CN103588707B - Polyazin and synthetic method thereof - Google Patents

Polyazin and synthetic method thereof Download PDF

Info

Publication number
CN103588707B
CN103588707B CN201310229542.1A CN201310229542A CN103588707B CN 103588707 B CN103588707 B CN 103588707B CN 201310229542 A CN201310229542 A CN 201310229542A CN 103588707 B CN103588707 B CN 103588707B
Authority
CN
China
Prior art keywords
benzyl
alkyl
arh
polyazin
amine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201310229542.1A
Other languages
Chinese (zh)
Other versions
CN103588707A (en
Inventor
麻生明
陈波
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CN201310229542.1A priority Critical patent/CN103588707B/en
Publication of CN103588707A publication Critical patent/CN103588707A/en
Application granted granted Critical
Publication of CN103588707B publication Critical patent/CN103588707B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to polyazin and synthetic method thereof. It is the synthetic method that a kind of neutralized verdigris participates in the nitrogen catenation of 2,3-connection alkene acid esters, amine, nitrile multi-component reaction, namely it is a kind of pyrazoles and the high-efficiency synthesis method of 1,2,4-triazole compounds. Use this synthetic method, whether can add 2,3-connection alkene acid esters by adjustment from simple amine and obtain the nitrogen catenation that two kinds have important physiologically active: pyrazoles or 1,2,4-triazole. This compound has following structural formula:?The present invention utilizes neutralized verdigris as oxygenant, and nitrile, as solvent and reactant, obtains two kinds from 2,3-connection alkene acid esters and amine and has physiologically active nitrogen catenation. The 1,2,4-triazole compounds 4a synthesized by the method can be converted into the triazolium salt compound with antiplasmodial activities according to known steps.

