CN110372530B - 一种含α取代苯基结构的化合物及其制备方法和消杀剂 - Google Patents
一种含α取代苯基结构的化合物及其制备方法和消杀剂 Download PDFInfo
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- CN110372530B CN110372530B CN201910720391.7A CN201910720391A CN110372530B CN 110372530 B CN110372530 B CN 110372530B CN 201910720391 A CN201910720391 A CN 201910720391A CN 110372530 B CN110372530 B CN 110372530B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 58
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 32
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- 239000000575 pesticide Substances 0.000 title description 2
- 229910052751 metal Inorganic materials 0.000 claims abstract description 22
- 239000002184 metal Substances 0.000 claims abstract description 22
- -1 3, 4-dihydroxyphenyl Chemical group 0.000 claims description 34
- 238000002156 mixing Methods 0.000 claims description 27
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
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- 238000005727 Friedel-Crafts reaction Methods 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 17
- 238000006482 condensation reaction Methods 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 239000003377 acid catalyst Substances 0.000 claims description 8
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 10
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
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- 239000012043 crude product Substances 0.000 description 8
- 238000007865 diluting Methods 0.000 description 8
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- PYHXGXCGESYPCW-UHFFFAOYSA-N diphenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
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- 230000008018 melting Effects 0.000 description 5
- 229910021642 ultra pure water Inorganic materials 0.000 description 5
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 4
- ZYICOGJXJIHDGF-UHFFFAOYSA-N 2,2-bis(3,4-dihydroxyphenyl)acetic acid Chemical compound OC=1C=C(C=CC=1O)C(C(=O)O)C1=CC(=C(C=C1)O)O ZYICOGJXJIHDGF-UHFFFAOYSA-N 0.000 description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 4
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 4
- DRCDFCKJRWYXPK-UHFFFAOYSA-N CC1=CC=C(C=C1)C(C2=CC=C(C=C2)O)C(=O)O Chemical compound CC1=CC=C(C=C1)C(C2=CC=C(C=C2)O)C(=O)O DRCDFCKJRWYXPK-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
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- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
