A preparation method of 1-phenyl-5-mercaptotetrazole

Abstract

The invention discloses a preparation method of 1-phenyl-5-mercaptotetrazole, comprising the steps of: mixing 1-phenyl-5-hydroxytetrazole, phosphorus pentasulfide, a siloxane compound or a polysiloxane compound, and an organic solvent, reacting under heating conditions, and obtaining 1-phenyl-5-mercaptotetrazole. The preparation method has a high yield, and the yield can reach more than 70%; there is no need for cumbersome reaction steps, strict dropwise addition conditions and temperature control reaction temperature are avoided, no strong acid or strong base is required to participate in the reaction, no carbon disulfide is involved in the reaction, and it is suitable for mass production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis of pharmaceutical chemistry, and more specifically, relates to a preparation method of 1-phenyl-5-mercaptotetrazole. Background Art

[0002] Rosuvastatin calcium, chemical name: bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), is a selective HMGCoA reductase inhibitor.

[0003] 1-Phenyl-5-mercaptotetrazolyl is an important intermediate in the preparation of rosuvastatin calcium. 1-Phenyl-5-mercaptotetrazolyl will generate a byproduct, 1-phenyl-5-hydroxytetrazolyl, in the subsequent reaction. If a method can be achieved to efficiently convert the byproduct 1-phenyl-5-hydroxytetrazolyl into 1-phenyl-5-mercaptotetrazolyl, it will greatly reduce production costs, reduce the waste of raw materials and the discharge of three wastes.

[0004] Patent Publication No. CN110627736A discloses a recycling method of 1-phenyl-5-hydroxytetrazolyl, wherein 1-phenyl-5-hydroxytetrazolyl first reacts with phosphorus pentachloride in toluene to obtain an intermediate 1-phenyl-5-chlorotetrazolyl, and the intermediate then reacts with thiourea in ethanol to obtain 1-phenyl-5-mercaptotetrazolyl. The total yield through the two-step reaction is only about 54%, and the yield is low; in addition, it is necessary to react through two steps, the reaction steps are cumbersome, and the amount of reagents used is large. Patent Publication No. CN113372286A discloses a one-pot method for synthesizing 1-phenyl-5-mercaptotetrazolyl compounds using 1-phenyl-5-hydroxytetrazolyl, phosphorus pentasulfide, carbon disulfide and hydrochloric acid, and the reaction requires strict dripping of materials and temperature control reaction temperature under strong acid conditions, which undoubtedly increases the difficulty of industrial operation and equipment requirements. In addition, the carbon disulfide used in the reaction system will decompose and produce toxic sulfide fumes during the reaction, which is harmful to human health. Summary of the invention

[0005] In view of the above-mentioned prior art problems, the object of the present invention is to provide a method for preparing 1-phenyl-5-mercaptotetrazole.

[0006] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0007] The present invention claims a method for preparing 1-phenyl-5-mercaptotetrazole, comprising the following steps: mixing 1-phenyl-5-hydroxytetrazole, phosphorus pentasulfide, a siloxane compound or a siloxane polymer, and an organic solvent, and reacting them under heating conditions to obtain 1-phenyl-5-mercaptotetrazole.

[0008] The present invention uses 1-phenyl-5-hydroxytetrazolyl as a raw material, phosphorus pentasulfide as a vulcanizing agent, and a siloxane compound or a siloxane polymer as an additive, and adopts a "one-pot method" to realize the preparation of 1-phenyl-5-mercaptotetrazolyl, with a high yield of more than 70%. The preparation method does not require cumbersome reaction steps, the reaction operation is simple, and the reaction conditions are relatively mild; in addition, strict dropwise addition conditions and temperature control reaction temperature are avoided, strong acid and strong base are not required to participate in the reaction, and carbon disulfide is not required to participate in the reaction, and it is suitable for mass production.

[0009] The invention provides a method for preparing 1-phenyl-5-mercaptotetrazole, which realizes efficient conversion of 1-phenyl-5-hydroxytetrazole, a byproduct in the preparation process of rosuvastatin calcium intermediate, into 1-phenyl-5-mercaptotetrazole, thereby reducing production costs and reducing the waste of raw materials.

[0010] In one or more embodiments, the siloxane compound is selected from one or both of hexamethyldisiloxane and disiloxane.