Description

Polyazin and synthetic method thereof
Technical field
The present invention relates to the synthesis of a kind of polyazin, refer to the efficient synthesis of a kind of pyrazoles and 1,2,4-triazole compounds specifically. Use this synthetic method, whether can add 2,3-connection alkene acid esters by adjustment from simple amine and obtain the heterogeneous ring compound that two kinds have important physiologically active: pyrazoles and 1,2,4-triazole.
Background technology
Having in the heterocycle of physiologically active various, pyrazole heterocycle is one of the most important skeleton, mainly due to its wide application prospect (Fustero, S. in pharmaceutical industry and agrochemistry; S �� nchez-Rosell ��, M.; Barrio, P.; Sim �� n-Fuentes, A.Chem.Rev.2011,111,6984-7034). Some contain pyrazol framework compound; such as Rimonabant (Rimonabant); Western music treasured (Celebrex); vigour (Viagra); medicine and sterilant (structural formula 1) [(a) Terrett, the N.K. of commercialization has been become with ethiprole (Fipronil); Bell, A.S.; Brown, D.; Ellis, P.Bioorg.Med.Chem.Lett.1996,6,1819 1824. (b) Christopoulou, F.D.; Kiortsis, D.N.J.Clin.Pharm.Ther.2011,36,10-18. (c) Gunasekara, A.S.; Truong, T.; Goh, K.S.; Spurlock, F.; Tjeerdema, R.S.J.Pestic.Sci.2007,32,189-199.]. In addition, pyrazole compound is also applied to polymkeric substance, supramolecular chemistry, makeup and uses as UV stabilizer. The pyrazole compound replaced is used in some transition metal-catalyzed reactions as part. Therefore, the method developing efficient, general synthesizing pyrazole skeleton has attracted the great interest of chemist.
Structural formula 1
It is well known that 1,2,4-triazole has very wide application (Moulin, A. in pharmaceutical chemistry; Bibian, M.; Blayo, A.-L.; ElHabnouni, S.; Martinez, J.; Fehrentz, J.-A.Chem.Rev.2010,110,1809-1827.). A lot of containing 1,2,4-triazole class compounds is listed as drug product, such as Arimidex (anastrozole), fluconazole (fluconazole), voriconazole (voriconazole), risatriptan (maxalt), DEFERASIROX (deferasirox), fluzilazol (fluotrimazole), Wocosin 50TK (Propiconazole), tebuconazole (tebuconazole) etc. (structural formula 2), all compounds (except Deferasirox) being listed are all containing with or without the 1,2,4-triazole female ring replaced below. Therefore, developing efficient, novel method to introduce different substituents to 1,2,4-triazole ring, for pharmaceutical compound, man is significant. Up to now, directly synthesize the full 1,2,4-triazole replaced by simple amine and nitrile have not been reported.
Structural formula 2
Multi-component reaction (MCR) is by one of simple raw material effective ways preparing complex compound, its can one pot of efficient structure realizing multiple chemical bond, and do not need to be separated or the intermediate of purification reaction. This kind of reaction has simple to operate, and step is few, pollutes the advantages such as little, and multi-component reaction has become the focus of organic chemist's research. Along with the development gradually of connection alkene chemistry, the multi-component reaction that connection alkene participates in also becomes one of effective means of building various heterocyclic skeleton. The present invention utilizes simple amine, and 2,3-joins the multi-component reaction of alkene acid esters, nitrile, it is provided that a class efficiently synthesizes the approach of multi-substituted pyrazol compounds. What is interesting is, when joining alkene acid esters without 2,3-, synthesized again 1,2,4-triazole class compounds.
The present invention utilizes neutralized verdigris as oxygenant, and nitrile, as solvent and reactant, obtains, from 2,3-connection alkene acid esters and amine, the heterogeneous ring compound that two kinds have physiologically active, has a very big significance for the synthesis of pyrazoles and the medicaments derivative of triazole species.
Summary of the invention
It is an object of the invention to provide a kind of nitrogen catenation and synthetic method thereof.
Furtherly, an object of the present invention is to provide multi-substituted pyrazol compounds.
The two of the object of the present invention are to provide a kind of method efficiently preparing multi-substituted pyrazol compounds.
The three of the object of the present invention are to provide a kind of 1,2,4-triazole class compounds.
The four of the object of the present invention are to provide a kind of efficient method preparing 1,2,4-triazole class compounds.
A kind of nitrogen catenation provided by the invention: multi-substituted pyrazol (Pyrzole) and 1,2,4-triazole class compounds (1,2,3-trazole) have following structural formula:
Wherein, R1=H or C1��C10Alkyl, prioritizing selection C1��C4Alkyl, R2=benzyl, R3=phenyl or C1��C10Alkyl, R4=C1��C12Alkyl, benzyl, halogeno-benzyl, C1��C4Alkyl benzyl or C1��C4Alkoxybenzyl, R5=phenyl, containing C1��C4Alkyl phenyl.
The synthetic method of a kind of nitrogen catenation provided by the invention, reaction formula is as follows:
Wherein, R1��R2��R3��R4��R5As previously mentioned.
