CN117327052A - 一种1,2,3-三氮唑类饲料添加剂及其制备方法和应用 - Google Patents
一种1,2,3-三氮唑类饲料添加剂及其制备方法和应用 Download PDFInfo
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- CN117327052A CN117327052A CN202310290013.6A CN202310290013A CN117327052A CN 117327052 A CN117327052 A CN 117327052A CN 202310290013 A CN202310290013 A CN 202310290013A CN 117327052 A CN117327052 A CN 117327052A
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- 239000003674 animal food additive Substances 0.000 title claims abstract description 20
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000000694 effects Effects 0.000 claims abstract description 9
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims abstract description 4
- 229960002555 zidovudine Drugs 0.000 claims abstract description 4
- 108010046334 Urease Proteins 0.000 claims abstract description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 128
- 238000006243 chemical reaction Methods 0.000 claims description 101
- 238000003756 stirring Methods 0.000 claims description 92
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 60
- 239000012074 organic phase Substances 0.000 claims description 53
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 26
- 238000010438 heat treatment Methods 0.000 claims description 22
- 239000001569 carbon dioxide Substances 0.000 claims description 19
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 16
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000012141 concentrate Substances 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 238000010992 reflux Methods 0.000 claims description 16
- 238000010898 silica gel chromatography Methods 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 229940095102 methyl benzoate Drugs 0.000 claims description 13
- 229960003433 thalidomide Drugs 0.000 claims description 13
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 12
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- 229960000688 pomalidomide Drugs 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- -1 alkyne compound Chemical group 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- YCPULGHBTPQLRH-UHFFFAOYSA-N 3-aminopiperidine-2,6-dione;hydron;chloride Chemical compound Cl.NC1CCC(=O)NC1=O YCPULGHBTPQLRH-UHFFFAOYSA-N 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 8