[0011] In one or more embodiments, the silicone polymer is selected from one or more of methyl silicone oil, ethyl silicone oil, dimethyl silicone oil or phenyl silicone oil.

[0012] In one or more embodiments, the viscosity of the silicone polymer is 50-300 cps.

[0013] In one or more embodiments, the organic solvent includes one or more of 1,4-dioxane, toluene, xylene, or anisole.

[0014] In one or more embodiments, the organic solvent includes a first solvent 1,4-dioxane and a second solvent selected from at least one of toluene, xylene, or anisole. The volume ratio of the first solvent to the second solvent is 9-24:1.

[0015] In one or more embodiments, the reaction temperature is 90-110°C.

[0016] In one or more embodiments, the molar ratio of 1-phenyl-5-hydroxytetrazolyl to phosphorus pentasulfide is 1:1.2-2.5.

[0017] In one or more embodiments, the molar ratio of the 1-phenyl-5-hydroxytetrazolyl to the siloxane compound or siloxane polymer is 1:1.2-2.5.

[0018] In one or more embodiments, the reaction time is 10 to 30 h.

[0019] In one or more embodiments, the method further comprises a refining step; the refining step is: subjecting the product to one or more of the following treatments: filtration, concentration, alkali washing, extraction, acidification precipitation or drying.

[0020] In one or more embodiments, the product can be dissolved in dichloromethane or ethyl acetate, followed by filtration and concentration. In one or more embodiments, the alkali solution used in the alkali wash is selected from one or more of sodium hydroxide, potassium hydroxide, saturated sodium carbonate, and saturated sodium bicarbonate. In one or more embodiments, hydrochloric acid is used for acidification and precipitation.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The present invention prepares 1-phenyl-5-thiotetrazolyl under air conditions by a "one-pot" one-step reaction with 1-phenyl-5-hydroxytetrazolyl, phosphorus pentasulfide and siloxane compounds or siloxane polymers. The preparation method has a high yield, and the yield can reach more than 70%. There is no need for cumbersome reaction steps, the reaction operation is simple, and the reaction conditions are relatively mild; in addition, strict dropwise addition conditions are avoided, no strong acid or strong base is required to participate in the reaction, no carbon disulfide is involved in the reaction, and the preparation can be achieved by heating under air conditions, which is suitable for mass production. The preparation method provided by the present invention can be applied to the recovery and reuse of the byproduct 1-phenyl-5-hydroxytetrazolyl in the preparation process of rosuvastatin calcium intermediates. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 1-phenyl-5-mercaptotetrazole prepared in Example 1 1 H NMR spectrum.

[0024] Figure 2 1-phenyl-5-mercaptotetrazole prepared in Example 1 13 C NMR spectrum.

[0025] Figure 3 The product purity of 1-phenyl-5-mercaptotetrazole prepared in Example 1. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0027] Example 1

[0028] (1) Add 10 mmol 1-phenyl-5-hydroxytetrazolyl, 15 mmol phosphorus pentasulfide, 15 mmol hexamethyldisiloxane, 15 mL 1,4-dioxane and a magnetic stirrer to a reaction flask, heat at 100 °C and react for 18 hours.

[0029] (2) After the reaction is completed, the reaction solution is filtered hot, and the solvent is removed by distillation under reduced pressure. The solution is then dissolved with dichloromethane, washed with a 2N sodium hydroxide solution, and extracted twice with dichloromethane (5 mL each time) to remove organic by-products. 3N hydrochloric acid is added for acidification, and the pH is adjusted to 2-3. A solid is precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole is obtained with a yield of 88% and a purity of 99%.

[0030] The H NMR spectrum of 1-phenyl-5-mercaptotetrazolyl is as follows Figure 1 The specific data are as follows: 1 H NMR (400MHz, DMSO-d) δ 7.88 ~ 7.86 (m, 2H), 7.64 ~ 7.56 (m, 3H). The carbon NMR spectrum of 1-phenyl-5-mercaptotetrazole is as follows Figure 2 The specific data are as follows: 13 C NMR (100 MHz, DMSO-d) δ 166.62, 136.73,132.33, 131.97(2C), 127.15(2C). The structure of the product obtained in this example was analyzed and compared with the literature reported by Kommula Dileep et al. [Org. Commun. 2017, 10 (3), 178-189.], and the results confirmed that the substance was 1-phenyl-5-mercaptotetrazole. The product purity of the prepared 1-phenyl-5-mercaptotetrazole is as follows: Figure 3 shown.

