WO2014089728A1

WO2014089728A1 - 1-substituted-5-chloro-2h-1,2,3-triazole-4-carboxylate derivative and preparation method therefor

Info

Publication number: WO2014089728A1
Application number: PCT/CN2012/001704
Authority: WO
Inventors: 江岳恒; 阙利民; 蔡彤�
Original assignee: 雅本化学股份有限公司
Priority date: 2012-12-14
Filing date: 2012-12-14
Publication date: 2014-06-19

Abstract

Dislcosed are a 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylate derivative and a preparation method therefor. The disclosed 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylate derivative has a structure as represented by formula (I), where R expresses either an alkyl, an aryl, an aralkyl, a cycloalkyl, a cycloalkylalkyl, a heteroaryl, a heteroarylalkyl or a heterocycloalkyl. The preparation method of the present invention is simple and easy, and acquires a high compound yield.

Description

1-substituted-5-chloro-2H-1, 2,3-triazole-4-carboxylic acid derivative and preparation method thereof

The present invention relates to a 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative and a process for the preparation thereof. Background technique

1-Substituted -5-Chloro-2H-1,2,3-triazole-4-carboxylic acid derivatives are a new class of compounds with great developmental value. Triazole-based compounds have a wide range of potential applications and are important intermediates for many drugs, herbicides, and insecticides. They are also the major pharmacophores in many drug molecules.

A process for the preparation of a 2-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative is described in detail in the applicant's patent application No. 201210304112.7. However, there is a lack of a process in the art for the preparation of 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivatives. Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative and a process for the preparation thereof.

In order to achieve the above object, the technical solution adopted by the present invention is as follows:

A 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative having the structure represented by the following formula I:

CI COO H

)=

^Κ Ν

Formula I

Wherein R represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, Heteroaryl fluorenyl or heterocyclic fluorenyl.

The 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative disclosed in the present invention is obtained by the following steps:

1) Dissolve the compound of the following formula II in the first organic solvent, cool to -78~0 ° C, add the first Grignard reagent, stir for 0.5 to 2 hours; pass chlorine or add chlorinating agent, stir 5~ After warming to room temperature for 30 minutes, it is quenched with a saturated aqueous solution of ammonium chloride or hydrochloric acid, and then extracted with a second organic solvent; the obtained first extract is dried and concentrated to dryness under reduced pressure, and the first concentrate obtained is first. Sub-recrystallization gives 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole as shown in the following formula III;

Br. Br CI Br

)=( )=(

^K N ^κ N

Wherein R represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group or a heterocyclic fluorenyl group;

2) The 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole obtained in the step 1) is dissolved in a third organic solvent, cooled to -20 to 30 ° C, and added to the second Grignard reagent, stirring for 0.5~5 hours, cooling to -50~20 V;

3) Pass carbon dioxide gas for about 10~30 minutes, warm to room temperature, adjust pH = 1~5 with hydrochloric acid, and extract with fourth organic solvent;

4) Step 3) The obtained second extract is dried and concentrated to dryness under reduced pressure, and the obtained second concentrate is subjected to a second recrystallization to obtain the 1-substituted-5-chloro-2H-1,2,3- Triazole-4-carboxylic acid derivative.

In the step 1) of the embodiment of the present invention, the mass to volume ratio of the compound of the formula II to the first organic solvent is 1: 2 to 20; the molar ratio of the compound of the formula II to the first Grignard reagent The ratio is 1: 0.8~1.5, preferably 1: 0.8~1.2; the molar ratio of the compound of the formula II to chlorine or chlorinating agent is 1:1~10; the first organic solvent is diethyl ether, tetrahydrofuran, 1,4-dioxane or methyltetrahydrofuran; the first Grignard reagent is isopropylmagnesium chloride or isopropylmagnesium chloride-lithium chloride complex; the chlorinating agent comprises N-chlorosuccinyl Imine and 1,3-dichloro-5,5-dimethylhydantoin. In the step 2) of the embodiment of the present invention, the mass-to-volume ratio of the 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole to the third organic solvent is 1:2. The molar ratio of the 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole to the second Grignard reagent is 1: 0.8-1.5, preferably 1: 0.8~. 1.2; the molar ratio of the 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole to carbon dioxide is 1: 1-10, preferably 1: 2~5; The triorganic solvent is diethyl ether, tetrahydrofuran, 1,4-dioxane or methyltetrahydrofuran; and the second Grignard reagent is an isopropylmagnesium chloride-lithium chloride complex.

The isopropylmagnesium chloride or the isopropylmagnesium chloride-lithium chloride complex of the present invention is a tetrahydrofuran solution, a 2-methyltetrahydrofuran solution or a diethyl ether solution of different molar concentrations, and the commercially available concentration is usually 1.0 to 2.0 mol/ Rise.

Further, in the step 1) or the step 3), the second organic solvent or the fourth organic solvent is one or a mixture of two or more of fatty acid esters or ethers, wherein the fatty acid esters include formic acid. Ethyl ester, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate , ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ethers include diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether.

