Method for preparing brinzolamide intermediate

Abstract

The present application belongs to the fields of pharmaceutical technology and organic synthesis technology, and particularly relates to a method for preparing a brinzolamide intermediate. In the present application, triacetyl-5-chloro-2-(benzylthio)thiophene is dissolved in ethyl acetate, water is added, stirring is performed at 2°C to 10°C while chlorine gas is slowly introduced, and washing with water is then performed to obtain a reaction product. Ammonia gas is slowly introduced into the reaction product, and after the introduction of ammonia gas is completed, the reaction product is sequentially washed with water and saturated brine. After concentrating under reduced pressure until no liquid flows out, tert-butyl methyl ether is added, and after stirring, a solid is collected by means of filtration. The solid is rinsed with tert-butyl methyl ether, and dried to obtain triacetyl-5-chloro-2-thiophene sulfonamide. In the present application, to perform the reaction, water is used for catalysis and chlorine gas is used as both a chlorinating agent and an oxidizing agent, and materials such as sodium tungstate are not used; the preparation method involves simple steps, a shortened reaction time, reduced reaction material consumption and reduced production costs, while achieving the high yield and high purity of a target product.

Description

Preparation method of brinzolamide intermediate

[0001] The present application claims priority to the Chinese patent application No. 202410462591.8, filed on April 17, 2024, and entitled "Preparation method of brinzolamide intermediate", the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine and organic synthesis, and specifically relates to a preparation method of a brinzolamide intermediate. BACKGROUND

[0003] Carbonic anhydrase CA is a widely distributed zinc-containing metalloenzyme that can reversibly catalyze the hydration of CO2 in the ciliary epithelium, thereby producing HCO3 - , which is involved in various physiological functions of the human body. The increase in intraocular pressure will make people prone to glaucoma. The role of carbonic anhydrase inhibitor CAIS is to reduce the osmotic pressure in the aqueous humor, thereby reducing the production of aqueous humor and lowering the intraocular pressure, thereby treating glaucoma.

[0004] Brinzolamide is a very valuable new anti-glaucoma drug and a new type of topical carbonic anhydrase inhibitor. Its chemical name is (R)-(+)-4-ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide, and its chemical structure is shown as formula I:

[0005] Brinzolamide is a heterocyclic sulfonamide drug, which was approved for marketing in the United States in 1998. Its eye drop product name is pilopine. Brinzolamide has high selectivity, high affinity, and can significantly inhibit the activity of carbonic anhydrase isozyme II, effectively reducing the intraocular pressure. It can quickly enter the ocular tissue after eye drops, and has a long half-life in the iris, ciliary body, choroid and retina, thus greatly prolonging the action time. Studies have shown that brinzolamide has less eye irritation, and its physiological value and suspension design make eye drops comfortable, with good tolerance and safety. The adverse reactions are relatively reduced and not serious compared with dorzolamide, and usually do not require treatment and can be relieved spontaneously.

[0006] The important intermediate (S)-6-chloro-3,4-dihydro-4H-thieno[3,2-e]-1,2-thiazine-4-hydroxy 1,1-dioxide for synthesizing brinzolamide has been proven to be a universal intermediate for synthesizing different carbonic anhydrase inhibitors in the laboratory, and its chemical structure is shown as formula II. It has good application value to study the synthesis thereof.

[0007] The existing synthetic route takes thiophene as a starting material, and synthesizes the ring-closed product (S)-6-chloro-3,4-dihydro-4H-thiopheno[3,2-E]-1,2-thiazine-4-hydroxy 1,1-dioxide through six steps of chlorination, C-acylation, sulfidation, sulfonamidation, carbonyl α-hydrobromination, and asymmetric reduction-cyclization, as shown in Formula III. The sulfonamide group -SO2NH2 plays a huge role in carbonic anhydrase inhibitors, and therefore, the sulfonamidation reaction in the fourth step is the most important step in the six steps.

[0008] The reagents and conditions for each reaction step in Formula III are as follows: a) NCS, HClO4; b) AcCl, AlCl3; c) NaSBn, NaOH; d) Cl2, NH3, Na2WO4, H2O2; e) PBP, H2SO4; f) (+)-Ipc2BCl, NaOH.

[0009] There are two methods for introducing the sulfonamide group -SO2NH2. One method is a two-step sulfonamidation method: using strong base n-BuLi for Li exchange at the 2-position, then introducing SO2 to form a sulfinate salt by polarization of the Li-C bond, and finally introducing the sulfonamide group under the amination of HOSA, as shown in Formula IV. However, n-BuLi is too active, and in order to reduce its activity, Li exchange needs to be carried out at a low temperature of -70°C, and the reaction needs to be carried out under anhydrous and anaerobic conditions. In addition, n-BuLi is corrosive and has a certain risk, and therefore, it is not suitable for large-scale industrial production. At the same time, n-BuLi has poor selectivity for this compound, and may have a certain selectivity for the 4-position and the 5-position, as shown in Formula V, to generate other substances. In addition, this method has a long reaction period, and it takes more than 3 days to complete.

[0010] The second method is to first sulfidate and then introduce the sulfonamide group, which is a brand-new method, i.e., the fourth step of sulfonamidation in Formula III. This step is a one-pot reaction, and triacetyl-5-chloro-2-thiophene sulfonamide is synthesized through three steps of chlorination, amination, and oxidation from triacetyl-5-chloro-2-(thiobenzyl) thiophene, as shown in Formula VI:

[0011] Specific operation is: triacetyl-5-chloro-2-(thiobenzyl) thiophene is dissolved in ethyl acetate, 1 eq chlorine is introduced under stirring at 2-10℃ until no triacetyl-5-chloro-2-(thiobenzyl) thiophene is detected; air is blown for 1h, then ammonia is introduced, the temperature is kept at 5-15℃, the reaction is carried out until the intermediate product sulfinyl chloride is completely converted; air is blown for 1h, water is added, and the temperature is cooled to 15℃; sodium tungstate trihydrate and hydrogen peroxide are added, the mixture is stirred at 35℃ for 2h, then stirred at room temperature for 16h; water is added to separate the organic layer, sodium bisulfite is added until no peroxide is detected, the organic layer is separated, first washed with saturated sodium bicarbonate until the pH value is 8, then washed with saturated brine, filtered, concentrated, and then tert-butyl methyl ether is added to the residue, the solid is collected by filtration, washed with tert-butyl methyl ether, and dried in air until the weight is constant, to obtain triacetyl-5-chloro-2-thiophene sulfonamide, the yield is 71%, and the melting point is 178-179℃. This method has very good effect, is simple to operate, and has stable yield, can successfully avoid the influence of low temperature of-70℃, and greatly shortens the reaction period. However, the disadvantage of this method is that sodium tungstate is harmful to health, hydrogen peroxide is a dangerous product, and the reaction is violent after the addition of hydrogen peroxide, which is easy to cause material overflow. SUMMARY

[0012] The purpose of the present application is to provide a preparation method of a brinzoamide intermediate, i.e. triacetyl-5-chloro-2-thiophene sulfonamide, the chemical structure of which is shown in formula VII:

[0013] The preparation method provided in the present application does not use materials such as sodium tungstate, hydrogen peroxide, sodium bisulfite and sodium bicarbonate for reaction, reduces the air blowing process, is safer in production, and can avoid material overflow.

[0014] In order to achieve the above purpose, the present application provides the following technical scheme:

[0015] The present application provides a preparation method of triacetyl-5-chloro-2-thiophene sulfonamide, which is divided into two steps, and the chemical reaction process is shown in formula VIII: (1) oxidative chlorination: triacetyl-5-chloro-2-(thiobenzyl) thiophene is used as raw material, chlorine is used as chlorinating agent and oxidizing agent, and sulfonyl chloride group-SO2Cl is generated; (2) sulfonamidation: ammonia is introduced into the reactant to obtain the triacetyl-5-chloro-2-thiophene sulfonamide;

[0016] The specific steps of one specific embodiment of the preparation method of triacetyl-5-chloro-2-thiophene sulfonamide provided in the present application are as follows.

[0017] (1) Triacetyl-5-chloro-2-(thiobenzyl) thiophene is dissolved in ethyl acetate, water is added, and chlorine is slowly introduced under stirring at 2-10℃, and then washed with water twice to obtain the reactant.

[0018] (2) Slowly pass ammonia gas into the reactant, then wash with water and saturated brine, concentrate under reduced pressure until no liquid flows, then add t-butyl methyl ether and stir for 30-60 min, collect the solid by filtration; wash the solid with t-butyl methyl ether, and dry by blowing air to obtain the triacetyl-5-chloro-2-thiophenesulfonamide.

[0019] Further, the weight ratio of the triacetyl-5-chloro-2-(thiobenzyl)thiophene, ethyl acetate and water is 1:16-20:1-4.

[0020] Further, the amount of chlorine gas passed is 3 eq-4 eq, and the amount of ammonia gas passed is 1.0 eq-1.2 eq.

[0021] The triacetyl-5-chloro-2-thiophenesulfonamide obtained by the preparation method provided in the application has a yield of 80% and a purity of 98%, and a melting point of 178-179°C.

[0022] The application provides a preparation method of triacetyl-5-chloro-2-thiophenesulfonamide. The sulfonamidation step in the dth step of formula III is improved, water is added for catalysis in the reaction, and chlorine gas is used as a chlorinating agent and an oxidizing agent to generate a sulfonyl chloride group -SO2Cl in one step; after passing ammonia gas, triacetyl-5-chloro-2-thiophenesulfonamide is generated in a second step. The application does not use sodium tungstate, hydrogen peroxide, sodium bisulfite and sodium bicarbonate and other materials for reaction, reduces the air blowing process, has higher production safety, and can avoid material flushing. The application uses water to catalyze the reaction process, the preparation method has simple steps, short reaction time, saves reaction materials and production cost, and has energy saving, environmental protection, less harmful substance discharge, high yield and high purity of the target product. DETAILED DESCRIPTION

[0023] In order to further illustrate the application, the scheme of the application will be described in detail below in combination with the drawings and examples, but they should not be understood as limiting the scope of protection of the application.

[0024] Example 1

[0025] (1) Dissolve 1 kg of triacetyl-5-chloro-2-(thiobenzyl)thiophene in 17 kg of ethyl acetate, add 1 kg of water, stir at 10°C, slowly pass 3 eq of chlorine gas, and pass for 3 h; then wash with water twice, each time with 10 L of water, to obtain the reactant.

[0026] (2) Slowly pass 1.1 eq of ammonia gas into the reactant of step (1), and after the ammonia gas is passed, wash with 10 L of water and 5 L of saturated brine in sequence; after concentrating under reduced pressure until no liquid flows out, add 20 L of t-butyl methyl ether, stir for 30 min, collect the solid by filtration; wash the solid with t-butyl methyl ether, and dry by blowing air to obtain triacetyl-5-chloro-2-thiophenesulfonamide with a yield of 81.8% and a purity of 98.7%.

[0027] Example 2

[0028] (1) Dissolve 1 kg of triacetyl-5-chloro-2-(thiobenzyl)thiophene in 16 kg of ethyl acetate, add 2 kg of water, stir at 7°C, and slowly pass 3.2 eq of chlorine gas for 3 h; then wash twice with 10 L of water each time to obtain the reactant.

[0029] (2) Slowly pass 1.0 eq of ammonia gas into the reactant of step (1), and after the ammonia gas is passed, wash with 10 L of water and 5 L of saturated brine in sequence; after concentrating under reduced pressure until no liquid flows out, add 20 L of t-butyl methyl ether, stir for 40 min, collect the solid by filtration; wash the solid with t-butyl methyl ether, and dry by blowing air to obtain triacetyl-5-chloro-2-thiophenesulfonamide with a yield of 85.2% and a purity of 99.2%.

[0030] Example 3

[0031] (1) Dissolve 1 kg of triacetyl-5-chloro-2-(thiobenzyl)thiophene in 18 kg of ethyl acetate, add 4 kg of water, stir at 4°C, and slowly pass 3.5 eq of chlorine gas for 3 h; then wash twice with 10 L of water each time to obtain the reactant.

[0032] (2) Slowly pass 1.2 eq of ammonia gas into the reactant of step (1), and after the ammonia gas is passed, wash with 10 L of water and 5 L of saturated brine in sequence; after concentrating under reduced pressure until no liquid flows out, add 20 L of t-butyl methyl ether, stir for 60 min, collect the solid by filtration; wash the solid with t-butyl methyl ether, and dry by blowing air to obtain triacetyl-5-chloro-2-thiophenesulfonamide with a yield of 82.6% and a purity of 99.4%.

[0033] Example 4

[0034] (1) Dissolve 1 kg of triacetyl-5-chloro-2-(thiobenzyl)thiophene in 20 kg of ethyl acetate, add 3 kg of water, stir at 2°C, and slowly pass 4.0 eq of chlorine gas for 3 h; then wash twice with 10 L of water each time to obtain the reactant.

[0035] (2) Slowly pass 1.1 eq of ammonia gas into the reactant of step (1), and after the ammonia gas is passed, wash with 10 L of water and 5 L of saturated brine in sequence; after the concentration under reduced pressure until no liquid flows out, add 20 L of t-butyl methyl ether, stir for 50 min, collect the solid by filtration; wash the solid with t-butyl methyl ether, and dry by air blowing to obtain triacetyl-5-chloro-2-thiophenesulfonamide with a yield of 81.3% and a purity of 98.9%.

[0036] The melting point of triacetyl-5-chloro-2-thiophenesulfonamide prepared in Examples 1-4 is 178-179°C.

[0037] Comparative Example 1

[0038] Comparative Example 1 is compared with Example 3, and no water is added in the reaction of step (1).

[0039] (1) Dissolve 1 kg of triacetyl-5-chloro-2-(thiobenzyl)thiophene in 18 kg of ethyl acetate, stir at 4°C, and slowly pass 3.5 eq of chlorine gas. During the reaction, the reactant gradually coagulates and hardens into a solid, and the reaction cannot continue to generate triacetyl-5-chloro-2-thiophenesulfonamide.

[0040] Although the above examples make a detailed description of the present application, it is only a part of the examples of the present application, not all the examples, and other examples can be obtained according to the present examples without creativity, which all belong to the protection scope of the present application.

Claims

1. A process for the preparation of triacetyl-5-chloro-2-thiophenesulfonamide, characterized in that, The method comprises the following steps: (1) using triacetyl-5-chloro-2-(thiobenzyl)thiophene as raw material, using chlorine as chlorinating agent and oxidant, performing oxidative chlorination reaction to generate sulfonyl chloride group-SO2Cl, to obtain a reactant; the oxidative chlorination reaction is performed in water; (2) introducing ammonia into the reactant to perform sulfonamidation reaction, to obtain the triacetyl-5-chloro-2-thiophenesulfonamide.

2. The production method according to claim 1, characterized by, The oxidative chlorination reaction is performed in ethyl acetate solvent and water.

3. The production method according to claim 2, characterized by, The weight ratio of the triacetyl-5-chloro-2-(thiobenzyl)thiophene, ethyl acetate and water is 1:16-20:1-4.

4. The production method according to claim 1, characterized by, The amount of chlorine introduced is 3eq-4eq, and the amount of ammonia introduced is 1.0eq-1.2eq.

5. The preparation method according to claim 1, characterized in that The temperature of the oxidative chlorination reaction is 2-10℃; the oxidative chlorination reaction is performed under stirring condition.

6. The method of claim 1, wherein, After the oxidative chlorination reaction, the obtained reaction product is further washed with water.

7. The production method according to claim 6, wherein The water washing is performed twice.

8. The method of claim 1, wherein, After the sulfonamidation reaction, the obtained sulfonamidation reaction product is further washed, and the washing is sequentially performed with water and saturated brine.

9. The production method according to claim 8, characterized by, After the washing, the obtained product is further concentrated under reduced pressure until no liquid flows out.

10. The method of claim 9, wherein, After the concentration under reduced pressure, the obtained product is further stirred with tert-butyl methyl ether, filtered, and the solid is collected.

11. The method of claim 10, wherein, The stirring time is 30-60min.

12. The method of claim 10, wherein, After the collection, the obtained solid is further washed with tert-butyl methyl ether.

13. The method of claim 12, wherein, After the washing, the obtained product is further dried.

14. The process according to any one of claims 1 to 13, characterized in that, The method comprises the following steps: (1) dissolving triacetyl-5-chloro-2-(thiobenzyl)thiophene in ethyl acetate, adding water, stirring at 2-10℃, slowly introducing chlorine, and then washing with water twice, to obtain a reactant; (2) slowly introducing ammonia into the reactant in step (1), and then sequentially washing with water and saturated brine; After the concentration under reduced pressure until no liquid flows out, tert-butyl methyl ether is added, stirred for 30-60min, filtered to collect solid, the solid is washed with tert-butyl methyl ether, and dried, to obtain the triacetyl-5-chloro-2-thiophenesulfonamide.

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