[0031] Example 2

[0032] (1) Add 10 mmol 1-phenyl-5-hydroxytetrazolyl, 15 mmol phosphorus pentasulfide, 22 mmol hexamethyldisiloxane, 15 mL 1,4-dioxane and a magnetic stirrer to a reaction flask, heat to 105 °C and react for 14 hours.

[0033] (2) After the reaction, the reaction solution was filtered hot, and the solvent was removed by distillation under reduced pressure. The solution was then dissolved with ethyl acetate, washed with 2N sodium hydroxide solution, and extracted twice with ethyl acetate (5 mL each time) to remove organic by-products. 3N sulfuric acid was added for acidification, and the pH was adjusted to 2-3. Solids were precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole, with a yield of 83%.

[0034] Example 3

[0035] (1) Add 10 mmol 1-phenyl-5-hydroxytetrazolyl, 17 mmol phosphorus pentasulfide, 22 mmol hexamethyldisiloxane, 15 mL 1,4-dioxane and a magnetic stirrer into a reaction flask, heat at 100 °C and react for 16 hours.

[0036] (2) After the reaction is completed, the reaction solution is filtered hot, and the solvent is removed by distillation under reduced pressure. The solution is then dissolved with dichloromethane, washed with 2N sodium hydroxide solution, and extracted twice with dichloromethane (5 mL each time) to remove organic by-products. 3N hydrochloric acid is added for acidification, and the pH is adjusted to 2-3. A solid is precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole is obtained, with a yield of 83%.

[0037] Example 4

[0038] (1) Add 10 mmol 1-phenyl-5-hydroxytetrazolyl, 12 mmol phosphorus pentasulfide, 22 mmol hexamethyldisiloxane, 15 mL of a mixed solvent of 1,4-dioxane and toluene (the volume ratio of 1,4-dioxane to toluene is 9:1) and a magnetic stirrer into a reaction flask, heat to 100°C, and react for 24 hours.

[0039] (2) After the reaction is completed, the reaction solution is filtered hot, and the solvent is removed by distillation under reduced pressure. The solution is then dissolved with dichloromethane, washed with 2N potassium hydroxide solution, and extracted twice with dichloromethane (5 mL each time) to remove organic by-products. 3N hydrochloric acid is added for acidification, and the pH is adjusted to 2-3. A solid is precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole is obtained, with a yield of 78%.

[0040] Example 5

[0041] (1) Add 10 mmol 1-phenyl-5-hydroxytetrazolyl, 15 mmol phosphorus pentasulfide, 22 mmol hexamethyldisiloxane, 15 mL of a mixed solvent of 1,4-dioxane and xylene (the volume ratio of 1,4-dioxane to xylene is 24:1) and a magnetic stirrer into a reaction flask, heat to 100°C, and react for 18 hours.

[0042] (2) After the reaction, the reaction solution was filtered while hot, and the solvent was removed by distillation under reduced pressure. The solution was then dissolved with dichloromethane, washed with a saturated sodium carbonate solution, and extracted twice with dichloromethane (5 mL each time) to remove organic byproducts. 3N hydrochloric acid was added for acidification, and the pH was adjusted to 2-3. Solids were precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole, with a yield of 74%.

[0043] Example 6

[0044] (1) Add 10 mmol of 1-phenyl-5-hydroxytetrazolyl, 15 mmol of phosphorus pentasulfide, 22 mmol of hexamethyldisiloxane, 15 mL of a mixed solvent of 1,4-dioxane and anisole (the volume ratio of 1,4-dioxane to anisole is 24:1) and a magnetic stirrer into a reaction flask, heat to 105°C, and react for 18 hours.

[0045] (2) After the reaction is completed, the reaction solution is filtered while hot, and the solvent is removed by distillation under reduced pressure. The solution is then dissolved with dichloromethane, washed with a saturated sodium bicarbonate solution, and extracted twice with dichloromethane (5 mL each time) to remove organic by-products. 3N hydrochloric acid is added for acidification, and the pH is adjusted to 2-3. A solid is precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole is obtained, with a yield of 79%.

