CN114957123B - 一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物及其制备方法和应用 - Google Patents
一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物及其制备方法和应用 Download PDFInfo
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- CN114957123B CN114957123B CN202210595040.XA CN202210595040A CN114957123B CN 114957123 B CN114957123 B CN 114957123B CN 202210595040 A CN202210595040 A CN 202210595040A CN 114957123 B CN114957123 B CN 114957123B
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- pyrazole
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- ethyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- IGQNDARULCASRN-UHFFFAOYSA-N Fluxapyroxad (bas 700 f)-tp cscd465008 Chemical compound OC(=O)C1=CNN=C1C(F)F IGQNDARULCASRN-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 12
- 230000002363 herbicidal effect Effects 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- KDVPGBVZKTVEIS-AATRIKPKSA-N ethyl (2e)-2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate Chemical compound CCO\C=C(C(=O)C(F)F)\C(=O)OCC KDVPGBVZKTVEIS-AATRIKPKSA-N 0.000 claims description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- RLOHOBNEYHBZID-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)C(C(F)F)=N1 RLOHOBNEYHBZID-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- 230000002829 reductive effect Effects 0.000 claims description 13
- -1 ethoxymethylene Chemical group 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000002390 rotary evaporation Methods 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- MRQQMVMIANXDKC-UHFFFAOYSA-N ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate Chemical compound CCOC(=O)C1=CN(C)N=C1C(F)F MRQQMVMIANXDKC-UHFFFAOYSA-N 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- MZGPCLIDFPCPTI-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carbonyl chloride Chemical compound CN1C=C(C(Cl)=O)C(C(F)F)=N1 MZGPCLIDFPCPTI-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
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- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- CBDPWKVOPADMJC-UHFFFAOYSA-N ethyl 4,4-difluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)F CBDPWKVOPADMJC-UHFFFAOYSA-N 0.000 claims description 5
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 5
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- 239000004009 herbicide Substances 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
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- 239000003480 eluent Substances 0.000 claims description 2
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- 239000000706 filtrate Substances 0.000 claims description 2