At 100-150 DEG C of temperature and in organic nitrile kind solvent, taking neutralized verdigris as oxygenant, join alkene acid esters as substrate taking amine and 2,3-, add or do not add molecular sieve water-removal agent, the reaction times is 6-48 hour, occur reaction to generate pyrazole compound; Wherein, described neutralized verdigris: it is 1-3:1-2:0-1:0-5 that amine: 2,3-joins the mol ratio of alkene acid esters and molecular sieve; Described mantoquita is preferably neutralized verdigris. What is interesting is, when described neutralized verdigris: amine: when the mol ratio of 2,3-connection alkene acid esters and molecular sieve is 1-3:1-2:0.5-1:0-5, obtain pyrazole compound; When the mol ratio of described neutralized verdigris: amine: 2,3-connection alkene acid esters and molecular sieve is 1-3:1-2:1:0:0-5, obtain 1,2,4-triazole class compounds. Described organic nitrile kind solvent can be C1��C10Alkyl, phenyl or containing C1��C4Alkyl phenyl, prioritizing selection cyanobenzene. Temperature of reaction preferably 120 DEG C.
Further described method can be:
Pyrazole compound synthesizes
Under argon atmosphere, adding 2,3-successively and join alkene acid benzyl ester in the reaction tubes of drying, amine and nitrile, after room temperature vigorous stirring 0.5h, add Cu (OAc)2, it being heated to 120 DEG C, TLC monitors reaction, and about after 6-48 hour, raw material transforms completely, is back to room temperature, adds the dilution of 50mL ether, and filter short column, filtrate concentrates, and silica gel column chromatography obtains pyrazole compound.
The synthesis of 1,2,4-triazole
Cu (OAc) is added successively in a dry reaction pipe2, amine, nitrile, 120 degree reaction 20-48h, be cooled to room temperature, add 50mL ether dilution, filter short column, filtrate concentrate, silica gel column chromatography obtains 1,2,4-triazole class compounds.
The inventive method has the following advantages: 1) in reaction, raw material is easy to preparation, and 2,3-joins alkene acid esters can prepare (Lang, R.W. in a large number; Hansen, H.-J.Org.Synth.1984,62,202.Rout, L.; Harned, A.M.Chem.Eur.J.2009,15,12926.), amine and nitrile are commercially available prod, and neutralized verdigris price is cheap; 2) efficiently polystep reaction one kettle way is realized; 3) blank of this type of framework compound synthetic method is filled up.
Embodiment
Following examples contribute to understanding the present invention, but are not limited to the content of the present invention.
Embodiment 1
Wherein, equiv represents equivalent, and h represents hour.
Under argon atmosphere, in the Schlenk pipe of drying, add 2,3-successively join alkene acid benzyl ester 1a (35.1mg, 0.2mmol), 2a (33.2mg, 0.3mmol) and cyanobenzene (1+1mL), after room temperature vigorous stirring 0.5h, add Cu (OAc)2(72.9mg; 0.4mmol), system puts into oil bath, and oil bath is heated to 120 DEG C; TLC monitors reaction; after about 6 hours, raw material transforms completely, is back to room temperature, adds the dilution of 50mL ether; filter short column; filtrate concentrates, and silica gel column chromatography (sherwood oil petroleumether/ ethyl acetate ethylacetate=20/1) obtains 3a (57.9mg, 75%): oil;1HNMR(300MHz,CDCl3)��7.63-7.52(m,2H,ArH),7.38-7.22(m,9H,ArH),7.19-7.10(m,4H,ArH),5.33(s,2H,OCH2),5.18(s,2H,NCH2),2.47(s,3H,CH3);13CNMR(75MHz,CDCl3) �� 163.8,152.9,144.6,135.81,135.77,133.3,129.4,128.8,128.3,128.1,128.0,127.8,127.7,126.8,109.6,65.6,53.3,11.5; IR (pure sample neat) 1702,1539,1454,1293,1209,1158,1130,1066, cm-1;MS(EI)(m/z)383((M+1)+,14.27),382(M+, 51.56), 91 (100); HRMS calculated value C25H22N2O2[M+]: 382.1681; Measured value (Found): 382.1679.
Embodiment 2
Operation reference example 1. 1a (35.1mg, 0.2mmol), 2b (37.5mg, 0.3mmol) Cu (OAc)2(73.1mg, 0.4mmol) is obtained by reacting 3b (64.8mg, 80%) (petroleumether/ethylacetate=10/1) in cyanobenzene (1+1mL), oil (oil);1HNMR(400MHz,CDCl3)��7.63-7.54(m,2H,ArH),7.40-7.24(m,6H,ArH),7.20-7.11(m,4H,ArH),7.04-6.93(m,2H,ArH),5.29(s,2H,OCH2),5.18(s,2H,NCH2),2.47(s,3H,CH3);13CNMR(75MHz,CDCl3)��163.7,162.3(d,J=245.0Hz),152.9,144.4,135.7,133.2,131.5(d,J=3.4Hz),129.3,128.6(d,J=8.1Hz),128.3,128.1,128.0,127.9,127.7,115.7(d,J=21.8Hz),109.7,65.6,52.5,11.4;19FNMR(CDCl3,376MHz)-114.0;IR(neat)2925,2853,1705,1606,1538,1510,1481,1450,1427,1375,1356,1318,1298,1215,1143,1111,1076cm-1;MS(EI)(m/z)401((M+1)+,11.06),400(M+, 39.29), 109 (100); HRMS calculated value C25H21N2O2F[M+]: 400.1587; Measured value: 400.1589.
Embodiment 3
Operation reference example 1. 1a (34.4mg, 0.2mmol), 2 (42.7mg, 0.3mmol), Cu (OAc)2(72.7mg, 0.4mmol) is obtained by reacting 3c (53.9mg, 65%) (petroleumether/ethylacetate=20/1to10/1) in cyanobenzene (1+1mL): oil;1HNMR(300MHz,CDCl3)��7.65-7.53(m,2H,ArH),7.41-7.22(m,8H,ArH),7.20-7.05(m,4H,ArH),5.28(s,2H,OCH2),5.18(s,2H,NCH2),2.46(s,3H,CH3);13CNMR(75MHz,CDCl3)��163.7,153.0,144.5,135.7,134.2,133.7,133.1,129.3,128.9,128.3,128.2,128.1,127.9,127.7,109.7,65.7,52.5,11.4;IR(neat)2923,2851,1693,1489,1453,1291,1215,1162,1092,1065,1013cm-1;MS(EI)(m/z)419((M(37Cl)+1)+,3.18),418(M(37Cl)+,11.66),417((M(35Cl)+1)+,9.49),416(M(35Cl)+, 32.75), 91 (100); HRMS calculated value C25H21N2O2 35Cl[M+]: 416.1292; Measured value: 416.1289.
Embodiment 4
