CN102603660B - Preparation method of 1H-1,2,3-triazole compound - Google Patents

Abstract

The invention discloses a preparation method of 1H-1,2,3-triazole compounds represented by formula (I). The preparation method is: combining the halogenated compound represented by formula (III) with the formula (II ) shown in the end group alkyne compound and sodium azide mixed, in the reaction solvent under the catalysis of porous copper at 25 ~ 80 ℃ for 5 ~ 85h, after the reaction, the reaction solution post-treatment to prepare the formula (I ) represented by 1H-1,2,3-triazole compounds; the solvent is deionized water, acetonitrile, absolute ethanol, toluene, acetone, N,N-dimethylformamide, tetrahydrofuran or dioxygen six rings. The invention adopts one-pot operation, the catalyst can be reused many times, the condition is mild, and the operation is simple and convenient.

Description

A kind of preparation method of 1H-1,2,3-triazole compound

(1) Technical field

The invention relates to a preparation method of 1H-1,2,3-triazole compound. the

(2) Background technology

Caspar Christensen，and Morten Melda.J.Org.Chem，2002，67，3057-3064)。3.以苯胺为原料，通过铜(II)催化重氮基的转移，然后在抗坏血酸钠的还原作用下，得到的铜(I)催化炔/叠氮的1，3-偶极环加成(Henning S.G.Beckmann and Valentin Wittmann.Org.Lett.2007，9(1)，1-4)。但上述制备方法仍存在很多缺陷：如催化剂昂贵、难以得到，容易生成副产物，收率不高，适用范围不广，局限性较大，条件苛刻，因此限制了其应用性。  1H-1,2,3-triazole compounds, as important chemical raw material intermediates, are widely used in the synthesis fields of pesticides and medicines. About the synthetic method of 1H-1,2,3-triazole compounds so far reported less: 1. by polystyrene sulfonyl hydrazide and 1,1-dichloroacetone, obtain α-dichlorocarbonylsulfonyl Hydrazone, and then prepared by cyclization with amine (Makam S. Raghavendra and Yulin Lam, Tetrahedron Letters, 2004, 45, 6129-6132). 2. Preparation via copper-catalyzed 1,3-dipolar cycloaddition (CuACC) click reaction of alkynes/azides (Christian W.

Caspar Christensen, and Morten Melda. J. Org. Chem, 2002, 67, 3057-3064). 3. With aniline as raw material, the transfer of diazo group is catalyzed by copper (II), and then under the reduction of sodium ascorbate, the copper (I) obtained catalyzes the 1,3-dipolar cycloaddition of alkyne/azide ( Henning SG Beckmann and Valentin Wittmann. Org. Lett. 2007, 9(1), 1-4). However, the above-mentioned preparation method still has many defects: such as expensive catalyst, difficult to obtain, easy to generate by-products, low yield, limited scope of application, large limitations, and harsh conditions, thus limiting its applicability.

(3) Contents of the invention

The purpose of the present invention is to improve various defects of the prior art, and to provide a one-pot method for preparing 1H-1,2,3-triazole compounds with easy-to-obtain catalyst, repeated use, mild conditions and easy operation. the

For realizing above-mentioned purpose of the invention, the technical scheme that the present invention adopts is:

A preparation method of 1H-1,2,3-triazole compounds shown in formula (I), the preparation method is: the halogenated compound shown in formula (III) and the compound shown in formula (II) The terminal alkyne compound and sodium azide are mixed, and reacted in a reaction solvent at 25-80° C. for 5-85 hours under the catalysis of porous copper. After the reaction is completed, the reaction solution is post-treated to obtain the compound shown in formula (I). 1H-1,2,3-triazole compounds; the reaction solvent is deionized water, acetonitrile, absolute ethanol, toluene, acetone, N,N-dimethylformamide, tetrahydrofuran or dioxane;

In formula (I), formula (II) or formula (III), X is halogen, OAc, OMs (mesylate) or OTf (trifluoromethanesulfonate); R ₁ is C1 to C13 alkyl, benzyl group, substituted benzyl or ethyl acetate group, the substituent on the substituted benzyl benzene ring is monosubstituted halogen or monosubstituted C1 to C5 alkyl; _R2 is C6 to C13 alkyl, 5 to 9 membered ring Alkenyl, phenyl, substituted phenyl, phthalimide methyl or pyridyl, the substituent of the substituted phenyl is monosubstituted C1 to C5 alkoxy or monosubstituted halogen.

Further, X is preferably Br, Cl or I. the

Further, R ₁ is preferably benzyl, C1 to C8 alkyl or ethyl acetate. Furthermore, the C1 to C8 alkyl group is preferably ethyl or butyl.

Further, R is _preferably phenyl, p-methoxyphenyl, p-ethoxyphenyl, p-chlorophenyl, m-fluorophenyl, 4-pyridyl, 1-cyclohexenyl, phthaloyl iminomethyl or C6 to C10 alkyl. Further, the C6 to C10 alkyl group is preferably an octyl group.

Concretely, the preferred terminal group alkynes represented by formula (II) in the present invention are phenylacetylene, 4-methoxyphenylacetylene, 4-ethoxyphenylacetylene, 4-chlorophenylacetylene, 3-fluorophenylacetylene, 1-phthalimidepropyne, 4-pyridineacetylene, 1-cyclohexenylacetylene or 1-octyne. the

Specifically, the preferred halide represented by formula (III) in the present invention is benzyl bromide, benzyl chloride, ethyl iodide, n-bromobutane or ethyl 1-bromoacetate. the

In the present invention, the reaction solvent is preferably deionized water, which has the advantages of environmental protection, low cost and high reaction yield. the

In the present invention, the catalyst is porous copper, and the pore diameter is preferably 5-150 μm, more preferably 5-50 μm, even more preferably 5-20 μm, most preferably 5 μm. In the present invention, a commercially available item is used for the porous copper. the

In the present invention, the ratio of the amount of the halogenated compound (III) to the terminal alkyne compound (II), sodium azide, copper catalyst is 1: 1.0～1.2: 1.2～2: 0.05～0.15 , most preferably 1:1.1:2:0.05. the

In the present invention, the volumetric amount of the reaction solvent is 4-10 ml/mmol, most preferably 4 ml/mmol, based on the number of moles of the halide (III). the

The reaction conditions of the present invention are mild, preferably the reaction temperature is 55-60° C., and the preferred reaction time is 8-50 h. the

In the present invention, after the reaction is completed, the obtained reaction liquid can be subjected to conventional aftertreatment to obtain the target product. The post-treatment method recommended by the present invention is as follows: after the reaction is finished, the resulting reaction solution is extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then mixed with petroleum ether and ethyl acetate at a volume ratio of 5:1. The ester is used as a developing agent, and the column chromatography is carried out, and the eluate with an _Rf value of 0.3-0.35 is collected, distilled under reduced pressure, and dried to obtain 1H-1,2,3-triazole compounds.

The present invention specifically recommends that the preparation method of the described 1H-1,2,3-triazole compound is carried out according to the following steps: the halogenated compound shown in formula (III) and the terminal alkyne compound shown in formula (II) Mix with sodium azide, react in deionized water under the catalysis of porous copper at 55°C-60°C for 8-50h, after the reaction, the obtained reaction solution is extracted with ethyl acetate, washed with saturated sodium chloride, and the organic phase Drying, concentrating, and then using sherwood oil and ethyl acetate with a volume ratio of 5:1 as a developing solvent, carrying out column chromatography, collecting the eluent with an _Rf value of 0.3 to 0.35, distilling under reduced pressure, and drying to obtain (I) Shown 1H-1,2,3-triazole compound; The ratio of the amount of the feed material of the halogenated compound (III) to the end group alkyne compound (II), sodium azide, porous copper is 1 : 1.1: 2: 0.05; the volumetric dosage of the deionized water is 4ml/mmol based on the moles of halide (III).

Compared with the prior art, the advantages of the preparation method of 1H-1,2,3-triazole compounds provided by the invention are:

(1) The present invention adopts a one-pot method to prepare 1H-1,2,3-triazole compounds with mild reaction conditions and convenient operation. the

(2) The present invention has selected cheap and easy-to-get porous copper as the catalyst, and the catalyst can be reused many times without treatment, which meets the principle of atom economy; simultaneously, the present invention has selected deionized water as the solvent, which is environmentally friendly and low cost Low, high reaction yield, good product quality. the

In view of the fact that 1H-1,2,3-triazole compounds have strong biological activities, such as anti-allergic, antibacterial, and anti-HIV activities, they are widely used in drug design, so the present invention has a wide range of industrial application prospects . the

(4) Specific implementation methods

The present invention will be further described below through examples, but the protection scope of the present invention is not limited thereto. the

The porous copper used in the embodiment of the present invention is produced by Changsha Liyuan New Material Co., Ltd. the

Embodiment 1: the preparation of 1-benzyl-4-phenyl-1,2,3-triazole shown in formula (I-1)

Benzyl bromide (171.0mg, 1mmol) shown in formula (III-1), sodium azide (130mg, 2mmol), phenylacetylene (112.3mg, 1.1mmol) shown in formula (II-1), porous copper (5 μm pore size, 3.2 mg, 0.05 mmol) were mixed in deionized water (4 ml), stirred and reacted in an oil bath at 55° C. for 29 h, followed by TLC. After the reaction, extract with ethyl acetate (10mL×3), wash with saturated brine, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether:ethyl acetate=5:1), The eluate with R _f value of 0.3-0.35 was collected, distilled under reduced pressure, and dried to obtain 224.6 mg of the target compound, with a yield of 95.47%, as white needle-like crystals.

¹ HNMR (CDCl ₃ ): δ=7.81-7.83 (m, 2H), 7.68 (s, 1H), 7.39-7.43 (m, 5H), 7.32-7.34 (m, 3H), 5.59 (s, 2H)

Example 2:

The amount of porous copper was increased to 6.4mg (0.10mmol), the reaction time was 10 hours, other operations were the same as in Example 1, and the yield was 94.9%. the

Example 3:

The amount of porous copper was increased to 9.6mg (0.15mmol), the reaction time was 29 hours, other operations were the same as in Example 1, and the yield was 94.81%. the

Example 4:

The amount of porous copper was increased to 12.8 mg (0.20 mmol), the reaction time was 27.5 hours, other operations were the same as in Example 1, and the yield was 94.25%. the

Embodiment 5:

Porous copper (5 μm) was changed to porous copper (20 μm), the reaction time was 28 hours, other operations were the same as in Example 1, and the yield was 87.20%. the

Embodiment 6:

Porous copper (5 μm) was changed to porous copper (50 μm), the reaction time was 43.5 hours, other operations were the same as in Example 1, and the yield was 65.76%. the

Embodiment 7:

Porous copper (5 μm) was changed to porous copper (150 μm), the reaction time was 85 hours, other operations were the same as in Example 1, and the yield was 27.30%. the

Embodiment 8:

The reaction temperature was increased to 80° C., the reaction time was 11 hours, other operations were the same as in Example 1, and the yield was 94.99%. the

Embodiment 9:

The solvent deionized water was replaced with acetonitrile, the reaction time was 22.5 hours, other operations were the same as in Example 1, and the yield was 10.20%. the

Embodiment 10:

The solvent deionized water was replaced with absolute ethanol, the reaction time was 34 hours, other operations were the same as in Example 1, and the yield was 44.17%. the

Example 11:

The solvent deionized water was replaced with toluene, and the reaction time was 28.5 hours. Other operations were the same as in Example 1, and the yield was a small amount. the

Example 12:

The solvent deionized water was replaced with acetone, and the reaction time was 24.5 hours. Other operations were the same as in Example 1, and the yield was 58.78%. the

Example 13:

The solvent deionized water was replaced with N,N-dimethylformamide, the reaction time was 52.5 hours, other operations were the same as in Example 1, and the yield was 28.10%. the

Example 14:

The solvent deionized water was replaced with tetrahydrofuran, and the reaction time was 54.5 hours. Other operations were the same as in Example 1, and the yield was 4.50%. the

Example 15:

The solvent deionized water was replaced with dioxane, and the reaction time was 69 hours. Other operations were the same as in Example 1, and the yield was 5.30%. the

Embodiment 16: Preparation of 1-benzyl-4-p-methoxyphenyl-1,2,3-triazole shown in formula (I-2)

145.4 mg (1.1 mmol) of 4-methoxyphenylacetylene (II-2) was used instead of phenylacetylene, and the other operations were the same as in Example 1 to obtain 257.9 mg of the target product (I-2), with a yield of 97.2%, as a white solid. the

¹ HNMR (CDCl ₃ ): δ=7.74(d, J=8.5Hz, 2H), 7.59(s, 1H), 7.39-7.41(m, 3H), 7.32-7.34(m, 2H), 6.95(d, J=8.5Hz, 2H), 5.58(s, 2H), 3.85(m, 3H)

Example 17: Preparation of 1-benzyl-4-(1-cyclohexenyl)-1,2,3-triazole

116.8mg (1.1mmol) 1-cyclohexenylphenylacetylene (II-3) was used to replace phenylacetylene, and other operations were the same as in Example 1 to obtain 135.5mg of the target product (I-3), with a yield of 56.60%, a white solid . the

¹ HNMR (CDCl ₃ ): δ=7.36-7.40 (m, 3H), 7.30 (s, 1H), 7.30-7.25 (m, 2H), 6.49-6.51 (m, 1H), 5.52 (s, 2H), 2.35-2.38(m, 2H), 2.17-2.22(m, 2H), 1.73-1.78(m, 2H), 1.64-1.69(m, 2H).

Example 18: Preparation of 1-benzyl-4-hexyl-1,2,3-triazole

121.2 mg (1.1 mmol) of 1-octyne (II-4) was used instead of phenylacetylene, and other operations were the same as in Example 1 to obtain 222.7 mg of the target product (I-4), with a yield of 91.50%. the

¹ HNMR (CDCl ₃ ): δ=7.36-7.38(m, 3H), 7.25-7.28(m, 2H), 7.19(s, 1H), 5.50(s, 2H), 2.69(t, J=7.8Hz, 2H), 1.63-1.68(m, 2H), 1.28-1.35(m, 6H), 0.88(t, J=6.9Hz, 3H)

Example 19: Preparation of 1-benzyl-4-p-ethoxyphenyl-1,2,3-triazole

160.8mg (1.1mmol) of 4-ethoxyphenylacetylene (II-5) was used instead of phenylacetylene, and the other operations were the same as in Example 1 to obtain 252.3mg of the target product (I-5) with a yield of 90.33% as a white solid. the

¹ HNMR (CDCl ₃ ): δ=7.71-7.73 (m, 2H), 7.58 (s, 1H), 7.39-7.41 (m, 3H), 7.32-7.7.33 (m, 2H), 6.93-6.94 (m , 2H), 5.58(s, 2H), 4.07(q, J=7.0Hz, 2H), 1.44(t, J=7.0Hz, 3H).

Example 20: Preparation of 1-benzyl-4-pyridyl-1,2,3-triazole

Substitute phenylacetylene with 153.5 mg (1.1 mmol) 4-pyridine acetylene hydrochloride (II-6), and other operations are the same as in Example 1 to obtain 92.1 mg of the target product (I-6), with a yield of 38.97%, a yellow-green solid . the

¹ HNMR (CDCl ₃ ): δ=8.65 (d, J=5.8Hz, 2H), 7.80 (s, 1H), 7.70-7.71 (m, 2H), 7.41-7.44 (m, 3H), 7.33-7.35 ( m, 2H), 5.62 (s, 2H).

Example 21: Preparation of 1-benzyl-4-phenyl-1,2,3-triazole

126.6 mg (1 mmol) benzyl chloride (III-2) was used to replace benzyl bromide, and other operations were the same as in Example 1 to obtain 221.2 mg of the target product (I-1), with a yield of 94.00%. the

Example 22: Preparation of 1-acetate ethyl-4-phenyl-1,2,3-triazole

166.0 mg (1 mmol) ethyl 1-bromoacetate (III-3) was used instead of benzyl bromide, and the other operations were the same as in Example 1 to obtain 228.2 mg of the target product (I-7) with a yield of 98.80% as a white solid. the

¹ HNMR (CDCl ₃ ): δ=7.93 (s, 1H), 7.86-7.87 (m, 2H), 7.43-7.46 (m, 2H), 7.35-7.38 (m, 1H), 5.22 (s, 2H), 4.31(q, J=7.2Hz, 2H), 1.33(t, J=7.2Hz, 3H).

Example 23: Preparation of 1-ethyl-4-phenyl-1,2,3-triazole

156.0 mg (1 mmol) ethyl iodide (III-4) was used instead of benzyl bromide, and the other operations were the same as in Example 1 to obtain 137.9 mg of the target product (I-8) with a yield of 79.60% as a white solid. the

¹ HNMR (CDCl ₃ ): 7.84-7.86 (m, 2H), 7.78 (s, 1H), 7.42-7.46 (m, 2H), 7.33-7.36 (m, 1H), 4.48 (q, J=7.4Hz, 2H), 1.62(t, J=7.4Hz, 3H).

Example 24:

1-Benzyl-4-phthalimidemethyl-1,2,3-triazole

Use 203.7mg (1.1mmol) phthalimide propyne (II-7) to replace phenylacetylene, and other operations are the same as in Example 1 to obtain 33.1mg of the target product (I-6), with a yield of 10.4%, white solid. the

¹ H NMR (CDCl ₃ ): δ=7.84(s, 1H), 7.72-7.81(m, 4H), 7.14-7.27(m, 5H), 5.81(s, 2H), 4.81(s, 2H).