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 8
- 239000012153 distilled water Substances 0.000 claims description 8
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000012071 phase Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 235000010233 benzoic acid Nutrition 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 4
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 4
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 4
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 4
- FEQPHYCEZKWPNE-UHFFFAOYSA-K trichlororhodium;triphenylphosphane Chemical compound Cl[Rh](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FEQPHYCEZKWPNE-UHFFFAOYSA-K 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 2
- MFUPLHQOVIUESQ-UHFFFAOYSA-N (1,5-dimethoxy-1,5-dioxopentan-2-yl)azanium;chloride Chemical compound Cl.COC(=O)CCC(N)C(=O)OC MFUPLHQOVIUESQ-UHFFFAOYSA-N 0.000 claims 2
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 claims 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 8
- 150000001345 alkine derivatives Chemical group 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YBZUEFXEQXEEPF-UHFFFAOYSA-N 3-amino-2-[(2-methylpropan-2-yl)oxycarbonyl]benzoic acid Chemical compound CC(C)(C)OC(=O)C1=C(N)C=CC=C1C(O)=O YBZUEFXEQXEEPF-UHFFFAOYSA-N 0.000 abstract 1
- 150000001540 azides Chemical class 0.000 abstract 1
- 238000012650 click reaction Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
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- 238000001228 spectrum Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 210000004767 rumen Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 2
- VHFLTICYUZLEII-UHFFFAOYSA-N 1-azido-4-fluorobenzene Chemical compound FC1=CC=C(N=[N+]=[N-])C=C1 VHFLTICYUZLEII-UHFFFAOYSA-N 0.000 description 2
- YVXDRCDGBCOJHX-UHFFFAOYSA-N 1-azido-4-methylbenzene Chemical compound CC1=CC=C(N=[N+]=[N-])C=C1 YVXDRCDGBCOJHX-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical group CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- KNPDKRVXJOVOQP-UHFFFAOYSA-N 1-azido-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1N=[N+]=[N-] KNPDKRVXJOVOQP-UHFFFAOYSA-N 0.000 description 1