Operation reference example 1. 1a (33.8mg, 0.2mmol), 2d (41.5mg, 0.3mmol) Cu (OAc)2(72.8mg, 0.4mmol) is obtained by reacting 3d (48.7mg, 61%) (petroleumether/ethylacetate=10/1) in cyanobenzene (1+1mL): oil;1HNMR(300MHz,CDCl3)��7.65-7.53(m,2H,ArH),7.37-7.29(m,3H,ArH),7.29-7.20(m,3H,ArH),7.20-7.08(m,4H,ArH),6.89-6.78(m,2H,ArH),5.26(s,2H,OCH2),5.17(s,2H,NCH2),3.75(s,3H,OMe),2.47(s,3H,CH3);13CNMR(75MHz,CDCl3)��163.8,159.2,152.7,144.3,135.8,133.4,129.4,128.28,128.26,128.0,127.9,127.8,127.6,114.1,109.6,65.6,55.2,52.8,11.4;IR(neat)1701,1612,1586,1539,1513,1484,1453,1295,1248,1210,1129,1067,1030cm-1;MS(EI)(m/z)413((M+1)+,3.77),412(M+, 13.05), 121 (100); HRMS calculated value C26H24N2O3[M+]: 412.1787; Measured value: 412.1789.
Embodiment 5
Operation reference example 1. 1a (35.1mg, 0.2mmol), 2e (37.0mg, 0.3mmol) Cu (OAc)2(72.5mg, 0.4mmol) is obtained by reacting 3e (56.9mg, 71%) (petroleumether/ethylacetate=20/1) in cyanobenzene (1+1mL): solid; M.p.86-87 DEG C of (hexane/Et2O);1HNMR(300MHz,CDCl3)��7.65-7.53(m,2H,ArH),7.39-7.26(m,6H,ArH),7.20-7.03(m,6H,ArH),5.29(s,2H,OCH2),5.17(s,2H,NCH2),2.47(s,3H,CH3),2.30(s,3H,CH3);13CNMR(75MHz,CDCl3)��163.8,152.8,144.4,137.6,135.8,133.3,132.7,129.40,129.35,128.3,128.0,127.9,127.8,127.7,126.8,109.5,65.6,53.1,21.0,11.5;IR(neat)1695,1541,1515,1486,1451,1432,1291,1214,1158,1064cm-1;MS(EI)(m/z)397((M+1)+,12.20),396(M+, 41.13), 105 (100); Ultimate analysis (elementalanalysis) calculated value C26H24N2O2: C78.76, H6.10, N7.07; Measured value: C78.44, H6.16, N6.97.
Embodiment 6
Operation reference example 1. 1a (35.8mg, 0.2mmol), 2f (22.5mg, 0.3mmol) Cu (OAc)2(72.7mg, 0.4mmol) is obtained by reacting 3f (47.9mg, 67%) (petroleumether/ethylacetate=15/1to10/1) in cyanobenzene (1+1mL): oil;1HNMR(400MHz,CDCl3)��7.58-7.51(m,2H,ArH),7.35-7.23(m,6H,ArH),7.20-7.11(m,2H,ArH),5.18(s,2H,OCH2),4.08(t,J=7.4Hz,2H,NCH2),2.55(s,3H,Me),1.87-1.75(m,2H,CH2),1.41-1.30(m,2H,CH2),0.94(t,J=7.4Hz,3H,CH3);13CNMR(100MHz,CDCl3)��163.9,152.6,143.8,135.9,133.5,129.3,128.2,128.0,127.84,127.78,127.6,108.8,65.5,49.0,31.9,19.8,13.6,11.3;IR(neat)1951,1879,1807,1701,1538,1454,1296,1208,1161,1128,1068cm-1;MS(EI)(m/z)349((M+1)+,13.05),348(M+, 53.02), 305 (100); HRMS calculated value C22H24N2O2[M+]: 348.1838; Measured value: 348.1840.
Embodiment 7
Operation reference example 1. 1a (36.6mg, 0.2mmol), 2g (31.7mg, 0.3mmol) Cu (OAc)2(72.4mg, 0.4mmol) is obtained by reacting 3g (44.4mg, 56%) (treatwith20mgNaBH in cyanobenzene (1+1mL)4, thenpetroleumether/ethylacetate=20/1): liquid;1HNMR(300MHz,CDCl3)��7.61-7.48(m,2H,ArH),7.35-7.23(m,6H,ArH),7.20-7.11(m,2H,ArH),5.18(s,2H,OCH2),4.07(t,J=7.4Hz,2H,NCH2),2.55(s,3H,Me),1.87-1.75(m,2H,CH2),1.40-1.23(m,6H,(CH2)3),0.88(t,J=6.9Hz,3H,CH3);13CNMR(75MHz,CDCl3)��163.9,152.6,143.8,135.9,133.6,129.3,128.3,128.0,127.84,127.78,127.6,108.8,65.5,49.3,31.3,29.9,26.2,22.4,13.9,11.3;IR(neat)1950,1879,1806,1701,1537,1514,1485,1453,1297,1249,1159,1128,1067cm-1;MS(EI)(m/z)377((M+1)+,8.67),376(M+, 32.26), 91 (100); HRMS calculated value C24H28N2O2[M+]: 376.2151; Measured value: 376.2150.
Embodiment 8
Operation reference example 1. 1a (35.4mg, 0.2mmol), 2h (39.0mg, 0.3mmol) Cu (OAc)2(72.7mg, 0.4mmol) is obtained by reacting 3h (49.3mg, 60%) (petroleumether/ethylacetate=20/1fortwice) in cyanobenzene (1+1mL): liquid (liquid);1HNMR(300MHz,CDCl3)��7.59-7.48(m,2H,ArH),7.37-7.23(m,6H,ArH),7.20-7.09(m,2H,ArH),5.18(s,2H,OCH2),4.08(t,J=7.2Hz,2H,NCH2),2.56(s,3H,Me),1.92-1.75(m,2H,CH2),1.40-1.23(m,10H,(CH2)5),0.87(t,J=6.8Hz,3H,CH3);13CNMR(75MHz,CDCl3)��163.9,152.7,143.8,135.9,133.5,129.3,128.3,128.0,127.9,127.8,127.7,108.8,65.5,49.3,31.7,30.0,29.09,29.07,26.6,22.6,14.0,11.3;IR(neat)1702,1537,1454,1297,1159,1128,1068cm-1;MS(EI)(m/z)405((M+1)+,7.52),404(M+, 24.60), 91 (100); HRMS calculated value C26H32N2O2[M+]: 404.2464; Measured value: 404.2463.
Embodiment 9
Operation reference example 1. 1a (33.8mg, 0.2mmol), 2i (30.0mg, 0.3mmol) Cu (OAc)2(72.9mg, 0.4mmol) is obtained by reacting 3i (37.6mg, 52%) (petroleumether/ethylacetate=20/1 twice) in cyanobenzene (1+1mL): oil;1HNMR(300MHz,CDCl3)��7.58-7.48(m,2H,ArH),7.36-7.22(m,6H,ArH),7.16-7.09(m,2H,ArH),5.17(s,2H,OCH2),4.05(tt,J=11.6,3.8Hz,1H,NCH),2.57(s,3H,Me),2.11-1.83(m,6H,(CH2)3), 1.75-1.64 (m, 1H, a proton (oneprotonin), CH2), 1.50-1.20 (m, 3H, three protons (threeprotonin), (CH2)2);13CNMR(75MHz,CDCl3)��164.2,152.3,143.0,136.0,133.9,129.4,128.3,128.0,127.8,127.6,108.6,65.5,57.7,32.3,25.5,25.0,11.0;IR(neat)2932,2856,1700,1537,1498,1451,1426,1299,1259,1221,1160,1151,1128,1091,1029cm-1;MS(EI)(m/z)375((M+1)+,8.73),374(M+, 32.55), 185 (100); HRMS calculated value C24H26N2O2[M+]: 374.1994; Measured value: 374.1993.
Embodiment 10
Wherein, equiv represents equivalent, and h represents hour, and MS represents molecular sieve.
Operation reference example 1. 1a (34.9mg, 0.2mmol), 2a (32.3mg, 0.3mmol),MS(50.0mg),Cu(OAc)2(72.9mg, 0.4mmol) existsnBuCN (1+1mL) is obtained by reacting 3j (35.4mg, 49%) (petroleumether/ethylacetate=10/1): oil;1HNMR(300MHz,CDCl3)��7.50-7.22(m,8H,ArH),7.15-7.04(m,2H,ArH),5.27(s,2H,OCH2),5.25(s,2H,NCH2),2.90-2.78(m,2H,CH2),2.42(s,3H,Me),1.68-1.52(m,2H,CH2),1.40-1.22(m,2H,CH2),0.87(t,J=7.2Hz,3H,CH3);13CNMR(75MHz,CDCl3)��164.2,154.9,144.4,136.2,136.1,128.7,128.5,128.3,128.1,127.7,126.6,109.1,65.6,52.9,31.7,28.2,22.7,13.9,11.4;IR(neat)2956,2930,1702,1546,1496,1455,1305,1235,1211,1189,1113,1086,1029cm-1;MS(EI)(m/z)362(M+, 2.90), 91 (100); HRMS calculated value C23H26N2O2[M+]: 362.1994; Measured value: 362.1996.