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- XQXWQICCJUEJCS-UHFFFAOYSA-N 2-(4-hydroxyphenyl)-2-phenyl-N-propan-2-ylacetamide Chemical compound OC1=CC=C(C=C1)C(C(=O)NC(C)C)C1=CC=CC=C1 XQXWQICCJUEJCS-UHFFFAOYSA-N 0.000 description 3
- SPKMGDPSFZJIEY-UHFFFAOYSA-N 2-cyclohexyl-2-(3,4-dihydroxyphenyl)-N-methylacetamide Chemical compound C1(CCCCC1)C(C(=O)NC)C1=CC(=C(C=C1)O)O SPKMGDPSFZJIEY-UHFFFAOYSA-N 0.000 description 3
- VLERBEOGTYLTHB-UHFFFAOYSA-N 2-cyclohexyl-2-(3,4-dihydroxyphenyl)acetic acid Chemical compound C1(CCCCC1)C(C(=O)O)C1=CC(=C(C=C1)O)O VLERBEOGTYLTHB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
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- 229940054441 o-phthalaldehyde Drugs 0.000 description 3
- 229960003742 phenol Drugs 0.000 description 3
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
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- OSDLLIBGSJNGJE-UHFFFAOYSA-N 4-chloro-3,5-dimethylphenol Chemical compound CC1=CC(O)=CC(C)=C1Cl OSDLLIBGSJNGJE-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 239000006916 nutrient agar Substances 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
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- DBGSRZSKGVSXRK-UHFFFAOYSA-N 1-[2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]acetyl]-3,6-dihydro-2H-pyridine-4-carboxylic acid Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CCC(=CC1)C(=O)O DBGSRZSKGVSXRK-UHFFFAOYSA-N 0.000 description 1
- 229910000975 Carbon steel Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
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- 238000009360 aquaculture Methods 0.000 description 1
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- 239000010962 carbon steel Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/10—Aromatic or araliphatic carboxylic acids, or thio analogues thereof; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
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Abstract
本发明涉及灭菌消毒材料技术领域,具体涉及一种含α取代苯基结构的化合物及其制备方法和消杀剂。本发明提供的含α取代苯基结构的化合物通过促使病原微生物的蛋白质凝固、变性而产生杀菌效果,尤其对大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌和枯草杆菌黑色变种芽孢等病原菌有良好的灭杀效果,且对金属无腐蚀作用,无刺激性气味,水溶性好,绿色环保,可以作为消杀剂的有效成分广泛应用于各行业。
Description
技术领域
本发明涉及灭菌消毒材料技术领域,具体涉及一种含α取代苯基结构的化合物及其制备方法和消杀剂。
背景技术
消杀剂广泛应用于医疗、畜牧业、林业及水产业领域,随着人们对卫生的要求日益提高,对消杀剂的需求也越来越大。目前市场上销售和使用的消杀剂可大致分为:含氯消杀剂、过氧化物类消杀剂、环氧乙烷消杀剂、醛类消杀剂和酚类消杀剂等九大类,但是普遍存在味道大、杀菌效果差等缺点。
发明内容
