CN103664784A - 一类含萘环的三芳基吡唑啉类衍生物及其制法 - Google Patents
一类含萘环的三芳基吡唑啉类衍生物及其制法 Download PDFInfo
- Publication number
- CN103664784A CN103664784A CN201210338382.XA CN201210338382A CN103664784A CN 103664784 A CN103664784 A CN 103664784A CN 201210338382 A CN201210338382 A CN 201210338382A CN 103664784 A CN103664784 A CN 103664784A
- Authority
- CN
- China
- Prior art keywords
- reaction
- naphthaldehyde
- recrystallization
- temperature
- organic solvent
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- JWGLGQHIGMBQRK-UHFFFAOYSA-N [3-(4-chlorophenyl)-5-thiophen-2-yl-3,4-dihydropyrazol-2-yl]-phenylmethanone Chemical class C1=CC(Cl)=CC=C1C1N(C(=O)C=2C=CC=CC=2)N=C(C=2SC=CC=2)C1 JWGLGQHIGMBQRK-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 125000001624 naphthyl group Chemical group 0.000 title abstract description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims abstract description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims abstract description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 238000001953 recrystallisation Methods 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 9
- 150000004002 naphthaldehydes Chemical class 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 claims description 7
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 7
- 229940067157 phenylhydrazine Drugs 0.000 claims description 7
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 150000008062 acetophenones Chemical class 0.000 claims description 3
- 239000006227 byproduct Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 238000005457 optimization Methods 0.000 claims description 3
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 12
- 229960004756 ethanol Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- YOMBUJAFGMOIGS-UHFFFAOYSA-N 2-fluoro-1-phenylethanone Chemical compound FCC(=O)C1=CC=CC=C1 YOMBUJAFGMOIGS-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 125000002755 pyrazolinyl group Chemical group 0.000 description 4
- 150000002790 naphthalenes Chemical class 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- WBPAOUHWPONFEQ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C(Cl)=C1 WBPAOUHWPONFEQ-UHFFFAOYSA-N 0.000 description 2
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- WRQKYTMPGPMLPI-UHFFFAOYSA-N Brc(cc1)ccc1C(CC1c2cccc3c2cccc3)=NN1c1ccccc1 Chemical compound Brc(cc1)ccc1C(CC1c2cccc3c2cccc3)=NN1c1ccccc1 WRQKYTMPGPMLPI-UHFFFAOYSA-N 0.000 description 1
- WYUIWKFIFOJVKW-UHFFFAOYSA-N Cc(cc1)cc(Cl)c1Cl Chemical compound Cc(cc1)cc(Cl)c1Cl WYUIWKFIFOJVKW-UHFFFAOYSA-N 0.000 description 1
- PANKHBYNKQNAHN-JTBLXSOISA-N Crocetin Natural products OC(=O)C(\C)=C/C=C/C(/C)=C\C=C\C=C(\C)/C=C/C=C(/C)C(O)=O PANKHBYNKQNAHN-JTBLXSOISA-N 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- -1 Lyeopene Chemical compound 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- PANKHBYNKQNAHN-JUMCEFIXSA-N carotenoid dicarboxylic acid Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C(=O)O)C=CC=C(/C)C(=O)O PANKHBYNKQNAHN-JUMCEFIXSA-N 0.000 description 1