Embodiment 11
Wherein, equiv represents equivalent, and h represents hour, and sealed represents envelope pipe
Operation reference example 1. 1a (34.7mg, 0.2mmol), 2a (32.4mg, 0.3mmol) Cu (OAc)2(72.8mg, 0.4mmol) is obtained by reacting 3k (38.3mg, 60%) (petroleumether/ethylacetate=10/1to5/1) in MeCN (1+1mL): oil;1HNMR(400MHz,CDCl3)��7.45-7.24(m,8H,ArH),7.13-7.04(m,2H,ArH),5.28(s,2H,OCH2),5.24(s,2H,NCH2),2.45(s,3H,CH3),2.43(s,3H,CH3);13CNMR(100MHz,CDCl3)��164.2,150.7,144.4,136.3,136.0,128.8,128.5,128.03,127.98,127.8,126.6,109.7,65.5,52.8,14.5,11.4;IR(neat)1685,1549,1495,1452,1430,1372,1295,1271,1205,1194,1115cm-1;MS(EI)(m/z)320(M+, 15.65), 91 (100); HRMS calculated value C20H20N2O2[M+]: 320.1525; Measured value: 320.1526.
Embodiment 12
Wherein, equiv represents equivalent, and h represents hour, and oilbath represents that oil bath is heated.
Cu (OAc) is added successively in a dry Schlenk reaction tubes2(367.9mg, 2mmol), n-Butyl Amine 99 BnNH2(108.6mg; 1mmol); PhCN (2mL), puts into the 120 DEG C of oil baths heated in advance by system after adding, reaction 20h; it is cooled to room temperature; adding the dilution of 50mL ether, filter short column, filtrate concentrates; silica gel column chromatography (eluent:petroleumether/ethylacetate=40/1to10/1) toafford4a (139.7mg, 44%): solid;1HNMR(300MHz,CDCl3)��8.25-8.14(m,2H,ArH),7.66-7.57(m,2H,ArH),7.52-7.27(m,9H,ArH),7.25-7.16(m,2H,ArH),5.46(s,2H,CH2).
Gram level synthesis 4a:
Cu (OAc) is added successively in a dry 100mL there-necked flask2(3.6321g,20mmol),BnNH2(1.0704g; 10mmol); PhCN (20mL). after adding, system is put into the 120 DEG C of oil baths heated in advance; reaction 48h, is cooled to room temperature, adds the dilution of 50mL ether; filter short column; filtrate concentrates, and silica gel column chromatography (eluent:petroleumether/ethylacetate=30/1to10/1) obtains 4a (1.3062g, 42%): solid;1HNMR(300MHz,CDCl3)��8.27-8.14(m,2H,ArH),7.64-7.52(m,2H,ArH),7.48-7.13(m,11H,ArH),5.40(s,2H,CH2).
Wherein, equiv represents equivalent, and mins represents minute, and MW represents microwave heating.
Cu (OAc) is added successively in a dry microwave reaction pipe2(363.9mg,2mmol),BnNH2(106.8mg, 1mmol), PhCN (5mL), tightens cock, puts into microwave reactor MILESTONES.r.lMicrowave heating (120 DEG C; 30minutes; maximumpower800W); then treat that system is cooled to room temperature; adding the dilution of 50mL ether, filter short column, filtrate removes major part solvent at oil pump decompression backspin; silica gel column chromatography (eluent:petroleumether/ethylacetate=10/1) obtains 4a (127.0mg, 41%): solid (solid); M.p.99-100 DEG C of (hexane hexane/ ether Et2O)(lit.m.p.98.5-99.5��);1HNMR(300MHz,CDCl3)��8.21(d,J=7.2Hz,2H,ArH),7.62-7.51(m,2H,ArH),7.48-7.13(m,11H,ArH),5.39(s,2H,CH2);13CNMR(CDCl3,75MHz)��161.4,156.0,135.9,130.9,130.0,129.0,128.70,128.67,128.6,128.4,127.9,127.8,126.6,126.3,52.6.IR(neat)3067,3035,2926,2854,1519,1497,1476,1463,1443,1406,1353,1266,1237,1131,1072,1016cm-1;MS(EI)(m/z)312((M+1)+,5.71),311(M+,27.09),91(100).
This compound is known compound, it is possible to by known steps one step (Vlahakis, J.Z.; Lazar, C.; Crandall, I.E.; Szarek, W.A.Biorg.Med.Chem.2010,18,6184) it is converted into the triazolium salt compound with antiplasmodial activitiesIC50(7.8��0.2��M)P.falciparum��
Embodiment 13
Operation reference example 13. Cu (OAc)2(362.4mg; 2mmol); 4-fluorine benzene methanamine 4-fluorobenzylamine (129.7mg; 97%purity; 1mmol); PhCN (5mL) is obtained by reacting 4b (150.3mg, 45%) (eluent:petroleumether/ethylacetate=10/1): oil;1HNMR(300MHz,CDCl3)��8.24-8.16(m,2H,ArH),7.64-7.52(m,2H,ArH),7.50-7.33(m,6H,ArH),7.20-7.10(m,2H,ArH),7.05-6.92(m,2H,ArH),5.37(s,2H,NCH2);13CNMR(CDCl3,75MHz)��162.2(d,J=245.9Hz),161.5,155.9,131.6(d,J=3.5Hz),130.8,130.2,129.2,128.8,128.63,128.61(d,J=8.1Hz),128.45,127.8,126.3,115.7(d,J=20.9Hz),51.9;19FNMR(CDCl3,282MHz)-113.9;IR(neat)1605,1509,1478,1458,1446,1405,1353,1222,1156,1141,1016cm-1;MS(EI)(m/z)330((M+1)+,11.24),329(M+, 49.41), 109 (100); HRMS calculated value C21H16N3F(M+): 329.1328, measured value: 329.1329.
Embodiment 14
Operation reference example 13. Cu (OAc)2(363.9mg, 2mmol), n-butylamine n-BuNH2(73.1mg, 1mmol), is obtained by reacting 4c (147.8mg, 53%) (leacheate eluent:petroleumether/ethylacetate=10/1) in PhCN (5mL): oil;1HNMR(300MHz,CDCl3)��8.19(d,J=7.2Hz,2H,ArH),7.66-7.61(m,2H,ArH),7.60-7.24(m,6H,ArH),4.18(t,J=7.2Hz,2H,NCH2),2.00-1.83(m,2H,CH2),1.40-1.21(m,2H,CH2),0.86(t,J=7.2Hz,3H,CH3);13CNMR(CDCl3,75MHz)��161.0,155.3,131.1,129.8,128.8,128.6,128.3,126.2,48.8,31.9,19.5,13.3;IR(neat)3068,2959,2933,2873,1957,1893,1815,1767,1519,1476,1463,1442,1410,1354,1132,1019cm-1;MS(EI)(m/z)278((M+1)+,11.49),277(M+, 55.63), 234 (100); HRMS calculated value C18H19N3(M+): 277.1579, measured value: 277.1578.
Cu(OAc)2(363.2mg,2mmol),n-BuNH2(74.0mg, 1mmol), is obtained by reacting 4c (125.3mg, 45%) (eluent:petroleumether/ethylacetate=10/1) at PhCN (2mL): oil;1HNMR(300MHz,CDCl3)��8.18(d,J=7.5Hz,2H,ArH),7.66-7.60(m,2H,ArH),7.59-7.30(m,6H,ArH),4.20(t,J=7.2Hz,2H,NCH2),2.00-1.80(m,2H,CH2),1.40-1.21(m,2H,CH2),0.87(t,J=7.2Hz,3H,CH3).