本发明的目的在于提供一种含α取代苯基结构的化合物及其制备方法和消杀剂,本发明提供的消杀剂对大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌和枯草杆菌黑色变种芽孢等病原菌有良好的灭杀效果,且无刺激性气味,绿色环保。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种含α取代苯基结构的化合物,具有式Ⅰ所示结构:
式I中,R1、R2和R3独立地为氢、羟基、氟或甲氧基;
R4为苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-羟基苯基、3-羟基苯基、4-羟基苯基、2,3-二羟基苯酚基、2-溴苯基、3-溴苯基、4-溴苯基、2-氟苯基、3-氟苯基、4-氟苯基、2,3-二甲基苯基、3,4-二甲基苯基、3,4,5-三甲基苯基、3,4,5-三甲氧基苯基、3,4,5-三羟基苯基、吡啶基、2-甲基吡啶、3-甲基吡啶、环己烷基、呋喃基或吡咯基;
R5为氢、甲基、乙基、异丙基、苯基或苄基;
X为-CH2-、-NH-、-O-或-S-。
优选地,所述含α取代苯基结构的化合物包括:
本发明提供了上述技术方案所述含α取代苯基结构的化合物的制备方法,当R5-X-为羟基时,所述含α取代苯基结构的化合物的制备方法包括以下步骤:
将所述式Ⅱ所示结构的化合物、R5-X-H和催化剂Ⅱ混合,发生缩合反应,得到具有式I所示结构的化合物;
优选地,所述傅克反应的温度为60~110℃,时间为4~8h。
优选地,所述催化剂Ⅱ为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐和N,N-二异丙基乙胺的混合物;所述2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐和N,N-二异丙基乙胺的摩尔比为1.1:(4~10)。
优选地,所述式Ⅱ所示结构的化合物、R5-X-H和催化剂Ⅱ的摩尔比为1:1.1:(3~7.1)。
优选地,所述缩合反应的温度为常温,时间为2~5h。
本发明还提供了一种消杀剂,有效成分包括上述技术方案所述含α取代苯基结构的化合物。
本发明提供了一种含α取代苯基结构的化合物,本发明采用式I所示结构的化合物,能够通过促使病原微生物的蛋白质凝固、变性而产生杀菌效果,或者通过抑制菌体氧化酶、去氢酶、催化酶等酶活性从而达到杀菌的效果,尤其对大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌和枯草杆菌黑色变种芽孢等病原菌有良好的灭杀效果,且对金属无腐蚀作用,无刺激性气味,水溶性好,绿色环保,可以作为消杀剂的有效成分广泛应用于各行业。由实施例检测结果可以看出,本发明提供的含α取代苯基结构的化合物水溶性较好,溶解度能达到15g/L;当浓度为3.125g/L时,1min对大肠杆菌ATCC 25922杀灭对数值≥5.00,15min对铜绿假单孢菌ATCC 27853杀灭对数值≥5.00;当浓度为6.25g/L时,15min对金黄色葡萄球菌ATCC 29213杀灭对数值≥5.00;当浓度为5g/L时,10min对枯草杆菌黑色变种芽孢杀灭的对数值≥5.00,且对金属无腐蚀性,符合酚类消毒剂卫生要求GB27947-2011和医疗器械消毒剂卫生要求GB/T27949-2011的规定。
本发明提供的含α取代苯基结构的化合物的制备方法简单,适宜规模化生产。
具体实施方式
本发明提供了一种含α取代苯基结构的化合物,具有式Ⅰ所示结构:
式I中,R1、R2和R3独立地为氢、羟基、氟或甲氧基;
R4为苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-羟基苯基、3-羟基苯基、4-羟基苯基、2,3-二羟基苯酚基、2-溴苯基、3-溴苯基、4-溴苯基、2-氟苯基、3-氟苯基、4-氟苯基、2,3-二甲基苯基、3,4-二甲基苯基、3,4,5-三甲基苯基、3,4,5-三甲氧基苯基、3,4,5-三羟基苯基、吡啶基、2-甲基吡啶、3-甲基吡啶、环己烷基、呋喃基或吡咯基;
R5为氢、甲基、乙基、异丙基、苯基或苄基;
X为-CH2-、-NH-、-O-或-S-。
在本发明中,所述含α取代苯基结构的化合物优选包括:
本发明提供了上述技术方案所述含α取代苯基结构的化合物的制备方法,当R5-X-为羟基时,所述含α取代苯基结构的化合物的制备方法包括以下步骤:
将所述式Ⅱ所示结构的化合物、R5-X-H和催化剂Ⅱ混合,发生缩合反应,得到具有式I所示结构的化合物;
在本发明中,若无特殊说明,所有原料均为本领域技术人员所熟知的市售产品。
在本发明中,当R5-X-为羟基时,所述含α取代苯基结构的化合物的制备方法包括以下步骤:
在本发明中,所述中的R1、R2和R3与前文式I所示结构中的R1、R2和R3一致,R4-H中的R4与前文式I所示结构中的R4一致,这里不再赘述;所述乙酸醛优选为一水合乙醛酸;所述催化剂I优选为强酸,所述强酸优选为硫酸或硝酸,在本发明的具体实施例中,采用固体强酸作为催化剂,有利于后处理。
在本发明中,优选先将部分R4-H、乙醛酸和催化剂I混合,然后再加入剩余这样有利于反应的控制与反应完全。在本发明中,所述部分占总质量的50%。在本发明中,所述混合优选在搅拌条件下进行,所述搅拌的速度优选为160~180r/min,更优选为180r/min。
在本发明中,所述傅克反应的温度优选为60~110℃,更优选为70~80℃。本发明优选采用TLC跟踪所述傅克反应的进程以确定反应结束时间,在本发明中,所述傅克反应的时间优选为4~8h,更优选为5~7h。所述傅克反应的时间具体是以所述催化剂I加入完毕开始计。