- KFGFVPMRLOQXNB-UHFFFAOYSA-N 3,5,5-trimethylhexanoyl 3,5,5-trimethylhexaneperoxoate Chemical compound CC(C)(C)CC(C)CC(=O)OOC(=O)CC(C)CC(C)(C)C KFGFVPMRLOQXNB-UHFFFAOYSA-N 0.000 description 1
- WENKGSGGXGQHSH-UHFFFAOYSA-N 3-(3-oxo-1h-isoindol-2-yl)piperidine-2,6-dione Chemical compound C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O WENKGSGGXGQHSH-UHFFFAOYSA-N 0.000 description 1
- LUEYUHCBBXWTQT-UHFFFAOYSA-N 4-phenyl-2h-triazole Chemical compound C1=NNN=C1C1=CC=CC=C1 LUEYUHCBBXWTQT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
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- 229940099797 HIV integrase inhibitor Drugs 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 1
- 229960002542 dolutegravir Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000003890 fistula Effects 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
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- 230000003993 interaction Effects 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical class [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical class Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07D401/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
- A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明公开了一种1,2,3‑三氮唑类饲料添加剂及其制备方法和应用,属于功能饲料添加剂合成技术领域。本发明的技术方案要点为:该1,2,3‑三氮唑类饲料添加剂分子具有结构其中n为1或者2;R为4‑甲基苯基、4‑氟苯基或齐多夫定。本发明以2‑Boc胺基苯甲酸为起始原料,先反应得到2‑(2,6‑二氧代哌啶‑3‑基)‑4‑胺基异吲哚啉‑1,3‑二酮,然后引入端基炔,最后与叠氮化合物经点击反应得到结构新型的目标分子,对脲酶具有一定抑制作用,可作为潜在的饲料添加剂。
Description
技术领域
本发明属于饲料添加剂的合成技术领域,具体涉及一种1,2,3-三氮唑类饲料添加剂及其制备方法和应用。
背景技术
1,2,3-三氮唑结构是一类非常重要的含氮杂环化合物,由3个氮原子和2个碳原子构建的五元杂环,分子式为C2N3H3。1,2,3-三氮唑具有特殊的平面刚性结构,使其拥有较强的嵌入DNA的能力,同时具有大偶极矩,能够与不同生物靶点形成疏水、氢键、范德华力和偶极-偶极键等多种非共价相互作用力,另外,1,2,3-三氮唑的结构特征允许其作为酰胺,酯,羧酸,烯烃刚性类似物等的电子等价取代物,因此具有广谱的生物活性,常作为重要的分子砌块用于活性化合物的合成,如制备抗菌、抗疟、抗真菌、抗病毒、抗结核和抗癌活性化合物等。多种临床药物和活性分子经1,2,3-三氮唑修饰改造后增强的原有的生物活性或获得新的生物活性,例如在HIV整合酶抑制剂药物度鲁特韦母核结构上引入端基炔,与2-三氟甲基苯基叠氮反应得到化合物DTHP,对多种肺癌细胞有良好的抑制活性,特别是针对H1975细胞,能够引起该细胞发生凋亡和增强ROS水平,小鼠体内实验抑制肿瘤效果也非常显著。
泊马度胺,化学名称为(RS)-4-氨基-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮,为口服小分子衍生物,是新上市的第三代免疫调节剂,由美国Celgene公司研发制成,是在第一代IMiD沙利度胺化学结构基础上修饰合成的药物,可增强T细胞和自然杀伤细胞介导的免疫反应、抑制单核细胞促炎性细胞因子的生成、诱导肿瘤细胞凋亡,在各类恶性肿瘤、免疫性疾病的治疗中受到广泛关注。是沙利度胺衍生物中应用非常广泛的一个。与沙利度按相比,泊马度胺苯环上连接的氨基使得自身化学性质更加稳定,且比沙利度胺具有更强的免疫调节作用。并且在临床应用方面,泊马度胺比沙利度胺的安全性更高,不良反应更少,它几乎没有致畸性和神经毒性,对多种血液病和实体恶性肿瘤都有作用。
鉴于在药物分子基团上引入苯基-1,2,3-三氮唑后有如此显著的效果,为寻找更加新型高效的抗肿瘤药物,我们对沙利度按和泊马度胺进行修饰改造,在其结构上引入1,2,3-三氮唑基团,因为三氮唑和两种度胺上面含有氮原子,可以作为饲料添加剂中的氮源,我们公司已经开发了了多种含有1,2,3-三氮唑的饲料添加剂,抑制脲酶活性良好,因此细胞对这两种度胺改造后也可以作为饲料添加剂使用。
发明内容
本发明解决的技术问题是提供了一种结构新颖泊马度胺衍生物的制备方法。
本发明为解决上述技术问题采用如下技术方案,一种泊马度胺衍生物的制备方法,其特征在于具体步骤为:
1、将一定量的2-N-Boc胺基苯甲酸加入二氯亚砜里面,在氮气保护下搅拌一段时间后真空浓缩反应体系,浓缩物用二氯甲烷溶解,然后在搅拌状态下缓慢滴加溶有2-氨基戊二酸二甲酯盐酸盐的二氯甲烷溶液,滴加完全后继续搅拌反应一段时间后浓缩反应体系,加入N,N-二甲基甲酰中,完全溶解后在氮气保护下加入一定量的叔丁基锂,氢氧化钡,碳酸铯和乙酸钯,保持氮气氛围,转移至高压反应釜中,高压釜内全程氮气保护,然后室温搅拌一段时间用二氧化碳置换釜内气体,然后通入二氧化碳,使釜内压力达到一定数值,缓慢加热至一定温度,反应一段时间后真空排除二氧化碳,同时降温至一定温度,然后通入氨气,使釜内压力达到一定数值,保持温度和压力搅拌反应一段时间,降至室温,把反应体系然后加入水和二氯甲烷,搅拌后过滤反应液,分出有机相,水相用二氯甲烷洗涤多次,然后分出有机相,有机相中加入2mol/L的稀盐酸,加热至30℃搅拌一段时间后用碳酸钾饱和溶液调节反应体系为中性,再次分出有机相,浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代哌啶-3-基)-4-胺基异吲哚啉-1,3-二酮。
2、将一定量的苯甲酸加入二氯亚砜里面,在氮气保护下搅拌后真空浓缩反应体系,浓缩物用二氯甲烷溶解,然后在0℃条件下缓慢滴加溶有2-氨基戊二酸二甲酯盐酸盐的二氯甲烷溶液,滴加完后升至室温搅拌一段时间,浓缩反应体系,加入N,N-二甲基甲酰胺中,完全溶解后在氮气保护下加入叔丁基锂,氢氧化钡,碳酸铯和乙酸钯,保持氮气氛围,转移至高压反应釜中,高压釜内全程氮气保护,然后室温搅拌30min,用二氧化碳置换釜内气体,然后通入二氧化碳,使釜内压力达到0.2MPa,缓慢加热至120℃,反应一段时间后真空排除二氧化碳,同时降温至80℃,然后通入氨气,使釜内压力达到0.12MPa,保持温度和压力搅拌反应一段时间,降至室温,把反应体系然后加入水和二氯甲烷,搅拌后过滤反应液,分出有机相,水相用二氯甲烷洗涤多次,然后分出有机相,浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮。
3、将一定量的苯甲酸甲酯和碳酸钙加入二氯乙烷溶液中,搅拌后再缓慢滴加溶有N-碘代琥珀酰亚胺的二氯乙烷溶液,滴加完后在室温条件下搅拌一段时间后再加入3-氨基哌啶-2,6-二酮盐酸盐和三乙胺和DCC试剂,在室温条件下搅拌反应一段时间,浓缩后用乙醚洗涤浓缩物多次,然后加入叔丁醇和甲基叔丁基醚的混合溶液中,置于高压反应釜中,再加入三苯基膦氯化铑和碳酸银和磷酸二氢钾,搅拌均匀反应一段时间再加入醋酸钯和三乙胺,真空排除反应釜内的空气,然后通入一氧化碳,使反应釜内压力达到0.5~0.8MPa,缓慢加热至100℃,保持反应釜内压力不变,反应结束后过滤反应液,然后用醋酸调节反应体系为中性,加入水,搅拌后分出有机相,浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮。
4、将一定量的苯甲酸甲酯和碳酸钙加入二氯乙烷溶液中,搅拌后再缓慢滴加溶有N-碘代琥珀酰亚胺的二氯乙烷溶液,滴加完后在室温条件下搅拌一段时间后再加入3-氨基哌啶-2,6-二酮盐酸盐和三乙胺和DCC试剂,在室温条件下搅拌反应一段时间,浓缩后用乙醚洗涤浓缩物多次,然后将浓缩物甲苯中,再加入三苯基膦和碘单质,加热至回流,通过分水器除去反应体系中的水份,然后再加入醋酸钯和三乙胺,氮气保护下搅拌后加入无水甲酸,保持氮气氛围,调节反应体系温度至80℃,反应结束趁热过滤反应液,加入水,搅拌后用二氯甲烷萃取多次,合并有机相,浓缩后经硅胶柱层析分离得到2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮。
5、把泊马度胺或沙利度胺和碳酸钾加入二氯甲烷,搅拌后加入3-溴丙炔或4-溴丁炔,搅拌加热至回流继续搅拌一段时间,向反应体系中加入饱和氯化钠溶液,搅拌后分出有机相,水相再用二氯甲烷萃取多次,合并有机相,浓缩后得到端基炔化合物。
6、将端基炔化合物和叠氮类化合物加入到蒸馏水、四氢呋喃和叔丁醇的混合溶剂中,再加入碘化亚铜,氮气保护,加热至80℃,回流反应一段时间后用二氯甲烷萃取多次,合并有机相,有机相浓缩后经硅胶柱层析分离得到产品。
附图说明
图1是实施例1制备得到的目标化合物的核磁氢谱图。
