Preparation method of 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs

Abstract

The invention discloses a method for preparing 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs. The invention adopts a "one-pot method", uses cyanoacetic acid or its ester compound, diphenyl phosphoazide, orthoformate compounds, 2-aminopyridine compounds to react in an organic solvent, adds water for crystallization after the reaction is completed, and filters to obtain high-purity 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs. The synthesis process is simple to operate, greatly reduces safety risks and production costs, generates less three wastes, and is environmentally friendly.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a new synthesis process of 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs. Background Art

[0002] 3-Amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs are important intermediates containing tetrazole structures, which are widely used in the fields of luminescent materials and drugs and have broad market prospects. However, the synthesis of such compounds has always been a focal issue in the chemical industry, among which the construction of the tetrazole ring is particularly important. Common preparation processes require the use of sodium azide, trimethylsilyl azide, tributyltin azide and other azide reagents. The use of sodium azide processes has a large production safety risk and is prone to explosions. Many casualties have been reported. Other types of azide reagents not only have safety risks, but are also expensive, which limits their large-scale application in industrial production. Summary of the invention

[0003] In view of the above problems, the present application provides a method for preparing 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs by a "one-pot method".

[0004] The structure of 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs described in the present application is:

[0005]

[0006] The method for preparing 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs disclosed in the present application adopts a "one-pot method", using cyanoacetic acid or its ester compound, diphenyl phosphoazide, orthoformate compounds, and 2-aminopyridine compounds to react in an organic solvent, adding water to crystallize and filtering after the reaction is completed to obtain high-purity 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs. The synthetic process is simple to operate, greatly reduces safety risks and production costs, generates less three wastes, and is environmentally friendly.

[0007] This application is implemented through the following technical solutions:

[0008] A method for preparing 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate and its analogs, the method comprising the following steps:

[0009] Step 1, dissolving cyanoacetic acid or its ester compound, orthoformate compound, and 2-aminopyridine compound in an organic acid, adding diphenylphosphoryl azide, and reacting at a reaction temperature to obtain a 3-amino-2-(1H-tetrazol-5-yl)-ethyl acrylate analog solution;

[0010] Step 2, cooling to room temperature, adding an appropriate amount of water to precipitate a solid, and obtaining the product 3-amino-2-(1H-tetrazol-5-yl)-acrylic acid ethyl ester analog.

[0011] Preferably, in step 1, cyanoacetic acid or its ester compound, orthoformate compound, and 2-aminopyridine compound are dissolved in an organic acid, the temperature is raised to the reaction temperature, and then diphenylphosphoryl azide is added.

[0012] Preferably, in step 1, the molar ratio of cyanoacetic acid or its ester compound, diphenyl phosphoryl azide, orthoformate compounds and 2-aminopyridine compounds is 1:0.8-5:0.8-5:0.8-3; further preferably, the molar ratio of cyanoacetic acid or its ester compound, diphenyl phosphoryl azide, orthoformate compounds and 2-aminopyridine compounds is 1:1-3:1-3:1-3; further preferably, the molar ratio of cyanoacetic acid or its ester compound, diphenyl phosphoryl azide, orthoformate compounds and 2-aminopyridine compounds is 1:1-2:1-2:1-2.

[0013] Preferably, the reaction temperature in step 1 is 60° C. to 120° C., and the reaction time is 2 to 24 hours.

[0014] Preferably, in step 1, the cyanoacetate compound is selected from any one of ethyl cyanoacetate, methyl cyanoacetate, propyl cyanoacetate or butyl cyanoacetate; the orthoformate compound is selected from any one of trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate or tributyl orthoformate; the 2-aminopyridine compound is selected from any one of 2-amino-3-methylpyridine, 2-amino-4-methylpyridine, 2-amino-5-methylpyridine or 2-amino-6-methylpyridine.

[0015] Preferably, in step 1, the organic acid is selected from one or a mixture of formic acid, acetic acid, propionic acid, and butyric acid; and the weight ratio of the organic solvent to cyanoacetic acid or its ester compound is 2 to 30:1.