完成所述傅克反应后,本发明优选将所得体系依次进行萃取和重结晶,得到式I所示结构的化合物(方式一);或者将傅克反应后所得体系用乙酸乙酯稀释、过滤,将过滤所得固体物料溶于二乙醚中,用碳酸钠水溶液萃取后,采用浓盐酸将萃取所得水层酸化至pH值为2,过滤后,得到式I所示结构的化合物(方式二)。
当采用方式一得到式I所示结构的化合物时,所述萃取优选是将傅克反应所得体系冷却至室温后,调节体系pH值至2,然后用乙酸乙酯萃取得到式I所示结构化合物的粗品。在本发明中,所述重结晶优选是将所述式I所示结构化合物的粗品用乙醇重结晶。
当采用方式二得到式I所示结构的化合物时,所述碳酸钠水溶液的浓度优选为1mol/L,萃取次数优选为3次。
将所述式Ⅱ所示结构的化合物、R5-X-H和催化剂Ⅱ混合,发生缩合反应,得到具有式I所示结构的化合物。
本发明将R4-H、乙醛酸和催化剂I混合,发生傅克反应,得到式Ⅱ所示结构的化合物。在本发明中,所述R4-H、乙醛酸和催化剂I的组分以及用量比、混合工艺、傅克反应的温度以及时间、后处理过程与前文所述当R5-X-为羟基时,制备式I所示结构的化合物的设置一致,这里不再赘述。
得到式Ⅱ所示结构的化合物后,本发明将所述式Ⅱ所示结构的化合物、R5-X-H和催化剂Ⅱ混合,发生缩合反应,得到具有式I所示结构的化合物。
在本发明中,R5-X-H中的R5-X-与前文式I所示结构中的R5-X-一致,这里不再赘述;所述催化剂Ⅱ优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)和N,N-二异丙基乙胺(DIPEA)的混合物;所述2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐和N,N-二异丙基乙胺的摩尔比优选为1.1:(4~10),更优选为1.1:6。
在本发明中,所述式Ⅱ所示结构的化合物、R5-X-H和催化剂Ⅱ的摩尔比优选为1:1.1:(3~7.1),更优选为1:1.1:3。
在本发明中,所述混合优选在二甲基甲酰胺(DMF)中进行。在本发明中,所述式Ⅱ所示结构的化合物与二甲基甲酰胺的摩尔比优选为1:(1~1.1),更优选为1:1.1。
在本发明中,优选依次按照式Ⅱ所示结构的化合物、催化剂Ⅱ和R5-X-H的加料顺序进行混合,这样有利于控制反应温度,保证缩合反应彻底进行。在本发明中,所述混合优选在搅拌条件下进行,所述搅拌的速度优选为160~180r/min,更优选为180r/min。
在本发明中,所述缩合反应的温度优选为常温,所述常温具体指25℃。本发明优选采用TLC跟踪所述缩合反应的进程以确定反应结束时间,在本发明中,所述缩合反应的时间优选为2~5h,更优选为2h。所述缩合反应的时间具体是以所述R5-X加入完毕开始计。
完成所述缩合反应后,本发明优选将缩合反应后的体系进行柱层析纯化,得到具有式I所示结构的化合物。本发明对所述柱层析纯化没有任何特殊的限定,采用本领域技术人员所熟知的柱层析纯化方法即可。在本发明的具体实施例中,所述柱层析纯化用流动相优选为环己烷和乙酸乙酯的混合溶液,所述环己烷和乙酸乙酯的摩尔比优选为100:(7~10)。
本发明还提供了一种消杀剂,有效成分包括上述技术方案所述含α取代苯基结构的化合物。在本发明中,所述消杀剂的制备方法优选为将所述含α取代苯基结构的化合物溶于水中,配制成浓度为0.1~15g/L的溶液;或者将所述含α取代苯基结构的化合物与其他助剂复配。本发明提供的消杀剂具有较好的灭菌、消毒效果,在灭菌、消毒用品中具有广阔的应用前景。
下面将结合本发明中的实施例,对本发明中的技术方案进行清楚、完整地描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
将500mg邻苯二酚、420mg环己烷和0.485mL一水合乙醛酸,依次加入到反应瓶中;以10mL水为溶剂,在769mg对甲苯磺酸催化剂存在下,80℃条件下,以160r/min的搅拌速度搅拌5h,TLC检测反应;待反应完全,冷却至室温后,调节反应液pH值至2,用乙酸乙酯萃取得到粗品2-环己基-2-(3,4-二羟基苯基)乙酸;然后用乙醇重结晶得到1g的2-环己基-2-(3,4-二羟基苯基)乙酸;
将上述2-环己基-2-(3,4-二羟基苯基)乙酸溶于10mLDMF中,分别依次加入1.8gHATU、3.3ml DIPEA和1mL质量分数为40%的甲胺水溶液,25℃条件下,以180r/min的搅拌速度搅拌2h,TLC检测反应,待反应进行完毕,使用柱层析纯化(流动相为环己烷/乙酸乙酯,环己烷/乙酸乙酯的摩尔比为100/7),得到2-环己基-2-(3,4-二羟基苯基)-N-甲基乙酰胺,所得2-环己基-2-(3,4-二羟基苯基)-N-甲基乙酰胺的结构式为:
所述2-环己基-2-(3,4-二羟基苯基)-N-甲基乙酰胺为土黄色固体,熔点>300℃,产率61%。分析结果如下:1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.94(s,1H),7.26(q,J=3.7Hz,1H),6.79(d,J=1.0Hz,1H),6.76(d,J=0.9Hz,2H),3.72(d,J=7.1,1.1Hz,1H),2.75(d,J=3.7Hz,3H),2.37(h,J=7.0Hz,1H),1.64-1.54(m,4H),1.53-1.49(m,2H),1.49-1.43(m,4H)。13C NMR(100MHz,CDCl3)δ173.98,145.55,144.52,132.88,121.97,116.51,115.87,58.78,39.82,28.65,26.23,25.91,25.89。
实施例2