- VTWKXBJHBHYJBI-VURMDHGXSA-N (nz)-n-benzylidenehydroxylamine Chemical class O\N=C/C1=CC=CC=C1 VTWKXBJHBHYJBI-VURMDHGXSA-N 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 38
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 6
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 abstract description 4
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- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 150000002367 halogens Chemical group 0.000 abstract description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
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- VTWKXBJHBHYJBI-SOFGYWHQSA-N (ne)-n-benzylidenehydroxylamine Chemical class O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 description 18
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
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- 230000015572 biosynthetic process Effects 0.000 description 6
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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Abstract
本发明公开了一种3‑(二氟甲基)‑吡唑‑4‑羧酸酯类衍生物及其制备方法和应用,3‑(二氟甲基)‑吡唑‑4‑羧酸酯类衍生物的结构式如式(Ⅰ)所示:
Description
技术领域
本发明属于化学合成技术领域,具体涉及一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物及其制备方法和应用。
背景技术
吡唑肟类化合物主要具有杀虫杀螨活性。典型性化合物有1985年日本NihonNohyaku公司研制开发的唑螨酯(Fenpyroximate),多年来一直作为农用杀虫杀螨剂在农作物保护方面发挥着重要作用。唑螨酯有E和Z两种构型,E体杀螨活性高、速度快。它对多种害螨有强烈的触杀作用,主要用于防治植食性螨类,对整个生长期都有活性,尤其是幼螨。对斜纹夜蛾、二化螟、稻飞虱等害虫及稻瘟病、白粉病、霜霉病等病害也有优良的防治效果。
吡唑肟酯类化合物由于含有吡唑、苄基等活性结构基团,通常具有高效、低毒、环境相容性好等性质,同样也具有广泛的生物活性,如抗肿瘤、抗菌、杀虫和除草等。
设计合成新型的吡唑肟脂类杀菌剂、除草剂对开发高效、低毒、低残留的新型农药具有重要意义,并且在农药创制中具有优势。
发明内容
针对上述技术问题,本发明的目的在于提供一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物及其制备方法和应用。本发明以氟唑菌酰胺(Fluxapyroxad)为根据,通过引入脂肪链延长中间部分,合成吡唑酰胺酯类化合物。然后在吡唑酰基上引入取代苯甲醛肟以考察对化合物生物活性的影响,设计合成了吡唑肟酯类化合物。
为达到上述目的,提出以下技术方案:
一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物,其结构式如式(Ⅰ)所示:
式(Ⅰ)中,苯环上的H被取代基R单取代、多取代或不取代,取代基R独立地为烷基、甲氧基、卤素、硝基或三氟甲基。
优选地,式(Ⅰ)中R为2-甲基、3-甲基、4-甲基、2-甲氧基、4-甲氧基、3,4,5-三甲氧基、2-溴、4-溴、2-硝基、4-硝基、4-氟、4-三氟甲基、4-氯或2,4-二氯。
一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物的制备方法,包括以下步骤:
1)将乙酸酐加入二氟乙酰乙酸乙酯和原甲酸三乙酯的混合溶液中,升温至回流,反应6-10h后,停止加热,待反应液冷却至室温后,减压蒸发除去低沸点物,得到如式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯;
2)将通过步骤1)所得的如式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯加入无水乙醇中,搅拌均匀,然后在冰盐浴条件下逐滴加入到甲基肼水溶液和无水乙醇的混合溶液中,滴加结束后加热至40-60℃,TLC跟踪反应,待反应结束后,减压蒸发去除溶剂,然后加入乙酸乙酯和水萃取,有机层再用饱和食盐水洗涤三次,经无水硫酸镁干燥,过滤,滤液浓缩除去溶剂,得如式(Ⅲ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯的粗产品;
3)向通过步骤2)所得的如式(Ⅲ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯的粗产品,加入氢氧化钠水溶液,升温至50-70℃搅拌,TLC跟踪反应,等到反应结束后冷却至室温,加入浓盐酸调节pH,析出大量固体,抽滤,水洗,烘干,得如式(Ⅳ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸的粗产品;
