Method for electrochemical synthesis of methyl 4-(5-adamantane-1-ylthio-1H-tetrazole-1-yl) benzoate

Abstract

The invention discloses a method for electrochemical synthesis of 4-(5-adamantane-1-yl thio-1H-tetrazole-1-yl) methyl benzoate, and the method comprises the following steps: taking 4-(5-adamantane-1-yl thio-1H-tetrazole-1-yl) methyl benzoate as a substrate; according to the method, adamantanethiol, 4-isonitrile methyl benzoate and an azide reagent are subjected to electrochemical reaction in an electrolyte solution to efficiently synthesize 4-(5-adamantane-1-ylthio-1H-tetrazole-1-yl) methyl benzoate drug active molecules, and the yield is as high as 80%. According to the method, extra catalysts and oxidizing agents do not need to be used, the reaction is carried out only through electrochemistry under mild conditions, meanwhile, gram-scale amplification synthesis can be carried out in the reaction, and the method is beneficial to development and exploration of a more efficient 5-sulfenyl tetrazole medicine synthesis method.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a 4-(5-adamantane-1-ylthio-1H-tetrazolyl-1-yl)benzoic acid methyl ester drug molecule, and belongs to the field of synthetic preparation of drug intermediates. Background Art

[0002] Tetrazolyl scaffolds represent an important class of five-membered nitrogen-rich heterocycles, which have important research value in many scientific fields including organometallic chemistry, medicine, agronomy, functional materials and high-energy materials. In particular, substituted 5-thiotetrazolies can interact with a variety of enzymes and receptors in the body and exhibit a wide range of biological activities (antibacterial, antiviral, anticancer, antiproliferative and antioxidant activities, etc.), which are of great significance in clinical drug treatment. For example, the typical substituted 5-thiotetrazolyl drug, Olmesartan, is a class I receptor antagonist used to treat angiotensin, hypertension and other diseases.

[0003] Methyl 4-(5-adamantan-1-ylthio-1H-tetrazolyl)benzoate is an important 5-thiotetrazolyl antiviral agent against H1N1 virus (EC 50 =2ug / mL) of bioactive molecules, because of its superior anti-H1N1 virus activity (EC 50 =5ug / mL), which has good development and application prospects. Related studies have shown that the synthesis of substituted 5-thiotetrazolyl compound molecules is generally completed by a two-step method: (1) in the presence of Lewis acid (ZnCl 2 (1) Under the catalytic conditions of iodine (such as iodine) and heating, the [3+2] cycloaddition reaction of isothiocyanate and sodium azide is used to synthesize 5-mercaptotetrazole; (2) 5-mercaptotetrazole reacts with aromatic or alkyl electrophiles under the action of transition metal catalysts (Cu, Ni and Bi, etc.) or aryl iodonium salts to undergo nucleophilic substitution reaction to synthesize substituted 5-thiotetrazole. However, the existing methods have great limitations in application, such as the use of transition metal catalysts and high boiling point solvents, difficulty in obtaining reaction precursors, long reaction time, cumbersome post-processing steps, poor functional group compatibility, and moderate yield of the target product (less than 60%). Therefore, the development of a simpler, more efficient and greener electrochemical synthesis method for the synthesis of methyl 4-(5-adamantan-1-ylthio-1H-tetrazol-1-yl)benzoate is of great significance for its early scale-up synthesis and clinical application in the field of biomedicine. Summary of the invention

[0004] The purpose of the present invention is to provide a simple and efficient electrochemical method for synthesizing 5-thiotetrazolyl anti-H1N1 virus active molecules.

[0005] The technical solution to achieve the purpose of the present invention is: a method for electrochemically synthesizing 4-(5-adamantan-1-ylthio-1H-tetrazol-1-yl)benzoic acid methyl ester drug molecules, comprising:

[0006] The step of electrochemically reacting adamantane thiol, methyl 4-isocyanobenzoate and an azide reagent in an electrolyte solution to synthesize a target product,

[0007]

[0008] Furthermore, the azide reagent is one of sodium azide, tetra-n-butylammonium azide, and trimethylsilyl azide, and trimethylsilyl azide is preferred as the nucleophilic reagent.