将500mg 4-羟基苯、456mg苯和0.568mL一水合乙醛酸,依次加入到反应瓶中;以10mL水为溶剂,在300mg固体强酸催化剂的存在下,70℃条件下,以160r/min的搅拌速度搅拌5h,TLC检测反应;待反应完全,冷却至室温后,调节反应液pH值至2,用乙酸乙酯萃取得到粗品2-(4-羟基苯基)-N-异丙基-2-苯乙酸;然后用乙醇重结晶得到1.1g的2-(4-羟基苯基)-N-异丙基-2-苯乙酸;
将上述2-(4-羟基苯基)-N-异丙基-2-苯乙酸溶于20mLDMF中,分别依次加入2.2gHATU、3.9DIPEA和1.1mL的异丙胺,25℃条件下,以180r/min的搅拌速度搅拌2h,TLC检测反应,待反应进行完毕,使用柱层析纯化(流动相为环己烷/乙酸乙酯,环己烷/乙酸乙酯的摩尔比为100/7)得到2-(4-羟基苯基)-N-异丙基-2-苯乙酰胺,所得2-(4-羟基苯基)-N-异丙基-2-苯乙酰胺的结构式为:
所述2-(4-羟基苯基)-N-异丙基-2-苯乙酰胺为土黄色固体,熔点>300℃,产率67%。分析结果如下:1H NMR(400MHz,CDCl3)δ7.84(s,1H),7.54(d,J=7.3Hz,1H),7.28(d,J=2.1Hz,3H),7.27-7.23(m,2H),7.21(t,J=1.0Hz,2H),6.72-6.69(m,2H),5.17(s,J=0.8Hz,1H),3.96(dq,J=13.7,6.9Hz,1H),1.22(d,J=6.8Hz,3H),1.17(d,J=6.8Hz,3H)。13C NMR(100MHz,CDCl3)δ173.60,156.72,138.18,132.74,129.33,129.17,128.47,127.71,115.40,58.62,44.34,22.81。
实施例3
将500mg 3,4-二氟苯、292mg苯和0.363mL一水合乙醛酸,依次加入到反应瓶中;以10mL水为溶剂,在260mg固体强酸催化剂的存在下,70℃条件下,以180r/min的搅拌速度搅拌5h,TLC检测反应;待反应完全,冷却至室温后,调节反应液pH值至2,用乙酸乙酯萃取得到粗品2-(3,4-二氟苯基)-N-甲基-2-苯乙酸;然后用乙醇重结晶得到800mg的2-(3,4-二氟苯基)-N-甲基-2-苯乙酸;
将上述2-(3,4-二氟苯基)-N-甲基-2-苯乙酸溶于10mLDMF中,分别依次加入1.3gHATU、2.3mlDIPEA和1mL质量分数为40%的甲胺水溶液,25℃条件下,以180r/min的搅拌速度搅拌2h,TLC检测反应,待反应进行完毕,使用柱层析纯化(流动相为环己烷/乙酸乙酯,环己烷/乙酸乙酯的摩尔比为10/1)得到2-(3,4-二氟苯基)-N-甲基-2-苯乙酰胺,所得2-(3,4-二氟苯基)-N-甲基-2-苯乙酰胺的结构式为:
所述2-(3,4-二氟苯基)-N-甲基-2-苯乙酰胺为土黄色固体,熔点>300℃,产率79%。
分析结果如下:1H NMR(400MHz,CDCl3)δ7.28(d,J=3.3Hz,3H),7.27-7.25(m,2H),7.25-7.22(m,1H),7.22-7.19(m,2H),4.99(s,1H),2.77(d,J=3.5Hz,3H)。13C NMR(100MHz,CDCl3)δ175.61,151.84,150.28,138.03,135.92,129.17,128.47,127.75,125.85,117.39,116.99,55.40,25.91。
实施例4
将500mg 4-羟基苯、538mg甲苯和0.568mL一水合乙醛酸,依次加入到反应瓶中;以20mL水为溶剂,在240mg固体强酸催化剂的存在下,100℃条件下,以180r/min的搅拌速度搅拌7h,TLC检测反应;待反应完全,冷却至室温后,用20mL乙酸乙酯稀释,过滤,将所得滤液真空浓缩,过滤所得固体物质溶解于二乙醚中,用1.0mol/L的碳酸钠水溶液萃取三次,每次萃取时碳酸钠水溶液的用量为15mL;采用浓盐酸将萃取所得水层酸化至pH为2,过滤收集所得固体为2-(4-羟基苯基)-2-对甲苯乙酸,所得2-(4-羟基苯基)-2-对甲苯乙酸的结构式为:
所述2-(4-羟基苯基)-2-对甲苯乙酸为固体粉末,产率84%。
分析结果如下:1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.29-7.25(m,2H),7.23-7.19(m,2H),7.19-7.16(m,2H),6.73-6.69(m,2H),5.04(s,J=0.9Hz,1H),2.35(s,J=1.0Hz,3H)。13C NMR(100MHz,CDCl3)δ178.06,156.74,137.83,136.16,131.64,129.42,129.08,128.75,115.43,58.72,20.98。
实施例5
将500mg 3,4-二羟基苯、1.1mol呋喃和1.3mL一水合乙醛酸,依次加入到反应瓶中;以20mL水为溶剂,在200mg固体强酸催化剂和催化量的对甲苯磺酸的存在下,70℃条件下,以180r/min的搅拌速度搅拌5h,TLC检测反应;待反应完全,冷却至室温后,调节反应液pH值至2,用乙酸乙酯萃取得到粗品2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酸;然后用乙醇重结晶得到860mg的2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酸;
将上述2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酸溶于10mLDMF溶液中,分别依次加入1.6g HATU、2.3mlDIPEA和1.2mL质量分数为40%的甲胺水溶液,25℃条件下,以180r/min的搅拌速度搅拌2h,TLC检测反应,待反应进行完毕,使用柱层析纯化(流动相为环己烷/乙酸乙酯,环己烷/乙酸乙酯的摩尔比为10/1)得到2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酰胺,所得2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酰胺的结构式为:
所述2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酰胺为土黄色固体,熔点>300℃,产率77%。
分析结果如下:1H NMR(400MHz,CDCl3)δ9.15(s,1H),8.96(s,1H),7.42(dd,J=7.4,1.5Hz,1H),7.30(q,J=3.5Hz,1H),6.87-6.83(m,2H),6.78(dt,J=7.6,0.8Hz,1H),6.34(t,J=7.4Hz,1H),6.28(dd,J=7.5,1.6Hz,1H),5.26(s,J=0.9Hz,1H),2.79(s,J=3.5Hz,3H)。13CNMR(100MHz,CDCl3)δ171.95,151.14,145.42,145.33,142.18,128.50,120.85,115.90,115.43,110.66,109.95,55.54,25.91。
实施例6
将500mg 3,4-二羟基苯、395mg吡啶和0.485mL一水合乙醛酸,依次加入到反应瓶中;以10mL水为溶剂,在200mg固体强酸催化剂的存在下,70℃条件下,以180r/min的搅拌速度搅拌5h,TLC检测反应;待反应完全,冷却至室温后,调节反应液pH值至2,用乙酸乙酯萃取得到粗品2-(3,4-二羟基苯基)-N-甲基-2-(4-吡啶)乙酸;然后用乙醇重结晶得到800mg的2-(3,4-二羟基苯基)-N-甲基-2-(4-吡啶)乙酸;
将上述2-(3,4-二羟基苯基)-N-甲基-2-(4-吡啶)乙酸溶于10mLDMF溶液中,分别依次加入1.4gHATU、2.7ml DIPEA和1.2mL质量分数为40%的甲胺水溶液,25℃条件下,以180r/min的搅拌速度搅拌2h,TLC检测反应,待反应进行完毕,使用柱层析纯化(流动相为环己烷/乙酸乙酯,环己烷/乙酸乙酯的摩尔比为10/1)得到2-(3,4-二羟基苯基)-N-甲基-2-(4-吡啶)乙酰胺,所得2-(3,4-二羟基苯基)-N-甲基-2-(4-吡啶)乙酰胺的结构式为:
所述2-(3,4-二羟基苯基)-N-甲基-2-(4-吡啶)乙酰胺为土黄色固体,熔点>300℃,产率60%。
分析结果如下:1H NMR(400MHz,DMSO)δ9.48(s,2H),7.49(s,1H),8.54-8.43(m,2H),7.27-7.01(m,2H),6.83(d,1H),6.81(s,1H),6.62(d,1H),5.02(s,1H),2.83(s,3H)。
实施例7
将500mg苯和0.684mL一水合乙醛酸,依次加入到反应瓶中;以20mL水为溶剂,在320mg固体强酸催化剂的存在下,80℃条件下,以180r/min的搅拌速度搅拌7h,TLC检测反应;待反应完全,冷却至室温后,用20mL乙酸乙酯稀释,过滤,将所得滤液真空浓缩,过滤所得固体物质溶解于二乙醚中,用1.0mol/L的碳酸钠水溶液萃取三次,每次萃取时碳酸钠水溶液的用量为15mL;采用浓盐酸将萃取所得水层酸化至pH为2,过滤收集所得固体为2,2-二苯基乙酸,所得2,2-二苯基乙酸的结构式为:
所述2,2-二苯基乙酸为固体粉末,产率83%。
分析结果如下:1H NMR(400MHz,DMSO)δ12.02(s,1H),7.37-.21(m,10H),4.93(s,1H)。
实施例8
将500mg邻苯二酚和0.485mL一水合乙醛酸,依次加入到反应瓶中;以20mL水为溶剂,在330mg固体强酸催化剂的存在下,80℃条件下,以180r/min的搅拌速度搅拌5h,TLC检测反应;待反应完全,冷却至室温后,调节反应液pH值至2,用乙酸乙酯萃取得到粗品2,2-二-(3,4-二羟基苯基)乙酸;然后用乙醇重结晶得到2,2-二-(3,4-二羟基苯基)乙酸,所得2,2-二-(3,4-二羟基苯基)乙酸的结构式为:
所述2,2-二-(3,4-二羟基苯基)乙酸为淡黄色固体粉末,产率90%。
分析结果如下:1H NMR(400MHz,DMSO)δ12.07(s,1H),9.50(s,4H),6.83-6.61(m,4H),4.91(s,1H)。
试验例1
(1)准备待测样品:
将4-氯-3,5-二甲基苯酚用质量分数为1%的二甲基亚砜(DMSO)水溶液溶解后,用灭菌的超纯水稀释成浓度为0.31g/L和0.15g/L的4-氯-3,5-二甲基苯酚溶液;
将苯酚用灭菌的超纯水溶解,稀释成浓度为6.25g/L、3.12g/L、1.56g/L、0.78g/L、0.31g/L和0.15g/L的苯酚溶液;
将实施例5制备得到的2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酰胺(待测药)用灭菌的超纯水溶解,稀释成浓度为6.25g/L、3.12g/L、1.56g/L、0.78g/L、0.31g/L和0.15g/L的待测药溶液。
(2)中和剂的配制方法:
a.将5mL吐温-80和0.2g卵磷脂进行加热溶解;
b.将0.2g组氨酸溶解于5mL纯净水中,于54℃水浴锅中加热溶解;
c.将溶解的吐温-80、卵磷脂加入冷却后的组氨酸溶液中,混合至100mL,高压灭菌处理。
(3)0.03mol/L的PBS缓冲液配方:称取3.36g的PBS溶于100mL的纯净水中,灭菌处理;
(4)选择中和剂的实验方法:
以大肠杆菌ATCC 25922和金黄色葡萄球菌ATCC 29213为实验菌株,待测药的浓度设置为2.5g/L,按悬液定量杀菌程序进行实验,重复三次,设六组平行:Ⅰ组:100μL(浓度为1×108cfu/mL的大肠杆菌ATCC 25922和浓度为1×108cfu/mL的金黄色葡萄球菌ATCC 29213)与400μL待测药作用5min,取50μL的混合液与450μL的PBS缓冲液混匀,稀释后活菌计数;Ⅱ组:100μL(浓度为1×108cfu/mL的大肠杆菌ATCC 25922和浓度为1×108cfu/mL的金黄色葡萄球菌ATCC 29213)与400μL待测药作用5min,取50μL的混合液与450μL的中和剂混匀,作用10min,稀释后活菌计数;Ⅲ组:10μL的菌悬液与40μL的无菌水与450μL的中和剂反应10min,稀释后活菌计数;Ⅳ组:40μL浓度为2.5g/L的待测药溶液与450μL中和剂反应10min后加入10μL的菌悬液,稀释后活菌计数;Ⅴ组:100μL的菌悬液与400μL的中和剂反应5min,取50μL的混合液与450μL的PBS缓冲液混匀,稀释后活菌计数;Ⅵ组:取培养液和PBS缓冲液接种培养做阴性对照。结果判定:第Ⅰ组无菌生长或有少量菌生长;第Ⅱ组有菌生长,且菌数不少于100CFU/mL,第Ⅲ,Ⅳ,Ⅴ组间菌数误差率≤15%,第Ⅵ组无菌生长。则表明中和剂及其浓度适宜。
(5)悬液定量实验操作方法:
a.取冻干菌种管,在无菌操作下打开,以毛细吸管加入适量营养肉汤,轻柔吹吸数次,使菌种融化分散。取含5.0mL~10.0mL营养肉汤培养基试管,滴入少许菌种悬液,置37℃培养18h~24h;用接种环取第1代培养的菌悬液,划线接种于营养琼脂培养基平板上,于37℃培养18h~24h;挑取上述第2代培养物中典型菌落,接种于营养琼脂斜面,于37℃培养18h~24h,即为第3代培养物;
b.分别挑取大肠杆菌ATCC 25922,金黄色葡萄球菌ATCC 29213,铜绿假单胞菌ATCC 27853的第三代培养物的单克隆菌株于3mL的MHB中,在恒温培养振荡器中摇菌3h,转速为220rpm,在此转速下摇菌3h后菌悬液浓度即为(1~5)×108CFU/mL。
c.在无菌试管中先加入0.5mL菌悬液,再加入0.5mL有机干扰物质(0.03mol/L的PBS缓冲溶液),混匀,置于20℃±1℃水浴中恒温5min后,用无菌吸管吸取4.0mL步骤(1)准备的待测样品注入混合液中,迅速混匀并立即记时;
d.待试验菌与待测样品相互作用至预定时间1min、5min、15min和30min后,分别吸取试验菌与待测样品混合液0.5mL加于4.5mL中和剂中,混匀;
e.中和作用10min后,分别吸取1.0mL样液,按活菌培养计数方法测定存活菌数,每管样液接种2个平皿,平板上生长的菌落数较多时,可进行10倍稀释,再进行活菌培养计数;
f.同时用PBS缓冲液代替待测样品,进行平行试验,作为阳性对照;
g.所有试验样本均置于37℃温箱中培养过夜,观察结果;
h.试验重复3次,计算各组的活菌浓度(CFU/mL),并换算为对数值(N),然后按下式计算杀灭对数值:
杀灭对数值(KL)=对照组平均活菌浓度的对数值(No)-试验组活菌浓度对数值(Nx)
计算杀灭对数值时,取小数点后两位值,可以进行数字修约。
检测结果见表1~4:
表1待测药对大肠杆菌和金黄色葡萄球菌的中和剂鉴定实验结果
表2待测样品对大肠杆菌ATCC 25922的杀菌效果(对数值)
表3待测样品对金黄色葡萄球菌ATCC 29213的杀菌效果(对数值)
表4待测样品对铜绿假单胞菌ATCC 27853的杀菌效果(对数值)
由表2~4试验结果可知,当浓度为3.125g/L时,1min对大肠杆菌ATCC25922杀灭对数值≥5.00,15min对铜绿假单孢菌ATCC 27853杀灭对数值≥5.00;当浓度为6.25g/L时,15min对金黄色葡萄球菌ATCC 29213杀灭对数值≥5.00,符合酚类消毒剂卫生要求GB27947-2011的要求,具有优异的杀菌效果。
试验例2
参照医疗器械消毒剂卫生要求GB/T27949-2011的规定进行试验;
(1)准备待测样品:
将邻苯二甲醛用灭菌的超纯水溶解,稀释成浓度为5g/L、10g/L和15g/L的邻苯二甲醛溶液;
将实施例4制备的2-(4-羟基苯基)-2-对甲苯乙酸(待测药)用灭菌的超纯水溶解,稀释成浓度为5g/L、10g/L和15g/L的待测药溶液。
(2)中和剂的配制方法:
a.将5mL吐温-80和0.2g卵磷脂进行加热溶解;
b.将0.2g组氨酸溶解于5mL的纯净水中,于54℃水浴锅中加热溶解;
c.将溶解的吐温-80、卵磷脂加入冷却后的组氨酸溶液中,混合至100mL,高压灭菌处理。
(3)0.03mol/L的PBS缓冲液配方:称取3.36g的PBS溶于100mL的纯净水中,灭菌处理。
(4)悬液定量实验操作方法:
a.取枯草芽孢杆菌ATCC 9372冻干菌种管,在无菌操作下打开,以毛细吸管加入适量营养肉汤,轻柔吹吸数次,使菌种融化分散;取含5.0mL~10.0mL营养肉汤培养基试管,滴入少许菌种悬液,置37℃培养18h~24h,用接种环取第1代培养的菌悬液;
b.挑取第1代培养物的单克隆菌株于3mLMHB中,在恒温培养振荡器中摇菌3h,转速为220rpm,在此转速下摇菌3h后菌悬液浓度即为1×108CFU/mL~5×108CFU/mL;
c.在无菌试管中先加入0.5mL菌悬液,再加入0.5mL有机干扰物质(0.03mol/L的PBS缓冲液),混匀,置于20℃±1℃水浴中恒温5min后,用无菌吸管吸取4.0mL步骤(1)准备的待测样品注入混合液中,迅速混匀并立即记时;
d.待试验菌与待测样品相互作用至各预定时间,分别吸取试验菌与消毒剂混合液0.5mL加于4.5mL中和剂中,混匀;
e.中和作用10min后,分别吸取1.0mL样液,按活菌培养计数方法测定存活菌数,每管样液接种2个平皿,平板上生长的菌落数较多时,可进行10倍稀释,再进行活菌培养计数;