- PANKHBYNKQNAHN-MQQNZMFNSA-N crocetin Chemical compound OC(=O)C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)C(O)=O PANKHBYNKQNAHN-MQQNZMFNSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 150000003219 pyrazolines Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
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
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明涉及一类含萘环的三芳基吡唑啉类衍生物及其制备方法。
背景技术
含有吡唑啉结构的化合物广泛存在并具有多样的生物活性,除作为除草剂、杀虫剂和植物生长调节剂被应用于农药外,在生物医药领域也有着十分重要的地位。现有上市药物可乐定(clonidine)即是此类化合物,作为中枢降压药,能够通过抑制血管运动中枢,使外周交感神经功能降低从而引起降压。此外,吡唑啉类衍生物还具有广谱抗菌活性,对于白血病和肿瘤也有效。以此类结构为核心衍生出一系列新型骨架结构,对于寻找高效低毒、高选择性的药物前体具有重要意义。
通过计算机辅助药物设计引入的萘环结构具有一定的杀生能力并被广泛应于合成医药中间体,由于其结构与藏红花酸、番茄红素、维生素A等具有一定相似性,对于改善化合物的生物活性有所裨益。
基于以上研究我们合成了一系列含萘环的三芳基吡唑啉类衍生物,此类化合物作为潜在的骨架结构,对于开展合理的分子设计和从天然生物活性物质中筛选新型活性分子,有着重要的理论指导价值,对在此基础上展开的系统性研究也有着先行者般的实际意义。
发明内容
本发明的目的在于提供一类新型的含萘环的三芳基吡唑啉类衍生物及其制备方法。
本发明的技术方案如下:
一类含萘环的三芳基吡唑啉类衍生物,其特征是它有如下通式:
结构式中R1为如下基团之一:
R2为如下基团之一:
特别的,当R1为对溴苯基时,R2为1-萘基;当R1为对甲氧基苯基时,R2为2-萘基。
一种制备上述含萘环和吡唑啉结构的硫脲类衍生物的方法,它包括如下步骤:
步骤1.将取代基苯乙酮,萘甲醛溶于有机溶剂中,磁搅拌使混合均匀,缓慢滴入NaOH溶液,磁搅拌,常温反应2h(TLC检测反应进行程度),产物以固体析出。反应结束后抽滤,并以大量的蒸馏水和冷乙醇洗涤固体,干燥,重结晶;
步骤2.将步骤1中所得产物与苯肼,以有机溶剂加热溶解,加热搅拌反应2h(TLC检测)。反应结束后,冷却,产物以固体形态析出,抽滤并以冷乙醇洗涤,重结晶得到目标化合物。
步骤1中所述的取代苯乙酮与萘甲醛的投料摩尔比为1∶(1-1.1),最优投料摩尔比为1∶1.05,所属的有机溶剂为乙醇,所述的磁搅拌时间为10min,所述的萘甲醛可以分别为1-萘甲醛或2-萘甲醛,所述pH值为8-10,最优pH值为9.1,所述的反应温度为常温,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶;
步骤2中所述的第一步产物与苯肼的投料摩尔比为1∶(1-1.1),最优投料摩尔比为1∶1.05,所述的有机溶剂为异丙醇或乙醇,所述的反应温度为75-85℃,最优反应温度为80℃,所述的冷却温度为5℃以下,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。
本发明的优点是:本发明所述的衍生物的吡唑啉骨架结构是许多药物常见结构,作为支持结构或药效基团都具有十分重要的地位,同时,能随pH环境的改变为药物前体提供亲水端,为分子在体内传输提供了帮助;在此基础上通过合理的分子设计引入的辅助基团萘环是医药中间体中常见的具有抗菌和抗肿瘤活性的结构,在增大了活性基团的比例的同时,又为分子提供了缺失的亲脂端,增大了其透过生物膜的可能,有利于分子与靶标的结合。
具体实施方式
通过以下实施例进一步详细说明本发明,但应注意本发明的范围并不受这些实施例的任何限制。
实施例一:3-(4-氟苯基)-5-(萘-1-基)-1-苯基-4,5-二氢-1H-吡唑(化合物1a)的制备
取5.0mmol对氟苯乙酮和5.25mmol 1-萘甲醛加入到50ml的圆底烧中,加入20ml无水乙醇,磁搅拌10min使混合均匀,缓慢滴入40%NaOH溶液10ml(pH值为9.1),磁搅拌,常温反应2h(TLC检测反应进行程度),产物以固体析出,抽滤,并以大量的蒸馏水洗涤固体物,用冷乙醇洗涤3次(每次3ml),干燥,产物用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶;在50ml烧瓶中加入2.0mmol上述产物,2.1mmol苯肼,以20ml无水乙醇加热至80℃溶解,80℃回流反应2h(TLC检测)。反应结束后,冷却至5℃以下,产物以固体形态析出,抽滤并以冷乙醇洗涤3次(每次3ml),用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶,得到纯净的化合物1a(白色晶体)。White crystal,Yield88%;mp:78-81℃.1H NMR(CDCl3,300MHz)δ:3.06-3.14(dd,J1=16.5Hz,J2=6.0Hz,1H),4.14-4.23(dd,J1=17.1Hz,J2=12.6Hz,1H),6.19(m,1H),6.70-6.75(t,J=7.2Hz,1H),6.94-6.97(d,J=7.8Hz,2H),7.12-7.17(t,J=7.8Hz,2H),7.22-7.28(m,3H),7.39-7.44(t,J=7.5Hz,1H),7.59-7.67(m,2H),7.78-7.88(m,3H),8.00-8.03(d,J=7.8Hz,1H),8.30-8.33(d,J=8.4Hz,1H).MS(ESI):367.15(C25H20FN2,[M+H]+).Anal.Calcd for C25H19FN2:C,81.94;H,5.23;F,5.18;N,7.64.Found:C,81.78;H,5.23;N,7.65.
实施例二:3-(4-溴苯基)-5-(萘-1-基)-1-苯基-4,5-二氢-1H-吡唑(化合物2a)的制备
制备方法同实施例一。以对溴苯乙酮代替实例一中的对氟苯乙酮,得到淡黄色晶体状目标化合物。Yellow crystal,Yield 84%,mp:148-151℃.1H NMR(CDCl3,300MHz)δ:3.08(m,1H),4.11-4.21(dd,J1=17.7Hz,J2=12.9Hz,1H),6.19(m,1H),6.69-6.74(t,J=7.2Hz,1H),6.93-6.95(d,J=7.8Hz,2H),7.10-7.16(t,J=7.8Hz,2H),7.22(m,1H),7.37-7.42(t,J=7.8Hz,1H),7.57-7.62(m,3H),7.67-7.70(m,3H),7.83-7.86(d,J=8.4Hz,1H),7.98-8.01(d,J=8.4Hz,1H),8.30(m,1H).MS(ESI):427.07(C25H20BrN2,[M+H]+).Anal.Calcd for C25H19BrN2:C,70.27;H,4.48;Br,18.70;N,6.56.Found:C,70.03;H,4.48;N,6.56.
实施例三:3-(3,4-二氯苯基)-5-(萘-1-基)-1-苯基-4,5-二氢-1H-吡唑(化合物3a)的制备
制备方法同实施例一。以3,4-二氯苯乙酮代替实例一中的对氟苯乙酮,得到淡黄色晶体状目标化合物。Yellow crystal,Yield 82%;mp:164-166℃.1H NMR(CDCl3,300MHz)δ:3.07-3.15(dd,J1=17.7Hz,J2=6.3Hz,1H),4.09-4.19(dd,J1=17.7Hz,J2=12.9Hz,1H),6.22(m,1H),6.71-6.76(t,J=7.2Hz,1H),6.95-6.98(d,J=8.1Hz,2H),7.11-7.16(t,J=7.8Hz,2H),7.22(m,1H),7.36-7.41(t,J=7.8Hz,1H),7.57-7.64(m,3H),7.71-7.74(dd,J1=8.4Hz,J2=1.8Hz,1H),7.83-7.86(d,J=8.1Hz,1H),7.92(s,1H),7.98-8.01(d,J=8.4Hz,1H),8.26(m,1H).MS(ESI):417.08(C25H19Cl2N2,[M+H]+).Anal.Calcd for C25H18Cl2N2:C,71.95;H,4.35;Cl,16.99;N,6.71.Found:C,71.72;H,4.36;N,6.72.
