CN108373453B - Triazole derivative and preparation method thereof - Google Patents

Triazole derivative and preparation method thereof Download PDF

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CN108373453B
CN108373453B CN201810290425.9A CN201810290425A CN108373453B CN 108373453 B CN108373453 B CN 108373453B CN 201810290425 A CN201810290425 A CN 201810290425A CN 108373453 B CN108373453 B CN 108373453B
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aryl diazonium
triazole derivative
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CN108373453A (en
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李海燕
李辉煌
王亚雄
万小兵
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Suzhou University
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    • 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
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/08—Halides
    • B01J27/122—Halides of copper

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Abstract

The invention discloses a triazole derivative and a preparation method thereof. The method used by the invention has the following characteristics: the method has the advantages of more economical reaction, wider substrate universality, easier post-functionalization, mild reaction conditions, capability of being carried out in the air, less catalyst consumption, simple and convenient post-treatment, and contribution to the purification and industrial application of products. Meanwhile, the reactants, the catalyst and other raw materials used in the invention are cheap and easy to obtain, the reaction composition is reasonable, no ligand is needed, the reaction steps are few, and higher yield can be obtained only by one-step reaction, so that the method meets the requirements and directions of modern green chemistry and pharmaceutical chemistry, and is suitable for screening high-activity triazole derivative drugs.

Description

Triazole derivative and preparation method thereof
Technical Field
The invention relates to a triazole derivative and a preparation method thereof, belonging to the technical field of organic synthesis.
Background
The triazole derivative is a valuable five-membered nitrogen-containing heterocyclic skeleton, widely exists in a plurality of functional molecules, and is applied to the fields of organic catalysis, material science and the like. In addition, the triazole derivative skeleton appears in many bioactive molecules, and has important application in pharmaceutical industry and pesticides. At present, the method for preparing the triazole derivative has the defects of more reaction steps, complex raw material preparation, complex reaction conditions, narrow substrate range and the like. For example:
(1) michael j Stocks et al report that primary amines, amide diacetal derivatives, hydrazide derivatives to prepare triazole derivatives, but require multi-step reactions with narrow substrate range (see: Michael j Stocks;Org. Lett.2004,6, 2969）；
(2) amidine hydrochloride derivatives, organonitriles, are reported by Hideko Nagasawa et alTriazole derivatives were prepared but at high reaction temperatures and with narrow substrate ranges (see: Hideko Nagasawa;J. Am. Chem. Soc.2009,131,15080）；
(3) recently, Bo Tang et al reported the preparation of triazole derivatives using aziridine derivatives, azodicarboxylate and bromide as reaction substrates, but the reaction was carried out in two steps and the starting material was synthesized in multiple steps (see: Bo Tang;Chem. Commun.2017,53, 9644）。
therefore, it is necessary to develop a preparation method with abundant raw material sources, high reaction activity, low cost and simple operation to effectively synthesize the triazole derivative compound.
Disclosure of Invention
The invention aims to provide a method for preparing triazole derivatives, which has the advantages of abundant sources of reaction raw materials, wide universality of reaction substrates, simple and convenient operation and convenience for later-stage functional synthesis of potential drug molecules.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a preparation method of triazole derivatives comprises the following steps of preparing triazole derivatives through cyclization reaction by taking aryl diazonium fluoroborate, diazo ester derivatives and organic nitrile as reaction substrates, copper salts as catalysts and inorganic base as additives;
wherein the chemical structural general formula of the aryl diazonium fluoroborate is shown in the specification
Figure 124639DEST_PATH_IMAGE001
Wherein Ar is selected from disubstituted aryl and naphthyl;
the structural formula of the diazo ester derivative is as follows:
Figure 778956DEST_PATH_IMAGE003
in the formula, R2Selected from ethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, benzyl;
the organic nitrile has the following chemical structural formula:
Figure 243435DEST_PATH_IMAGE005
in the formula, R3Selected from methyl, isopropyl, tert-butyl, benzyl;
the chemical structural formula of the triazole derivative is as follows:
Figure 177893DEST_PATH_IMAGE006
。
the invention discloses application of aryl diazonium salt, diazo ester derivative and organic nitrile as raw materials in preparation of triazole derivative; the chemical structural formula of the triazole derivative is as follows:
Figure 171257DEST_PATH_IMAGE006
。
the invention also discloses the application of the halogen copper salt catalyst and/or the inorganic base additive in the preparation of triazole derivatives; or the application of halogen copper salt catalyst and/or inorganic base additive in catalyzing aryl diazonium salt of fluoroboric acid, diazo ester derivative and organic nitrile cyclization reaction; the chemical structural formula of the triazole derivative is as follows:
Figure 191166DEST_PATH_IMAGE006
。
in the technical scheme, the reaction temperature of the cyclization reaction is 40 ℃, and the reaction time is 1 hour; the cyclization reaction was carried out in air.
In the above technical scheme, the copper salt is a halogen copper salt; the additive is selected from one of lithium carbonate, potassium carbonate, cesium carbonate, sodium acetate and lithium tert-butoxide; preferably, the copper halide salt is cuprous bromide and the additive is lithium carbonate.
In the technical proposal, the device comprises a base,
the chemical structural formula of the disubstituted aryl is as follows:
Figure 69123DEST_PATH_IMAGE007
。
in the technical scheme, the using amount of the catalyst is 20 percent of the molar weight of the aryl diazonium fluoroborate; the dosage of the additive is 1 time of the molar weight of the aryl diazonium fluoroborate.
In the technical scheme, the dosage of the organic nitrile is 20-50 times of the molar weight of the aryl diazonium fluoroborate; the diazo ester derivative is 3 times of the molar weight of the aryl diazonium salt of the fluoroboric acid.
The cyclization reaction is carried out in the air, ethyl acetate is used for quenching after the reaction is finished, then a rotary evaporator is used for removing the solvent and silica gel adsorption, and finally the mixed solvent of ethyl acetate and petroleum ether is used for carrying out simple column chromatography to obtain the triazole derivative. Therefore, the invention also discloses the triazole derivative prepared by the method.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. in the invention, cuprous bromide is preferably used as a catalyst, lithium carbonate is used as an additive to realize cyclization reaction of the aryl diazonium salt of fluoroboric acid, the diazo ester derivative and the organic nitrile to prepare the triazole derivative, and compared with the prior art, which has the advantages of pre-preparation of raw materials, more reaction steps and harsh conditions, the preparation method has the advantages of more economical reaction, wider substrate universality, easily obtained raw materials and easier later-stage functionalization.
2. The method disclosed by the invention has the advantages of mild reaction conditions, capability of being carried out in the air, small catalyst consumption, simple and convenient post-treatment, contribution to purification and large-scale industrial application of products and easier implementation of one-step functionalization of commercial medicines.
3. The method has the advantages of cheap and easily obtained raw materials such as reactants, catalysts and the like, reasonable reaction composition, no need of ligands, less reaction steps, high yield by only one-step reaction, accordance with the requirements and directions of modern green chemistry and pharmaceutical chemistry, and suitability for screening high-activity triazole derivative drugs.
Detailed Description
The invention is further described below with reference to the following examples:
the raw materials, the catalyst and the additive are all commercial products which can be purchased directly or prepared according to the conventional technology, for example, aryl diazonium fluoroborate can be obtained by the reaction of commercial aromatic amine, sodium nitrite and fluoroboric acid; the diazo ester derivative can be synthesized by simple raw materials such as marketable alcohol, bromoacetyl bromide, p-toluenesulfonyl hydrazide, p-toluenesulfonyl chloride and the like.
Example one
Figure 592508DEST_PATH_IMAGE008
A reaction flask was charged with Compound 1p (0.2 mmol, 50.6 mg), CuBr (0.04 mmol, 5.8mg), and Li in that order2CO3(14.8 mmol), Compound 3a (0.5mL), Compound 2a (0.6 mmol, 72.1 mg). Then the system is magnetically stirred and reacts for 1 hour at the temperature of 40 ℃ in the air, and then the reaction product is quenched by ethyl acetate, the solvent is removed by a rotary evaporator, the reaction product is adsorbed by silica gel, and the product 4p can be obtained by simple column chromatography, wherein the yield is 63%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) δ 7.39 – 7.30 (m, 2H), 7.28 – 7.23 (m, 1H),4.33 (q, J = 8.0 Hz, 2H), 2.56 (s, 3H), 2.08 (s, 3H), 1.28 (t, J = 8.0 Hz,3H).13C NMR (101 MHz, CDCl3) δ 161.96, 156.60, 146.00, 137.50, 135.30,131.80, 130.53, 129.05, 127.32, 62.43, 17.68, 13.95, 13.82. HRMS (ESI-TOF):Anal. Calcd. For C13H14ClN3O2+Na+: 302.0667, Found: 302.0677; IR (neat, cm-1):υ 2969.18, 1729.02, 1448.87, 1231.15, 1119.39, 1086.66, 1039.00, 800.42。
Example two
Figure 287932DEST_PATH_IMAGE009
The reaction flask was charged with compound 1q (0.2 mmol, 52.9) in that order mg），CuBr (0.04 mmol, 5.8mg), Li2CO3(14.8 mmol), Compound 3a (0.5mL), Compound 2a (0.6 mmol, 72.1 mg). Then the system is magnetically stirred and reacts for 1 hour at the temperature of 40 ℃ in the air, and then the reaction product is quenched by ethyl acetate, the solvent is removed by a rotary evaporator, the reaction product is adsorbed by silica gel, and the product 4q is obtained by simple column chromatography, wherein the yield is 41%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) δ 8.15 (d,J= 2.2 Hz, 1H), 7.64 (dd,J= 8.2,2.2 Hz, 1H), 7.49 (d,J= 8.3 Hz, 1H), 4.41 (q,J= 8.0 Hz, 2H), 2.70 (s,3H), 2.52 (s, 3H), 1.38 (t,J= 8.0 Hz, 3H).13C NMR (101 MHz, CDCl3) δ161.58, 157.13, 148.59, 144.79, 136.25, 135.09, 133.11, 129.91, 122.26,62.88, 20.41, 13.94, 13.73. HRMS (ESI-TOF): Anal. Calcd. For C13H14N4O4+Na+:313.0907, Found: 313.0915; IR (neat, cm-1): υ 2922.97, 1726.18, 1532.44,1483.18, 1349.06, 1295.79, 1123.24, 1079.32。
EXAMPLE III
Figure 795137DEST_PATH_IMAGE010
A reaction flask was charged with Compound 1r (0.2 mmol, 55.6 mg), CuBr (0.04 mmol, 5.8mg), Li in that order2CO3(14.8 mmol), Compound 3a (0.5mL), Compound 2a (0.6 mmol, 72.1 mg). Then the system is magnetically stirred and reacts for 1 hour at the temperature of 40 ℃ in the air, and then the reaction product is quenched by ethyl acetate, the solvent is removed by a rotary evaporator, the reaction product is adsorbed by silica gel, and the product 4r can be obtained by simple column chromatography, wherein the yield is 39%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) δ 8.03 (d,J= 2.3 Hz, 1H), 7.48 (dd,J= 8.2,2.4 Hz, 1H), 7.38 (d,J= 8.2 Hz, 1H), 4.38 (q,J= 8.0 Hz, 2H), 3.90 (s,3H), 2.69 (s, 3H), 2.52 (s, 3H), 1.35 (t,J= 8.0 Hz, 3H).13C NMR (101 MHz,CDCl3) δ 166.47, 161.15, 157.22, 144.77, 142.09, 135.57, 132.16, 129.86,128.82, 127.87, 62.59, 52.04, 21.55, 13.93, 13.76. HRMS (ESI-TOF): Anal.Calcd. For C15H17N3O4+Na+: 326.1111, Found: 326.1123; IR (neat, cm-1): υ2921.53, 1723.83, 1509.26, 1310.41, 1222.22, 1119.70, 1086.25, 781.90。
Example four
Figure 70260DEST_PATH_IMAGE011
The reaction flask was charged with Compound 1s (0.2 mmol, 51.0 mg), CuBr (0.04 mmol, 5.8mg), and Li in that order2CO3(14.8 mmol), Compound 3a (0.5mL), Compound 2a (0.6 mmol, 72.1 mg). Then the system is magnetically stirred and reacts for 1 hour at the temperature of 40 ℃ in the air, and then the reaction product is quenched by ethyl acetate, the solvent is removed by a rotary evaporator, the reaction product is adsorbed by silica gel, and the product can be obtained by simple column chromatography for 4s, wherein the yield is 61%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR (400 MHz, CDCl3) δ 7.91 (m, 4H), 7.62 – 7.46 (m, 3H), 4.36 (q,J= 8.0 Hz, 2H), 2.55 (s, 3H), 1.30 (t,J= 8.0 Hz, 3H).13C NMR (101 MHz,CDCl3) δ 161.08, 157.33, 144.95, 135.14, 133.19, 132.66, 128.75, 128.28,127.80, 127.23, 127.02, 124.43, 123.25, 62.51, 13.92, 13.81. HRMS (ESI-TOF):Anal. Calcd. For C16H15N3O2+Na+: 304.1056, Found: 304.1066; IR (neat, cm-1): υ2935.17, 1727.51, 1302.74, 1246.98, 1109.87, 1057.21, 811.15, 745.81。

Claims (4)

1. A preparation method of triazole derivatives is characterized by comprising the following steps of preparing triazole derivatives through cyclization reaction by taking aryl diazonium fluoroborate, diazo ester derivatives and organic nitrile as reaction substrates, cuprous bromide as a catalyst and lithium carbonate as an additive;
wherein the chemical structural general formula of the aryl diazonium fluoroborate is shown in the specification
Figure DEST_PATH_IMAGE002
Wherein Ar is selected from disubstituted aryl and naphthyl; the chemical structural formula of the disubstituted aryl is as follows:
Figure DEST_PATH_IMAGE004
the structural formula of the diazo ester derivative is as follows:
Figure DEST_PATH_IMAGE006
in the formula, R2Selected from ethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, benzyl;
the organic nitrile has the following chemical structural formula:
Figure DEST_PATH_IMAGE008
in the formula, R3Selected from methyl, isopropyl, tert-butyl, benzyl;
the chemical structural formula of the triazole derivative is as follows:
Figure DEST_PATH_IMAGE010
。
2. the preparation method of the triazole derivatives according to claim 1, which is characterized in that: the reaction temperature of the cyclization reaction is 40 ℃, and the reaction time is 1 hour; the cyclization reaction was carried out in air.
3. The preparation method of the triazole derivatives according to claim 1, which is characterized in that: the dosage of the catalyst is 20 percent of the molar weight of the aryl diazonium fluoroborate; the dosage of the additive is 1 time of the molar weight of the aryl diazonium fluoroborate.
4. The preparation method of the triazole derivatives according to claim 1, which is characterized in that: the dosage of the organic nitrile is 20-50 times of the molar weight of the aryl diazonium fluoroborate; the diazo ester derivative is 3 times of the molar weight of the aryl diazonium salt of the fluoroboric acid.
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