In the step 1) of the embodiment of the present invention, the first extract is dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and the first recrystallization includes the following steps: according to the mass to volume ratio of 1: 1 to 100 A concentrate is added to the first solvent, stirred at -20 to 50 ° C for 0.5 to 24 hours, filtered, and vacuum dried to obtain the 1-substituted-4-bromo-5-chloro-1H-1,2,3- Triazole.

In the step 4) of the embodiment of the present invention, the second extract is dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and the second recrystallization comprises the following steps: according to the mass to volume ratio of 1: 1 to 100 The second concentrate is added to the second solvent, stirred at -20 to 50 ° C for 0.5 to 24 hours, filtered, and vacuum dried to obtain the 1-substituted-5-chloro-2H-1,2,3-triazole- 4-carboxylic acid derivative.

Further, in the step 1) or the step 4), the first solvent or the second solvent is one or more of water, alcohols, fatty acid esters, ketones, ethers and hydrocarbons in any ratio. Mixing, wherein the alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and the fatty acid esters include ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, Propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, Methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ketones including acetone,

2-butanone, cyclopentanone and cyclohexanone, ethers including diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane and petroleum ether, hydrocarbons including垸, cyclohexanyl, methylcyclohexanide and n-glycan.

The preparation of 1-substituted-4,5-dibromo-1H-1,2,3-triazole (Formula II) has been described in detail in the applicant's patent applications No. 201110166067.9 and No. 201210051904.8.

The reaction formula of the above-mentioned preparation method of the 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative provided by the present invention is as follows:

Formula II, Formula V, Formula III

Formula III Formula IV Formula I The preparation method of the 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative of the present invention is simple and easy, and the obtained compound has high yield. . BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further illustrated by the following examples, but is not intended to limit the application of the present invention. Example 1 Preparation of 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole

Example 1.1

r

Dissolve 3.0 g (12.45 mmol) of 1-methyl-4,5-dibromo-2H-1,2,3-triazole in 25 ml of tetrahydrofuran, cool to -15~0 °C, and slowly drip in 30 minutes. Add 7.47 ml (14.95 mmol) 2.0M Isopropyl magnesium chloride tetrahydrofuran solution. After the addition is complete, continue stirring for 30 to 60 minutes. Chlorine gas is slowly introduced until the reaction liquid does not heat up. The reaction mixture was added with aq. EtOAc (EtOAc m. 1/3), heated to reflux for 1 hour, cooled to 0~10 V, stirring was continued for 1 hour, filtered, and dried under vacuum at <40 °C. There was obtained 2.01 g of 1-methyl-4-bromo-5-chloro-2H-1,2,3-triazole solid in a yield of 82%. NMR (CDC1 ₃ , 400 MHz): δ 4.02 (s, 3H); ¹³ C NMR (CDC1 ₃ , 400 MHz) : δ 125.9, 119.0, 35.9. Example 1.2

Br, Br

N, , , N N, , ,N

N N

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 3.17 g (12.45 mmol) of 1-ethyl-4,5-dibromo -2H-1,2,3-triazole. There was obtained 2.33 g of 1-ethyl-4-bromo-5-chloro-2H-1,2,3-triazole solid in a yield of 89%. NMR (CDC1 ₃ , 400 MHz): δ 4.38 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H); ¹³ C NMR (CDC1 ₃ , 400 MHz) δ 124.9, 119.2, 44.9 , 14.5. Example 1.3

, Br Br, .CI

N, , , N N, , .N

N N

The procedure was the same as in Example 1. Substituting 1-methyl-4,5-dibromo-2H-1,2,3-triazole to 3.35 g (12.45 mmol) 1-n-propyl-4,5-di Bromo-2H-1,2,3-triazole. There was obtained 1.58 g of 1-n-propyl-4-bromo-5-chloro-2H-1,2,3-triazole oil in a yield of 92%. NMR (CDC1 ₃ , 400 MHz): 5 4.31 (t, / = 7.2 Hz, 2H), 1.97-1.90 (m, 2H), 0.97 (t, / = 7.2 Hz, 3H); ¹³ C NMR (CDC1 ₃ , 400 MHz) : δ 125.2, 119.1, 51.1, 22.7, 10.9. Example 1.4

The operation method is the same as in Example 1, and 1-methyl-4,5-dibromo-2H- g (12.45 mmol) 1-cyclopropylmethyl-4,5-dibromo-2H-1,2,3-triazole. There was obtained 2.71 g of 1-cyclopropylmethyl-4-bromo-5-chloro-2H-1,2,3-triazole oil in a yield of 92%. NMR (CDC1 ₃ , 400 MHz): δ 4.22 (d, J = 7.2 Hz, 2H), 1.40-1.32 (m, IH), 0.67 (m, 2H), 0.53 (m, 2H); ¹³ C NMR (CDC1 ₃ , 400 MHz): δ 124.9, 119.2, 54.3, 10.7, 4.3.

Example 1.5

B

The procedure was the same as in Example 1. Substituting 1-methyl-4,5-dibromo-2H-1,2,3-triazole to 3.67 g (12.45 mmol) of 1-cyclobutylmethyl-4,5-di Bromo-2H-1,2,3-triazole. 2.84 g of 1-cyclobutylmethyl-4-bromo-5-chloro-2H-1,2,3-triazole oil was obtained in a yield of 91%. _{NMR (CDC1 3, 400 MHz)} : δ 4.36 (d, / = 7.2 Hz, 2H), 2.93-2.85 (m, IH), 2.12-2.06 (m, 2H), 1.96-1.82 (m, 4H); 13 C NMR (CDC1 ₃ , 400 MHz): δ 124.0, 117.9, 53.0, 33.7, 24.6, 16.9.

