N1 DWYHDSLIWMUSOO-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 150000001556 benzimidazoles Chemical class 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 4
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- PYRWEZBEXFMUHH-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1h-benzimidazole Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=CC=C2N1 PYRWEZBEXFMUHH-UHFFFAOYSA-N 0.000 description 3
- ZUKYCLYMFNPDCT-UHFFFAOYSA-N 2-cyclohexyl-1h-benzimidazole Chemical compound C1CCCCC1C1=NC2=CC=CC=C2N1 ZUKYCLYMFNPDCT-UHFFFAOYSA-N 0.000 description 3
- XBHOUXSGHYZCNH-UHFFFAOYSA-N 2-phenyl-1,3-benzothiazole Chemical compound C1=CC=CC=C1C1=NC2=CC=CC=C2S1 XBHOUXSGHYZCNH-UHFFFAOYSA-N 0.000 description 3
- YNFBMDWHEHETJW-UHFFFAOYSA-N 2-pyridin-2-yl-1h-benzimidazole Chemical compound N1=CC=CC=C1C1=NC2=CC=CC=C2N1 YNFBMDWHEHETJW-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 3
- 238000006356 dehydrogenation reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 2
- LCZUOKDVTBMCMX-UHFFFAOYSA-N 2,5-Dimethylpyrazine Chemical compound CC1=CN=C(C)C=N1 LCZUOKDVTBMCMX-UHFFFAOYSA-N 0.000 description 2
- JCBPETKZIGVZRE-UHFFFAOYSA-N 2-aminobutan-1-ol Chemical compound CCC(N)CO JCBPETKZIGVZRE-UHFFFAOYSA-N 0.000 description 2
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 2
- RJRKURJUHLRUPD-UHFFFAOYSA-N 2-heptyl-1h-benzimidazole Chemical compound C1=CC=C2NC(CCCCCCC)=NC2=C1 RJRKURJUHLRUPD-UHFFFAOYSA-N 0.000 description 2
- WXSDHOPIGKDWTF-UHFFFAOYSA-N 3-(3,4-diaminophenyl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C1=CC=C(N)C(N)=C1 WXSDHOPIGKDWTF-UHFFFAOYSA-N 0.000 description 2
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 2
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- UYJUZNLFJAWNEZ-UHFFFAOYSA-N fuberidazole Chemical compound C1=COC(C=2NC3=CC=CC=C3N=2)=C1 UYJUZNLFJAWNEZ-UHFFFAOYSA-N 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 239000000852 hydrogen donor Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000005691 oxidative coupling reaction Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 229940100595 phenylacetaldehyde Drugs 0.000 description 2
- 150000004986 phenylenediamines Chemical class 0.000 description 2
- 229950009195 phenylpropanol Drugs 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- ZPHGMBGIFODUMF-UHFFFAOYSA-N thiophen-2-ylmethanol Chemical compound OCC1=CC=CS1 ZPHGMBGIFODUMF-UHFFFAOYSA-N 0.000 description 2
- HCFJVKDUASLENU-WCCKRBBISA-N (2s)-pyrrolidine-2-carboxylic acid;zinc Chemical compound [Zn].OC(=O)[C@@H]1CCCN1 HCFJVKDUASLENU-WCCKRBBISA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- MNEIJGDSFRHGMS-UHFFFAOYSA-N 1-(phenylmethyl)benzimidazole Chemical compound C1=NC2=CC=CC=C2N1CC1=CC=CC=C1 MNEIJGDSFRHGMS-UHFFFAOYSA-N 0.000 description 1
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- 239000001934 2,5-dimethylpyrazine Substances 0.000 description 1
- QQLPPRIZUPEKMV-UHFFFAOYSA-N 2-(2-phenylethenyl)-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1C=CC1=CC=CC=C1 QQLPPRIZUPEKMV-UHFFFAOYSA-N 0.000 description 1
- FECNOIODIVNEKI-UHFFFAOYSA-N 2-[(2-aminobenzoyl)amino]benzoic acid Chemical class NC1=CC=CC=C1C(=O)NC1=CC=CC=C1C(O)=O FECNOIODIVNEKI-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- XDXPOGUNVDBTHC-UHFFFAOYSA-N 2-ethyl-5-phenyl-1h-pyrrole Chemical compound N1C(CC)=CC=C1C1=CC=CC=C1 XDXPOGUNVDBTHC-UHFFFAOYSA-N 0.000 description 1