4)向通过步骤3)所得的如式(Ⅳ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸的粗产品,加入氯化亚砜,加热回流,等到反应液由浑浊变为澄清透明后,继续反应20-40分钟,停止加热,减压旋转蒸发除去多余的氯化亚砜,得如式(Ⅴ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯;
5)将通过步骤4)所得的如式(Ⅴ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯溶解在二氯甲烷中,在冰盐浴条件下逐滴滴加入到溶有如式(Ⅵ)所示的取代苯甲醛肟和三乙胺的二氯甲烷中,边滴加边搅拌,滴加完毕常温搅拌,TLC跟踪反应,等到反应结束后加入柱层析硅胶,减压旋转蒸发除去溶剂,经柱层析提纯得如式(Ⅰ)所示的3-(二氟甲基)-吡唑-4-羧酸酯类衍生物;
苯环上的H被取代基R取代或不取代,取代时,取代基R为2-甲基、3-甲基、4-甲基、2-甲氧基、4-甲氧基、3,4,5-三甲氧基、2-溴、4-溴、2-硝基、4-硝基、4-氟、4-三氟甲基、4-氯或2,4-二氯。
进一步地,步骤3)中加入浓盐酸调节pH至1-4。
进一步地,步骤1)中,所述乙酸酐、二氟乙酰乙酸乙酯和原甲酸三乙酯的投料摩尔比为3:1-3:2-5;步骤2)中,式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯和甲基肼的投料摩尔比为1:1~5;步骤3)中,式(Ⅲ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯和氢氧化钠的投料摩尔比为1:1~4;步骤4)中,氯化亚砜的用量要过量;步骤5)中,式(Ⅴ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯和如式(Ⅵ)所示的取代苯甲醛肟的投料摩尔比为1:1.1~1.5。
进一步地,步骤2)中溶解式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯的无水乙醇的体积用量以式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯的物质的量计为0.1~0.5mL/mmol,步骤4)中氯化亚砜的体积用量以式(Ⅳ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸的物质的量计为0.1~0.6mL/mmol。
进一步地,步骤5)中用于溶解1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯的二氯甲烷的体积用量以式(Ⅴ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯的物质的量计为1~3mL/mmol。
进一步地,步骤5)中柱层析分离的洗脱剂均采用体积比2:3的乙酸乙酯和石油醚混合液。
本发明3-(二氟甲基)-吡唑-4-羧酸酯类衍生物的合成工艺路线如下:
苯环上的H被取代基R取代或不取代,取代时,取代基R为2-甲基、3-甲基、4-甲基、2-甲氧基、4-甲氧基、3,4,5-三甲氧基、2-溴、4-溴、2-硝基、4-硝基、4-氟、4-三氟甲基、4-氯或2,4-二氯。
一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物在制备杀菌剂中的应用。
一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物在制备除草剂中的应用。
与现有技术相比,本发明的有益效果主要体现在:本发明提供了一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物及其制备方法与其在制备杀菌剂和除草剂中的应用,其制备方法简单、操作方便,得到的化合物在50ppm有效浓度下对水稻稻瘟病菌的抑制率高达85.7%,对黄瓜灰霉病的抑制率达69%,本发明所述化合物为具有杀菌活性的新化合物,为新农药的研发提供了基础。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。
3-(二氟甲基)-吡唑-4-羧酸酯类衍生物的合成工艺路线如下:
苯环上的H被取代基R取代或不取代,取代时,取代基R为2-甲基、3-甲基、4-甲基、2-甲氧基、4-甲氧基、3,4,5-三甲氧基、2-溴、4-溴、2-硝基、4-硝基、4-氟、4-三氟甲基、4-氯或2,4-二氯。
实施例1(E)-苯甲醛O-(3-(二氟甲基)-1H-吡唑-4-羰基)肟的制备
1)(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯(Ⅱ)的合成:
在100mL的反应瓶中加入乙酸酐(15.3g,150.0mmol),然后加入二氟乙酰乙酸乙酯(9.2g,50.0mmol)和原甲酸三乙酯(22.2g,150.0mmol),升温至回流,反应8h后,停止加热,待反应液冷却至室温后减压旋转蒸发去除低沸点物,得式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯的粗产品;
2)1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯(Ⅲ)的合成:
在含48.0mmol式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯的粗产品中加入无水乙醇(10mL),搅拌均匀,然后在冰盐浴条件下逐滴加入到质量百分比浓度40%甲基肼水溶液(甲基肼72.0mmol)和无水乙醇(15mL)的混合溶液中,边滴边搅拌,滴加结束后加热至50℃,TLC(VEA/VPE=1/2)跟踪反应,等到反应结束后减压旋转蒸发去除溶剂,然后加入乙酸乙酯(20mL)和水萃取,有机层再用饱和食盐水洗涤三次,无水硫酸镁干燥后减压旋转蒸发,得式(Ⅲ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯的粗产品;
3)1-甲基-3-二氟甲基-1H-吡唑-4-甲酸(Ⅳ)的合成:
在100mL的反应瓶中加入含41mmol式(Ⅲ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯的粗产品,然后加入质量浓度10%氢氧化钠溶液(氢氧化钠82.0mmol),搅拌升温至60℃,TLC(VEA/VPE=1/1)跟踪反应,等到反应结束后冷却至室温,加入浓盐酸调节pH到2.0左右,析出大量固体,抽滤,水洗,烘干,得式(Ⅳ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸的粗产品;
4)1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯(Ⅴ)的合成:
在100mL反应瓶中加入含27.0mmol的式(Ⅳ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸的粗产品,然后加入过量氯化亚砜(10mL),加热回流,等到反应液由浑浊变为澄清透明后,继续反应30分钟,停止加热,减压旋转蒸发除去过量的氯化亚砜,得(Ⅴ)所示1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯;
5)(E)-苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A1)的合成:
在式(Ⅴ)所示1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯(6.0mmol)中加入二氯甲烷(10mL),在50mL反应瓶中加入苯甲醛肟(7.5mmol),然后加入二氯甲烷(10mL)和三乙胺(1mL),搅拌均匀后,将(Ⅴ)所示1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯的二氯甲烷溶液在冰盐浴条件下逐滴加入到反应瓶中,边滴加边搅拌,滴加完毕常温搅拌,TLC(VEA/VPE=1/2)跟踪反应,等到反应结束后加入柱层析硅胶,减压旋转蒸发除去溶剂,经柱层析提纯得到(A1)化合物,洗脱剂采用体积比为2:3的乙酸乙酯和石油醚混合溶液;
其中式(Ⅰ)结构式中苯环上的H不取代,形成了式(A1)化合物的分子结构。
(E)-苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:73.2%,熔点:171-177℃;1H NMR(CDCl3,500MHz),δ:8.48(s,1H,CH),8.05(s,1H,Pyrazole),7.80(d,J=6.9Hz,2H,Ph),7.53-7.50(m,1H,Ph),7.49-7.45(m,2H,Ph),7.14(t,J=53.8Hz,1H,CHF2),4.02(s,3H,CH3);HRMS(ESI)for C13H11F2N3O2 m/z:Calculated,280.0892,Found,280.0898[M+H]+.
实施例2(E)-2-甲基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A2)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的2-甲基苯甲醛肟,其他操作同实施例1,制得(A2)化合物。
(E)-2-甲基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:71.9%,熔点:120-123℃;1H NMR(CDCl3,500MHz),δ:8.73(s,1H,CH),8.05(s,1H,Pyrazole),7.89(d,J=7.8Hz,1H,Ph),7.39(t,J=7.5Hz,1H,Ph),7.30-7.26(m,2H,Ph),7.15(t,J=53.8Hz,1H,CHF2),4.02(s,3H,CH3),2.53(s,3H,CH3);HRMS(ESI)forC14H13F2N3O2 m/z:Calculated,294.1049,Found,294.1054[M+H]+.
实施例3(E)-3-甲基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A3)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的3-甲基苯甲醛肟,其他操作同实施例1,制得(A3)化合物。
(E)-3-甲基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:71.4%,熔点:119-123℃;1H NMR(CDCl3,500MHz),δ:8.44(s,1H,CH),8.04(s,1H,Pyrazole),7.66(s,1H,Ph),7.54(d,J=7.3Hz,1H,Ph),7.36-7.31(m,2H,Ph),7.14(t,J=53.8Hz,1H,CHF2),4.01(s,3H,CH3),2.40(s,3H,CH3);HRMS(ESI)for C14H13F2N3O2 m/z:Calculated,294.1049,Found,294.1054[M+H]+.
实施例4(E)-4-甲基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A3)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的4-甲基苯甲醛肟,其他操作同实施例1,制得(A3)化合物。
(E)-4-甲基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:70.9%,熔点:147-150℃;1H NMR(CDCl3,500MHz),δ:8.43(s,1H,CH),8.04(s,1H,Pyrazole),7.68(d,J=8.1Hz,2H,Ph),7.26(d,J=8.0Hz,2H,Ph),7.14(t,J=53.8Hz,1H,CHF2),4.01(s,3H,CH3),2.42(s,3H,CH3);HRMS(ESI)for C14H13F2N3O2 m/z:Calculated,294.1049,Found,294.1054[M+H]+.
