A preparation method of a compound and its use

Abstract

The invention discloses a preparation method of a compound, and in particular relates to a preparation method of a 1-substituted-5-mercapto-tetrazolyl compound. The method comprises preparing 1-substituted-5-mercapto-tetrazolyl by reacting isothiocyanate and nitrite with hydrazine hydrate under alkaline conditions. The method has simple process steps, rapid reaction, few product impurities, high purity, and is easy for industrial production. The obtained 1-substituted-5-mercapto-tetrazolyl or its salt is used for the production of medicines, which can further broaden the industrial production of medicines.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, in particular to the preparation of a compound, and more particularly to a method for preparing a tetrazole compound. Background Art

[0002] Tetrazol compounds are five-membered heterocyclic compounds containing four nitrogen atoms. They have a low nitrogen content and good stability. As organic synthesis intermediates, they are widely used in the fields of medicine, energetic materials, agriculture, preparation of coordination polymers, solid catalysts, photosensitive materials, etc. For example, 1-methyl-5-mercapto-tetrazole, 1-sulfomethyl-5-mercapto-tetrazole, 1-hydroxyethyl-5-mercapto-tetrazole, 1-phenyl-5-mercapto-tetrazole, 1-(N,N-dimethylaminoethyl)-5-mercapto 1-Methyl-5-mercapto-tetrazole can be used as important pharmaceutical intermediates for the synthesis and preparation of cephalosporins, especially 1-methyl-5-mercapto-tetrazole, which is an important raw material for the third, fourth and fifth generation of cephalosporin antibiotics, and can be used as an intermediate for many cephalosporin drugs such as cefoperazone sodium, cefmandole, cefmenoxime, cefmetazole, cefotetan, cefpiramide, cefbuperazone, cefminox, etc.; 1-phenyl-5-mercapto-tetrazole can be used as an electroplating additive, a photographic antifogging agent, and a stabilizer for electronic chemicals. With the popularization and application of cephalosporin antibiotics, the market demand for tetrazole compounds will continue to expand.

[0003] The synthesis method of tetrazole structure mainly includes the addition reaction of hydrazoic acid, azide ion and azide organic matter to carbon-nitrogen multiple bonds. For example, for the synthesis of 1-methyl-5-mercapto-tetrazole, methyl isothiocyanate and sodium azide are used for synthesis (as described in "Chang Xiangna, Zhang Jianyu, Ning Xiaoxiao, et al. Study on the Phase Transfer Synthesis Process of Pharmaceutical Intermediate 1-Methyl-5-Mercapto-1H-tetrazole [J]. Journal of Shaanxi University of Science and Technology: Natural Science Edition, 2015, 35(1): 5."). These synthesis methods often have the disadvantages of poor environmental friendliness, low yield, cumbersome operation, need to add catalysts, high cost, etc., which limit their application in industrial production and other aspects. Summary of the invention

[0004] In order to overcome the deficiencies of the prior art, the present invention provides a method for preparing 1-substituted-5-mercapto-tetrazolyl or a salt thereof, which comprises the following steps:

[0005] (1) dissolving isothiocyanate and nitrite in solvent I to obtain solution I;

[0006] (2) dissolving hydrazine hydrate and a base in solvent II to obtain solution II;

[0007] (3) mixing solution II and solution I, heating and refluxing to obtain solution III;

[0008] (4) adding acid to solution III;

[0009] (5) separating and purifying the product after the reaction in step (4) to obtain 1-substituted-5-mercapto-tetrazole.

[0010] Specifically, the isothiocyanate structure is shown in Formula I:

[0011]

[0012] Wherein, R1 is selected from any one of an alkyl group, a hydroxyalkyl group, an aryl group, and a disubstituted aminoalkyl group.

[0013] Specifically, the alkyl group is selected from C 1-4 The alkyl group is more preferably selected from methyl or ethyl.

[0014] Specifically, the hydroxyalkyl group is selected from hydroxymethyl or hydroxyethyl.

[0015] Specifically, the aryl group is phenyl.

[0016] Specifically, the disubstituted aminoalkyl group is dimethylaminoethyl.

[0017] In some embodiments of the present invention, the isothiocyanate is methyl isothiocyanate, ethyl isothiocyanate, phenyl isothiocyanate, hydroxymethyl isothiocyanate, hydroxyethyl isothiocyanate, 2-dimethylaminoethyl isothiocyanate.

[0018] Specifically, the nitrite is R2ONO, wherein R2 is C 1-6 alkyl.

[0019] Preferably, the nitrite is methyl nitrite, ethyl nitrite, n-propyl nitrite, isopropyl nitrite, n-butyl nitrite, isobutyl nitrite, isoamyl nitrite.

[0020] Specifically, isothiocyanate and nitrite are dissolved in solvent I successively or together to obtain solution I. If nitrite is selected from liquid propyl nitrite, isopropyl nitrite, butyl nitrite, isobutyl nitrite or isoamyl nitrite, it can be dissolved in solvent I together with nitrite, or dissolved separately in solvent I. If nitrite is selected from gaseous methyl nitrite or ethyl nitrite, isocyanate can be first dissolved in solvent I, and then nitrite is introduced for absorption to obtain solution I; or nitrite is first introduced into solvent I for absorption, and then isocyanate is added to dissolve to obtain solution I.

[0021] In one embodiment of the present invention, the nitrite is methyl nitrite, which can be derived from nitromethane tail gas generated by the reaction of dimethyl sulfate and nitrite to produce nitromethane.

[0022] Specifically, the absorption process of the nitromethane tail gas in step (1) is carried out under pressurized conditions. Pressurization can accelerate the absorption rate of the nitromethane tail gas, and the specific pressure can be adjusted according to the amount of the nitromethane tail gas, such as adding 0.5-1 MPa of atmospheric pressure to the absorption container.

[0023] Specifically, the absorption process of nitromethane tail gas in step (1) can be carried out at a conventional production environment temperature, and the tail gas treatment temperature is not particularly limited.

[0024] In another embodiment of the present invention, the nitrite is selected from the group consisting of n-propyl nitrite, isopropyl nitrite, butyl nitrite, isobutyl nitrite, and isoamyl nitrite.

[0025] Specifically, the structure of 1-substituted-5-mercapto-tetrazolyl is shown in Formula II:

[0026]

[0027] Wherein, R1 is selected from any one of an alkyl group, a hydroxyalkyl group, an aryl group, and a disubstituted aminoalkyl group.

[0028] Specifically, the alkyl group is selected from C 1-4 The alkyl group is more preferably selected from methyl or ethyl.

[0029] Specifically, the hydroxyalkyl group is selected from hydroxymethyl or hydroxyethyl.

[0030] Specifically, the aryl group is phenyl.

[0031] Specifically, the disubstituted aminoalkyl group is a dimethyl substituted aminoethyl group.

[0032] In some embodiments of the present invention, 1-substituted-5-mercapto-tetrazolyl is 1-methyl-5-mercapto-tetrazolyl 1-Phenyl-5-mercapto-tetrazolyl 1-Hydroxymethyl-5-mercapto-tetrazolyl 1-Hydroxyethyl-5-mercapto-tetrazolyl 1-(2-Dimethylaminoethyl)-1H-5-mercapto-tetrazolyl wait.

[0033] Specifically, the solvent I in step (1) is an organic solvent, especially an alcohol, such as methanol or ethanol.

[0034] Specifically, the solvent II in step (2) is an organic solvent, especially an alcohol, such as methanol or ethanol.

[0035] Specifically, the base in step (2) is a strong base, preferably sodium hydroxide or potassium hydroxide.

[0036] Specifically, the operation of mixing solution II and solution I in step (3) can be performed by slowly adding solution II into solution I, or slowly adding solution I into solution II.

[0037] Specifically, the time of heating reflux in step (3) can be appropriately adjusted by those skilled in the art according to actual conditions, such as 1 h, 2 h, and the present invention does not make any specific limitation.

[0038] Specifically, the temperature of the heating reflux reaction in step (3) is 70-80°C.

[0039] Specifically, the acid in step (4) is an inorganic acid, such as hydrochloric acid, sulfuric acid, etc.

[0040] Specifically, after adding the acid in step (4), the solution becomes acidic, such as pH=1, pH=2, etc.

[0041] Specifically, in the method of the present invention, isothiocyanate and nitrite can be directly used as corresponding commercial products, or can be prepared according to methods known in the prior art.

[0042] Specifically, isothiocyanate, nitrite and hydrazine hydrate are reacted under alkaline conditions to prepare 1-substituted-5-mercapto-tetrazole, and the reaction process is as follows:

[0043]

[0044] In order to prevent side reactions, isothiocyanate, nitrite and hydrazine hydrate are preferably added in a molar ratio of 1:1:1, and a ring-forming reaction is carried out under alkaline conditions to generate 1-substituted-5-mercapto-tetrazole.

[0045] In a second aspect of the present invention, a method for preparing a cephalosporin intermediate is provided, which comprises the following steps:

[0046] (1) dissolving isothiocyanate and nitrite (sequentially or together) in solvent I to obtain solution I;

[0047] (2) dissolving hydrazine hydrate and a base in solvent II to obtain solution II;

[0048] (3) adding solution II to solution I, heating and refluxing to obtain solution III;

[0049] (4) adding acid to solution III;

[0050] (5) separating and purifying the product after the reaction in step (4);

[0051] (6) synthesizing a cephalosporin intermediate using the product 1-substituted-5-mercapto-tetrazolyl obtained in step (5);

[0052] The structure of the cephalosporin intermediate is shown in Formula III:

[0053]

[0054] Wherein, R1 is selected from alkyl, hydroxyalkyl, aryl, disubstituted aminoalkyl;

[0055] R3 is selected from the group consisting of: hydrogen, alkoxy.

[0056] Specifically, R1 is selected from: C 1-4 Alkyl (preferably methyl or ethyl), hydroxymethyl, hydroxyethyl, phenyl, dimethyl substituted aminoethyl.

[0057] In particular, R3 is hydrogen or methoxy.

[0058] In some embodiments of the present invention, the cephalosporin intermediate is:

[0059]

[0060] Specifically, the conditions of steps (1)-(5) are as described in the first aspect of the present invention.

[0061] Specifically, step (6) comprises reacting compound IV with 1-substituted-5-mercapto-tetrazolyl, the structure of the compound being as shown in formula IV:

[0062]

[0063] Wherein, R3 is selected from: hydrogen, alkoxy, preferably, R3 is hydrogen or methoxy,

[0064] For example, the process for preparing methoxycephalosporin intermediate 7-MAC in patent CN102250122A is adopted, and 1-methyl-5-mercapto-tetrazole prepared by the present invention is reacted with compound IV to prepare cephalosporin intermediate 7-MAC.

[0065] In a third aspect of the present invention, a method for preparing a cephalosporin antibiotic compound or a pharmaceutically acceptable salt thereof is provided, comprising the following steps:

[0066] (1) dissolving isothiocyanate and nitrite (sequentially or together) in solvent I to obtain solution I;

[0067] (2) dissolving hydrazine hydrate and a base in solvent II to obtain solution II;

[0068] (3) adding solution II to solution I, heating and refluxing to obtain solution III;

[0069] (4) adding acid to solution III;

[0070] (5) separating and purifying the product after the reaction in step (4);

[0071] (6) Synthesizing a cephalosporin antibiotic compound or a pharmaceutically acceptable salt thereof with the 1-substituted-5-mercapto-tetrazolyl product obtained in step (5).

[0072] Specifically, the conditions of steps (1)-(5) are as described in the first aspect of the present invention.

[0073] Specifically, the cephalosporin antibiotic compound can be selected from any one of: cefoperazone, cefmenoxime, cefmandole, cefoperazone, cefazolin, cefmetazole, cefotetan, cefpiramide, cefbuperazone, cefminox and the like.

[0074] In the fourth aspect of the present invention, there is provided use of the method described in the first aspect in the preparation of drugs and intermediates thereof.

[0075] Specifically, 1-substituted-5-mercapto-tetrazole (which has the structure of Formula II described above in the present invention) or its salt is used to prepare drugs such as cephalosporin antibiotic compounds or pharmaceutically acceptable salts thereof; or cephalosporin intermediates such as those having the structure of Formula III described above in the present invention are prepared; or statins are prepared, such as statins are prepared from 1-phenyl-5-mercapto-tetrazole.

[0076] Beneficial Effects

[0077] 1. The present invention adopts a one-pot method to synthesize 1-substituted-5-mercapto-tetrazolyl, and the reaction does not require the synthesis, separation or use of highly toxic and explosive sodium azide, and the process steps are simple;

[0078] 2. The product of the method of the present invention has few impurities, high yield, and is easy to industrialize. The obtained 1-substituted-5-mercapto-tetrazole or its salt is used in the production of medicines, which can further expand the industrial production of medicines. DETAILED DESCRIPTION

[0079] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0080]

[00136] Various publications, patents, and published patent specifications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0081] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0082] Example 1

[0083] (1) dissolving 14.6 g (0.2 mol) of methyl isothiocyanate in 80 g of anhydrous ethanol to obtain solution A;

[0084] (2) Solution A was transferred into a laboratory micro-absorption tower, and the circulation pump of the absorption tower was turned on. Methyl nitrite was passed into the absorption tower at a flow rate of 0.1 L / min to absorb 12.2 g (0.2 mol) of methyl nitrite. The resulting solution I was transferred into a reaction bottle;

[0085] (3) Dissolve 12.5 g (0.2 mol) of 80% hydrazine hydrate and 13.2 g (0.2 mol) of 85% KOH in 90 g of anhydrous ethanol to obtain solution II;

[0086] (4) Slowly drip solution II into solution I, heat to 75°C and reflux for 1 h to obtain solution III;

[0087] (5) Solution III was cooled, concentrated hydrochloric acid was added dropwise until the pH value was less than 2, and the by-products were removed by filtration. The filtrate was evaporated and concentrated, and then the temperature was lowered to precipitate crystals. The filter cake was filtered and dried to obtain 1-methyl-5-mercaptotetrazole with a purity of 99.8% and a yield of 84.7%.

[0088] Example 2

[0089] (1) dissolving 14.6 g (0.2 mol) of methyl isothiocyanate in 80 g of anhydrous ethanol to obtain solution A;

[0090] (2) Transfer solution A to a laboratory micro-absorption tower, start the absorption tower circulation pump, and pass ethyl nitrite into the absorption tower at a flow rate of 0.1 L / min for absorption, so that 17.4 g (0.2 mol) of ethyl nitrite is absorbed, and the resulting solution I is transferred to a reaction bottle;

[0091] (3) Dissolve 12.5 g (0.2 mol) of 80% hydrazine hydrate and 13.2 g (0.2 mol) of 85% KOH in 90 g of anhydrous ethanol to obtain solution II;

[0092] (4) Solution II was slowly dripped into solution I, and the mixture was heated to 70°C and refluxed for 1.5 h to obtain solution III;

[0093] (5) Solution III was cooled, concentrated hydrochloric acid was added dropwise until the pH value was less than 2, and the by-products were removed by filtration. The filtrate was evaporated and concentrated, and then cooled to precipitate crystals. The filter cake was filtered and dried to obtain 1-methyl-5-mercaptotetrazole with a purity of 99.6% and a yield of 85.1%.

[0094] Example 3

[0095] (1) 14.6 g (0.2 mol) of methyl isothiocyanate and 20.6 g (0.2 mol) of isobutyl nitrite were dissolved in 80 g of anhydrous ethanol to obtain solution I;

[0096] (2) Dissolve 12.5 g (0.2 mol) of 80% hydrazine hydrate and 13.2 g (0.2 mol) of 85% KOH in 90 g of anhydrous ethanol to obtain solution II;

[0097] (3) Slowly drip solution II into solution I, heat to 80°C and reflux for 1.5 h to obtain solution III;

[0098] (4) Solution III was cooled, concentrated hydrochloric acid was added dropwise until the pH value was less than 2, and the by-products were removed by filtration. The filtrate was evaporated and concentrated, and then the temperature was lowered to precipitate crystals. The filter cake was filtered and dried to obtain 1-methyl-5-mercaptotetrazole with a purity of 99.7% and a yield of 84.7%.

[0099] Example 4

[0100] (1) Dissolve 27.0 g (0.2 mol) of phenyl isothiocyanate and 23.4 g (0.2 mol) of isoamyl nitrite in 80 g of anhydrous ethanol to obtain solution I;

[0101] (2) Dissolve 12.5 g (0.2 mol) of 80% hydrazine hydrate and 10.0 g (0.2 mol) of 80% NaOH in 80 g of anhydrous ethanol to obtain solution II;

[0102] (3) Slowly drip solution I into solution II, heat to 75°C and reflux for 2 h to obtain solution III;

[0103] (4) Solution III was cooled, concentrated sulfuric acid was added dropwise until the pH value was less than 2, and after evaporation and concentration, anhydrous ethanol was added, and the by-products were removed by filtration. The filtrate was evaporated and concentrated, cooled, and crystals were precipitated. The crystals were filtered and dried to obtain 1-phenyl-5-mercaptotetrazole with a purity of 99.7% and a yield of 86.3%.

[0104] Example 5

[0105] (1) Dissolve 17.4 g (0.2 mol) of ethyl isothiocyanate and 17.8 g (0.2 mol) of isopropyl nitrite in 80 g of anhydrous ethanol to obtain solution I;

[0106] (2) Dissolve 12.5 g (0.2 mol) of 80% hydrazine hydrate and 10.0 g (0.2 mol) of 80% NaOH in 80 g of anhydrous methanol to obtain solution II;

[0107] (3) Slowly drip solution I into solution II, heat to 75°C and reflux for 2 h to obtain solution III;

[0108] (4) Solution III was cooled, concentrated sulfuric acid was added dropwise until the pH value was less than 2, and after evaporation and concentration, anhydrous ethanol was added, and the by-products were removed by filtration. The filtrate was evaporated and concentrated, cooled, and crystals were precipitated. The crystals were filtered and dried to obtain 1-ethyl-5-mercaptotetrazole with a purity of 99.6% and a yield of 84.6%.

[0109] Example 6

[0110] (1) Dissolve 20.6 g (0.2 mol) of hydroxyethyl isothiocyanate and 20.6 g (0.2 mol) of n-butyl nitrite in 80 g of anhydrous ethanol to obtain solution I;

[0111] (2) Dissolve 12.5 g (0.2 mol) of 80% hydrazine hydrate and 10.0 g (0.2 mol) of 80% NaOH in 80 g of anhydrous ethanol to obtain solution II;

[0112] (3) Solution I was slowly dripped into solution II, heated to 75°C and refluxed for 1.5 h to obtain solution III;

[0113] (4) Solution III was cooled, concentrated sulfuric acid was added dropwise until the pH value was less than 2, and after evaporation and concentration, anhydrous ethanol was added, and by-products were removed by filtration. The filtrate was evaporated and concentrated, cooled, and crystals were precipitated. 1-hydroxyethyl-5-mercaptotetrazole was obtained by filtration and drying. The purity was 99.6% and the yield was 84.2%.

[0114] Example 7

[0115] (1) dissolving 14.6 g (0.2 mol) of methyl isothiocyanate in 80 g of anhydrous ethanol to obtain solution A;

[0116] (2) Transfer solution A to a laboratory micro-absorption tower, start the absorption tower circulation pump, and pass the nitromethane tail gas produced by the nitrite replacement method into the absorption tower at a flow rate of 0.1 L / min for absorption. When the weight of solution A no longer increases, stop passing the tail gas, and transfer the resulting solution I to a reaction bottle;

[0117] (3) Dissolve 12.5 g (0.2 mol) of 80% hydrazine hydrate and 13.2 g (0.2 mol) of 85% KOH in 90 g of anhydrous ethanol to obtain solution II;

[0118] (4) Slowly drip solution II into solution I, heat to 75°C and reflux for 1 h to obtain solution III;

[0119] (5) Solution III was cooled, concentrated hydrochloric acid was added dropwise until pH = 2, by-products were removed by filtration, the filtrate was evaporated and concentrated, the temperature was lowered, crystals were precipitated, the filter cake was filtered and dried, and the product 1-methyl-5-mercaptotetrazole was obtained with a purity of 99.6% and a yield of 85.1%.

[0120] Example 8

[0121] Synthesis of Cefmenoxime Hydrochloride

[0122] Referring to the experimental method described in Part 2 of "Li Aijun, Zhou Xueqin, Li Wei, et al. Synthesis of Cefmenoxime Hydrochloride [J]. Chinese Journal of Antibiotics, 2005, 30 (3)", Cefmenoxime Hydrochloride was prepared using 1-methyl-5-mercaptotetrazole, the product prepared in Example 1, to obtain Cefmenoxime Hydrochloride as an off-white crystalline powder.

[0123] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

[0124] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience and preference of those skilled in the art.

[0125] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. A method for preparing 1-substituted-5-mercapto-tetrazolyl, comprising the following steps: (1) dissolving isothiocyanate and nitrite in solvent I to obtain solution I; (2) dissolving hydrazine hydrate and a base in solvent II to obtain solution II; (3) Mixing solution II and solution I, heating and refluxing, to obtain solution III; (4) Adding acid to solution III; (5) separating and purifying the product after the reaction in step (4) to obtain 1-substituted-5-mercapto-tetrazolyl; The solvent I in step (1) is methanol or ethanol; The solvent II in step (2) is methanol or ethanol; The base in step (2) is sodium hydroxide or potassium hydroxide; The acid in step (4) is hydrochloric acid or sulfuric acid; The isothiocyanate is methyl isothiocyanate, ethyl isothiocyanate, phenyl isothiocyanate, hydroxymethyl isothiocyanate, hydroxyethyl isothiocyanate or 2-dimethylaminoethyl isothiocyanate; The nitrite is methyl nitrite, ethyl nitrite, n-propyl nitrite, isopropyl nitrite, n-butyl nitrite, isobutyl nitrite or isoamyl nitrite; The molar ratio of the isothiocyanate, the nitrite and the hydrazine hydrate is 1:1:

1.

2. The method according to claim 1, characterized in that The 1-substituted-5-mercapto-tetrazolyl has the following structure: 。 3. The method according to claim 1, characterized in that The solvent I in step (1) is ethanol; The solvent II in step (2) is ethanol.

4. The method according to claim 1, characterized in that The temperature of the heating reflux reaction in step (3) is 70-80°C.

5. The method according to claim 1, characterized in that The nitrite is methyl nitrite, and the methyl nitrite is derived from nitromethane tail gas produced by the reaction of dimethyl sulfate and nitrite to produce nitromethane.

6. Use of the method according to any one of claims 1 to 5 in the synthesis of drugs and intermediates thereof.

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