- SLWJBYKFHXHBEG-UHFFFAOYSA-N 2-heptan-2-yl-1H-benzimidazole Chemical compound C1=CC=C2NC(C(C)CCCCC)=NC2=C1 SLWJBYKFHXHBEG-UHFFFAOYSA-N 0.000 description 1
- FIISKTXZUZBTRC-UHFFFAOYSA-N 2-phenyl-1,3-benzoxazole Chemical compound C1=CC=CC=C1C1=NC2=CC=CC=C2O1 FIISKTXZUZBTRC-UHFFFAOYSA-N 0.000 description 1
- IQVAERDLDAZARL-UHFFFAOYSA-N 2-phenylpropanal Chemical compound O=CC(C)C1=CC=CC=C1 IQVAERDLDAZARL-UHFFFAOYSA-N 0.000 description 1
- XXCGVPNWMZKOER-UHFFFAOYSA-N 2-thiophen-2-yl-1h-benzimidazole Chemical compound C1=CSC(C=2NC3=CC=CC=C3N=2)=C1 XXCGVPNWMZKOER-UHFFFAOYSA-N 0.000 description 1
- DZTRFEMKGXEPBX-UHFFFAOYSA-N 3,5-dibenzylpyridine Chemical compound C=1N=CC(CC=2C=CC=CC=2)=CC=1CC1=CC=CC=C1 DZTRFEMKGXEPBX-UHFFFAOYSA-N 0.000 description 1
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 1
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 1
- JKTYGPATCNUWKN-UHFFFAOYSA-N 4-nitrobenzyl alcohol Chemical compound OCC1=CC=C([N+]([O-])=O)C=C1 JKTYGPATCNUWKN-UHFFFAOYSA-N 0.000 description 1
- YQDGQEKUTLYWJU-UHFFFAOYSA-N 5,6,7,8-tetrahydroquinoline Chemical compound C1=CC=C2CCCCC2=N1 YQDGQEKUTLYWJU-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229910016374 CuSO45H2O Inorganic materials 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- UHSJCMHHTWEGKJ-UHFFFAOYSA-N N-hydroxyquinoxaline-2-carboximidoyl chloride Chemical compound ON=C(Cl)c1cnc2ccccc2n1 UHSJCMHHTWEGKJ-UHFFFAOYSA-N 0.000 description 1
- 229910004879 Na2S2O5 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000012425 OXONE® Substances 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940033495 antimalarials Drugs 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 229940121383 antituberculosis agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- YDVGDXLABZAVCP-UHFFFAOYSA-N azanylidynecobalt Chemical compound [N].[Co] YDVGDXLABZAVCP-UHFFFAOYSA-N 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000010364 biochemical engineering Methods 0.000 description 1
- BVLXNPRUOXPBII-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)gallanyl trifluoromethanesulfonate Chemical compound [Ga+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BVLXNPRUOXPBII-UHFFFAOYSA-K 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000000080 chela (arthropods) Anatomy 0.000 description 1
- 229940117916 cinnamic aldehyde Drugs 0.000 description 1
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000005913 hydroamination reaction Methods 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000005415 magnetization Effects 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 239000002923 metal particle Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- PEQJBOMPGWYIRO-UHFFFAOYSA-N n-ethyl-3,4-dimethoxyaniline Chemical compound CCNC1=CC=C(OC)C(OC)=C1 PEQJBOMPGWYIRO-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229960002164 pimobendan Drugs 0.000 description 1
- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- MSGRFBKVMUKEGZ-UHFFFAOYSA-N quinoxalin-6-amine Chemical compound N1=CC=NC2=CC(N)=CC=C21 MSGRFBKVMUKEGZ-UHFFFAOYSA-N 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- NLDYACGHTUPAQU-UHFFFAOYSA-N tetracyanoethylene Chemical group N#CC(C#N)=C(C#N)C#N NLDYACGHTUPAQU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/10—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0006—Oxidoreductases (1.) acting on CH-OH groups as donors (1.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/008—Preparation of nitrogen-containing organic compounds containing a N-O bond, e.g. nitro (-NO2), nitroso (-NO)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/14—Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/30—Nucleotides
- C12P19/32—Nucleotides having a condensed ring system containing a six-membered ring having two N-atoms in the same ring, e.g. purine nucleotides, nicotineamide-adenine dinucleotide
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
- C12Y101/01—Oxidoreductases acting on the CH-OH group of donors (1.1) with NAD+ or NADP+ as acceptor (1.1.1)
- C12Y101/01001—Alcohol dehydrogenase (1.1.1.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
- C12Y101/01—Oxidoreductases acting on the CH-OH group of donors (1.1) with NAD+ or NADP+ as acceptor (1.1.1)
- C12Y101/01255—Mannitol dehydrogenase (1.1.1.255)
-
- 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Pyridine Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明公开了一种酶‑化学级联法制备含氮杂环化合物及其衍生物的方法,将醇、胺、醇脱氢酶、黄素分子和辅酶于溶剂中反应,即得。与现有技术相比,本发明是一种绿色经济的酶‑化学级联方法的构建,用于合成含氮杂环类化合物及其衍生物。与一般有毒化学催化剂相比,本发明选择醇脱氢酶作为催化剂,具有高度的底物专一性,无污染,催化效率高,不使用有毒溶剂,后处理简单等特点。此外,本发明中黄素分子的作用有两个方面,一构成前面酶法再生体系,二在后面化学法中作为氧化剂,整个级联反应中不需要再添加其它氧化剂。
Description
技术领域
本发明属于生物化工领域,具体涉及一种酶-化学级联法制备含氮杂环类化合物及其衍生物的新方法。
背景技术
含氮杂环化合物及其衍生物为杂环化合物家族中的重要成员,广泛存在于天然产物和药物分子中。这些化合物表现出广泛的生物活性和药理学活性,在生物、医药、材料等多个领域有着至关重要的作用。我们围绕含氮杂环化合物及其衍生物的新方法研究展开,构建了一种酶-化学级联催化合成不同含氮杂环化合物及其衍生物的绿色新方法,包括五元(吡咯,吡咯烷酮,吡唑,咪唑等),六元(吡啶,吡嗪等),稠合(吲哚,苯并咪唑等)和其他含氮杂环化合物及其衍生物。
含吡咯的N-杂环是重要的结构基序,广泛应用于药物、农药、催化剂、功能性材料和超分子化学中。已经开发出很多新的合成方法来构建这类药物中间体,例如金属催化的环化、环加成、重排、多组分氧化偶联、加氢胺化/环化等方法。在酸性条件,存在金属催化剂的条件下从1,4-二羰基化合物开始,通过Paal-Knorr缩合与伯胺合成N-取代的吡咯,开发的钴-氮催化剂可耐受酸性液态氢供体(HCOOH),这可能归因于高度分散的金属颗粒,这些颗粒被固态碳质载体的氮物种配位并稳定。非贵金属催化剂的这种独特的非均质特征不仅能够显着减少反应过程中金属种类的损失和总体生产成本,而且还提供了使用可持续的HCOOH代替可燃氢气作为H+供应者;在非贵金属配合物(例如钴或锰的钳子配合物)上进行1,4-丁二醇或1,4-取代的1,4-丁二醇和胺的无催化脱氢偶联,尽管这些均相催化体系在Paal-Knorr缩合反应中表现出出色的性能,但催化剂回收的困难将导致额外的成本和对环境的负面影响;Michlik和Kempe报告了在叔丁醇钠和有机铱催化剂存在下,通过连续脱氢反应由乙醇脱氢引发的可持续仲醇和氨基醇合成2,5-二取代吡咯;合成吡咯的另一种方法是在酸催化剂(例如Al2O3和TiO2)存在下,用伯胺对生物衍生的呋喃化合物进行催化胺化,该吡咯衍生物的收率高20-60%;Li等人开发了一种不需要催化剂或外部氢的通用策略,该方法涉及从N-甲酰基物质(例如HCONH2)与H2O进行原位控制释放HCOOH进行胺和其他酮酸的环化反应。无催化剂的反应体系对于生产吡咯烷酮而言似乎更具可持续性和经济性,而其反应速率远低于金属或酸催化的过程。
吡啶是一种具有共轭结构的六元杂环化合物,吡啶及其衍生物广泛应用于农药、医药、天然产物的合成中,如抗生素头孢立新、抗溃疡药奥美拉唑、降压药比那地尔等,吡啶环与苯环是生物电子等排体,吡啶环取代苯环时化合物的活性得到明显提高,毒性大幅下降,该类含氮杂环类化合物的应用范围广泛,在国内外受到学者们的广泛关注,其工业化生产和科研发展速度迅猛。目前,已经报道了多种构建吡啶取代物的方法,传统上,吡啶的合成主要由胺和羰基化合物缩合制备,包括1,5-二羰基和胺的缩合,Hantzsch吡啶的(2+2+1+1)的缩合,以及1,3-二羰基衍生物与插烯酰胺的(3+3)环化反应。尽管一些合成方法比较高效,但是由于前体不稳定、金属催化剂昂贵且污染环境、操作繁琐直接限制了其在构建一些实用但敏感的吡啶衍生物方面的应用。因此,灵活、高效、绿色的合成方法值得期望。
苯并咪唑类化合物具有特殊的结构、生理活性和反应活性等,其具有重要的生物活性,是医药领域重要的生物活性分子,苯并咪唑及其衍生物是医药工业的重要组成部分。其具有调节血脂、降压、抗癌、抗惊厥、镇痛、镇静、消炎、调节免疫系统、抑制氧化、抑制血凝、抗糖尿病、调节激素水平及中枢神经系统兴奋的功能,还有抵御微生物、杀灭病毒和寄生虫、预防溃疡及杀灭真菌等作用。所以,苯并咪唑类化合物的应用十分广泛,几十年来对苯并咪唑及其衍生物的合成及应用研究从未间断,至今仍十分活跃。随着对苯并咪唑类化合物应用研究的不断开展,相关的合成研究也引起了研究者的广泛重视。人们试图放弃传统的强酸催化、高温反应等苛刻的反应条件,为适应“绿色化学”的要求,研究人员不断努力开发更加高效且环境友好的合成新方法。苯并咪唑类化合物的合成有两种通用方法,一种是将羧酸或衍生物(腈,亚氨酸酯或原酸酯)与苯二胺偶联,通常在强酸性、苛刻的脱水条件下(通常需要高温)或使用诸如磷酸酐的试剂进行偶联;另一种方法是苯胺席夫碱的氧化环脱氢反应,通常是苯二胺和醛的缩合反应原位产生,以MnO2、Pb(OAc)4、PhI(OAc)2、单过硫酸氢钾、2,3-二氯-5,6-二氰对苯醌(DDQ)、I2,1,4-苯醌、四氰基乙烯、苯并呋喃、NaHSO3、Na2S2O5、(NH4)2S2O8和DMF(高沸点氧化剂/溶剂)等试剂可以作为氧化剂来进行脱氢步骤。尽管上面两种方法是实用的,但其仍存在相应的问题,如使用危险或有毒的试剂,或是在苯胺席夫碱的氧化环脱氢反应过程中,可能会形成N-苄基苯并咪唑副产物,从而降低反应选择性以及产率。上述这些反应路径均存在一定的缺点,如:有毒催化剂的使用,反应时间长,温度高,存在副产物,选择性低等,因此,需要开发一种化学酶法制备苯并咪唑衍生物的绿色方法。