实施例5(E)-2-甲氧基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A5)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的2-甲氧基苯甲醛肟,其他操作同实施例1,制得(A5)化合物。
(E)-2-甲氧基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:淡黄色固体,收率:69.7%,熔点:116-120℃;1H NMR(CDCl3,500MHz),δ:8.87(s,1H,CH),8.04(s,1H,Pyrazole),8.03(d,J=6.3Hz,1H,Ph),7.47(t,J=7.0,7.5,1.8Hz,1H,Ph),7.17(t,J=53.8Hz,1H,CHF2),7.02(t,J=7.5Hz,1H,Ph),6.95(d,J=8.5Hz,1H,Ph),4.01(s,3H,CH3),3.90(s,3H,OCH3);HRMS(ESI)for C14H13F2N3O3 m/z:Calculated,310.0998,Found,310.1003[M+H]+.
实施例6(E)-4-甲氧基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A6)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的4-甲氧基苯甲醛肟,其他操作同实施例1,制得(A6)化合物。
(E)-4-甲氧基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:淡黄色固体,收率:69.5%,熔点:131-138℃;1H NMR(CDCl3,500MHz),δ:8.41(s,1H,CH),8.04(s,1H,Pyrazole),7.74(d,J=8.8Hz,2H,Ph),7.14(t,J=53.8Hz,1H,CHF2),6.97(d,J=8.8Hz,2H,Ph),4.02(s,3H,CH3),3.88(s,3H,OCH3);HRMS(ESI)for C14H13F2N3O3 m/z:Calculated,310.0998,Found,310.1003[M+H]+.
实施例7(E)-3,4,5-三甲氧基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A7)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的3,4,5-三甲氧基苯甲醛肟,其他操作同实施例1,制得(A7)化合物。
(E)-3,4,5-三甲氧基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:67.9%,熔点:153-157℃;1H NMR(CDCl3,500MHz),δ:8.39(s,1H,CH),8.04(s,1H,Pyrazole),7.11(t,J=53.8Hz,1H,CHF2),7.01(s,2H,Ph),4.02(s,3H,CH3),3.92(s,6H,OCH3),3.92(s,3H,OCH3);HRMS(ESI)for C16H17F2N3O5 m/z:Calculated,370.1209,Found,370.1215[M+H]+.
实施例8(E)-2-溴苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A8)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的2-溴苯甲醛肟,其他操作同实施例1,制得(A8)化合物。
(E)-2-溴苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:淡黄色固体,收率:70.1%,熔点:124-130℃;1H NMR(CDCl3,500MHz),δ:8.87(s,1H,CH),8.12(d,J=7.6Hz,1H,Ph),8.07(s,1H,Pyrazole),7.64(d,J=7.8Hz,1H,Ph),7.41-7.34(m,2H,Ph),7.15(t,J=53.8Hz,1H,CHF2),4.02(s,3H,CH3);HRMS(ESI)for C13H10BrF2N3O2 m/z:Calculated,357.9997,Found,358.0003[M+H]+.
实施例9(E)-4-溴苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A9)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的4-溴苯甲醛肟,其他操作同实施例1,制得(A9)化合物。
(E)-4-溴苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:淡黄固体,收率:69.2%,熔点:180-183℃;1H NMR(CDCl3,500MHz),δ:8.43(s,1H,CH),8.05(s,1H,Pyrazole),7.67(d,J=8.5Hz,2H,Ph),7.60(d,J=8.5Hz,2H,Ph),7.10(t,J=53.8Hz,1H,CHF2),4.02(s,3H,CH3);HRMS(ESI)for C13H10BrF2N3O2 m/z:Calculated,357.9997,Found,358.0003[M+H]+.
实施例10(E)-2-硝基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A10)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的2-硝基苯甲醛肟,其他操作同实施例1,制得(A10)化合物。
(E)-2-硝基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:72.5%,熔点:146-149℃;1H NMR(CDCl3,500MHz),δ:9.10(s,1H,CH),8.21(d,J=6.9Hz,1H,Ph),8.17(d,J=6.2Hz,1H,Ph),8.08(s,1H,Pyrazole),7.77(t,J=7.6Hz,1H,Ph),7.71(t,J=7.8Hz,1H,Ph),7.15(t,J=53.7Hz,1H,CHF2),4.04(s,3H,CH3);HRMS(ESI)forC13H10F2N4O4 m/z:Calculated,325.0743,Found,325.0748[M+H]+.