实施例四:3-(4-氟苯基)-5-(萘-2-基)-1-苯基-4,5-二氢-1H-吡唑(化合物1b)的制备
制备方法同实施例一。以2-萘甲醛代替实例一中的1-萘甲醛,得到白色晶体状目标化合物。White crystal,Yield 86%,mp:125-127℃.1H NMR(CDCl3,300MHz)δ:3.18-3.23(dd,J1=10.5Hz,J2=4.2Hz,1H),3.97-4.03(dd,J1=10.5Hz,J2=7.5Hz,1H),5.61-5.65(dd,J1=7.5Hz,J2=4.2Hz,1H),6.68-6.71(t,J=4.2Hz,1H),7.04-7.06(d,J=4.5Hz,2H),7.11-7.15(t,J=4.8Hz,2H),7.25-7.29(t,J=5.4Hz,2H),7.41-7.43(dd,J1=5.1Hz,J2=0.9Hz,1H),7.47-7.51(m,2H),7.80-7.82(m,2H),7.86-7.91(m,4H).MS(ESI):367.15(C25H20FN2,[M+H]+).Anal.Calcd forC25H19FN2:C,81.94;H,5.23;F,5.18;N,7.64.Found:C,81.76;H,5.24;N,7.64.
实施例五:3-(4-甲氧基苯基)-5-(萘-2-基)-1-苯基-4,5-二氢-1H-吡唑(化合物2b)的制备
制备方法同实施例一。以对甲氧基苯乙酮代替实例一中的对氟苯乙酮并以2-萘甲醛代替实例一中的1-萘甲醛,得到白色晶体状目标化合物。White crystal,Yield84%,mp:162-164℃.1H NMR(CDCl3,300MHz)δ:3.14-3.19(dd,J1=10.5Hz,J2=4.2Hz,1H),3.80(s,3H),3.95-4.00(dd,J1=10.5Hz,J2=7.2Hz,1H),5.55-5.59(dd,J1=7.2Hz,J2=3.9Hz,1H),6.66-6.69(t,J=4.2Hz,1H),6.99-7.03(m,4H),7.10-7.13(t,J=4.8Hz,2H),7.41-7.43(d,J=4.8Hz,1H),7.47-7.51(m,2H),7.70-7.72(d,J=5.4Hz 2H),7.86-7.91(m,4H).MS(ESI):379.17(C26H23N2O,[M+H]+).Anal.Calcd for C26H22N2O:C,82.51;H,5.86;N,7.40;O,4.23.Found:C,82.33;H,5.86;N,7.41.
实施例六:3-(3,4-二氯苯基)-5-(萘-2-基)-1-苯基-4,5-二氢-1H-吡唑(化合物3b)的制备
制备方法同实施例一。以3,4-二氯苯乙酮代替实例一中的对氟苯乙酮并以2-萘甲醛代替实施例一中的1-萘甲醛,得到淡黄色晶体状目标化合物。Yellow crystal,Yield 83%,mp:169-172℃.1H NMR(CDCl3,300MHz)δ:3.21-3.26(dd,J1=10.5Hz,J2=3.9Hz,1H),3.96-4.02(dd,J1=10.5Hz,J2=7.5Hz,1H),5.69-5.73(dd,J1=7.5Hz,J2=3.9Hz,1H),6.71-6.74(t,J=4.2Hz,1H),7.07-7.09(d,J=4.8Hz,2H),7.13-7.16(t,J=4.5Hz,2H),7.39-7.41(dd,J1=5.1Hz,J2=0.9Hz,1H),7.47-7.51(m,2H),7.67-7.69(d,J=4.8Hz,1H),7.73-7.76(dd,J1=5.1Hz,J2=1.2Hz,1H),7.85-7.91(m,4H),7.94(s,1H).MS(ESI):417.08(C25H19Cl2N2,[M+H]+).Anal.Calcd for C25H18Cl2N2:C,71.95;H,4.35;Cl,16.99;N,6.71.Found:C,71.77;H,4.35;N,6.71.