喹喔啉及其衍生物是有机合成中的重要中间体,含喹喔啉单元的化合物因其独特的结构可广泛的应用于医药领域,如制造强心剂、兴奋剂、抗疟药、强效抗结核和抗菌剂等,喹喔啉及其衍生物也被应用于染料中间体、聚合物太阳能电池、发光材料等领域,因此喹喔啉衍生物的合成研究受到科研工作者的重视。常用的喹啉衍生物方法主要有:邻苯二胺和α-溴代酮经过串联环化反应;芳醛、6-氨基喹喔啉和季酮酸为原料三组分一锅法合成;以α-氯代喹喔啉-2-甲醛肟与乙酰乙酸乙酯的钠盐经1,3-偶极环加成;α-溴代酮与芳香1,2-二胺氧化缩合;芳香醛与邻苯二胺一锅法反应。常用催化剂包括Yb(OTf)3、CuSO45H2O、三氟甲磺酸镓、锌-L-脯氨酸等,这些方法中有的起始原料简单成本低,产率较高。但存在合成过程较为复杂、反应时间长、反应条件苛刻、催化剂昂贵或有毒害、后处理繁琐不利于环保等问题。
从以上几种含氮杂环化合物及其衍生物合成方法来说,一般都存在使用金属催化剂,酸碱条件,高温,副产物生成、后处理困难等困难亟待解决,因此我们构建了一种酶-化学级联催化高效经济绿色合成含氮杂环化合物及其衍生物的新方法。
发明内容
发明目的:本发明所要解决的技术问题是针对现有技术的不足,提供一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法。
发明思路:本发明首先通过酶的表达与纯化得到纯的醇脱氢酶,再以醇脱氢酶为催化剂,醇为底物,构建氧化还原反应;同时,通过添加催化量的黄素分子及辅酶构成再生体系,以黄素分子作为辅酶的再生催化剂,并与依赖辅酶的醇脱氢酶催化的氧化偶联,构成辅酶的再生循环体系,生物催化醇氧化生成醛;生成的醛与进一步与胺发生缩合反应,通过进一步的化学氧化得到含氮杂环类化合物及其衍生物。具体地,醇在醇脱氢酶及辅酶NAD+的作用下生成醛和NADH,黄素分子再生辅酶NAD+生成醛,所生成的醛和胺反应,在黄素分子的化学氧化作用下,生成含氮杂环化合物及其衍生物,从而构成了一个完整的催化体系。
为了解决上述技术问题,本发明公开了一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法,在溶剂中,以醇和胺为原料,在由醇脱氢酶、黄素分子和辅酶组成的化学酶-化学级联催化体系中反应,即得。
其中,所述的含氮杂环化合物的结构式包括但不限于式I所示:
其中,所述的醇为脂肪醇、环烷醇和芳香醇中的任意一种或几种组合;优选地,所述的醇为苯甲醇、对甲氧基苯甲醇、2-呋喃甲醇、2-噻吩甲醇、2-吡啶甲醇、肉桂醇、正辛醇、环己基甲醇、苯乙醇、环己醇、苯丙醇、苯丙氨醇、2-氨基-1-丙醇和对甲氧基苯甲醇中的任意一种或几种组合;进一步优选地,所述的醇为苯甲醇、对甲氧基苯甲醇、2-呋喃甲醇、2-吡啶甲醇、肉桂醇、正辛醇、环己基甲醇、苯乙醇、苯丙氨醇、2-氨基-1-丙醇和对甲氧基苯甲醇中的任意一种或几种组合;更进一步优选地,所述的醇为苯甲醇、对甲氧基苯甲醇、2-呋喃甲醇、环己基甲醇、肉桂醇和苯乙醇中的任意一种或几种组合。
其中,醇的终浓度为0.5mM-10M;优选地,醇的终浓度为1~10mM;进一步优选地,醇的终浓度为5mM。
其中,所述的胺为芳香胺和脂肪胺中的任意一种或两种组合;优选地,所述的胺为环烷二胺;进一步优选地,所述的胺为邻苯二胺、邻氨基苯硫酚、3-氨基丙醇、3-氨基-2-甲基丙烷-1-醇和6-(3,4二氨基苯基)-4,5二氢-5-甲基-3(2H)-酞嗪酮中的任意一种或几种组合;更进一步优选地,所述的胺为邻苯二胺。
其中,胺的终浓度为0.5mM-10M;优选地,胺的终浓度为1~10mM;进一步优选地,胺的终浓度为6mM。
其中,当所述的醇为含有-NH,即当所述的醇为醇胺时,不需要再额外加入胺;优选地,所述醇胺的终浓度为0.5mM-10M;进一步优选地,所述醇胺的终浓度为1~10mM;更进一步优选地,所述醇胺的终浓度为5mM。
其中,所述的醇胺优选为为2-氨基-1-丙醇。
其中,所述的醇脱氢酶(酶学编号为EC 1.1.1.1)为乙醇脱氢酶(酶活为0.01-1000U/mL)、马肝醇脱氢酶(酶活为0.01-1000U/mL)、酵母醇脱氢酶(酶活为0.01-1000U/mL)和甘露醇脱氢酶(酶活为0.01-1000U/mL)中的任意一种或几种组合;优选地,所述的醇脱氢酶为马肝醇脱氢酶。
酶活定义:在特定条件下,1分钟内转化1微摩尔乙醇所需的酶量为一个活力单位(U)。温度规定为25度,其他条件取反应的最适条件。
其中,醇脱氢酶于整个反应体系中的用量为0.01U/mL-1000U/mL;优选地,醇脱氢酶于整个反应体系中的用量为0.01~100U/mL;进一步优选地,醇脱氢酶于整个反应体系中的用量为0.01~10U/mL;更进一步优选地,醇脱氢酶于整个反应体系中的用量为0.01~100U/mL。
其中,所述的黄素分子为天然黄素和人工合成黄素类似物中的任意一种;优选地,所述的黄素分子为人工合成黄素类似物。
其中,所述的天然黄素为FMN、FAD等,其结构式如下所示:
其中,所述的人工合成黄素类似物为式II所示,其可参考现有技术自行合成[1],或直接购买;
其中,R1和R2分别独立地选自氢、甲基、三氟甲基、甲氧基、卤原子、硝基或氨基;R3选自氢、C1~C5的烷基、苯基或苄基中;X-选自卤离子、硝酸根或三氟甲磺酸根。
优选地,所述的人工合成黄素类似物为式II-1所示的7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物、式II-2所示的8-氯-1,10-乙撑基异咯嗪氯化盐,和式II-3所示的1,10-乙撑基异咯嗪氯化盐中的任意一种。
其中,所述的黄素分子的终浓度为0.1mM-1M;优选地,所述的黄素分子的终浓度为0.5mM-1mM;进一步优选地,所述的黄素分子的终浓度为0.5mM。
其中,所述的辅酶为天然辅酶和人工辅酶中的任意一种或两种组合;优选地,所述的辅酶为天然辅酶。
其中,所述的辅酶为NADP+和NAD+中的任意一种或两种组合;优选地,所述的辅酶为NAD+。
其中,辅酶的终浓度为0.1mM-1M。
其中,所述的溶剂为缓冲溶液;优选地,所述的溶剂为缓冲水溶液;进一步优选地,所述的溶剂为磷酸钾缓冲液、磷酸钠缓冲液、Tris-HCl缓冲液中的任意一种;更进一步优选为磷酸钾缓冲液;再更进一步优选地,所述的溶剂为pH4-10的磷酸钾缓冲液;最优选地,所述的溶剂为pH7,50mM磷酸钾缓冲水溶液。
其中,所述的反应为在pH 4-10,30-70℃反应2-60h。
上述反应是在空气氛围下进行反应的。
有益效果:与现有技术相比,本发明具有如下优势:
(1)本发明是一种绿色经济的酶-化学级联方法的构建,用于合成含氮杂环化合物及其衍生物。
(2)与一般有毒化学催化剂相比,本发明选择醇脱氢酶作为催化剂,具有高度的底物专一性,无污染,催化效率高等特点,溶剂为缓冲水溶液,无有毒溶剂使用,无副产物生成,产物易分离。
(3)本发明中黄素分子的作用有两个方面,一构成前面酶法再生体系,二在后面化学法中作为氧化剂,整个级联反应中不需要再添加其它氧化剂。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明,本发明的上述和/或其他方面的优点将会变得更加清楚。
图1为实施例1的反应原理图,其中,HLADH为马肝醇脱氢酶,F4为人工合成黄素类似物。
图2为实施例1产物2-苯基苯并咪唑的氢谱图。
图3为实施例1产物2-苯基苯并咪唑的碳谱图。
图4为实施例2产物2-(4-甲氧基苯基)苯并咪唑的氢谱图。
图5为实施例2产物2-(4-甲氧基苯基)苯并咪唑的碳谱图。