实施例11(E)-4-硝基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A11)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的4-硝基苯甲醛肟,其他操作同实施例1,制得(A11)化合物。
(E)-4-硝基苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:淡黄色固体,收率:71.3%,熔点:172-176℃;1H NMR(CDCl3,500MHz),δ:8.60(t,J=1.9Hz,1H,Ph),8.57(s,1H,CH),8.37(d,J=8.2Hz,1H,Ph),8.21(d,J=7.8Hz,1H,Ph),8.08(s,1H,Pyrazole),7.68(t,J=8.0Hz,1H,Ph),7.09(t,J=53.8Hz,1H,CHF2),4.03(s,3H,CH3);HRMS(ESI)forC13H10F2N4O4 m/z:Calculated,325.0743,Found,325.0748[M+H]+.
实施例12(E)-4-氟苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A12)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的4-氟苯甲醛肟,其他操作同实施例1,制得(A12)化合物。
(E)-4-氟苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:淡黄色固体,收率:70.8%,熔点:144-147℃;1H NMR(CDCl3,500MHz),δ:8.45(s,1H,CH),8.04(s,1H,Pyrazole),7.81(d,J=5.4Hz,1H,Ph),7.79(d,J=5.4Hz,1H,Ph),7.15(t,J=8.6Hz,2H,Ph),7.11(t,J=53.8Hz,1H,CHF2),4.02(s,3H,CH3);HRMS(ESI)for C13H10F3N3O2 m/z:Calculated,298.0798,Found,298.0803[M+H]+.
实施例13(E)-4-(三氟甲基)苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A13)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的4-三氟甲基苯甲醛肟,其他操作同实施例1,制得(A13)化合物。
(E)-4-(三氟甲基)苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:70.1%,熔点:129-133℃;1H NMR(CDCl3,500MHz),δ:8.52(s,1H,CH),8.06(s,1H,Pyrazole),7.92(d,J=8.1Hz,2H,Ph),7.72(d,J=8.2Hz,2H,Ph),7.10(t,J=53.8Hz,1H,CHF2),4.02(s,3H,CH3);HRMS(ESI)for C14H10F5N3O2 m/z:Calculated,348.0766,Found,348.0771[M+H]+.
实施例14(E)-4-氯苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A14)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的4-氯苯甲醛肟,其他操作同实施例1,制得(A14)化合物。
(E)-4-氯苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:68.9%,熔点:163-169℃;1H NMR(CDCl3,500MHz),δ:8.44(s,1H,CH),8.05(s,1H,Pyrazole),7.74(d,J=8.5Hz,2H,Ph),7.45(d,J=8.5Hz,2H,Ph),7.11(t,J=53.8Hz,1H,CHF2),4.02(s,3H,CH3);HRMS(ESI)for C13H10ClF2N3O2 m/z:Calculated,314.0502,Found,314.0508[M+H]+.
实施例15(E)-2,4-二氯苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟(A15)的制备
将实施例1步骤5)中的苯甲醛肟替换为同等摩尔量的2,4-二氯苯甲醛肟,其他操作同实施例1,制得(A15)化合物。
(E)-2,4-二氯苯甲醛O-(1-甲基-3-(二氟甲基)-1H-吡唑-4-羰基)肟:白色固体,收率:67.4%,熔点:173-176℃;1H NMR(CDCl3,500MHz),δ:8.85(s,1H,CH),8.11(d,J=8.5Hz,1H,Ph),8.06(s,1H,Pyrazole),7.49(s,1H,Ph),7.35(d,J=8.5Hz,1H,Ph),7.13(t,J=53.8Hz,1H,CHF2),4.03(s,3H,CH3);
HRMS(ESI)for C13H9Cl2F2N3O2 m/z:Calculated,348.0113,Found,348.0118[M+H]+.