Example 1.6

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 3.67 g (12.45 mmol) of 1-cyclopentyl-4,5-di. Bromo-2H-1,2,3-triazole. 2.87 g of 1-cyclopentyl-4-bromo-5-chloro-2H-1,2,3-triazole oil was obtained in a yield of 92%. NMR (CDC1 ₃ , 400 MHz): δ 4.86-4.80 (m, IH), 2.21-2.16 (m, 4H), 1.99-1.95 (m, 2H), 1.79-1.74 (m, 2H); ¹³ C NMR ( CDC1 ₃ , 400 MHz): δ 124.8, 119.3, 61.3, 32.3, 24.4.

Example 1.7

Β

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 3.87. g (12.45 mmol) 1-(tetrahydrofuran-3-methyl)-4,5-dibromo-2H-1,2,3-triazole, a saturated aqueous solution of ammonium chloride was replaced with a hydrochloric acid solution. 1-(tetrahydrofuran-3-methyl)-4-bromo-5-chloro-2H-1,2,3-triazole oil 3.05 g, yield 92% _3⁄4 NMR (CDC1 ₃ , 400 MHz): δ 4.33 (d, J = 7.6 Hz, 2H), 3.66 (dd, / = 4.8, 9.2 Hz, IH), 2.94-2.87 (m, IH), 2.12-2.03 (m, IH), 1.76-1.68 (m , IH); ¹³ C NMR (CDC1 ₃ , 400 MHz): δ 125.4, 119.3, 70.6, 67.5, 51.7, 39.0, 29.5. Example 1.8

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 3.87 g (12.45 mmol) of 1-(4-tetrahydropyran). 4,5-Dibromo-2H-1,2,3-triazole. 1-(4-Tetrahydropyran)-4-bromo-5-chloro-2H-1,2,3-triazole solid 3.15 g was obtained in a yield of 95%. ^NMR (CDC1 ₃ , 400 MHz): δ 4.60-4.53 (m, IH), 4.15 (dt, / = 2.0, 10.0 Hz, 2H), 3.56 (dt, / = 2.0, 12.0 Hz, 2H), 2.36 ( Dq, J = 4.4, 12.0 Hz, 2H), 2.02 (dd, /= 2.0, 12.8 Hz, 2H); ¹³ C NMR (CDC1 ₃ , 400 MHz): δ 124.5, 119.5, 66.6, 57.0, 31.8. Example 1.9

^Br N, , .N ^c - ^l

NN was operated as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 3.32 g (12.45 mmol) 1-allyl-4,5- Dibromo-2H-1,2,3-triazole. There was obtained 2.49 g of 1-allyl-4-bromo-5-chloro-2H-1,2,3-triazole oil in a yield of 90%. NMR (CDC1 ₃ , 400 MHz): δ 6.00-5.90 (m, IH), 5.36 (dd, /=0.4, 10.0 Hz, IH), 5.25 (dd, J = 0.4, 17.2 Hz, IH), 4.97 (dd , / = 1.6, 6.0 Hz, 2H); ¹³ C NMR (CDC1 ₃ , 400 MHz): δ 129.5, 125.5, 120.5, 119.4, 51.9. Example 1.10

The procedure was the same as in Example 1. Substituting 1-methyl-4,5-dibromo-2H-1,2,3-triazole to 4.12 g (12.45 mmol) 1-phenylethyl-4,5-di Bromo-2H-1,2,3-triazole. There was obtained 1.10 g of 1-phenylethyl-4-bromo-5-chloro-2H-1,2,3-triazole oil in a yield of 87%. ^ NMR (CDC1 ₃ , 400 MHz) : δ 7.32-7.24 (m, 3Η), 7.13 (d, / = 7.2 Hz, 2H), 4.56 (t, / = 7.6 Hz, 2H), 3.21 (t, J = 1.6 Hz, 2H); ¹³ C NMR (CDC1 ₃ , 400 MHz) : δ 136.1 , 128.9, 128.7, 127.4, 125.5, 119.1, 50.7, 35.8 o

Example 1.11

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 4.17 g (12.45 mmol) 1-p-fluorobenzyl-4,5. -Dibromo-2H-1,2,3-triazole. A solid of 1-p-fluorobenzyl-4-bromo-5-chloro-2H-1,2,3-triazole was obtained in an amount of 3.18 g, yield 88%. NMR (CDC1 ₃ , 400 MHz) : δ 7.33-7.26 (m, 2H), 7.06 (dd, / = 8.4, 8.8 Hz, 2H), 5.50 (s, 2H); ¹³ C NMR (CDC1 ₃ , 400 MHz) : δ 163.0 (d, J = 248.0 Hz), 130.0 (d, J = 9.0 Hz), 128.9 (d, / = 3.0 Hz), 125.3, 119.7, 116.2 (d, / = 21.0 Hz), 52.5.