图2是实施例2制备得到的目标化合物的核磁氢谱图。
图3是实施例5制备得到的目标化合物的核磁氢谱图。
图4是实施例6制备得到的目标化合物的核磁氢谱图。
图5是实施例8制备得到的目标化合物的核磁氢谱图。
图6是实施例12制备得到的目标化合物的核磁氢谱图。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
在带有搅拌装置的反应瓶中,将2-N-Boc胺基苯甲酸2.4g加入二氯亚砜50mL里面,在氮气保护下搅拌1h,然后真空浓缩反应体系,浓缩物用二氯甲烷100mL搅拌溶解,然后在0℃条件下缓慢滴加溶有2-氨基-1,5-戊二酸二甲酯盐酸盐2.3g的二氯甲烷溶液70mL,滴加完后升至室温搅拌5h,真空浓缩反应体系,然后加入N,N-二甲基甲酰胺200mL中搅拌,完全溶解后在氮气保护下加入叔丁基锂1.28g,氢氧化钡3.4g,碳酸铯6.5g和乙酸钯0.45g,保持氮气氛围,转移至高压反应釜中,高压釜内全程氮气保护,然后室温搅拌10min,用二氧化碳置换釜内气体,然后通入二氧化碳,使釜内压力达到0.2MPa,缓慢加热至100℃,反应20h后真空置换排除二氧化碳,同时降温至70℃,然后通入氨气,使釜内压力达到0.1MPa,保持温度和压力搅拌反应15h,降至室温,把反应体系然后加入水200mL和二氯甲烷200mL,搅拌后过滤反应液,分出有机相,水相用二氯甲烷100mL洗涤四次,然后分出有机相,有机相中加入2mol/L的稀盐酸50mL,加热至30℃搅拌2h,然后用碳酸钾饱和溶液调节反应体系为中性,分出有机相,浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代哌啶-3-基)-4-胺基异吲哚啉-1,3-二酮2.31g;1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.48(s,1H),7.02(s,2H),6.53(s,2H),5.06(s,1H),3.11-2.58(m,3H),2.04(s,1H)。
实施例2
在带有搅拌装置的反应瓶中,将苯甲酸1.25g加入二氯亚砜50mL里面,在氮气保护下搅拌1h,然后真空浓缩反应体系,浓缩物用二氯甲烷100mL溶解,然后在0℃条件下缓慢滴加溶有2-氨基-1,5-戊二酸二甲酯盐酸盐2.3g的二氯甲烷溶液70mL,滴加完后升至室温搅拌2h,真空浓缩反应体系,然后加入N,N-二甲基甲酰胺180mL中,完全溶解后在氮气保护下加入叔丁基锂1.28g,氢氧化钡3.4g,碳酸铯6.5g和乙酸钯0.45g,保持氮气氛围,转移至高压反应釜中,高压釜内全程氮气保护,然后室温搅拌30min,用二氧化碳置换釜内气体,然后通入二氧化碳,使釜内压力达到0.2MPa,缓慢加热至120℃,反应10h后真空排除二氧化碳,同时降温至80℃,然后通入氨气,使釜内压力达到0.12MPa,保持温度和压力搅拌反应8h,降至室温,把反应体系然后加入水100mL和二氯甲烷150mL,搅拌后过滤反应液,分出有机相,水相用二氯甲烷50mL洗涤多次,然后分出有机相,真空浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮2.27g;1HNMR(400MHz,DMSO-d6)δ11.14(s,1H),7.95-7.89(m,4H),5.20-5.15(m,1H),2.95-2.86(m,2H),2.73-2.53(m,2H),2.10-2.07(m,1H)。
实施例3
在带有搅拌装置的反应瓶中,将苯甲酸甲酯1.4g和碳酸钙3g加入二氯乙烷100mL溶液中,搅拌后再缓慢滴加溶有N-碘代琥珀酰亚胺2.5g的二氯乙烷溶液100mL,滴加完后在室温条件下搅拌1.5h,然后再加入3-氨基哌啶-2,6-二酮盐酸盐1.7g和三乙胺1g和DCC试剂2g,在室温条件下搅拌反应15h,真空浓缩后用乙醚40mL和石油醚20mL洗涤浓缩物多次,然后浓缩物加入叔丁醇100mL和甲基叔丁基醚100mL的混合溶液中,置于高压反应釜中,再加入三苯基膦氯化铑0.14g和碳酸银0.55g和磷酸二氢钾1.7g,搅拌均匀反应1h再加入醋酸钯0.22g和三乙胺1g,补加无水甲苯50mL,真空排除反应釜内的空气,然后通入一氧化碳,使反应釜内压力达到0.8MPa,缓慢加热至100℃,保持反应釜内压力不变,反应5h,停止反应,降温后过滤反应液,然后用醋酸调节反应体系为中性,真空浓缩除去部分溶解,然后加入水150mL和二氯甲烷150mL,搅拌后分出有机相,有机相浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮2.09g。
实施例4
在带有搅拌装置和分水器的反应瓶中,将苯甲酸甲酯1.4g和碳酸钙3g加入二氯乙烷100mL溶液中,搅拌后再缓慢滴加溶有N-碘代琥珀酰亚胺2.5g的二氯乙烷溶液100mL,滴加完后在室温条件下搅拌1.5h,然后再加入3-氨基哌啶-2,6-二酮盐酸盐1.7g和三乙胺1g和DCC试剂2g,在室温条件下搅拌反应15h,浓缩后用乙醚40mL和石油醚20mL洗涤浓缩物多次,然后将浓缩物甲苯150mL中,再加入三苯基膦2.6g和碘单质3g,加热至回流,通过分水器除去反应体系中的水份,然后再加入醋酸钯0.23g和三乙胺1g,补加无水甲苯50mL,氮气保护下搅拌30min,然后加入无水甲酸1.5g,保持氮气氛围,调节反应体系温度至80℃,反应13h,停止反应,趁热过滤反应液,加入水250mL,搅拌后用二氯甲烷100mL萃取多次,合并有机相,浓缩后经硅胶柱层析分离得到2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮2.15g。
实施例5
在带有搅拌的反应瓶中,把2-(2,6-二氧代哌啶-3-基)-4-胺基异吲哚啉-1,3-二酮2.75g和碳酸钾1.4g加入二氯甲烷150mL,搅拌后加入3-溴丙炔1.43g,搅拌30min,加热至回流继续搅拌4h,向反应体系中加入氯化钠饱和溶液100mL,搅拌后分出有机相,水相再用二氯甲烷100mL萃取多次,合并有机相,浓缩后得到N-丙炔基泊马度胺2.64g;1H NMR(400MHz,DMSO)1H NMR(400MHz,DMSO)δ7.48(t,J1=4.0Hz,J2=4.0Hz,1H),7.02(t,J1=4.0Hz,J2=8.0Hz,2H),6.54(s,2H),5.20(t,J1=4.0Hz,J2=8.0Hz,1H),4.41-4.35(m,2H),3.11-3.10(m,1H),3.06-3.00(m,1H),2.82-2.78(m,1H),2.60-2.53(m,1H),2.06-1.99(m,1H)。
实施例6
在带有搅拌的反应瓶中,把2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮2.6g和碳酸钾1.4g加入二氯甲烷150mL,搅拌后加入3-溴丙炔1.43g,搅拌30min,加热至回流继续搅拌4h,向反应体系中加入氯化钠饱和溶液100mL,搅拌后分出有机相,水相再用二氯甲烷100mL萃取多次,合并有机相,浓缩后经硅胶柱层析分离提纯得到N-丙炔基沙利度胺2.52g;1H NMR(400MHz,DMSO-d6)δ7.96-7.90(m,4H),5.32(dd,J1=4.0Hz,J2=4.0Hz,1H),4.39(s,2H),3.11(s,1H),3.07-3.01(m,1H),2.84-2.80(m,1H),2.62-2.55(m,1H),2.13-2.09(m,1H)。
实施例7
在带有搅拌的反应瓶中,把2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮2.6g和碳酸钾1.4g加入二氯甲烷150mL,搅拌后加入4-溴丁炔1.6g,搅拌30min,加热至回流继续搅拌6.5h,向反应体系中加入饱和氯化钠溶液100mL,搅拌后分出有机相,水相再用二氯甲烷100mL萃取多次,合并有机相,有机相用无水硫酸镁干燥后,再经过真空浓缩后得到N-丁炔基沙利度胺2.77g,MS(ESI+)m/z:311[M+H]+。
实施例8
在带有搅拌装置的反应瓶中,将N-丙炔基泊马度胺3.1g和4-氟苯基叠氮1.65g加入到蒸馏水、四氢呋喃和叔丁醇的混合溶剂120mL中(三者体积比为1:1:1),再加入碘化亚铜0.38g,氮气保护,加热至80℃,回流反应9h后过滤反应液,滤液用二氯甲烷50mL萃取多次,合并有机相,有机相浓缩后经硅胶柱层析分离得到产品3.77g,1H NMR(400MHz,DMSO-d6)1HNMR(400MHz,DMSO)δ8.50(s,1H),7.93-7.90(m,2H),7.49-7.43(m,3H),7.02(t,J1=8.0Hz,J2=8.0Hz,2H),6.51(s,2H),5.23(dd,J1=8.0Hz,J2=4.0Hz,1H),5.06-4.96(m,2H),3.09-3.00(m,1H),2.83(d,J=16.0Hz,1H),2.69-2.59(m,1H),2.12-2.08(m,1H)。
实施例9
在带有搅拌装置的反应瓶中,将N-丙炔基泊马度胺3.1g和齐多夫定3.2g加入到蒸馏水、四氢呋喃和叔丁醇的混合溶剂150mL中(三者体积比为1:1:1),再加入碘化亚铜0.38g,氮气保护,加热至80℃,回流反应9h后过滤反应液,滤液用二氯甲烷70mL萃取多次,合并有机相,有机相浓缩后经硅胶柱层析(PE:EA=12:1)分离得到产品4.27g。
实施例10
在带有搅拌装置的反应瓶中,将N-丙炔基泊马度胺3.1g和4-甲基苯基叠氮1.6g加入到蒸馏水、四氢呋喃和叔丁醇的混合溶剂120mL中(三者体积比为1:1:1),再加入碘化亚铜0.38g,氮气保护,加热至80℃,回流反应10h后过滤反应液,滤液用二氯甲烷50mL萃取多次,合并有机相,有机相浓缩后经硅胶柱层析分离得到产品3.58g,1H NMR(600MHz,DMSO-d6)δ8.51(s,1H),7.79(d,J=6.0Hz,2H),7.53-7.43(m,3H),7.06(t,J1=6.0Hz,J2=6.0Hz,2H),6.57(s,2H),5.29(dd,J1=6.0Hz,J2=6.0Hz,1H),5.06(dd,J1=12.0Hz,J2=18.0Hz,2H),3.12-3.06(m,1H),2.88(d,J=18.0Hz,1H),2.72-2.64(s,1H),2.42(s,3H),2.15-2.13(m,1H)。