本发明的优点是:本发明所述的衍生物的吡唑啉骨架结构是许多药物常见结构,作为支持结构或药效基团都具有十分重要的地位,同时,能随pH环境的改变为药物前体提供亲水端,为分子在体内传输提供了帮助;在此基础上通过合理的分子设计引入的辅助基团萘环是医药中间体中常见的具有抗菌和抗肿瘤活性的结构,在增大了活性基团的比例的同时,又为分子提供了缺失的亲脂端,增大了其透过生物膜的可能,有利于分子与靶标的结合。
Claims (6)
2.根据权利要求1所述的含萘环的三芳基吡唑啉类衍生物,其特征是所述衍生物由以下步骤制备:
步骤1、将取代基苯乙酮,萘甲醛溶于有机溶剂中,磁搅拌使混合均匀,缓慢滴入NaOH溶液,磁搅拌,常温反应2h,产物以固体析出。反应结束后抽滤,并以大量的蒸馏水和冷乙醇洗涤固体,干燥,重结晶;
步骤2、将步骤1中所得产物与苯肼,以有机溶剂加热溶解,加热搅拌反应2h,反应结束后,冷却,产物以固体形态析出,抽滤并以冷乙醇洗涤,重结晶得到目标化合物。
3.根据权利要求1或2所述的含萘环的三芳基吡唑啉类衍生物,其特征是步骤1中所述的取代苯乙酮与萘甲醛的投料摩尔比为1∶(1-1.1),最优投料摩尔比为1∶1.05,所述的有机溶剂为乙醇,所述的磁搅拌时间为10min,所述的萘甲醛可以分别为1-萘甲醛或2-萘甲醛,所述pH值为8-10,最优pH值为9.1,所述的反应温度为常温,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。
4.根据权利要求1或2所述的含萘环的三芳基吡唑啉类衍生物,其特征是步骤2中所述的第一步产物与苯肼的投料摩尔比为1∶(1-1.1),最优投料摩尔比为1∶1.05,所述的有机溶剂为异丙醇或乙醇,所述的反应温度为75-85℃,最优反应温度为80℃,所述的冷却温度为5℃以下,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。
5.一类含萘环的三芳基吡唑啉类衍生物的制备方法,其特征是所述方法包括以下步骤:
步骤1、将取代基苯乙酮,萘甲醛溶于有机溶剂中,磁搅拌使混合均匀,缓慢滴入NaOH溶液,磁搅拌,常温反应2h,产物以固体析出。反应结束后抽滤,并以大量的蒸馏水和冷乙醇洗涤固体,干燥,重结晶;
步骤2、将步骤1中所得产物与苯肼,以有机溶剂加热溶解,加热搅拌反应2h,反应结束后,冷却,产物以固体形态析出,抽滤并以冷乙醇洗涤,重结晶得到目标化合物。
6.根据权利要求5所述的含萘环的三芳基吡唑啉类衍生物的制备方法,其特征是:
步骤1中所述的取代苯乙酮与萘甲醛的投料摩尔比为1∶(1-1.1),最优投料摩尔比为1∶1.05,所述的有机溶剂为乙醇,所述的磁搅拌时间为10min,所述的萘甲醛可以分别为1-萘甲醛或2-萘甲醛,所述pH值为8-10,最优pH值为9.1,所述的反应温度为常温,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶;
步骤2中所述的第一步产物与苯肼的投料摩尔比为1∶(1-1.1),最优投料摩尔比为1∶1.05,所述的有机溶剂为异丙醇或乙醇,所述的反应温度为75-85℃,最优反应温度为80℃,所述的冷却温度为5℃以下,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210338382.XA CN103664784A (zh) | 2012-09-13 | 2012-09-13 | 一类含萘环的三芳基吡唑啉类衍生物及其制法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210338382.XA CN103664784A (zh) | 2012-09-13 | 2012-09-13 | 一类含萘环的三芳基吡唑啉类衍生物及其制法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103664784A true CN103664784A (zh) | 2014-03-26 |
Family
ID=50303664
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210338382.XA Pending CN103664784A (zh) | 2012-09-13 | 2012-09-13 | 一类含萘环的三芳基吡唑啉类衍生物及其制法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103664784A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106146399A (zh) * | 2016-06-27 | 2016-11-23 | 南京大学 | 一类含二氢吡唑结构的苯甲酰肼衍生物及其制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101735150A (zh) * | 2009-12-16 | 2010-06-16 | 南京大学 | 一类含有吡唑环的硫脲类衍生物及其制法和用途 |
-
2012
- 2012-09-13 CN CN201210338382.XA patent/CN103664784A/zh active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101735150A (zh) * | 2009-12-16 | 2010-06-16 | 南京大学 | 一类含有吡唑环的硫脲类衍生物及其制法和用途 |
Non-Patent Citations (3)
Title |
---|
G. R.SUBBANWAD等: "Studies on synthesis and antimicrobial activity of some new pyrazolines and N-phenylpyrazolines", 《JOURNAL OF THE INDIAN CHEMICAL SOCIETY》 * |