[0009] Further, the electrolyte in the electrolyte solution is one of tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium tetrafluoroborate, tetra-n-butylammonium hexafluorophosphate and tetra-n-butylammonium perchlorate, preferably tetra-n-butylammonium chloride as the electrolyte; the solvent is one or more of methanol, acetonitrile, acetone, dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, hexafluoroisopropanol, preferably acetonitrile: hexafluoroisopropanol = 9:1. .

[0010] Furthermore, the molar equivalent ratio of adamantane thiol, methyl 4-isonitrobenzoate and azide reagent is 1:1.5:4.

[0011] Furthermore, the equivalent ratio of the electrolyte to the adamantane thiol is 0.6:1.

[0012] Furthermore, the positive electrodes of the electrochemical reaction are a Pt electrode and a C electrode, the negative electrode is preferably a Pt electrode, and the positive electrode is preferably a C electrode.

[0013] Furthermore, the current is 5-20 mA, and the time is 1.75-7 h, preferably 10 mA, 3.5 h.

[0014] Furthermore, after the electrochemical reaction is completed, column chromatography is used for post-treatment, and the eluent used for column chromatography is ethyl acetate: petroleum ether = 1:5 (v / v).

[0015] Compared with the prior art, the present invention has the following significant advantages:

[0016] (1) No additional catalysts or oxidants are required, and the reaction can be carried out under mild conditions through electrochemistry.

[0017] (2) The "one-pot" reaction greatly improves efficiency, with a yield of up to 80%, which is better than the 57% of the traditional two-step synthesis method. When the reaction time is 3.5 h, the Faraday efficiency reaches 1.3 F / mol;

[0018] (3) The atom economy after the reaction is good, the post-processing procedure is relatively simple, and it is environmentally friendly to a certain extent;

[0019] (4) The electrochemical reaction produces hydrogen energy (H) with additional added value at the cathode. 2 ).

[0020] The present invention is further described in detail below in conjunction with the accompanying drawings.

[0021] Attachment

[0022] Figure 1 It is the hydrogen nuclear magnetic spectrum of methyl 4-(5-adamantan-1-ylthio-1H-tetrazolyl-1-yl)benzoate of the present invention.

[0023] Figure 2 It is the nuclear magnetic carbon spectrum of methyl 4-(5-adamantan-1-ylthio-1H-tetrazol-1-yl)benzoate of the present invention.

[0024] Figure 3 It is a high-resolution mass spectrum of methyl 4-(5-adamantan-1-ylthio-1H-tetrazol-1-yl)benzoate of the present invention. DETAILED DESCRIPTION

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] On the basis of organometallic electrochemistry, the present invention realizes the one-pot synthesis of the anti-H1N1 virus drug molecule - methyl 4-(5-adamantan-1-ylthio-1H-tetrazol-1-yl)benzoate at room temperature by constructing the coupling and [3+2] cycloaddition reaction of three components: adamantane thiol, methyl 4-isonitrobenzoate and trimethylsilyl azide.

[0032] Embodiment 1:

[0033] 84.1 mg (0.5 mmol) of adamantane thiol, 120.9 mg (0.75 mmol) of methyl 4-isocyanatobenzoate, 230.4 mg (2.0 mmol) of trimethylsilyl azide, 83.4 mg (0.3 mmol) of tetra-n-butylammonium chloride and 10 mL of a mixed solvent (acetonitrile: hexafluoroisopropanol = 9:1 v / v) were added to a 25 mL electrochemical reaction cell. The electrolytic cell was equipped with a graphite rod anode ( 90mm) as the anode, and a Pt sheet (10mm×10mm×0.1mm) as the cathode. The mixed solution was electrolyzed at 25°C at a constant current (10mA) for 3.5h, and the Faraday efficiency was 1.3F / mol. After the reaction was completed, the organic solvent was removed under reduced pressure to obtain a residue, which was purified by column chromatography using a mixture of petroleum ether / ethyl acetate = 5:1 as the eluent to obtain the product 4-(5-(adamantan-1-ylthio)-1H-tetrazol-1-yl)benzoic acid methyl ester (148.2mg, yield 80%) as a white solid.