Example 1.12

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 4.17 g (12.45 mmol) 1-m-fluorobenzyl-4,5. -Dibromo-2H-1,2,3-triazole. Get 1-m-fluorobenzoate The base 4-bromo-5-chloro-2H-1,2,3-triazole solid was 2.98 g, and the yield was 83%. NMR (CDC1 ₃ , 400 MHz): δ 7.37-7.32 (m, 1H), 7.08 (d, /= 0.8 Hz, 1H), 7.06-7.03 (m, 1H), 6.99 (d, /=8.6 Hz, 1H ), 5.52 (s, 2H); ¹³ C NMR (CDC1 ₃ , 400 MHz): δ 163.0 (d, J = 247.0 Hz), 135.3 (d, J = 8.0 Hz), 130.9 (d, J = 8.0 Hz) , 125.5, 123.5 (d, J=3.0 Hz), 119.7, 116.1 (d, /=20.0 Hz), 115.0 (d, / = 22.0 Hz), 52.5 (d, J = 1.0 Hz). Example 1.13

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 4.38 g (12.45 mmol) of 1-p-chlorobenzyl-4,5. -Dibromo-2H-1,2,3-triazole. A solid of 3.25 g of 1-p-chlorobenzyl-4-bromo-5-chloro-2H-1,2,3-triazole was obtained in a yield of 85%. NMR (CDC1 ₃ , 400 MHz): 57.35 (ABq, J = 8.0 Hz, 2H), 7.25 (ABq, J = 8.0 Hz, 2H), 5.50 (s, 2H); ¹³ C NMR (CDC1 ₃ , 400 MHz) : δ 135.1, 131.5, 129.4, 129.3, 125.4, 119.7, 52.5.

Example 1.14

The procedure was the same as in Example 1. Substituting 1-methyl-4,5-dibromo-2Η-1,2,3-triazole to 4.38 g (12.45 mmol) 1-m-chlorobenzyl-4,5 -Dibromo-2H-1,2,3-triazole. 1-7% of m-chlorobenzyl-4-bromo-5-chloro-2H-1,2,3-triazole solid was obtained in a yield of 83%. _3⁄4 NMR (CD ₃ COCD ₃ , 400 MHz): 57.4-7.41 (m, 3H), 7.31 (d, /=6.8Hz, 1H), 5.74 (s, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 137.4, 135.1, 131.6, 129.6, 128.8, 127.4, 125.8, 119.7, 52.9.

Example 1.15 Br, Br ^{Br cl}

The procedure was the same as in Example 1. Substituting 1-methyl-4,5-dibromo-2H-1,2,3-triazole to 4.93 g (12.45 mmol) 1-p-bromobenzyl-4,5 -Dibromo-2H-1,2,3-triazole. There was obtained 3.90 g of 1-p-bromobenzyl-4-bromo-5-chloro-2H-1,2,3-triazole solid in a yield of 89%. _3⁄4 NMR (CD ₃ COCD ₃ , 400 MHz): δ 7.60 (ABq, / = 8.4 Hz, 2H), 7.33 (ABq, J = 8.4 Hz, 2H), 5.71 (s, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 134.4, 132.9, 131.1, 130.9, 125.7, 119.7, 53.0.

Example 1.16

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 4.90 g (12.45 mmol) of 1-p-trifluoromethoxybenzyl. -4,5-Dibromo-2H-1,2,3-triazole. There was obtained 3.53 g of 1-trifluoromethoxybenzyl-4-bromo-5-chloro-2H-1,2,3-triazole solid in a yield of 83%. _3⁄4 NMR (CDC1 ₃ , 500 MHz): δ 7.35 (ABq, /= 8.5 Hz, 2H), 7.22 (ABq, / = 8.5 Hz _: 2H), 5.53 (s, 2H); ¹³ C NMR (CDC1 ₃ , 500 MHz): δ 149.6 (d, /= 2.0 Hz), 131.7, 129.7, 125.5, 121.5 (d, J = 1.0 Hz), 120.3 (q, J = 256.0 Hz), 119.7, 112.6, 52.3.

Example 1.17

The procedure was the same as in Example 1. Substituting 1-methyl-4,5-dibromo-2H-1,2,3-triazole to 3.95 g (12.45 mmol) 1-benzyl-4,5-dibromo -2H-1,2,3-triazole. There was obtained 2.88 g of 1-benzyl-4-bromo-5-chloro-2H-1,2,3-triazole oil in a yield of 85%. NMR (CDC1 ₃ , 500 MHz): δ 7.40-7.35 (m, 3H), 7.31-7.29 (m, 2H), 5.53 (s, 2H); ¹³ C NMR (CDC1 ₃ , 500 MHz): δ 133.1, 129.1 , 129.0, 128.0, 125.4, 119.6, 53.3.

Example 1.18

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 4.80 g (12.45 mmol) 1-p-trifluoromethylbenzyl- 4,5-Dibromo-2H-1,2,3-triazole. 1-1.8% trifluoromethylbenzyl-4-bromo-5-chloro-2H-1,2,3-triazole solid was obtained in a yield of 75%. _3⁄4 NMR (CDC1 ₃ , 500 MHz): δ 7.64 (ABq, /= 8.0 Hz, 2H), 7.41 (ABq, / = 8.0 Hz _: 2H), 5.59 (s, 2H); ¹³ C NMR (CDC1 ₃ , 500 MHz): δ 136.9 (d, J = 1.3 Hz), 131.3 (q, / = 32.6 Hz), 128.3, 126.2 (q, / = 3.9 Hz), 125.6, 123.7 (q, / = 270.6 Hz), 119.8, 52.5.

Example 1.19

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 4.32 g (12.45 mmol) 1-p-methoxybenzyl-4 , 5-dibromo-2H-1,2,3-triazole. There was obtained 3.37 g of 1-p-methoxybenzyl-4-bromo-5-chloro-2H-1,2,3-triazole solid in a yield of 90%. NMR (CDC1 ₃ , 400 MHz): δ 7.31 (ABq, J = 8.8 Hz, 2H), 6.89 (ABq, J = 8.8 Hz, 2H), 5.41 (s, 2H), 3.80 (s, 3H); ¹³ C NMR (CDC1 ₃ , 400 MHz): δ 160.1, 137.3, 130.0, 125.9, 121.1, 114.3, 59.8, 55.

Example 1.20

Br Br

The procedure was the same as in Example 1, replacing 1-methyl-4,5-dibromo-2H-1,2,3-triazole with 4.30 g (12.45 mmol) 1-p-methylbenzyl-4. 5-Dibromo-2H-1,2,3-triazole. 1-0.3% of p-methoxybenzyl-4-bromo-5-chloro-2H-1,2,3-triazole solid was obtained in a yield of 88%. NMR (CDC1 ₃ , 400 MHz): δ 7.20 (ABq, J = 8.0 Hz, 2H), 7.16 (ABq, J = 8.0 Hz, 2H), 5.48 (s, 2H), 2.34 (s, 3H); ¹³ C NMR (CDC1 ₃ , 400 MHz): δ 139.0, 130.1, 129.8, 128.0, 125.3, 119.6, 53.1, 21.2.

Example 1.21

r

The procedure was the same as in Example 1, replacing chlorine with 1.66 g (12.45 mmol) of N-chlorosuccinimide. There was obtained 1.67 g of 1-methyl-4-bromo-5-chloro-2H-1,2,3-triazole solid in a yield of 68%. _3⁄4 NMR (CDC1 ₃ , 400 MHz): δ 4.15 (s, 3H); ¹³ C NMR (CDC1 ₃ , 400 MHz): δ 137.0, 120.8, 43.1 o

Example 2 Preparation of 1-substituted 5-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative

Example 2.1

^Br l=\

N, zN ^c , ^l HOOC CI

N, - , N - NN 1.96 g (10 mmol) of 1-methyl-4-bromo-5-chloro-1,2,3-triazole was dissolved in 20 ml of tetrahydrofuran and cooled to -20~-10 °C. 9.0 ml (11.71 mmol) of a 2.0 M isopropylmagnesium chloride lithium chloride complex tetrahydrofuran solution was slowly added dropwise over 30 minutes. After the addition is complete, continue stirring for 30 to 60 minutes. Slowly pass carbon dioxide for about 1 minute until the reaction solution does not heat up. Add 30 ml of reaction solution Mole / liter of hydrochloric acid solution, extracted with 60 ml of ethyl acetate, the extract is back-extracted with 20 ml of 0.5 mol / liter of potassium carbonate solution, and then adjusted to pH = 3 with hydrochloric acid, extracted with 80 ml of ethyl acetate, the extract is anhydrous sodium sulfate Dry, concentrate to dryness under reduced pressure, and add residual solid to 20 ml of methyl tert-butyl ether / hexane.

(1/5), heated to reflux for 1 hour, cooled to 0-10 ° C, stirring was continued for 1 hour, filtered, and dried at <40 ° C under vacuum. 1-methyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid was obtained as a white solid (yield: 85%). NMR (CD ₃ COCD ₃ , 400 MHz): δ 4.11 (s, 3H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 161.5, 135.8, 130.8, 35.4.

Example 2.2

Br^ ^ ^ 1 HOOC^ ^ ^CI

N, , .N -^/ " N, , N ^/

N

The procedure was the same as in Example 1, replacing 2-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.10 g (10 mmol) 1-ethyl-4-chloro-5. -Bromo-2H-1,2,3-triazole. 1.55 g of 1-ethyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid solid was obtained in a yield of 88%. ^ NMR CDsCOCDs OO MHz): δ 4.51 (q, / = 7.2 Hz, 2H), 1.54 (t, / = 7.2 Hz, 3H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.9, 135.5, 130.1, 44.6, 14.6.

Example 2.3

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.24 g (10 mmol) 1-n-propyl-4-chloro- 5-bromo-2H-1,2,3-triazole. 1-60 mg of 1-n-propyl-5-chloro-2H- 1,2,3-triazole-4-carboxylic acid was obtained in a yield of 85%. NMR (CD ₃ COCD ₃ , 400 MHz): δ 4.44 (t, J = 7.2 Hz, 2H), 2.02-1.93 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.9, 135.4, 130.5, 50.7, 33.2, 11.1.