实施例16杀菌活性测试
试验对象:番茄早疫病菌(Alternaria solani)、小麦赤霉病菌(Gibberellazeae)、水稻稻瘟病菌(Pyrazolericularia oryae)、辣椒疫病菌(Phytophthora capsici)、油菜菌核病菌(Sclerotinia sclerotiorum)、黄瓜灰霉病菌(Botrytis cinerea)、水稻纹枯病菌(Riziocotinia solani)、黄瓜枯萎病菌(Fusarium oxysporum)、花生褐斑病菌(Cercospora arachidicola)以及苹果轮纹病菌(Physalospora piricola)。
将实施例1~15制备的(A1)~(A15)所示化合物,分别标记为待测化合物,并按以下方式进行杀菌活性测试:
试验处理:各化合物用DMSO溶解成1%乳油母液备用。采用抑菌圈法测试各化合物在50ppm剂量下对10种病菌的室内杀菌活性。
试验方法;用移液枪吸取150μL的母液,溶于蒸馏水中配成3mL的500ppm药液。用移液枪吸取1mL药液放入已灭菌的培养皿中,再放入9mL的PDA培养基,摇匀,冷却。将打孔器在酒精灯外焰充分灼烧,冷却后(一定要保证切口冷却)打取圆形菌饼,后用灭菌接种针挑取菌饼,菌丝面朝下贴于培养皿中央,然后将培养皿置于培养箱27℃中培养,48h后测量菌落直径菌落纯生长量为菌落平均直径于菌饼直径的差值,抑菌率(%)计算方法参照如下公式进行计算。
上述计算公式中的对照菌落纯生长量,是指清水对照测试下的菌落纯生长量。
杀菌活性测试结果如表1所示。
表1 50ppm下各化合物的杀菌活性(%防效)
该系列化合物对番茄早疫病菌、小麦赤霉病菌、辣椒疫霉病菌和黄瓜枯萎病菌的杀菌效果都不太理想,对番茄早疫病菌的抑制率低于35%;对小麦赤霉病菌和黄瓜枯萎病菌的抑制率较差,均低于30%;对辣椒疫霉病菌的抑制率最次,低于20%。A7对水稻稻瘟病菌的抑制率最好,高达85.7%,A8对黄瓜灰霉病菌的抑制率达到了75%,A9对油菜菌核病菌的抑制率达71.4%。从杀菌种类、杀菌效果方面来看,A10化合物都是最好的,其对水稻稻瘟病菌的抑制率达71.4%,对苹果轮纹病菌的抑制率达62.5%,对水稻纹枯抑制率达55.2%,对花生褐斑病菌的抑制率达47.1%。
实施例17除草活性测试
除草活性试验对象:生菜,剪股颖。
除草活性试验方法:所有种子在生物测定之前与5%高乐氏漂白水混合约10min,进行表面灭菌。用去离子水(Millipore系统)彻底冲洗种子并在无菌环境中风干。在无菌非热解聚苯乙烯24-孔细胞培养板上进行生物测定,对照组用200μL无菌水,样品组含有180μL水和20μL适当稀释的本发明样品。每个孔中放入5颗生菜或者剪股颖种子,盖子用封口膜密封。26℃下,在培养箱中连续光照培养7天后,观察对照组与样品组小苗的生长情况。通过光照条件下化合物对生菜,剪股颖幼苗株高的生长抑制来测试待测药物的除草作用强弱。待测药物的测试浓度:1mM,重复两次。除草活性指标:株高生长抑制率(%)。活性分级指标:4级:抑制率≥80%;3级:抑制率为60~79%;2级:抑制率为40~59%;1级:抑制率为≤20~39%,0级:抑制率≤20。
表2各待测化合物的除草活性(生长抑制%,1mM)
该系列化合物对生菜和剪股颖具有一定的抑制作用。
本说明书所述的内容仅仅是对发明构思实现形式的列举,本发明的保护范围不应当被视为仅限于实施例所陈述的具体形式。
Claims (7)
1.一种3-(二氟甲基)-吡唑-4-羧酸酯类衍生物在制备除草剂中的应用,其特征在于,其结构式如式(Ⅰ)所示:
式(Ⅰ)中,取代基R为2,4-二氯。
2.如权利要求1所述的应用,其特征在于,3-(二氟甲基)-吡唑-4-羧酸酯类衍生物的制备方法包括以下步骤:
1)将乙酸酐加入二氟乙酰乙酸乙酯和原甲酸三乙酯的混合溶液中,升温至回流,反应6-10h后,停止加热,待反应液冷却至室温后,减压蒸发除去低沸点物,得到如式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯;
2)将通过步骤1)所得的如式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯加入无水乙醇中,搅拌均匀,然后在冰盐浴条件下逐滴加入到甲基肼水溶液和无水乙醇的混合溶液中,滴加结束后加热至40-60℃,TLC跟踪反应,待反应结束后,减压蒸发去除溶剂,然后加入乙酸乙酯和水萃取,有机层再用饱和食盐水洗涤三次,经无水硫酸镁干燥,过滤,滤液浓缩除去溶剂,得如式(Ⅲ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯的粗产品;
3)向通过步骤2)所得的如式(Ⅲ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯的粗产品,加入氢氧化钠水溶液,升温至50-70℃搅拌,TLC跟踪反应,等到反应结束后冷却至室温,加入浓盐酸调节pH,析出大量固体,抽滤,水洗,烘干,得如式(Ⅳ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸的粗产品;
4)向通过步骤3)所得的如式(Ⅳ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸的粗产品,加入氯化亚砜,加热回流,等到反应液由浑浊变为澄清透明后,继续反应20-40分钟,停止加热,减压旋转蒸发除去多余的氯化亚砜,得如式(Ⅴ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯;
5)将通过步骤4)所得的如式(Ⅴ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯溶解在二氯甲烷中,在冰盐浴条件下逐滴滴加入到溶有如式(Ⅵ)所示的取代苯甲醛肟和三乙胺的二氯甲烷中,边滴加边搅拌,滴加完毕常温搅拌,TLC跟踪反应,等到反应结束后加入柱层析硅胶,减压旋转蒸发除去溶剂,经柱层析提纯得如式(Ⅰ)所示的3-(二氟甲基)-吡唑-4-羧酸酯类衍生物;
取代基R为2,4-二氯。
3.如权利要求2所述的应用,其特征在于,步骤3)中加入浓盐酸调节pH至1-4。
4.如权利要求2所述的应用,其特征在于,步骤1)中,所述乙酸酐、二氟乙酰乙酸乙酯和原甲酸三乙酯的投料摩尔比为3:1-3:2-5;步骤2)中,式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯和甲基肼的投料摩尔比为1:1~5;步骤3)中,式(Ⅲ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸乙酯和氢氧化钠的投料摩尔比为1:1~4;步骤4)中,氯化亚砜的用量要过量;步骤5)中,式(Ⅴ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯和如式(Ⅵ)所示的取代苯甲醛肟的投料摩尔比为1:1.1~1.5。
5.如权利要求2所述的应用,其特征在于,步骤2)中溶解式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯的无水乙醇的体积用量以式(Ⅱ)所示的(E)-2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯的物质的量计为0.1~0.5mL/mmol,步骤4)中氯化亚砜的体积用量以式(Ⅳ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酸的物质的量计为0.1~0.6mL/mmol。
6.如权利要求2所述的应用,其特征在于,步骤5)中用于溶解1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯的二氯甲烷的体积用量以式(Ⅴ)所示的1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯的物质的量计为1~3mL/mmol。
7.如权利要求2所述的应用,其特征在于,步骤5)中柱层析分离的洗脱剂采用体积比2:3的乙酸乙酯和石油醚混合液。
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