[0016] Preferably, the amount of water added in step 2 is 1 to 3 times the volume of the organic acid in step 1.

[0017] Beneficial effects of this application:

[0018] The present application uses diphenyl phosphoazide to release azide ions under the joint action of 2-aminopyridine compounds and organic acids to complete the reaction. The reaction route is novel and avoids the use of dangerous reagents such as sodium azide. In addition, the present application is a "one-pot method" for preparing 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate analogs. The product does not require special treatment and only needs to be separated and purified by adding water. The purity can meet the requirements of chemical production. It greatly reduces the safety production risks and industrialization costs in the process of chemical production of tetrazole analogs, improves production efficiency, and reduces the discharge of three wastes, which is more environmentally friendly. DETAILED DESCRIPTION

[0019] The exemplary embodiments of the present invention will be described in more detail below. The following exemplary embodiments should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided to enable a more thorough understanding of the present invention and to enable the scope of the present invention to be fully communicated to those skilled in the art.

[0020] Example 1

[0021] Reaction equation:

[0022]

[0023] Reaction process:

[0024] Step 1: Add 150 mL of acetic acid, 17.0 g of ethyl cyanoacetate, 45.4 g of diphenylphosphoryl azide (DPPA), 24.6 g of triethyl orthoformate, and 16.2 g of 2-amino-3-methylpyridine to a 500 mL reaction bottle, and heat to 105-110° C. with stirring for 5 h.

[0025] Step 2: After cooling, 300 mL of purified water was added to precipitate a large amount of solid, which was filtered and dried to obtain 13.1 g of light green solid with a yield of 31.9%.

[0026] The characterization results are as follows:

[0027] HPLC purity: 98.906%; ESI-MS: 275.13 [M+1] + ,H-NMR(400MHz,d 6-DMSO): δ=14.3145(1H,s),11.4538(1H,d,J=12.67Hz),9.2367(1H,d,J=13.01Hz),8.2576(1H,d,J=5.63Hz),7.7769(1 H, d, J = 8.20Hz), 7.1236 (1H, dd, J = 5.63Hz, 8.08Hz), 4.3876 (2H, q, J = 8.20Hz), 2.4351 (3H, s), 1.3526 (3H, t, J = 8.00Hz).

[0028] Example 2

[0029] Reaction equation:

[0030]

[0031] Reaction process:

[0032] Step 1: add 120 mL of acetic acid, 13.5 g of ethyl cyanoacetate, 19.7 g of triethyl orthoformate, and 13.0 g of 2-amino-3-methylpyridine to a 500 mL reaction bottle, heat to 105-110° C. with stirring, add 37.1 g of diphenylphosphoryl azide (DPPA) dropwise, and continue the reaction for 5 h.

[0033] Step 2: After cooling, 280 mL of purified water was added to precipitate a large amount of solid, which was filtered and dried to obtain 21.8 g of light green solid with a yield of 66.1%.

[0034] The characterization results are as follows:

[0035] HPLC purity: 99.813%; ESI-MS: 275.16[M+1] + ,H-NMR(400MHz,d 6 -DMSO): δ = 14.3133 (1H, s), 11.4535 (1H, d, J = 12.12Hz), 9.2356 (1H, d, J = 13.06Hz), 8.2531 (1H, d, J = 5.44Hz), 7.7737 (1 H, d, J = 8.42Hz), 7.1241 (1H, dd, J = 5.60Hz, 8.28Hz), 4.3896 (2H, q, J = 8.41Hz), 2.4356 (3H, s), 1.3534 (3H, t, J = 8.52Hz).

[0036] Example 3

[0037] Reaction equation:

[0038]

[0039] Reaction process:

[0040] Step 1: Add 150 mL of acetic acid, 17.1 g of ethyl cyanoacetate, 93.5 g of diphenylphosphoryl azide (DPPA), 31.6 g of tripropyl orthoformate, and 24.5 g of 2-amino-4-methylpyridine to a 500 mL reaction bottle, and heat to 90-105° C. with stirring for 7 h.