图6为实施例3产物2-呋喃基-苯并咪唑的氢谱图。
图7为实施例3产物2-呋喃基-苯并咪唑的碳谱图。
图8为实施例4产物2-噻吩-苯并咪唑的氢谱图。
图9为实施例4产物2-噻吩-苯并咪唑的碳谱图。
图10为实施例5产物2-吡啶基-苯并咪唑的氢谱图。
图11为实施例5产物2-吡啶基-苯并咪唑的碳谱图。
图12为实施例7产物2-庚基-苯并咪唑的氢谱图。
图13为实施例7产物2-庚基-苯并咪唑的碳谱图。
图14为实施例8产物2-环己基-苯并咪唑的氢谱图。
图15为实施例8产物2-环己基-苯并咪唑的碳谱图。
图16为实施例9产物2-苯基-苯并噻唑的氢谱图。
图17为实施例9产物2-苯基-苯并噻唑的碳谱图。
具体实施方式
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
以下结合具体实施例,对本发明做进一步说明。应理解,以下实施例仅用于说明本发明而非用于限制本发明的范围。以下实施例中,所述的涉及醇、胺、黄素分子和辅酶的浓度均指该体系中的终浓度;所述的醇脱氢酶的用量是相对于整个反应体系的用量。
本发明的含氮类杂环化合物及其衍生物的生产方法是以醇为底物,在氧气或空气气氛条件下,利用NAD+依赖的马肝醇脱氢酶,催化量的人工合成黄素类似物和辅酶催化生产醛,产生的醛,进一步与胺反应,在人工合成黄素类似物的作用下,生成含氮杂环化合物及其衍生物。
以下实施例中,所述的马肝醇脱氢酶的酶活为5U/mL。
实施例1:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化苯甲醇制备苯甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的苯甲醛与1,2-苯二胺反应,生成2-苯基苯并咪唑,其反应原理图如图1所示。苯甲醇在以马肝醇脱氢酶为催化剂,人工合成黄素类似物和辅酶构成的再生反应体系下,生成苯甲醛。生成的苯甲醛与1,2-苯二胺继续反应,在人工合成黄素类似物的氧化催化下生成最终的产物2-苯基苯并咪唑。
在30℃,200rpm摇床中,在2mL 100mM的pH7的磷酸钾缓冲液中,苯甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应48h,通过HPLC定量分析,产率99%,产物的核磁如图2和图3所示。
实施对照1:
同实施例1,试验其他量保持不变,其他量保持不变,7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物变为0.1mM,反应48小时,通过HPLC定量分析,产率68%。
实施对照2:
同实施例1,实施对照试验其他量保持不变,其他量保持不变,7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物变为0.2mM,反应48小时,通过HPLC定量分析,产率76%。
实施例2:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化对甲氧基苯甲醇制备对甲氧基苯甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的对甲氧基苯甲醛与1,2-苯二胺反应,生成2-(4甲氧基苯基)苯并咪唑。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,对甲氧基苯甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应4h,通过HPLC定量分析,产率99%,产物的核磁如图4和图5所示。
实施例3:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化2-呋喃甲醇制备2-呋喃甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的2-呋喃甲醛与1,2-苯二胺反应,生成麦穗宁。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,2-呋喃甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物1mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应12h,通过HPLC定量分析,产率88%,产物的核磁如图6和图7所示。
对照实施例3:
同实施例3,其他量保持不变,7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物变为0.5mM,反应24小时,通过HPLC定量分析,产率67%。
实施例4:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化2-噻吩甲醇制备2-噻吩甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的2-噻吩甲醛与1,2-苯二胺反应,生成2(2噻吩基)1h苯并咪唑。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,2-噻吩甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物1mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应24h,通过HPLC定量分析,产率57%,产物的核磁如图8和图9所示。
实施例5:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化2-吡啶甲醇制备2-吡啶甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的2-吡啶甲醛与1,2-苯二胺反应,生成2(2吡啶基)1h苯并咪唑。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,2-吡啶甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物1mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应24h,通过HPLC定量分析,产率87%,产物的核磁如图10和图11所示。
对照实施例4:
同实施例5,其他量保持不变,7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物变为2mM,反应24小时,通过HPLC定量分析,产率63%。
实施例6:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化肉桂醇制备肉桂醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的肉桂醛与1,2-苯二胺反应,生成2-(2-苯基乙烯基)-1H-苯并咪唑。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,肉桂醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应12h,通过HPLC定量分析,产率82%。
实施例7:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化正辛醇制备正辛醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的正辛醛与1,2-苯二胺反应,生成2-(2-庚基)-苯并咪唑。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,正辛醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物1mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应12h,通过HPLC定量分析,产率72%,产物的核磁如图12和图13所示。
实施例8:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化环己基甲醇制备环己基甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的环己基甲醛与1,2-苯二胺反应,生成2环己基1h苯并咪唑。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,环己基甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应48h,通过HPLC定量分析,产率91%,产物的核磁如图14和图15所示。
实施例9:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化苯甲醇制备苯甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的苯甲醛与邻氨基苯硫酚反应,生成2-苯基苯并噻唑。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,苯甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,邻氨基苯硫酚6mM,反应液与外界空气相连通,反应24h,通过HPLC定量分析,产率18%,产物的核磁如图16和图17所示。
实施例10:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化苯甲醇制备苯甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的苯甲醛与邻氨基苯酚反应。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,苯甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,邻氨基苯酚6mM,反应液与外界空气相连通,反应24h,未监测到2-苯基苯并恶唑生成。
实施例11:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化对硝基苯甲醇制备对硝基苯甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的对硝基苯甲醛与1,2-苯二胺反应。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,对硝基苯甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,1,2-苯二胺6mM,反应液与外界空气相连通,反应24h,通过HPLC定量分析,产率15%。
实施例12:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化苯乙醇制备苯乙醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的苯乙醛与2-氨基-1-丁醇反应。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,苯乙醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,2-氨基-1-丁醇6mM,反应液与外界空气相连通,反应24h,通过HPLC定量分析,生成2-乙基-5-苯基-1H-吡咯,产率92%。
实施例13:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化环己醇制备环己醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的环己醛与3-氨基丙醇反应。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,环己醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,3-氨基丙醇6mM,反应液与外界空气相连通,反应24h,通过HPLC定量分析,生成5,6,7,8-四氢喹啉,产率40%。
实施例14:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化苯丙醇制备苯丙醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的苯丙醛与3-氨基-2-甲基丙烷-1-醇反应。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,苯丙醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,3-氨基-2-甲基丙烷-1-醇6mM,反应液与外界空气相连通,反应24h,通过HPLC定量分析,生成3-苄基-5-苯甲基吡啶,产率50%。
实施例15:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化2-氨基-1-丙醇,7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂进一步氧化反应。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,2-氨基-1-丙醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,反应液与外界空气相连通,反应24h,通过HPLC定量分析,生成2,5-二甲基吡嗪,产率45%。
实施例16:
以7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为再生NAD+的催化剂与马肝醇脱氢酶偶联催化对甲氧基苯甲醇制备对甲氧基苯甲醛。7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物作为氧化剂,产生的对甲氧基苯甲醛与6-(3,4-二氨基苯基)-4,5-二氢-5-甲基-3(2H)-哒嗪酮反应。
在30℃,200rpm摇床中,在2mL 100mM的pH7磷酸钾缓冲液中,对甲氧基苯甲醇5mM、NAD+1mM、7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物0.5mM、马肝醇脱氢酶5U/mL,6-(3,4-二氨基苯基)-4,5-二氢-5-甲基-3(2H)-哒嗪酮6mM,反应液与外界空气相连通,反应24h,通过HPLC定量分析,生成药物中间体匹莫苯丹,产率50%。
本发明提供了一种酶-化学级联法制备含氮杂环化合物及其衍生物的思路及方法,具体实现该技术方案的方法和途径很多,以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。
Claims (5)
1.一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法,其特征在于,将醇、胺、醇脱氢酶、黄素分子和辅酶于溶剂中反应,即得;
其中,所述含氮杂环化合物及其衍生物为式I所示中的任意一种;