Example 2.4

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.51 g (10 mmol) of 1-cyclopentyl-4-chloro- 5-bromo-2H-1, 2,3-triazole. 1.90 g of 1-cyclopentyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid solid was obtained in a yield of 88%. ^ NMR (CD ₃ COCD ₃ , 400 MHz) : δ 5.09-5.02 (m, IH), 2.31-2.24 (m, 2H), 2.21, 2.13 (m, 2H), 1.99-1.93 (m, 2H), 1.85 -1.77 (m, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz) : δ 161.0, 135.6, 130.2, 61.1, 33.1, 25.1.

Example 2.5

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2Η-1,2,3-triazole with 2.67 g (10 mmol) of 1-(tetrahydrofuran-3-methyl). 4-chloro-5-bromo-2H-1,2,3-triazole. 2.13 g of 1-(tetrahydrofuran-3-methyl)-5-chloro-2H-1,2,3-triazole-4-carboxylic acid solid was obtained in a yield of 92%. _3⁄4 NMR (CD ₃ COCD ₃ , 400 MHz) : δ 4.49 (m, 2H), 3.92-3.86 (m, IH), 3.78 (dd, J = 6.8, 8.8 Hz, IH), 3.72 (q, J = 8.0 Hz, IH), 3.64 (dd, J = 5.2, 8.8 Hz, IH), 2.97-2.92 (m, IH), 2.12-2.05 (m, IH), 1.81-1.73 (m, IH) ; ¹³ C NMR ( CD ₃ COCD ₃ , 400 MHz) : δ 160.8, 135.4, 130.8, 71.0, 67.8, 51.4, 39.8, 30.2. Example 2.6

The procedure was the same as in Example 1. Substituting 1-methyl-4-chloro-5-bromo-2Η-1,2,3-triazole with 2.67 g (10 mmol) of 1-(4-tetrahydropyranyl) ) -4-Chloro-5-bromo-2H-1,2,3-triazole. There was obtained 1.78 g of 1-(4-tetrahydropyranyl)-5-chloro-2H-1,2,3-triazole-4-carboxylic acid as a solid, yield 77%. NMR (CD ₃ COCD ₃ , 400 MHz) : δ 4.88-4.80 (m, IH), 4.09 (dd, J = 4.2, 10.4 Hz, 2H), 3.63 (dt, J = 2.0, 12.0 Hz, 2H), 2.26 (dq, J = 4.4, 12.8 Hz, 2H), 2.11 (dd, J = 2.0, 12.8 Hz, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz) : δ 160.9, 135.5, 129.9, 66.9, 56.7 , 32.9. Example 2.7

B

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.36 g (10 mmol) of 1-cyclopropylmethyl-4- Chloro-5-bromo-2H-1,2,3-triazole. A solid 1.80 g of 1-cyclopropylmethyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 90%. ^NMR (CD ₃ COCD ₃ , 400 MHz): δ 4.35 (d, /= 7.6 Hz, 2H), 1.42-1.36 (m, 1H), 0.66-0.62 (m, 2H), 0.53 (m, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.9, 135.5, 130.1, 53.7, 11.3, 4.4. Example 2.8

Br, , CI HOO

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.50 mmol) 1-cyclobutylmethyl-4-chloro-5-bromo -2H-1,2,3-triazole. A solid 1.96 g of 1-cyclobutylmethyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 92%. ^NMR (CD ₃ COCD ₃ , 400 MHz): δ 4.49 (d, J = 7.2 Hz, 2H), 2.99-2.92 (m, 1H), 2.12-2.06 (m, 2H), 1.94-1.90 (m, 4H) ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.9, 135.3, 130.4, 53.7, 35.7, 26.3, 18.6. Example 2.9

^Br HOOC CI

N,, .N ^c - ^l N, , .N- NN were operated in the same manner as in Example 1, and 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole was replaced with 2.22. g (10 mmol) 1-allyl-4-chloro-5-bromo-2H-1,2,3-triazole. The solid was 1-allyl-5-chloro-2H- 1,2,3-triazole-4-carboxylic acid 1.44 g, yield 77%. NMR (CD ₃ COCD ₃ , 400 MHz): δ 6.14-6.05 (m, 1H), 5.34 (dd, J=0.S, 10.4 Hz, 1H), 5.19 (dd, / = 0.8, 17.6 Hz, 1H), 5.13 (dd, / = 1.6, 4.0 Hz, 2H); "C NMR (CD 3 COCD 3, 400 MHz): δ 160.8, 135.6, 131.6, 130.8, 119.6, 51.4.

Example 2.10

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.87 g (10 mmol) of 1-phenylethyl-4-chloro- 5-bromo-2H-1,2,3-triazole. There was obtained 1.19 g of 1-phenylethyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid as a solid, yield 87%. NMR (CD ₃ COCD ₃ , 400 MHz): δ 7.30-7.20 (m, 5H), 4.70 (t, J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.8, 138.0, 135.2, 130.9, 129.7, 129.5, 127.8, 50.4, 36.0.