KHAIRY A,H,M.EL-BAYOUKI等: "Synthesis and biological screening of some new naphthyl-pyrazolines, pyrazoles and their carbanilide derivatives", 《EGYPT. J. CHEM.》 * |
REGAILA等: "Synthesis of newer N-acetyl-, N-arylpyrazoline, -isoxazole, and -benzodioxane derivatives of biological activity", 《EGYPTIAN JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106146399A (zh) * | 2016-06-27 | 2016-11-23 | 南京大学 | 一类含二氢吡唑结构的苯甲酰肼衍生物及其制备方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Reddy et al. | PEG-SO3H catalyzed synthesis and cytotoxicity of α-aminophosphonates | |
JP6732744B2 (ja) | ルテニウム触媒作用によるアゾベンゾール類からのビフェニルアミン類の製造方法 | |
CN104447599A (zh) | 一种四氮唑类杂环化合物及其制备方法 | |
Łukasik et al. | Simple Synthesis of 2-Aminoaryliminophosphoranes from N-Aryl-2-nitrosoanilines and Their Application in 2-Aminobenzimidazole Synthesis | |
Sharma et al. | Organocatalytic enantioselective conjugate addition of pyrazolin-5-ones to arylomethylidene malonates | |
KR20190033946A (ko) | 3번 위치에 아릴기가 치환된 퀴녹살린온 유도체의 제조방법 | |
CN112939988B (zh) | 茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性研究 | |
CN103664784A (zh) | 一类含萘环的三芳基吡唑啉类衍生物及其制法 | |
Zhang et al. | Copper (I)‐Catalyzed Intramolecular N‐N Coupling of Cyclopropyl O‐Acyl Ketoximes: Synthesis of Spiro‐fused Pyrazolin‐5‐ones | |
FR3001967A1 (fr) | Procede de fabrication de pyrazoles, nouveaux pyrazoles et leurs applications | |
CN105820174A (zh) | 一种多取代噻吩并吲哚衍生物的制备方法 | |
CN105439966B (zh) | 化合物及其制备方法和应用 | |
CN103724267B (zh) | 一类由水杨醛制备的吡唑啉类衍生物及其制法 | |
CN108997221B (zh) | 3-羟基-2-萘甲酸协同二氯二茂钛合成1,2-二取代苯并咪唑类化合物的方法 | |
CN103664783A (zh) | 一类含萘环和吡唑啉结构的硫脲类衍生物及其制法 | |
Hajishaabanha et al. | Synthesis of furan-fused quinoxaline tetracyclic scaffolds via a three-component isocyanide-based reaction | |
CN103374020B (zh) | 一类含萘环的噻唑[4,5-b]并喹喔啉类衍生物及其制法 | |
KR20150032539A (ko) | N-치환된 술폭시민 피리딘 n-옥시드의 제조 | |
CN108912124A (zh) | 一种利用离子液体催化制备含砜基吡唑杂环化合物的方法 | |
CN103724337A (zh) | 一类含萘环和噻唑啉酮结构的吡唑啉类衍生物及其制法 | |
CN103304584B (zh) | 一类2-腙-噻唑并[4,5-b]喹喔啉类化合物及其制法与用途 | |
CN103044380A (zh) | 一种简便的合成4h-苯并吡喃环杂环化合物的新方法 | |
CN112939839B (zh) | 一种2-芳香酰吡咯类化合物的合成方法 | |
KR101146808B1 (ko) | 스피로옥시인돌 유도체의 친환경적 합성방법 | |
DUMITRAŞCU et al. | New substituted indolizines by 1, 3-dipolar cycloaddition reactions. Part 2. 7-Cyanoindolizines |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
EXSB | Decision made by sipo to initiate substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140326 |
|
RJ01 | Rejection of invention patent application after publication |