h.同时用PBS缓冲液代替待测样品,进行平行试验,作为阳性对照;
f.所有试验样本均置于37℃温箱中培养过夜,观察结果;
g.试验重复3次,计算各组的活菌浓度(CFU/mL),并换算为对数值(N),然后按下式计算杀灭对数值:
杀灭对数值(KL)=对照组平均活菌浓度的对数值(No)-试验组活菌浓度对数值(Nx)
计算杀灭对数值时,取小数点后两位值,可以进行数字修约。
(5)载体浸泡定量杀菌试验操作方法:
a.取无菌小平皿,标明所注入待测样品的浓度,按每片5.0mL的量,吸取相应浓度的待测样品注入平皿中;
b.用无菌镊子分别放3片枯草杆菌黑色变种芽孢菌片于平皿中,并使之浸透于待测样品中;
c.待菌药相互作用至各预定时间,用无菌镊子将菌片取出分别移入一含5.0mL中和剂的试管中,将试管在手掌上振敲80次,使菌片上的细菌被洗脱进中和液中,再放置10min使中和作用充分,最终进一步混匀后,吸取1.0mL直接接种平皿,每管接种2个平皿,测定存活菌数;
d.另取一平皿,注入10.0mLPBS缓冲液代替待测样品,放入2片菌片,作为阳性对照组,其随后的试验步骤和活菌培养计数与上述试验组相同;
e.所有试验样本均在37℃温箱中培养培养过夜,观察结果;
f.试验重复3次(包括对照),计算各组的活菌量(CFU/片),并换算为对数值(N)。
(6)消毒剂对金属腐蚀性的测定方法:
将碳钢、不锈钢、铜与铝制成圆片,直径为24.0±0.1mm,厚度为1.0mm,有一直径约2.0mm的小孔,表面积总值约为9.80cm2;磨去表面氧化层,清洗、干燥后,称重,测其直径、孔径与厚度,作为金属样片;
将金属样片浸入待测样品中,浸泡时,每一金属样片需浸泡在200mL待测样品中,一次性浸泡72h,每次试验放置3片金属样片;每一金属样片相隔1cm以上,可在同一容器内(含600mL消毒液)进行;浸泡72h后,取出金属样片,先用自来水冲洗,再用毛刷去除腐蚀产物;金属样片除去腐蚀产物并清洗后,用粗滤纸吸干水分,置于垫有滤纸的平皿中,放入50℃烘箱,干燥1h,用镊子夹取,待其温度降至室温后分别放在天平上称重;称重时,和试验前都应戴洁净手套,勿以手直接接触金属样片;
观察与记录金属样片颜色变化,并以金属腐蚀速率(R)平均值表达,在计算时应减去空白对照组样片的失重值,计算公式如下:
[R为腐蚀速率,mm/a(毫米/年);m为试验前金属样片重量,g;mt为试验后金属样片重量,g;mk为化学处理去除腐蚀产物金属样片失重值,g,试验中未进行化学清除处理者,计算时在公式中删去mk值;S为金属样片的表面积总值,cm2;t为试验时间,h;d为金属材料密度,kg/m3]。
腐蚀性分级标准
检测结果见表5~7:
表5待测样品对枯草杆菌黑色变种芽孢杆菌ATCC 9372的杀菌对数值(悬液法)
表6待测样品对枯草杆菌黑色变种芽孢ATCC 9372的杀菌对数值(载体法)
表7金属片腐蚀实验结果
由表5~7试验结果可知,本发明提供的消杀剂的水溶性较好,溶解度能达到15g/L;当浓度为5g/L时,10min对枯草杆菌黑色变种芽孢杀灭的对数值≥5.00,且对金属无腐蚀性,符合医疗器械消毒剂卫生要求GB/T27949-2011的规定。
试验例3
按照试验例1中的试验方法对实施例1~4和实施例6~8所得消杀剂进行杀菌试验,检测结果见表8~10;
表8对大肠杆菌ATCC 25922的杀菌对数值(悬液法)
表9对金黄色葡萄球菌ATCC 29213的杀菌对数值(悬液法)
表10对铜绿假单胞菌ATCC 27853的杀菌对数值(悬液法)
试验例4
按照试验例2中的试验方法对实施例1~3和实施例5~8所得消杀剂进行杀菌试验,检测结果见表11;
表11对枯草黑色变种芽孢ATCC 9372的杀菌对数值(悬液法)
待测样品 | 浓度(g/L) | 作用时间(min) | 活性(杀菌对数值) |
实施例1 | 15 | 30 | 1.35 |
实施例2 | 15 | 30 | 0.98 |
实施例3 | 15 | 30 | 2.07 |
实施例4 | 15 | 30 | 1.54 |
实施例5 | 15 | 30 | 5.60 |
实施例6 | 15 | 30 | 0.76 |
实施例7 | 15 | 30 | 1.97 |
实施例8 | 15 | 30 | 2.13 |
由表8~11的试验结果可知,本发明提供的消杀剂对大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌和枯草杆菌黑色变种芽孢等病原菌有良好的灭杀效果。
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。
Claims (5)
2.权利要求1所述含α取代苯基结构的化合物的制备方法,包括以下步骤:
将3,4-二羟基苯、呋喃、乙醛酸和固体强酸催化剂混合,发生傅克反应,得到2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酸;
将所述2-(3,4-二羟基苯基)-2-(2-呋喃)-N-甲基乙酸、甲胺、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐和N,N-二异丙基乙胺混合,发生缩合反应,得到具有式I所示结构的化合物。
3.根据权利要求2所述的制备方法,其特征在于,所述傅克反应的温度为70℃,时间为5h。
4.根据权利要求2所述的制备方法,其特征在于,所述缩合反应的温度为25℃,时间为2h。
5.一种应用于金属表面的消杀剂,其特征在于,有效成分包括权利要求1所述含α取代苯基结构的化合物。
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