Electro-synthesis method of alpha-aminomethyl tetrazole

Abstract

The invention discloses an electro-synthesis method of alpha-aminomethyl tetrazole, which comprises the following steps: by taking a platinum sheet as a cathode, a carbon rod as an anode and tetrabutylammonium tetrafluoroborate as an electrolyte under the catalysis of constant current, coupling tertiary amine, isonitrile and azido trimethylsilane by a one-pot method to prepare an alpha-aminomethyl tetrazole derivative, and carrying out post-treatment on the obtained reaction mixed solution, and carrying out column chromatography separation to obtain a pure alpha-aminomethyl tetrazole product. The alpha-aminomethyl tetrazole can be obtained only through one-step reaction, the operation steps are few, a large number of oxidizing agents and additives are not used, the post-treatment process is simple, and the product is easy to separate.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a method for preparing alpha-aminomethyltetrazolyl. Background Art

[0002] α-Aminomethyltetrazolyl derivatives are a class of organic synthesis intermediates with various biological activities and are widely used in the fields of chemistry, materials and drug design. So far, the classic Ugi-azide reaction still provides strong support for the synthesis of α-aminomethyltetrazolyl derivatives. In this reaction, primary or secondary amines, aldehydes or ketones, isonitriles and azides are the four starting components. However, tertiary amines are still not suitable for this reaction due to their own structural limitations, because the key intermediate imino ion depends on the condensation reaction of primary or secondary amines with aldehydes or ketones. Therefore, it is extremely necessary to prepare α-aminomethyltetrazolyl derivatives from tertiary amines.

[0003] In addition, there are reports on the synthesis of α-aminomethyltetrazolyl derivatives through tertiary amines, but the substrates used in these synthesis methods are different, and the routes are different. When designing different synthesis strategies, they can be selected as needed. However, some of these routes often have problems such as long reaction time, the use of additives and external oxidants, and low yield. Finding green and efficient alternative methods is an important research content. Among them, electrochemical organic synthesis is an important method in the current green alternative technology. Summary of the invention

[0004] The object of the present invention is to provide a green and efficient method for preparing α-aminomethyltetrazolyl from tertiary amine, isonitrile and azidotrimethylsilane.

[0005] The technical solution for achieving the purpose of the present invention is:

[0006] In a first aspect, the present invention provides a method for preparing α-aminomethyltetrazolyl, comprising the steps of subjecting a tertiary amine, an isonitrile and azidotrimethylsilane to an electrochemical reaction in an electrolyte solution to synthesize a target product,

[0007] The general reaction formula is as follows:

[0008]

[0009] In the formula, R 1 Including but not limited to any group selected from methyl, tert-butyl, methoxy, phenyl, halogen, trifluoromethyl; R 2 Including but not limited to any group of alkyl, benzyl, aryl.

[0010] Furthermore, the electrolyte in the electrolyte solution is tetrabutylammonium tetrafluoroborate, and the solvent is a mixed solvent of acetonitrile and hexafluoroisopropanol in a volume ratio of 5 to 10:1, preferably 7:1.

[0011] Furthermore, the electrochemical reaction uses a carbon rod as an anode and a platinum sheet as a cathode, and the current is a constant current of 3 mA to 20 mA, preferably a constant current of 10 mA.

[0012] Furthermore, the electrochemical reaction is carried out at 0-40°C, preferably room temperature.

[0013] Furthermore, the electrochemical reaction time is not less than 2 hours.

[0014] Furthermore, the molar ratio of the electrolyte dosage to the tertiary amine dosage is 0.2-1 times, preferably 1 times.

[0015] Furthermore, the molar ratio of the amount of azidotrimethylsilane used is 1-3 times, preferably 1 time, of the amount of the tertiary amine used.