[0041] Step 2: After cooling, 250 mL of purified water was added to precipitate a large amount of solid, which was filtered and dried to obtain 12.6 g of light green solid with a yield of 30.4%.

[0042] The characterization results are as follows:

[0043] HPLC purity: 98.935%; ESI-MS: 275.14 [M+1] + ,H-NMR(400MHz,d 6 -DMSO): δ = 14.3076 (1H, s), 11.5252 (1H, d, J = 12.10Hz), 9.1357 (1H, d, J = 13.10Hz), 8.2547 (1H, d, J = 5.43Hz), 7.4758(1H,d,J=8.12Hz), 7.3235(1H,s), 4.3751(2H,q,J=8.10Hz), 2.3362(3H,s), 1.3702(3H,t,J=8.02Hz).

[0044] Example 4

[0045] Reaction equation:

[0046]

[0047] Reaction process:

[0048] Step 1: Add 80 mL of acetic acid, 7.5 g of methyl cyanoacetate, 29.4 g of diphenylphosphoryl azide (DPPA), 12.9 g of triethyl orthoformate, and 9.1 g of 2-amino-5-methylpyridine to a 250 mL reaction bottle, and heat to 90-105° C. with stirring for 4 h.

[0049] Step 2: After cooling, 90 mL of purified water was added to precipitate a large amount of solid, which was filtered and dried to obtain 10.5 g of yellow-green solid with a yield of 57.7%.

[0050] The characterization results are as follows:

[0051] HPLC purity: 99.910%; ESI-MS: 261.24 [M+1] + ,H-NMR(400MHz,d6 -DMSO): δ = 14.3148 (1H, s), 11.4566 (1H, d, J = 12.67Hz), 9.2382 (1H, d, J = 12.86Hz), 8.3016 (1H,s),7.7608(1H,d,J=7.20Hz),7.0657(1H,d,J=6.62Hz),2.5106(3H,s),3.6758(3H,s).

[0052] Example 5

[0053] Reaction equation:

[0054]

[0055] Reaction process:

[0056] Step 1: Add 180 mL of propionic acid, 17.5 g of ethyl cyanoacetate, 22.6 g of diphenylphosphoryl azide (DPPA), 12.9 g of triethyl orthoformate, and 9.1 g of 2-amino-3-methylpyridine to a 500 mL reaction bottle, and heat to 90-105° C. with stirring for 4 h.

[0057] Step 2: After cooling, 180 mL of purified water was added to precipitate a large amount of solid, which was filtered and dried to obtain 10.1 g of yellow-green solid with a yield of 43.8%.

[0058] The characterization results are as follows:

[0059] HPLC purity: 99.933%; ESI-MS: 275.09[M+1] + ,H-NMR(400MHz,d 6 -DMSO): δ=14.3144(1H,s),11.4539(1H,d,J=12.64Hz),9.2370(1H,d,J=13.06Hz),8.2574(1H,d,J=5.62Hz),7.7770(1 H, d, J = 8.22Hz), 7.1234 (1H, dd, J = 5.60Hz, 8.12Hz), 4.3877 (2H, q, J = 8.22Hz), 2.4352 (3H, s), 1.3526 (3H, t, J = 8.00Hz).

[0060] Example 6

[0061] Reaction equation:

[0062]

[0063] Reaction process:

[0064] Step 1: Add 60 mL of propionic acid, 10.5 g of cyanoacetic acid, 70.1 g of diphenylphosphoryl azide (DPPA), 21.9 g of triethyl orthoformate, and 14.6 g of 2-amino-3-methylpyridine to a 250 mL reaction bottle, and heat to 80-105° C. with stirring for 3 h.

[0065] Step 2: After cooling, 120 mL of purified water was added to precipitate a large amount of solid, which was filtered and dried to obtain 7.5 g of brown solid with a yield of 24.7%.

[0066] The characterization results are as follows:

[0067] HPLC purity: 98.987%; ESI-MS: 247.67[M+1] + ,245.06[M-1] - ,H-NMR(400MHz,d 6 -DMSO): δ=14.3351(1H,s),11.4637(1H,d,J=11.88Hz),9.2856(1H,d,J=12.66Hz),8.2597(1 H, d, J = 5.78Hz), 7.7864 (1H, d, J = 8.42Hz), 7.1307 (1H, dd, J = 5.66Hz, 8.28Hz), 2.4206 (3H, s).

[0068] Example 7

[0069] Reaction equation:

[0070]

[0071] Reaction process:

[0072] Step 1: add 60 mL of propionic acid, 10.5 g of cyanoacetic acid, 21.9 g of triethyl orthoformate, and 14.8 g of 2-amino-3-methylpyridine to a 250 mL reaction bottle, heat to 80-105° C. with stirring, add 70.1 g of diphenylphosphoryl azide (DPPA) dropwise, and continue the reaction for 3 h.

[0073] Step 2: After cooling, 120 mL of purified water was added to precipitate a large amount of solid, which was filtered and dried to obtain 19.8 g of brown solid with a yield of 65.2%.

[0074] The characterization results are as follows:

[0075] HPLC purity: 98.996%; ESI-MS: 247.77[M+1] + ,245.12[M-1] - ,H-NMR(400MHz,d 6-DMSO):δ=14.3372(1H,s),11.4639(1H,d,J=11.56Hz),9.2843(1H,d,J=12.6Hz),8.2582(1H,d,J=5.65Hz),7.7852(1H,d,J=8.26Hz),7.1307(1H,dd,J=5.68Hz,8.30Hz),2.4210(3H,s)。

Claims

1. A method for preparing 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate analogs, It is characterized in that The method comprises the following steps: Step 1, dissolving cyanoacetic acid or its ester compound, orthoformate compound, and 2-aminopyridine compound in an organic acid, raising the temperature to the reaction temperature, and then adding diphenylphosphoryl azide to react to obtain a 3-amino-2-(1H-tetrazol-5-yl)-ethyl acrylate analog solution; Step 2, cooling to room temperature, adding an appropriate amount of water to precipitate a solid, and obtaining the product 3-amino-2-(1H-tetrazolyl-5-yl)-acrylic acid ethyl ester analog; Wherein, in step 1, the molar ratio of cyanoacetic acid or its ester compound, diphenylphosphoryl azide, orthoformate compound and 2-aminopyridine compound is 1:0.8~5:0.8~5:0.8~3; Step 1: The reaction temperature is 60°C to 120°C and the reaction time is 2 to 24 hours; Wherein, the cyanoacetate compound in step 1 is selected from any one of ethyl cyanoacetate, methyl cyanoacetate, propyl cyanoacetate or butyl cyanoacetate; the orthoformate compound is selected from any one of trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate or tributyl orthoformate; the 2-aminopyridine compound is selected from any one of 2-amino-3-methylpyridine, 2-amino-4-methylpyridine, 2-amino-5-methylpyridine or 2-amino-6-methylpyridine; The structure of the 3-amino-2-(1H-tetrazolyl-5-yl)-ethyl acrylate analog is: , , or .

2. The preparation method according to claim 1, It is characterized in that The molar ratio of cyanoacetic acid or its ester compound, diphenylphosphoryl azide, orthoformate compound and 2-aminopyridine compound is 1:1-3:1-3:1-3.

3. The preparation method according to claim 2, It is characterized in that The molar ratio of cyanoacetic acid or its ester compound, diphenylphosphoryl azide, orthoformate compound and 2-aminopyridine compound is 1:1-2:1-2:1-2.

4. The preparation method according to any one of claims 1 to 3, It is characterized in that In step 1, the organic acid is selected from one or a mixture of formic acid, acetic acid, propionic acid and butyric acid.

5. The preparation method according to any one of claims 1 to 3, It is characterized in that In step 1, the weight ratio of the organic acid to cyanoacetic acid or its ester compound is 2-30:

1.

6. The preparation method according to any one of claims 1 to 3, It is characterized in that The amount of water added in step 2 is 1 to 3 times the volume of the organic acid in step 1.

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