其中,所述的醇为苯甲醇、对甲氧基苯甲醇、2-呋喃甲醇、环己基甲醇、肉桂醇和苯乙醇中的任意一种或几种组合;
其中,所述的胺为邻苯二胺、邻氨基苯硫酚、3-氨基丙醇、3-氨基-2-甲基丙烷-1-醇和6-(3,4二氨基苯基)-4,5二氢-5-甲基-3(2H)-酞嗪酮中的任意一种或几种组合;
其中,所述的辅酶为NADP+和NAD+中的任意一种或两种组合;
其中,所述的黄素分子为式II所示人工合成黄素类似物中的任意一种;
其中,R1和R2分别独立地选自氢、甲基、三氟甲基、甲氧基、卤原子、硝基或氨基;R3选自氢、C1~C5的烷基;X-选自卤离子、硝酸根或三氟甲磺酸根。
2.根据权利要求1所述的方法,其特征在于,所述的醇脱氢酶为乙醇脱氢酶、马肝醇脱氢酶、酵母醇脱氢酶和甘露醇脱氢酶中的任意一种或几种组合。
3.根据权利要求1所述的方法,其特征在于,所述的人工合成黄素类似物为7-三氟甲基-N1,N10-乙烯基异咯嗪氯化物、8-氯-1,10-乙撑基异咯嗪氯化盐和1,10-乙撑基异咯嗪氯化盐中的任意一种。
4.根据权利要求1所述的方法,其特征在于,所述的溶剂为缓冲水溶液。
5.根据权利要求1所述的方法,其特征在于,所述的反应为在pH 4-10,30-70℃反应,反应时间2-60h。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011362322.2A CN112375040B (zh) | 2020-11-27 | 2020-11-27 | 一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 |
PCT/CN2021/113184 WO2022110916A1 (zh) | 2020-11-27 | 2021-08-18 | 一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 |
CA3200381A CA3200381C (en) | 2020-11-27 | 2021-08-18 | Method for preparing nitrogen-containing heterocyclic compound and derivative thereof by enzymatic-chemical cascade method |
GB2307487.5A GB2616743B (en) | 2020-11-27 | 2021-08-18 | Preparation of nitrogen-containing heterocyclic compounds by an enzymatic-chemical cascade method |
US18/253,861 US20240026400A1 (en) | 2020-11-27 | 2021-08-18 | Method for preparing nitrogen-containing heterocyclic compound and derivative thereof by enzymatic-chemical cascade method |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011362322.2A CN112375040B (zh) | 2020-11-27 | 2020-11-27 | 一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112375040A CN112375040A (zh) | 2021-02-19 |
CN112375040B true CN112375040B (zh) | 2022-03-04 |
Family
ID=74588488
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011362322.2A Active CN112375040B (zh) | 2020-11-27 | 2020-11-27 | 一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20240026400A1 (zh) |
CN (1) | CN112375040B (zh) |
CA (1) | CA3200381C (zh) |
GB (1) | GB2616743B (zh) |
WO (1) | WO2022110916A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112375040B (zh) * | 2020-11-27 | 2022-03-04 | 南京工业大学 | 一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 |
CN114672526B (zh) * | 2022-04-20 | 2024-01-26 | 南京工业大学 | 一种利用氧化还原中和体系从醇胺合成卤化吲哚的方法 |
CN115710271B (zh) * | 2022-11-18 | 2024-03-22 | 上海交通大学 | 一种可聚合的维生素b2类似物及其制备方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6785223B2 (ja) * | 2015-03-31 | 2020-11-18 | 武田薬品工業株式会社 | 単環式化合物 |
CN105622693B (zh) * | 2016-01-08 | 2018-01-30 | 南京工业大学 | 一种氧化型辅酶nad(p)+的化学再生方法 |
CN109836377B (zh) * | 2017-11-29 | 2022-04-29 | 中国科学院大连化学物理研究所 | 一种烟酰胺腺嘌呤二核苷酸类似物及其合成方法与应用 |
CN108823258B (zh) * | 2018-07-11 | 2022-02-11 | 南京工业大学 | 一种利用全细胞作为催化剂的氧化方法 |
CN110964764B (zh) * | 2018-09-30 | 2022-10-25 | 中国科学院大连化学物理研究所 | 一种利用甲醇还原nad类似物的方法 |
CN112375040B (zh) * | 2020-11-27 | 2022-03-04 | 南京工业大学 | 一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 |
-
2020
- 2020-11-27 CN CN202011362322.2A patent/CN112375040B/zh active Active
-
2021
- 2021-08-18 WO PCT/CN2021/113184 patent/WO2022110916A1/zh active Application Filing
- 2021-08-18 CA CA3200381A patent/CA3200381C/en active Active
- 2021-08-18 US US18/253,861 patent/US20240026400A1/en active Pending
- 2021-08-18 GB GB2307487.5A patent/GB2616743B/en active Active
Also Published As
Publication number | Publication date |
---|---|
WO2022110916A1 (zh) | 2022-06-02 |
CA3200381A1 (en) | 2022-06-02 |
GB2616743A (en) | 2023-09-20 |