[0016] Furthermore, the molar ratio of the amount of the isonitrile to the amount of the tertiary amine is 0.5-1 times, preferably 0.5 times. Compared with the prior art, the present invention has the following significant advantages:

[0017] (1) The synthesis method of the present invention is simple and efficient, and α-aminomethyltetrazole can be obtained by a one-step reaction, with fewer operation steps, avoiding the use of a large amount of oxidants and additives, and the post-treatment process is simple. The product is easy to separate, which greatly simplifies the operation requirements;

[0018] (2) The reaction conditions of the present invention are easy to implement, and do not require harsh conditions such as low temperature, high temperature, light, pressure, strong acid and strong base, etc., thus avoiding special requirements such as biocatalysis and precious metal catalysis;

[0019] (3) The tertiary amine used in the present invention exhibits excellent reactivity under electrochemical conditions, allowing azidotrimethylsilane, tertiary amine, and isonitrile to be coupled to α-aminomethyltetrazole. In contrast, exogenous oxidants, iodine reagents, metal catalysts, etc. are difficult to achieve efficient and short-time conversion. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of ethyl 2-(5-((((4-(tert-butyl)phenyl)(methyl)amino)methyl)-1H-tetrazol-1-yl)acetate prepared in Example 2 of the present invention.

[0021] Figure 2 This is the carbon nuclear magnetic resonance spectrum of ethyl 2-(5-((((4-(tert-butyl)phenyl)(methyl)amino)methyl)-1H-tetrazol-1-yl)acetate prepared in Example 2 of the present invention.

[0022] Figure 3 It is a high-resolution mass spectrum of ethyl 2-(5-((((4-(tert-butyl)phenyl)(methyl)amino)methyl)-1H-tetrazol-1-yl)acetate prepared in Example 2 of the present invention.

[0023] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of N-((1-benzyl-1H-tetrazol-5-yl)methyl)-N-methylaniline prepared in Example 5 of the present invention.

[0024] Figure 5 This is the carbon nuclear magnetic resonance spectrum of N-((1-benzyl-1H-tetrazol-5-yl)methyl)-N-methylaniline prepared in Example 5 of the present invention.

[0025] Figure 6 This is a high-resolution mass spectrum of N-((1-benzyl-1H-tetrazol-5-yl)methyl)-N-methylaniline prepared in Example 5 of the present invention. DETAILED DESCRIPTION

[0026] The present application is further described below in conjunction with specific embodiments.

[0027] It should be noted that the terms such as "upper", "lower", "left", "right", "middle", etc. cited in this specification are only for the convenience of description and are not used to limit the scope of implementation. Changes or adjustments to their relative relationships should be regarded as the scope of implementation of this application without substantially changing the technical content.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application belongs; the term "and / or" used herein includes any and all combinations of one or more of the associated listed items.

[0029] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0030] As used herein, the term "about" is used to provide flexibility and imprecision associated with a given term, measurement or value. The degree of flexibility for a particular variable can be easily determined by one skilled in the art.

[0031] As used herein, the term "at least one of" is intended to be synonymous with "one or more of." For example, "at least one of A, B, and C" expressly includes only A, only B, only C, and combinations of each thereof.

[0032] Concentration, amount and other numerical data can be presented in range format herein.It should be understood that such range format is only used for convenience and simplicity, and should be flexibly interpreted as not only including the numerical value clearly described as range limit, but also including all single numerical values ​​or sub-ranges contained in the range, just as each numerical value and sub-range are clearly described.For example, the numerical range of about 1 to about 4.5 should be interpreted as not only including the limit value of 1 to about 4.5 clearly described, but also including single numerals (such as 2,3,4) and sub-ranges (such as 1 to 3,2 to 4, etc.).The same principle is applicable to the scope of only narrating a numerical value, such as "less than about 4.5", which should be interpreted as including all the above-mentioned values ​​and ranges.In addition, no matter how the breadth of the described range or feature is, this explanation should be applicable.

[0033] The method for preparing α-aminomethyltetrazole of the present invention comprises the following steps:

[0034] (1) In a dry three-necked flask, acetonitrile and hexafluoroisopropanol are used as a mixed solvent, tetrabutylammonium tetrafluoroborate is used as an electrolyte, a carbon rod is used as an anode, and a platinum sheet is used as a cathode under a constant current. (2) Tertiary amine, isonitrile, and trimethylsilyl azide are added to the three-necked flask and stirred and energized. (3) The reaction mixture is treated until the reaction is complete, and the resulting reaction mixture is separated by a chromatographic column to obtain pure α-aminomethyltetrazolyl.

[0035] Embodiment 1:

[0036] In a graphite rod anode ( 90mm) and a platinum cathode (10mm×10mm×0.2mm) were added to a dry three-necked flask (20mL) with a magnetic particle and tetrabutylammonium tetrafluoroborate (0.2mmol, 1 equivalent). Then acetonitrile (7mL), hexafluoroisopropanol (1mL), azidotrimethylsilane (2 equivalents), N,N-dimethylaniline (0.4mmol, 2 equivalents), and ethyl isocyanate (1 equivalent) were injected into the flask respectively through a syringe. The reaction mixture was stirred and electrolyzed at a constant current of 10mA for 2.5 hours (4.7F / mol) at room temperature. After the reaction was completed, the solvent was removed under reduced pressure. Flash column chromatography was performed on silica gel with a mixture of petroleum ether / ethyl acetate = 3:1 as the eluent to obtain the α-aminomethyltetrazolyl product with an isolated yield of 86%.

[0037] Ethyl 2-(5-((methyl(phenyl)amino)methyl)-1H-tetrazol-1-yl)acetate. 1H NMR (500MHz, CDCl3) δ7.18(t,J=7.6Hz,2H),6.80(t,J=7.3Hz,1H),6.73(d,J=8.4Hz,2H ),5.02(s,2H),4.71(s,2H),4.07(q,J=6.8Hz,2H),2.80(s,3H),1.13(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ165.4,153.5,148.8,129.5,119.9,114.6,62.6,48.6,47.8,39.9,13.9.

[0038] Embodiment 2:

[0039] According to the method of Example 1, 4-tert-butyl-N,N-dimethylaniline was used instead of N,N-dimethylaniline, and other conditions remained unchanged to obtain α-aminomethyltetrazolyl product with an isolated yield of 92%. NMR and high-resolution mass spectrometry characterization are shown in Figure 1 and Figure 2 .

[0040] Ethyl 2-(5-((((4-(tert-butyl)phenyl)(methyl)amino)methyl)-1H-tetrazol-1-yl)acetate. 1 H NMR(500MHz, CDCl3) δ7.31(d,J=8.8Hz,2H),6.80(d,J=8.8Hz,2H),5.15(s,2H),4. 78(s,2H),4.15(q,J=7.1Hz,2H),2.88(s,3H),1.31(s,9H),1.22(t,J=7.2Hz,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ165.4,153.5,146.5,142.6,126.1,114.4,62.3,48.5,47.9,40.0,33.7,31.2,13.8.HRMS(ESI):calcd for C 17 H 25 N5O2Na[M+Na] + :354.1906;Found:354.1908.

[0041] Embodiment 3:

[0042] According to the method of Example 1, 4-methyl-N,N-dimethylaniline was used instead of N,N-dimethylaniline, and other conditions remained unchanged to obtain α-aminomethyltetrazole product with an isolated yield of 90%.

[0043] Ethyl 2-(5-((methyl(p-tolyl)amino)methyl)-1H-tetrazol-1-yl)acetate. 1 H NMR(500MHz, CDCl3) δ7.04(d,J=8.5Hz,2H),6.71(d,J=8.5Hz,2H),5.09(s,2H),4. 70(s,2H),4.14(q,J=7.1Hz,2H),2.81(s,3H),2.24(s,3H),1.20(t,J=7.2Hz,3H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ165.4,153.5,146.7,129.9,129.5,115.1,62.4,48.6,48.1,40.3,20.2,13.8.

[0044] Embodiment 4:

[0045] According to the method of Example 1, tert-butyl isocyanide was used instead of ethyl isocyanoacetate, and other conditions remained unchanged to obtain α-aminomethyltetrazolyl product with an isolated yield of 87%.

[0046] N-((1-(tert-butyl)-1H-tetrazol-5-yl)methyl)-N-methylaniline. 1 HNMR (500MHz, CDCl3) δ7.19 (t, J = 8.0 Hz, 2H), 6.79–6.76 (m, 3H), 4.69 (s, 2H), 2.85 (s, 3H), 1.67 (s, 9H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ151.8,149.4,129.3,119.2,114.6,61.4,47.7,39.3,29.4.