Example 25:

1-Benzyl-4-p-chlorophenyl-1,2,3-triazole

150.2mg (1.1mmol) p-chlorophenylacetylene (II-8) was used instead of phenylacetylene, and the other operations were the same as in Example 1 to obtain 243.6mg of the target product (I-10), with a yield of 90.3%, as a white solid. the

¹ H NMR (CDCl ₃ ): δ=7.74-7.76 (m, 2H), 7.66 (s, 1H), 7.33-7.42 (m, 7H), 5.60 (s, 2H).

Example 26:

1-Benzyl-4-m-fluorophenyl-1,2,3-triazole

132.1 mg (1.1 mmol) m-fluorophenylacetylene (II-9) was used instead of phenylacetylene, and the other operations were the same as in Example 1 to obtain 221.9 mg of the target product (I-11), a white solid with a yield of 87.6%. the

¹ H NMR (CDCl ₃ ): δ=7.68(s, 1H), 7.53-7.58(m, 2H), 7.32-7.44(m, 6H), 7.00-7.04(m, 1H), 5.60(s, 2H) .

Example 27:

137.0 mg (1 mmol) of 1-bromobutane (III-5) was used instead of benzyl bromide, and the other operations were the same as in Example 1 to obtain 58.2 mg of the target product (I-12), with a yield of 28.91%, as a white solid. the

¹ H NMR (CDCl ₃ ): δ=7.85-7.87(m, 2H), 7.77(s, 1H), 7.43-7.46(m, 2H), 7.33-7.37(m, 1H), 4.43(t, J= 7.2Hz, 2H), 1.93-1.99(m, 2H), 1.38-1.46(m, 2H), 1.00(t, J=7.5Hz, 3H).

Claims (7)

1. the 1H-1 shown in a formula I, 2, the preparation method of 3-triazole class compounds, described preparation method is: the halides shown in formula III is mixed with end-group alkyne compounds and sodiumazide shown in formula II, in reaction solvent under the katalysis of Porous Cu in 25～80 ℃ reaction 5～85h, reaction finish after, reaction solution aftertreatment makes the 1H-1 shown in formula I, 2,3-triazole class compounds; Described solvent is deionized water; The aperture of described Porous Cu is 5～20 μ m;

In formula I, formula II or formula III, X is halogen; R ₁for C1 to C13 alkyl, benzyl, substituted benzyl or ethyl acetate base, the substituting group on described substituted benzyl phenyl ring is monosubstituted halogen or monosubstituted C1 to C5 alkyl; R ₂for C6 to C13 alkyl, 5 yuan to 9 yuan cycloalkenyl groups, phenyl, substituted-phenyl or pyridyl, the substituting group of described substituted-phenyl is monosubstituted C1 to C5 alkoxyl group or monosubstituted halogen.

2. 1H-1 as claimed in claim 1, the preparation method of 2,3-triazole class compounds, is characterized in that: X is Br, Cl or I; R ₁for benzyl, C1 to C4 alkyl or ethyl acetate base; R ₂for phenyl, p-methoxyphenyl, to ethoxyl phenenyl, rubigan, a fluorophenyl, 4-pyridyl, 1-cyclohexenyl or C6 to C10 alkyl.

3. 1H-1 as claimed in claim 1, the preparation method of 2,3-triazole class compounds, is characterized in that: the aperture of described Porous Cu is 5 μ m.

4. 1H-1 as claimed in claim 1 or 2,2, the preparation method of 3-triazole class compounds, is characterized in that: described halides is 1:1.0～1.2:1.2～2:0.05～0.15 with the ratio of the amount of substance of end-group alkyne compounds, sodiumazide, Porous Cu.

5. 1H-1 as claimed in claim 3,2, the preparation method of 3-triazole class compounds, it is characterized in that: described halides is 1:1.1:2:0.05 with the ratio of the amount of substance of end-group alkyne compounds, sodiumazide, Porous Cu, and the volumetric usage of described reaction solvent is counted 4ml/mmol with the mole number of halides.

6. 1H-1 as claimed in claim 1 or 2, the preparation method of 2,3-triazole class compounds, is characterized in that: temperature of reaction is 55～60 ℃, the reaction times is 8～50h.

7. 1H-1 as claimed in claim 5, the preparation method of 2,3-triazole class compounds, is characterized in that: temperature of reaction is 55～60 ℃, the reaction times is 8～50h.