Example 2.11

^Br HOOC CI

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.90 g (10 mmol) 1-p-fluorobenzyl-4- Chloro-5-bromo-2H-1,2,3-triazole. The solid of 1-p-fluorobenzyl-5-chloro-2H- 1,2,3-triazole-4-carboxylic acid was obtained in a yield of 81%. _3⁄4 NMR (CD ₃ COCD ₃ , 400 MHz): δ 7.36 (dd, /= 5.6, 8.4 Hz, 2H), 7.05 (dd, /= 8.4, 8.8 Hz, 2H), 5.68 (s, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 161.9 (d, / = 244.0 Hz), 160.5, 135.0, 130.3 (d, / = 3.0 Hz), 130.1 (d, / = 8.0 Hz), 129.4, 115.7 ( d, /= 22.0 Hz) 50.7.

Example 2.12 ^Br HOOC CI

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.90 g (10 mmol) of 1-m-fluorobenzyl-4- Chloro-5-bromo-2H-1,2,3-triazole. There was obtained 1.00 g of 1-m-fluorobenzyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid as a solid, yield 78%. NMR (CD ₃ COCD ₃ 400 MHz): δ 6.91 (dd, /= 5.6, 8.4 Hz, 2H), 6.78-6.74 (m, 2H), 5.23 (s, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 163.8 (d, / = 244.0 Hz), 160.7, 137.8 (d, J = 7.0 Hz), 135.9, 131.9 (d, /= 8.0 Hz), 130.9, 124.6 (d, /= 3.0 Hz) , 116.2 (d, /= 21.0 Hz), 115.6 (d, /= 23.0 Hz), 52.0 (d, /= 1.0 Hz).

Example 2.13

HOOC CI

^Br

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 2.72 g (10 mmol) 1-benzyl-4-chloro-5. -Bromo-2H-1,2,3-triazole. There was obtained 1.09 g of 1-benzyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid as a solid, yield 88%. ^NMR (CD ₃ COCD ₃ , 400 MHz): δ 7.44-7.35 (m, 5 Η), 5.73 (s, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.8, 135.8, 135.2, 130.7 , 129.8, 129.4, 128.7, 52.7. Example 2.14

Br. , CI HOOC CI

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 3.51 g (10 mmol) 1-p-bromobenzyl-4- Chloro-5-bromo-2H-1,2,3-triazole. 1-tert-bromobenzyl -5-Chloro-2H-1,2,3-triazole-4-carboxylic acid solid 2.69 g, yield 85%. ^ NMR (CD ₃ COCD _3: 400 MHz): δ 7.61 (ABq, / = 8.4 Hz, 2H), 7.35 (ABq, J = 8.4 Hz, 2H), 5.74 (s _: 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.8, 135.9, 134.6, 132.9, 130.9 _: 130.8, 123.0, 52.0.

Example 2.15

The same procedure as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 3.02 mmol) 1-p-methoxybenzyl-4-chloro -5-Bromo-2H-1,2,3-triazole. A solid of 1-p-methoxybenzyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid 2.55 g was obtained in a yield of 95%. _3⁄4 NMR (CD ₃ COCD ₃ , 400 MHz) δ 7.34 (ABq, / = 8.8 Hz, 2H), 6.95 (ABq, / = 8.8 Hz, 2H), 5.63 (s, 2H), 3.79 (s, 3H). ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz) δ 160.9, 160.8, 135.8, 130.4, 127.0, 115.1, 55.7, 52.3.

Example 2.16

Β HOOC CI

The procedure was the same as in Example 1. Substituting 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole to 2.86 g (10 mmol) 1-p-tolylmethyl-4-chloro -5-Bromo-2H-1,2,3-triazole. There was obtained 2.28 g of 1-p-tolylmethyl-5-chloro-2H- 1,2,3-triazole-4-carboxylic acid as a solid, yield 88%. NMR (CD ₃ COCD ₃ , 400 MHz): δ 7.26 (ABq, /= 8.0 Hz, 2H), 7.21 (ABq, /= 8.0 Hz, 2H), 5.66 (s, 2H), 2.31 (s, 3H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.8, 139.2, 135.8, 132.2, 130.6, 130.4, 128.8, 52.5, 21.1 ο

Example 2.17 HOOC CI

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 3.56 g (10 mmol) of 1-p-trifluoromethoxybenzene. Base-4-chloro-5-bromo-2H-1,2,3-triazole. There was obtained 1.27 g of 1-p-trifluoromethoxybenzyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid as a solid, yield 80%. _3⁄4 NMR (CD ₃ COCD ₃ , 400 MHz): δ 7.53 (ABq, J = 8.4 Hz, 2H), 7.39 (ABq, J = 8.4 Hz, 2H), 5.80 (s, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.7, 149.9 (d, / = 0.8 Hz), 135.8, 134.5, 131.6 ( , J = 10.0 Hz), 130.8, 122.4, 121.4 (q, J = 255.0 Hz), 54.6.

Example 2.18

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 3.07 g (10 mmol) 1-p-chlorobenzyl-4- Chloro-5-bromo-2H-1,2,3-triazole. There was obtained 2.39 g of 1-p-chlorobenzyl-5-chloro-2H- 1,2,3-triazole-4-carboxylic acid as a solid, yield 88%. NMR (CD ₃ COCD ₃ , 400 MHz): δ 7.53 (ABq, /= 8.4 Hz, 2H), 7.39 (ABq, /= 8.4 Hz, 2H), 5.80 (s, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.7, 149.9 (d, / = 0.8 Hz), 135.8, 134.5, 131.6 (q, / = 10.0 Hz), 130.8, 122.4, 121.4 (q, / = 255.0 Hz) _: 54.6.