Embodiment 15
Operation reference example 13. Cu (OAc)2(362.5mg, 2mmol), isobutyl-amine isobutylNH2(74.1mg, 1mmol), is obtained by reacting 4d (132.4mg, 47%) (eluent:petroleumether/ethylacetate=10/1) in PhCN (5mL): oil;1HNMR(300MHz,CDCl3)��8.19(d,J=7.2Hz,2H,ArH),7.68-7.57(m,2H,ArH),7.55-7.30(m,6H,ArH),4.02(d,J=7.2Hz,2H,NCH2),2.45-2.25(m,1H,CH),0.86(d,J=6.6Hz,6H,(CH3)2);13CNMR(CDCl3,75MHz)��161.0,156.0,131.1,129.8,128.9,128.7,128.5,128.4,126.3,56.2,29.2,19.7;IR(neat)3069,2940,2872,1958,1894,1815,1730,1519,1476,1463,1442,1409,1391,1354,1285,1193,1174,1132,1071,1018cm-1;MS(EI)(m/z)278((M+1)+,14.65),277(M+, 67.21), 104 (100); HRMS calculated value C18H19N3(M+): 277.1579, measured value: 277.1577.
Embodiment 16
Operation reference example 13. Cu (OAc)2(363.3mg, 2mmol), n-pentyl amine n-C5H11NH2(88.1mg, 1mmol), is obtained by reacting 4e (135.1mg, 46%) (eluent:petroleumether/ethylacetate=15/1) in PhCN (5mL): oil;1HNMR(300MHz,CDCl3)��8.18(d,J=7.5Hz,2H,ArH),7.72-7.60(m,2H,ArH),7.55-7.30(m,6H,ArH),4.19(t,J=7.4Hz,2H,NCH2),2.00-1.82(m,2H,CH2),1.38-1.20(m,4H,-(CH2)2-),0.85(t,J=5.9Hz,3H,CH3);13CNMR(CDCl3,75MHz)��161.1,155.4,131.1,129.9,128.9,128.7,128.4,126.3,49.2,29.7,28.5,22.0,13.8;IR(neat)2958,2926,2856,1476,1463,1441,1408,1355cm-1;MS(EI)(m/z)292((M+1)+,12.96),291(M+, 59.60), 234 (100); HRMS calculated value C19H21N3(M+): 291.1735, measured value: 291.1734.
Embodiment 17
Operation reference example 13. Cu (OAc)2(363.1mg, 2mmol), cyclo-hexylamine CyNH2(99.4mg, 1mmol), PhCN (5mL) is obtained by reacting 19f (137.7mg, 45%) (eluent:petroleumether/ethylacetate=10/1): solid, 107-108 DEG C of (petroleumether/Et2O)(lit.2m.p.106-107��);1HNMR(300MHz,CDCl3)��8.18(d,J=7.8Hz,2H,ArH),7.68-7.57(m,2H,ArH),7.56-7.47(m,3H,ArH),7.46-7.30(m,3H,ArH),4.22(tt,J=11.4,4.1Hz,1H,NCH2),2.23-2.02(m,2H,CH2),2.02-1.80(m,4H,-(CH2)2-),1.78-1.61(m,1H,oneprotoninCH2),1.40-1.20(m,3H,threeprotonin(CH2)2);13CNMR(CDCl3,75MHz)��160.9,154.6,131.4,129.8,128.9,128.8,128.7,128.4,126.3,58.0,33.1,25.4,24.9;IR(neat)3060,3032,2928,2853,1476,1439,1402,1380,1350,1326,1300,1263,1174,1026cm-1;MS(EI)(m/z)304((M+1)+,8.77),303(M+,36.94),221(100).
Embodiment 18
Operation reference example 13. Cu (OAc)2(363.5mg, 2mmol), positive hexyl amine n-hexylNH2(102.0mg, 1mmol), is obtained by reacting 4g (146.1mg, 48%) (eluent:petroleumether/ethylacetate=10/1) in PhCN (5mL): oil;1HNMR(400MHz,CDCl3)��8.17(d,J=7.2Hz,2H,ArH),7.70-7.63(m,2H,ArH),7.59-7.50(m,3H,ArH),7.49-7.35(m,3H,ArH),4.21(t,J=7.4Hz,2H,NCH2),2.00-1.87(m,2H,CH2),1.36-1.20(m,6H,-(CH2)3-),0.85(t,J=6.8Hz,3H,CH3);13CNMR(CDCl3,75MHz)��161.1,155.4,131.2,129.9,128.9,128.8,128.4,126.3,49.2,31.1,30.0,26.1,22.4,13.9;IR(neat)3069,2954,2929,2857,1956,1893,1814,1764,1519,1476,1442,1410,1353,1132,1071,1018cm-1;MS(EI)(m/z)306((M+1)+,11.44),305(M+, 50.21), 234 (100); HRMS calculated value C20H23N3(M+): 305.1892, measured value: 305.1893.
Embodiment 19
Operation reference example 13. Cu (OAc)2(363.8mg, 2mmol), n-octylamine n-C8H17NH2(128.5mg, 1mmol), is obtained by reacting 4h (166.9mg, 50%) (eluent:petroleumether/ethylacetate=15/1) in PhCN (5mL): oil;1HNMR(300MHz,CDCl3)��8.18(d,J=7.8Hz,2H,ArH),7.67-7.60(m,2H,ArH),7.53-7.30(m,6H,ArH),4.19(t,J=7.4Hz,2H,NCH2),2.00-1.83(m,2H,CH2),1.38-1.07(m,10H,-(CH2)5-),0.85(t,J=6.5Hz,3H,CH3);13CNMR(CDCl3,75MHz)��161.0,155.4,131.1,129.8,128.9,128.7,128.4,126.2,49.1,31.6,30.0,28.9,28.8,26.3,22.5,13.9;IR(neat)2926,2855,1955,1893,1813,1727,1519,1476,1442,1354,1133,1071cm-1;MS(EI)(m/z)334((M+1)+,3.84),333(M+,17.96),221(100).
Operation reference example 13. Cu (OAc)2(363.4mg,2mmol),n-C8H17NH2(128.9mg, 1mmol), in PhCN (2mL), oil bath is obtained by reacting 4h (143.6mg, 43%) (eluent:petroleumether/ethylacetate=10/1): oil;1HNMR(300MHz,CDCl3)��8.22(m,2H,ArH),7.69-7.60(m,2H,ArH),7.55-7.30(m,6H,ArH),4.20(t,J=7.4Hz,2H,NCH2),2.00-1.84(m,2H,CH2),1.38-1.10(m,10H,-(CH2)5-),0.86(t,J=6.8Hz,3H,CH3).
Embodiment 20
Operation reference example 13. Cu (OAc)2(363.4mg, 2mmol), dodecyl amine n-C12H25NH2(185.7mg, 1mmol), is obtained by reacting 4i (214.7mg, 55%) (eluent:petroleumether/ethylacetate=10/1) in PhCN (5mL): oil;1HNMR(300MHz,CDCl3)��8.17(d,J=7.5Hz,2H,ArH),7.72-7.60(m,2H,ArH),7.58-7.30(m,6H,ArH),4.20(t,J=7.2Hz,2H,NCH2),2.00-1.82(m,2H,CH2),1.38-1.12(m,18H,-(CH2)9-),0.88(t,J=6.0Hz,3H,CH3);13CNMR(CDCl3,75MHz)��161.1,155.5,131.2,129.9,128.9,128.81,128.79,128.4,126.3,49.2,31.8,30.1,29.5,29.4,29.34,29.27,28.9,26.4,22.6,14.1;IR(neat)2924,2853,1953,1891,1812,1763,1464,1442,1354,1018cm-1;MS(EI)(m/z)390((M+1)+,5.76),389(M+, 19.41), 221 (100); HRMS calculated value C26H35N3(M+): 389.2831, measured value: 389.2832.
Embodiment 21
Operation reference example 13. Cu (OAc)2(363.4mg, 2mmol), benzylamine BnNH2(107.1mg, 1mmol), is obtained by reacting 4j (163.8mg, 48%) (eluent:petroleumether/ethylacetate=15/1) in PhCN (2mL): oil;1HNMR(300MHz,CDCl3)��8.10-7.95(m,2H,ArH),7.46(s,1H,ArH),7.39-7.15(m,10H,ArH),5.40(s,2H,NCH2),2.38(s,3H,Me),2.33(s,3H,Me);13CNMR(CDCl3,75MHz)��161.4,156.0,138.5,138.0,136.0,130.7,130.0,129.8,129.4,128.6,128.5,128.3,127.71,127.67,126.8,126.6,125.4,123.4,52.5,21.19,21.14;IR(neat)1611,1592,1512,1496,1452,1433,1358,1339,1301,1262,1143cm-1;MS(EI)(m/z)340((M+1)+,23.42),339(M+, 94.69), 91 (100); HRMS calculated value C23H21N3(M+): 339.1735, measured value: 339.1736.