实施例11
在带有搅拌装置的反应瓶中,将N-丁炔基沙利度胺3.1g和齐多夫定3.2g加入到蒸馏水、四氢呋喃和叔丁醇的混合溶剂150mL中(三者体积比为1:1:1),再加入碘化亚铜0.38g,氮气保护,加热至80℃,回流反应5h后过滤反应液,滤液用二氯甲烷70mL萃取多次,合并有机相,有机相浓缩后经硅胶柱层析(PE:EA=12:1)分离得到产品2.94g。
实施例12
在带有搅拌装置的反应瓶中,将N-丁炔基沙利度胺3.1g和4-甲基苯基叠氮1.6g加入到蒸馏水、四氢呋喃和叔丁醇的混合溶剂120mL中(三者体积比为1:1:1),再加入碘化亚铜0.38g,氮气保护,加热至80℃,回流反应11h后过滤反应液,滤液用二氯甲烷50mL萃取多次,合并有机相,有机相浓缩后经硅胶柱层析分离得到产品3.36g,1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.89(dd,J1=4.0Hz,J2=4.0Hz,2H),7.77(dd,J1=4.0Hz,J2=4.0Hz,2H),7.61(d,J=8.0Hz,2H),7.30(d,J=8.0Hz,2H),5.28-5.17(m,2H),2.84-2.75(m,2H),2.42(s,3H),2.18-2.11(m,1H),1.72-1.62(m,3H),1.00-0.94(m,1H)。
实施例13
在带有搅拌装置的反应瓶中,将N-丙炔基沙利度胺3.0g和4-氟苯基叠氮1.65g加入到蒸馏水、四氢呋喃和叔丁醇的混合溶剂120mL中(三者体积比为1:1:1),再加入碘化亚铜0.38g,氮气保护,加热至80℃,回流反应9h后过滤反应液,滤液用二氯甲烷50mL萃取多次,合并有机相,有机相浓缩后经硅胶柱层析(PE:EA=10:1)分离得到产品3.08g,MS(ESI+)m/z:434[M+H]+。
实施例14
我们对所得到的6个目标化合物进行体外脲酶抑制实验:选择12个月左右的黄牛,经过饲喂1h后,用特制瘤胃液采集器经人工瘤胃瘘管采集瘤胃液400mL,通过4层纱布过滤后备用。每个培养管按下表中的量加入相应的试剂后,滴加4滴液体石蜡,置(39.0±0.5)℃恒温水浴振荡器上轻摇。分别培养8h,从各组取出部分培养管,立即加入4滴饱和氯化汞溶液并摇匀,以终止反应。用凯氏半微量-饱和氧化镁蒸馏法测定各管氨态氮含量。我们可以发现所设计的得到的实施例8和实施例11两种产物随着时间的延长对脲酶的抑制活性越来越显著,具有非常显著的抑制作用。
抑制率(%)=(对照组氨含量-试验组氨含量)÷对照组氨含量×100%
编号 | 时间(h) | 对照组抑制率 | 试验1组抑制率 | 试验2组抑制率 |
实施例8产物 | 8 | 0% | 33.71% | 56.09% |
实施例9产物 | 8 | 0% | 31.88% | 47.79% |
实施例10产物 | 8 | 0% | 14.05% | 21.70% |
实施例11产物 | 8 | 0% | 35.94% | 60.18% |
实施例12产物 | 8 | 0% | 18.78% | 25.13% |
实施例13产物 | 8 | 0% | 28.06% | 40.92% |
以上实施例描述了本发明的基本原理、主要特征及优点,本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明原理的范围下,本发明还会有各种变化和改进,这些变化和改进均落入本发明保护的范围内。
Claims (8)
1.一种1,2,3-三氮唑类饲料添加剂及其制备方法和应用,其特征在于该1,2,3-三氮唑类饲料添加剂的结构为:其中n为1或者2;R为4-甲基苯基、4-氟苯基或齐多夫定。
2.根据权利要求1所述的一种1,2,3-三氮唑类饲料添加剂,其特征在于其制备方法的具体过程为:将一定量的2-N-Boc胺基苯甲酸加入二氯亚砜里面,在氮气保护下搅拌一段时间后真空浓缩反应体系,浓缩物用二氯甲烷溶解,然后在搅拌状态下缓慢滴加溶有2-氨基戊二酸二甲酯盐酸盐的二氯甲烷溶液,滴加完全后继续搅拌反应一段时间后浓缩反应体系,加入N,N-二甲基甲酰中,完全溶解后在氮气保护下加入一定量的叔丁基锂,氢氧化钡,碳酸铯和乙酸钯,保持氮气氛围,转移至高压反应釜中,高压釜内全程氮气保护,然后室温搅拌一段时间用二氧化碳置换釜内气体,然后通入二氧化碳,使釜内压力达到一定数值,缓慢加热至一定温度,反应一段时间后真空排除二氧化碳,同时降温至一定温度,然后通入氨气,使釜内压力达到一定数值,保持温度和压力搅拌反应一段时间,降至室温,把反应体系然后加入水和二氯甲烷,搅拌后过滤反应液,分出有机相,水相用二氯甲烷洗涤多次,然后分出有机相,有机相中加入2mol/L的稀盐酸,加热至30℃搅拌一段时间后用碳酸钾饱和溶液调节反应体系为中性,再次分出有机相,浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代哌啶-3-基)-4-胺基异吲哚啉-1,3-二酮;所述的2-N-Boc胺基苯甲酸与2-氨基戊二酸二甲酯盐酸盐的投料量摩尔比为1:1~1.1;所述的2-N-Boc胺基苯甲酸与叔丁基锂与氢氧化钡与碳酸铯与乙酸钯的投料量摩尔比为1:2:2:2:0.2;所述的二氧化碳反应体系压力为0.15~0.2MPa;所述的二氧化碳反应体系温度为100~110℃;所述的氨气反应体系压力为0.1~0.12MPa;所述的氨气反应体系温度为60~70℃。