CA3200381C (en) | 2023-11-28 |
GB2616743B (en) | 2024-04-03 |
US20240026400A1 (en) | 2024-01-25 |
CN112375040A (zh) | 2021-02-19 |
GB202307487D0 (en) | 2023-07-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112375040B (zh) | 一种酶-化学级联法制备含氮杂环化合物及其衍生物的方法 | |
Pratap et al. | Bakers’ yeast catalyzed synthesis of benzothiazoles in an organic medium | |
Fu et al. | Access to Oxoquinoline Heterocycles by N‐Heterocyclic Carbene Catalyzed Ester Activation for Selective Reaction with an Enone | |
Du et al. | A rapid and efficient synthesis of benzimidazoles using hypervalent iodine as oxidant | |
Yang et al. | A versatile method for the synthesis of benzimidazoles from o-nitroanilines and aldehydes in one step via a reductive cyclization | |
Zhang et al. | Silver-catalyzed intramolecular hydroamination of alkynes in aqueous media: Efficient and regioselective synthesis for fused benzimidazoles | |
Liu et al. | Recent developments in the synthesis of nitrogen-containing heterocycles through C–H/N–h bond functionalizations and oxidative cyclization | |
Ravi et al. | Zn-proline catalyzed selective synthesis of 1, 2-disubstituted benzimidazoles in water | |
Liu et al. | Copper Chloride‐Catalyzed Aerobic Oxidative Annulation of N‐Furfuryl‐β‐Enaminones: Access to Polysubstituted Pyrroles and Indoles | |
Cai et al. | Catalyst-free oxidative N–N coupling for the synthesis of 1, 2, 3-triazole compounds with tBuONO | |
Porcheddu et al. | Base‐mediated Transition‐metal‐free Dehydrative C− C and C− N Bond‐forming Reactions from Alcohols | |
Xue et al. | Phosphine-mediated sequential annulations of allenyl ketone and isocyanide: a bicyclization strategy to access a furan-fused eight-membered ring and a spirocycle | |
Guo et al. | C–H alkenylation/cyclization and sulfamidation of 2-phenylisatogens using N-oxide as a directing group | |
Ghorai et al. | Divergent Functionalization of N‐Alkyl‐2‐alkenylanilines: Efficient Synthesis of Substituted Indoles and Quinolines | |
Yue et al. | Rapid abnormal [3+ 2]-cycloaddition of isatin N, N′-cyclic azomethine imine 1, 3-dipoles with chalcones | |
Li et al. | Enantioselective synthesis of pyrazolone derivatives catalysed by a chiral squaramide catalyst | |
Choudhary et al. | Recent scenario for the synthesis of benzimidazole moiety (2020–2022) | |
Tashrifi et al. | Reactions involving multiple isocyanide insertions | |
Chen et al. | Asymmetric synthesis of oxazolines bearing α-stereocenters through radical addition–enantioselective protonation enabled by cooperative catalysis | |
Rostamizadeh et al. | Very fast and efficient synthesis of some novel substituted 2-arylbenzimidazoles in water using ZrOCl 2· nH 2 O on montmorillonite K10 as catalyst | |
Chen et al. | Rh (iii)-catalyzed [4+ 1] cyclization of aryl substituted pyrazoles with cyclopropanols via C–H activation | |
Kutasevich et al. | Unexpected Aldehyde-Catalyzed Reaction of Imidazole N-Oxides with Ethyl Cyanoacetate | |
CN108976241B (zh) | 一种手性1,4-二氢吡喃并[2,3-c]吡唑类化合物的合成方法 | |
Cao et al. | Access to Fully Substituted Dihydropyrimidines via Dual Copper/Photoredox‐Catalyzed Domino Annulation of Oxime Esters and Imines | |
Jing et al. | Persulfate promoted carbamoylation of N-arylacrylamides and N-arylcinnamamides with 4-carbamoyl-Hantzsch esters |
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 |