[0046] Example 7

[0047] (1) Add 10 mmol of 1-phenyl-5-hydroxytetrazolyl, 15 mmol of phosphorus pentasulfide, 15 mmol of dimethyl silicone oil (viscosity 50 cps), 15 mL of 1,4-dioxane and a magnetic stirrer into a reaction flask, heat to 100°C, and react for 20 hours.

[0048] (2) After the reaction is completed, the reaction solution is filtered while hot, and the solvent is removed by distillation under reduced pressure. The solution is then dissolved with dichloromethane, washed with 2N sodium hydroxide solution, and extracted twice with dichloromethane (5 mL each time) to remove organic by-products. 3N hydrochloric acid is added for acidification, and the pH is adjusted to 2-3. A solid is precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole is obtained, with a yield of 78%.

[0049] Example 8

[0050] (1) Add 10 mmol of 1-phenyl-5-hydroxytetrazolyl, 15 mmol of phosphorus pentasulfide, 15 mmol of dimethyl silicone oil (viscosity 100 cps), 15 mL of 1,4-dioxane and a magnetic stirrer to a reaction flask, heat to 105°C, and react for 18 hours.

[0051] (2) After the reaction is completed, the reaction solution is filtered while hot, and the solvent is removed by distillation under reduced pressure. The solution is then dissolved with dichloromethane, washed with 2N sodium hydroxide solution, and extracted twice with dichloromethane (5 mL each time) to remove organic by-products. 3N hydrochloric acid is added for acidification, and the pH is adjusted to 2-3. A solid is precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole is obtained, with a yield of 81%.

[0052] Example 9

[0053] (1) Add 10 mmol 1-phenyl-5-hydroxytetrazolyl, 15 mmol phosphorus pentasulfide, 15 mmol dimethyl silicone oil (viscosity 300 cps), 15 mL 1,4-dioxane and a magnetic stirrer to a reaction flask, heat to 100°C, and react for 24 hours.

[0054] (2) After the reaction is completed, the reaction solution is filtered while hot, and the solvent is removed by distillation under reduced pressure. The solution is then dissolved with dichloromethane, washed with 2N sodium hydroxide solution, and extracted twice with dichloromethane (5 mL each time) to remove organic by-products. 3N hydrochloric acid is added for acidification, and the pH is adjusted to 2-3. A solid is precipitated, filtered, and vacuum dried to obtain a solid, i.e., 1-phenyl-5-mercaptotetrazole is obtained, with a yield of 73%.

[0055] The foregoing examples are merely illustrative and are used to explain some features of the method of the present invention. The appended claims are intended to require the widest possible range that can be imagined, and the embodiments presented herein are demonstrated by the applicant's actual test results. Therefore, the applicant's intention is that the appended claims are not limited by the selection of examples that illustrate the features of the present invention. Some numerical ranges used in the claims also include sub-ranges therein, and changes in these ranges should also be interpreted as being covered by the appended claims where possible.

Claims

1. A method for preparing 1-phenyl-5-mercaptotetrazole, characterized in that: The method comprises the following steps: mixing 1-phenyl-5-hydroxytetrazolyl, phosphorus pentasulfide, a siloxane compound or a siloxane polymer, and an organic solvent, and reacting the mixture under heating conditions to obtain 1-phenyl-5-mercaptotetrazolyl; The siloxane compound is selected from one or both of hexamethyldisiloxane and disiloxane; The siloxane polymer is selected from one or more of methyl silicone oil, ethyl silicone oil, dimethyl silicone oil or phenyl silicone oil.

2. The preparation method according to claim 1, characterized in that: The viscosity of the silicone polymer is 50-300 cps.

3. The preparation method according to claim 1, characterized in that: The organic solvent includes one or more of 1,4-dioxane, toluene, xylene or anisole.

4. The preparation method according to claim 1, characterized in that: The reaction temperature is 90-110°C.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the 1-phenyl-5-hydroxytetrazolyl to phosphorus pentasulfide is 1:1.2-2.

5.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the 1-phenyl-5-hydroxytetrazolyl to the siloxane compound or siloxane polymer is 1:1.2-2.

5.

7. The preparation method according to claim 1, characterized in that: The reaction time is 10 to 30 h.

8. The preparation method according to claim 1, characterized in that: The method further comprises a refining step, wherein the refining step comprises subjecting the product to at least one of the following treatments: filtration, concentration, alkali washing, extraction, acidification precipitation or drying.

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