Example 2.19

The procedure was the same as in Example 1, replacing 1-methyl-4-chloro-5-bromo-2H-1,2,3-triazole with 3.07 g (10 mmol) 1-m-chlorobenzyl-4- Chloro-5-bromo-2H-1,2,3-triazole. 2.31 g of 1-m-chlorobenzyl-5-chloro-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 85%. NMR (CD ₃ COCD ₃ , 400 MHz): δ 7.53 (ABq, /= 8.4 Hz, 2H), 7.39 (ABq, /= 8.4 Hz, 2H), 5.80 (s, 2H); ¹³ C NMR (CD ₃ COCD ₃ , 400 MHz): δ 160.7, 149.9 (d, / = 0.8 Hz), 135.8, 134.5, 131.6 (q, / = 10.0 Hz), 130.8, 122.4, 121.4 (q, / = 255.0 Hz) _: 54.6. The above is only the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention; the invention is modified or equivalently substituted without departing from the spirit and scope of the invention. Within the scope of protection.

Claims

Claim

A 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative characterized by having the structure represented by the following formula I:

CI COO H

)=

^Κ Ν

Formula I

Wherein R represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group or a heterocyclic fluorenyl group.

A method for producing a 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative according to claim 1, which comprises the steps of:

1) Dissolve the compound of the following formula II in the first organic solvent, cool to -78~0 ° C, add the first Grignard reagent, stir for 0.5 to 2 hours; pass chlorine or add chlorinating agent, stir 5~ After heating to room temperature for 30 minutes, it is quenched with a saturated aqueous solution of ammonium chloride or hydrochloric acid, and then extracted with a second organic solvent; the obtained first extract is dried and concentrated to dryness under reduced pressure to give a first concentrate. Recrystallization to obtain 4-bromo-5-chloro-1H-1,2,3-triazole of the following formula III;

^{Cl Br}

Ν ^κ Ν Formula II Formula III wherein R represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group or a heterocyclic fluorenyl group;

4) Step 3) The obtained second extract is dried and concentrated to dryness under reduced pressure to obtain a second concentrated solution. The 1-resubstituted 5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative is obtained by a second recrystallization.

The preparation method according to claim 2, wherein, in step 1), the mass to volume ratio of the compound of the formula II to the first organic solvent is 1: 2 to 20; The molar ratio of the compound to the first Grignard reagent is 1: 0.8 to 1.5; the molar ratio of the compound of the formula II to chlorine or chlorinating agent is 1:1 to 10.

The preparation method according to claim 3, wherein in the step 1), the first organic solvent is diethyl ether, tetrahydrofuran, 1,4-dioxane or methyltetrahydrofuran; The reagent is isopropylmagnesium chloride or isopropylmagnesium chloride-lithium chloride complex; the chlorinating agent includes N-chlorosuccinimide and 1,3-dichloro-5,5-dimethyl sea because.

The preparation method according to claim 4, wherein in step 2), the

The mass-to-volume ratio of 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole to the third organic solvent is 1 :

2-20; the molar ratio of the 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole to the second Grignard reagent is 1: 0.8-1.5; The molar ratio of 4-bromo-5-chloro-1H-1,2,3-triazole to carbon dioxide is 1:1 to 10.

The preparation method according to claim 5, wherein in the step 2), the third organic solvent is diethyl ether, tetrahydrofuran, 1,4-dioxane or methyltetrahydrofuran; The reagent is an isopropylmagnesium chloride-lithium chloride complex.

The preparation method according to claim 6, wherein in the step 1) or the step 3), the second organic solvent or the fourth organic solvent is one or two of a fatty acid ester or an ether. a mixture of any of the above, wherein the fatty acid esters include ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, Amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ethers including diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl Ether.

The preparation method according to claim 7, wherein in the step 1), the first recrystallization comprises the steps of: adding the first concentrate to the first solvent at a mass to volume ratio of 1: 1 to 100; The mixture is stirred at -20 to 50 ° C for 0.5 to 24 hours, filtered, and vacuum dried to obtain the 1-substituted-4-bromo-5-chloro-1H-1,2,3-triazole.

The preparation method according to claim 7, wherein in step 4), the The second recrystallization comprises the following steps: adding the second concentrate to the second solvent at a mass to volume ratio of 1:1 to 100, stirring at -20 to 50 ° C for 0.5 to 24 hours, filtering, and drying under vacuum to obtain the 1-substituted-5-chloro-2H-1,2,3-triazole-4-carboxylic acid derivative.

The preparation method according to claim 8 or 9, wherein the first solvent or the second solvent is one of water, an alcohol, a fatty acid ester, a ketone, an ether, and a hydrocarbon or Mixing of two or more of any ratio, wherein the alcohol includes methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, and the fatty acid esters include ethyl formate, propyl formate, butyl formate, and acetic acid Ester, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, propionic acid Butyl ester and amyl propionate, ketones including acetone, 2-butanone, cyclopentanone and cyclohexanone, ethers including diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4 - Dioxane and petroleum ether, hydrocarbons include n-hexyl, cyclohexanyl, methylcyclohexanide and n-glyoxime.