Claims (5)

1. a polyazin, it has the multi-substituted pyrazol of following structural formula:
Wherein, R1=H or C1��C10Alkyl, R2=benzyl, R3=phenyl or C1��C10Alkyl, R4=benzyl, halogeno-benzyl, C1��C4Alkyl substituted benzyl base or C1��C4Alkoxyl group substituted benzyl.
2. a synthetic method for polyazin, be is characterized in that described polyazin is 1,2,4-triazole class compounds, is obtained by following step:
At 100-150 DEG C of temperature and in organic nitrile kind solvent, taking neutralized verdigris as oxygenant, amine is substrate, reacts 6-48 hour, generates 1,2,4-triazole class compounds; Wherein, described neutralized verdigris: the mol ratio of amine is 1-3:1-2; Described R4=C1��C12Alkyl, benzyl, halogeno-benzyl, C1��C4Alkyl substituted benzyl base or C1��C4Alkoxyl group substituted benzyl, R5=phenyl, containing C1��C4Alkyl-substituted phenyl.
3. a synthetic method for polyazin, be is characterized in that described polyazin is multi-substituted pyrazol, is obtained by following step:
At 100-150 DEG C of temperature and in organic nitrile kind solvent, take neutralized verdigris as oxygenant, amine and 2, it is substrate that 3-joins alkene acid esters, adding or do not add molecular sieve water-removal agent, the reaction times is 6-48 hour, generates pyrazole compound, it is 1-3:1-2:0.5-1:0-5 that described neutralized verdigris: amine: 2,3-joins the mol ratio of alkene acid esters and molecular sieve; Described R1=H or C1��C10Alkyl, R2=benzyl, R3=phenyl or C1��C10Alkyl, R4=C1��C12Alkyl, benzyl, halogeno-benzyl, C1��C4Alkyl substituted benzyl base or C1��C4Alkoxyl group substituted benzyl.
4. the synthetic method of polyazin as claimed in claim 2, is characterized in that, R in described 1,2,4-triazole class compounds5=phenyl, containing C1��C4Alkyl-substituted phenyl, R4=halogeno-benzyl, C1��C4Alkyl substituted benzyl base or C1��C4Alkoxyl group substituted benzyl.
5. the synthetic method of polyazin as claimed in claim 2, is characterized in that: described product dilutes through ether, and short column is separated, and filtrate concentrates, purification by silica gel column chromatography.
CN201310229542.1A 2013-06-09 2013-06-09 Polyazin and synthetic method thereof Active CN103588707B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310229542.1A CN103588707B (en) 2013-06-09 2013-06-09 Polyazin and synthetic method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310229542.1A CN103588707B (en) 2013-06-09 2013-06-09 Polyazin and synthetic method thereof