[0047] Embodiment 5:

[0048] According to the method of Example 1, benzyl isocyanide was used instead of ethyl isocyanide, and other conditions remained unchanged to obtain α-aminomethyl tetrazole product with an isolated yield of 81%. NMR and high-resolution mass spectrometry characterization are shown in Figure 3 and Figure 4 .

[0049] N-((1-Benzyl-1H-tetrazol-5-yl)methyl)-N-methylaniline. 1H NMR (500MHz, CDCl3) δ7.25(d,J=5.6Hz,3H),7.17(t,J=8.0Hz,2H),6.98(d,J=7.7Hz,2H ),6.79(t,J=7.3Hz,1H),6.68(d,J=8.4Hz,2H),5.46(s,2H),4.52(s,2H),2.68(s,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ152.5,149.0,133.3,129.4,129.0,128.7,127.2,119.6,114.7,51.1,46.7,39.4.HRMS(ESI):calcd for C 16 H 17 N5Na[M+Na] + :302.1382;Found:302.1385.

[0050] Embodiment 6:

[0051] According to the method of Example 1, other electrolytes were used instead of tetra-n-butylammonium tetrafluoroborate, and other conditions remained unchanged to obtain the α-aminomethyltetrazolyl product ethyl 2-(5-((methyl(phenyl)amino)methyl)-1H-tetrazol-1-yl)acetate. The isolated yield is shown in Table 1.

[0052] Table 1: Effect of electrolyte type on target product yield

[0053]

[0054]

[0055] Embodiment 7:

[0056] According to the method of Example 1, other solvents were used instead of acetonitrile, and other conditions remained unchanged to obtain the α-aminomethyltetrazole product ethyl 2-(5-((methyl(phenyl)amino)methyl)-1H-tetrazol-1-yl)acetate. The isolated yield is shown in Table 2.

[0057] Table 2: Effect of organic solvents on the yield of target products

[0058]

[0059] Embodiment 8:

[0060] According to the method of Example 1, the constant current and reaction time were changed, and other conditions remained unchanged to obtain the α-aminomethyltetrazole product ethyl 2-(5-((methyl(phenyl)amino)methyl)-1H-tetrazol-1-yl)acetate. The isolated yield is shown in Table 3.

[0061] Table 3: Target product yields at different currents and reaction times

[0062]

[0063] The above-mentioned implementation cases are only preferred implementation cases in the present invention, but the implementation methods of the present invention are not limited to the above-mentioned implementation cases. For example, various forms of combinations of the schemes in the embodiments, any other changes, modifications, substitutions, and combinations made without departing from the spirit and principles of the present invention should be equivalent replacement methods and are within the protection scope of the present invention.

Claims

1. A method for preparing α-aminomethyltetrazole, characterized in that: include: The step of electrochemically reacting a tertiary amine, an isonitrile and trimethylsilyl azide in an electrolyte solution to synthesize a target product, The general reaction formula is as follows: In the formula, R 1 Including but not limited to any group selected from methyl, tert-butyl, methoxy, phenyl, halogen, trifluoromethyl; R 2 Including but not limited to any group of alkyl, benzyl, aryl.

2. The method according to claim 1, characterized in that The electrolyte in the electrolyte solution is tetrabutylammonium tetrafluoroborate, and the solvent is a mixed solvent of acetonitrile and hexafluoroisopropanol in a volume ratio of 5 to 10:1, preferably 7:

1.

3. The method according to claim 1, characterized in that The electrochemical reaction uses a carbon rod as an anode and a platinum sheet as a cathode, and the current is a constant current of 3 mA to 20 mA, preferably a constant current of 10 mA.

4. The method according to claim 1, characterized in that The electrochemical reaction is carried out at 0-40°C, preferably room temperature.

5. The method according to claim 1, characterized in that The electrochemical reaction time is not less than 2 hours.

6. The method according to claim 1, characterized in that The molar ratio of the electrolyte dosage to the tertiary amine dosage is 0.2-1 times, preferably 1 times.

7. The method according to claim 1, characterized in that The molar ratio of the amount of azidotrimethylsilane used is 1-3 times, preferably 1 time, of the amount of the tertiary amine used.

8. The method according to claim 1, characterized in that The molar ratio of the isonitrile used is 0.5-1 times, preferably 0.5 times, of the tertiary amine used.

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