[0034] The characterization spectra of the obtained products are as follows Figures 1 to 3 The relevant data are as follows: 1 HNMR (500 MHz, DMSO-d 6)δ8.19(d,J=8.7Hz,2H),7.83(d,J=8.6Hz,2H),3.91(s,3H),2.02(s,9H),1.63(s,6H). 13 C{ 1 H}NMR (126 MHz, DMSO-d 6 )δ165.29,151.17,136.97,131.40,130.67,125.96,53.76,52.71,42.58,35.26,29.61.HRMS(ESI):theoretical value C 19 H 23 N 4 O 2 S[M+H] + 371.1536; measured value 371.1535.

[0035] Embodiment 2:

[0036] 84.1 mg (0.5 mmol) of adamantane thiol, 120.9 mg (0.75 mmol) of methyl 4-isocyanatobenzoate, 130.0 mg (2.0 mmol) of tetra-n-butylammonium azide, 83.4 mg (0.3 mmol) of tetra-n-butylammonium chloride and 10 mL of a mixed solvent (acetonitrile: hexafluoroisopropanol = 9:1) were added to a 25 mL electrochemical reaction cell. The electrolytic cell was equipped with a graphite rod anode ( 90mm) as the anode, and a Pt sheet (10mm×10mm×0.1mm) as the cathode. The mixed solution was electrolyzed at 25°C at a constant current (10mA) for 3.5h. After the reaction was completed, the organic solvent was removed under reduced pressure to obtain a residue, which was purified by column chromatography using a mixture of petroleum ether / ethyl acetate = 5:1 as the eluent to obtain the product 4-(5-(adamantan-1-ylthio)-1H-tetrazol-1-yl)benzoic acid methyl ester (129.5mg, yield 70%) as a white solid.

[0037] Embodiment 3:

[0038] 84.1 mg (0.5 mmol) of adamantane thiol, 120.9 mg (0.75 mmol) of methyl 4-isocyanatobenzoate, 130.0 mg (2.0 mmol) of sodium azide, 83.4 mg (0.3 mmol) of tetra-n-butylammonium chloride and 10 mL of a mixed solvent (acetonitrile: hexafluoroisopropanol = 9:1) were added to a 25 mL electrochemical reaction cell. The electrolytic cell was equipped with a graphite rod anode ( 90mm) as the anode, and a Pt sheet (10mm×10mm×0.1mm) as the cathode. The mixed solution was electrolyzed at a constant current (10mA) for 3.5h at 25°C. After the reaction was completed, the organic solvent was removed under reduced pressure to obtain a residue, which was purified by column chromatography using a mixture of petroleum ether / ethyl acetate = 5:1 as the eluent to obtain the product 4-(5-(adamantan-1-ylthio)-1H-tetrazol-1-yl)benzoic acid methyl ester (29.6mg, yield 16%) as a white solid.

[0039] Embodiment 4:

[0040] 84.1 mg (0.5 mmol) of adamantane thiol, 120.9 mg (0.75 mmol) of methyl 4-isocyanobenzoate, 130.0 mg (2.0 mmol) of diphenylphosphoryl azide, 83.4 mg (0.3 mmol) of tetra-n-butylammonium chloride and 10 mL of a mixed solvent (acetonitrile: hexafluoroisopropanol = 9:1) were added to a 25 mL electrochemical reaction cell. The electrolytic cell was equipped with a graphite rod anode ( 90mm) as the anode, and a Pt sheet (10mm×10mm×0.1mm) as the cathode. The mixed solution was electrolyzed at a constant current (10mA) for 3.5h at 25°C. After the reaction, the organic solvent was removed under reduced pressure to obtain a residue, which was purified by column chromatography using a mixture of petroleum ether / ethyl acetate = 5:1 as the eluent. The product 4-(5-(adamantan-1-ylthio)-1H-tetrazolyl-1-yl)benzoic acid methyl ester was not obtained. HRMS detection [M+H] + =276.0533, raw material diphenylphosphoryl azide; [M+H] + =162.0550, which is the raw material methyl 4-isonitrobenzoate.

[0041] Embodiment 5:

[0042] The other conditions were the same as those in Example 1, and the effects of different organic solvent systems on the yield of the target product were examined. The experimental results are shown in Tables 1 and 2.

[0043] Table 1: Effect of single organic solvent on target product yield

[0044]

[0045] Table 2: Effect of mixed organic solvents on the yield of target products

[0046]

[0047] Embodiment 6:

[0048] The other conditions were the same as those in Example 1. The effects of different electrolytes on the yield of the target product were tested. The results are shown in Table 3.

[0049] Table 3: Effect of electrolyte type on target product yield

[0050]

[0051] Embodiment 7:

[0052] The other conditions were the same as in Example 1, and the effect of different equivalent ratios of reactants on the yield of the target product was tested. The results are shown in Table 4.

[0053] Table 4: Effect of different equivalent ratios of reactants on the yield of target products

[0054]

[0055]

[0056] Embodiment 8:

[0057] The other conditions were the same as those in Example 1, and the effect of different equivalents of electrolyte on the yield of the target product was tested. The results are shown in Table 5.

[0058] Table 5: Effect of different equivalents of electrolyte on the yield of target product

[0059]

[0060] Embodiment 9:

[0061] The other conditions were the same as those in Example 1, and the effects of different electrode materials on the yield of the target product were examined. The results are shown in Table 6.

[0062] Table 6: Different electrode materials for target product yield

[0063]

[0064] Embodiment 10:

[0065] The other conditions were the same as in Example 1, and the effects of different currents and reaction times on the yield of the target product were tested. The results are shown in Table 7.

[0066] Table 7: Target product yields at different currents and reaction times

[0067]

[0068]

[0069] Embodiment 11:

[0070] Based on Example 1, an amplification test was performed, and the process and synthetic route are as follows:

[0071] 1.177 g (7 mmol) of adamantane thiol, 2.369 mg (10.5 mmol) of methyl 4-isocyanatobenzoate, 3.226 mg (28 mmol) of trimethylsilyl azide, 1.168 g (4.2 mmol) of tetra-n-butylammonium chloride and 100 mL of a mixed solvent (acetonitrile: hexafluoroisopropanol = 9:1) were added to a 25 mL electrochemical reaction cell. The electrolytic cell was equipped with a graphite rod anode ( 90mm) as the cathode, and Pt sheet (10mm×30mm×0.2mm) as the anode to electrolyze the mixed solution at 25°C at a constant current (20mA) for 12h. After the reaction, the organic solvent was removed under reduced pressure to obtain a residue, which was purified by column chromatography using a mixture of petroleum ether / ethyl acetate = 5:1 as the eluent to obtain the product 4-(5-(adamantan-1-ylthio)-1H-tetrazol-1-yl)benzoic acid methyl ester (1.945g, 75%) as a white solid. The scaled-up experiment confirmed that electrochemical technology has important research value and application potential for the industrial preparation of 5-thiotetrazolyl drug intermediates and the development of clinical drugs.

[0072]

[0073] 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 electrochemically synthesizing methyl 4-(5-adamantan-1-ylthio-1H-tetrazol-1-yl)benzoate, characterized in that: include: The step of electrochemically reacting adamantane thiol, methyl 4-isocyanobenzoate and an azide reagent in an electrolyte solution to synthesize a target product, 2. The method according to claim 1, characterized in that The azide reagent is one of sodium azide, tetra-n-butylammonium azide and trimethylsilane, preferably trimethylsilane.

3. The method according to claim 1, characterized in that The electrolyte in the electrolyte solution is one of tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium tetrafluoroborate, tetra-n-butylammonium hexafluorophosphate and tetra-n-butylammonium perchlorate, and tetra-n-butylammonium chloride is preferred as the electrolyte; the solvent is one or more of methanol, acetonitrile, acetone, dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, and hexafluoroisopropanol, and the preferred solvent is acetonitrile:hexafluoroisopropanol=9:1 (v / v).

4. The method according to claim 1, characterized in that The molar equivalent ratio of adamantanethiol, methyl 4-isonitrobenzoate and the azide reagent is 1:1.5:

4.

5. The method according to claim 1, characterized in that The equivalent ratio of electrolyte to adamantanethiol is 0.6:

1.

6. The method according to claim 1, characterized in that The positive electrodes of the electrochemical reaction are Pt electrode and C electrode, the negative electrode is preferably Pt electrode, and the positive electrode is preferably C electrode.

7. The method according to claim 1, characterized in that The current is 5-20 mA, the time is 1.75-7 h, preferably 10 mA, 3.5 h.

8. The method according to claim 1, characterized in that After the electrochemical reaction, column chromatography was used for post-treatment. The eluent used for column chromatography was ethyl acetate: petroleum ether = 1:5 (v / v).

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