3.根据权利要求1所述的一种1,2,3-三氮唑类饲料添加剂,其特征在于其制备方法的具体过程为:将一定量的苯甲酸加入二氯亚砜里面,在氮气保护下搅拌后真空浓缩反应体系,浓缩物用二氯甲烷溶解,然后在0℃条件下缓慢滴加溶有2-氨基戊二酸二甲酯盐酸盐的二氯甲烷溶液,滴加完后升至室温搅拌一段时间,浓缩反应体系,加入N,N-二甲基甲酰胺中,完全溶解后在氮气保护下加入叔丁基锂,氢氧化钡,碳酸铯和乙酸钯,保持氮气氛围,转移至高压反应釜中,高压釜内全程氮气保护,然后室温搅拌后用二氧化碳置换釜内气体,然后通入二氧化碳,使釜内压力达到0.2MPa,缓慢加热至120℃,反应一段时间后真空排除二氧化碳,同时降温至80℃,然后通入氨气,使釜内压力达到0.12MPa,保持温度和压力搅拌反应一段时间,降至室温,把反应体系然后加入水和二氯甲烷,搅拌后过滤反应液,分出有机相,水相用二氯甲烷洗涤多次,然后分出有机相,浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮;所述的苯甲酸与2-氨基戊二酸二甲酯盐酸盐的投料量摩尔比为1:1~1.1;所述的苯甲酸与叔丁基锂与氢氧化钡与碳酸铯与乙酸钯的投料量摩尔比为1:2:1.5:2:0.2。
4.根据权利要求1所述的一种1,2,3-三氮唑类饲料添加剂,其特征在于其制备方法的具体过程为:将一定量的苯甲酸甲酯和碳酸钙加入二氯乙烷溶液中,搅拌后再缓慢滴加溶有N-碘代琥珀酰亚胺的二氯乙烷溶液,滴加完后在室温条件下搅拌一段时间后再加入3-氨基哌啶-2,6-二酮盐酸盐和三乙胺和DCC试剂,在室温条件下搅拌反应一段时间,浓缩后用乙醚洗涤浓缩物多次,然后加入叔丁醇和甲基叔丁基醚的混合溶液中,置于高压反应釜中,再加入三苯基膦氯化铑和碳酸银和磷酸二氢钾,搅拌均匀反应一段时间再加入醋酸钯和三乙胺,真空排除反应釜内的空气,然后通入一氧化碳,使反应釜内压力达到0.5~0.8MPa,缓慢加热至80~100℃,保持反应釜内压力不变,反应结束后过滤反应液,然后用醋酸调节反应体系为中性,加入水,搅拌后分出有机相,浓缩后经硅胶柱层析分离提纯得到2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮;所述的苯甲酸甲酯与碳酸钙与N-碘代琥珀酰亚胺的投料量摩尔比为1:3:1.1;所述的苯甲酸甲酯与3-氨基哌啶-2,6-二酮盐酸盐与三乙胺与DCC的投料量摩尔比为1:1:1:1;所述的苯甲酸甲酯与三苯基膦氯化铑的投料量质量比为1:0.1;所述的苯甲酸甲酯与碳酸银和磷酸二氢钾的投料量摩尔比为1:0.2:1.2。
5.根据权利要求1所述的一种1,2,3-三氮唑类饲料添加剂的制备方法,其特征在于其制备方法的具体过程为:将一定量的苯甲酸甲酯和碳酸钙加入二氯乙烷溶液中,搅拌后再缓慢滴加溶有N-碘代琥珀酰亚胺的二氯乙烷溶液,滴加完后在室温条件下搅拌一段时间后再加入3-氨基哌啶-2,6-二酮盐酸盐和三乙胺和DCC试剂,在室温条件下搅拌反应一段时间,浓缩后用乙醚洗涤浓缩物多次,然后将浓缩物甲苯中,再加入三苯基膦和碘单质,加热至回流,通过分水器除去反应体系中的水份,然后再加入醋酸钯和三乙胺,氮气保护下搅拌后加入无水甲酸,保持氮气氛围,调节反应体系温度至80℃,反应结束趁热过滤反应液,加入水,搅拌后用二氯甲烷萃取多次,合并有机相,浓缩后经硅胶柱层析分离得到2-(2,6-二氧代-哌啶-3-基)-异吲哚-1,3-二酮;所述的苯甲酸甲酯与碳酸钙与N-碘代琥珀酰亚胺的投料量摩尔比为1:3:1.1;所述的苯甲酸甲酯与3-氨基哌啶-2,6-二酮盐酸盐与三乙胺与DCC的投料量摩尔比为1:1:1:1;所述的苯甲酸甲酯与三苯基膦与碘单质的投料量摩尔比为1:1.2:1.2。
6.根据权利要求1所述的一种1,2,3-三氮唑类饲料添加剂的制备方法,其特征在于其制备方法的具体过程为:把2-(2,6-二氧代哌啶-3-基)-4-胺基异吲哚啉-1,3-二酮或2-(2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮和碳酸钾加入二氯甲烷,搅拌后加入3-溴丙炔或4-溴丁炔,搅拌加热至回流继续搅拌一段时间,向反应体系中加入饱和氯化钠溶液,搅拌后分出有机相,水相再用二氯甲烷萃取多次,合并有机相,浓缩后得到泊马度胺或沙利度胺端基炔化合物。
7.根据权利要求1所述的一种1,2,3-三氮唑类饲料添加剂的制备方法,其特征在于其制备方法的具体过程为:将泊马度胺或沙利度胺端基炔化合物和叠氮类化合物加入到蒸馏水、四氢呋喃和叔丁醇的混合溶剂中,再加入碘化亚铜,氮气保护,加热至80℃,回流反应一段时间后用二氯甲烷萃取多次,合并有机相,有机相浓缩后经硅胶柱层析分离得到产品。
8.如权利要求1所述的1,2,3-三氮唑类饲料添加剂在抑制脲酶活性方面的作用。
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