Publications (2)

Publication Number Publication Date
CN103588707A CN103588707A (en) 2014-02-19
CN103588707B true CN103588707B (en) 2016-06-01

Family

ID=50079060

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310229542.1A Active CN103588707B (en) 2013-06-09 2013-06-09 Polyazin and synthetic method thereof

Country Status (1)

Country Link
CN (1) CN103588707B (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0016787D0 (en) * 2000-07-07 2000-08-30 Pfizer Ltd Compounds useful in therapy
KR101005834B1 (en) * 2008-08-04 2011-01-05 이화여자대학교 산학협력단 Process of preparing pyrazoles
DE102010013282A1 (en) * 2010-03-29 2011-09-29 Westfälische-Wilhelms Universität Münster Pyrazole synthesis by coupling of carboxylic acid derivatives and enamines

Also Published As

Publication number Publication date
CN103588707A (en) 2014-02-19

Similar Documents

Publication Publication Date Title
CN113336689B (en) Synthesis method and anticancer activity of 3- (alpha-fluorovinyl/carbonyl) indole compound
CN110452270B (en) Azacarbene palladium complex crystal, synthesis method thereof and application thereof in preparation of alpha, beta-unsaturated ketone compound
Liu et al. Bistrifluoromethylated organocuprate [Ph 4 P]+[Cu (CF 3) 2]−: synthesis, characterization and its application for trifluoromethylation of activated heteroaryl bromides, chlorides and iodides
CN109232363B (en) Synthetic method of 3-selenocyanoindole compound
CN106699632A (en) Preparation method of 3-methylene isoindole-1-one derivatives
CN103588707B (en) Polyazin and synthetic method thereof
Magyar et al. Application of a ball milling technique for the condensation of anthranilic hydrazides with aromatic aldehydes towards 4-quinazolinone derivatives
EP1903035A3 (en) High purity butoconazole nitrate with specified particle size and a process for preparation of thereof
CN104961684A (en) Preparation method of 1,3,5-triaryl-4-trifluoromethyl-1-H pyrazol compounds
CN104610267B (en) Method for efficiently synthesizing 6-alkyl pyrazolo [1,5-c ] quinazoline framework compound under non-catalytic condition
CN108191735B (en) The method for the polysubstituted indoles of ketones with Enamino-esters Cyclization that iodine promotes
CN106892826A (en) A kind of preparation method and application of amine and imines N-methyl
Ma et al. Alkali salt-catalyzed aza-Michael addition of 1, 2, 4-triazole to α, β-unsaturated ketones and imides
CN110526853A (en) Bis- substitution -2- indolone derivatives of 3,3- and preparation method thereof
CN108675950A (en) A kind of synthetic method of 2- alkenyls Benzazole compounds
CN105646326B (en) A kind of preparation method of the ketone compounds of polysubstituted indoles 2
CN114539157A (en) Method for preparing 4-iodo-N-arylpyrazole compound by iodine-promoted oxidation method
CN107382899B (en) Polysubstituted 2-hydroxy-1, 4-benzoxazine derivative
CN106336378A (en) Method for preparing quinoline-2-formic acid ester series substances
CN111793021A (en) Method for preparing 6-cyano-pyridine-2-ketone derivative through safe cyanidation
CN108276268B (en) Preparation method of 1, 3-diaryl propine ketone
WO2020084094A1 (en) Nitration
CN112442025A (en) Method for synthesizing imidazo [1, 2a ] pyridine compound
CN108558734A (en) A kind of method of copper catalysis synthesis 2- aryl -3- aryl sulfonyl -1H- indoles
CN104262256B (en) Utilize the method that α, beta-unsaturated carbonyl compound prepare multi-substituted pyrazol compounds

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant