A method for synthesizing indapamide intermediate-N-amino-2-methylindoline hydrochloride

Abstract

The invention discloses a method for synthesizing an indapamide intermediate, N-amino-2-methylindoline hydrochloride. The invention uses 2-methylindoline as a raw material, reacts with sodium nitrite to obtain a nitrosated solution, adds the nitrosated solution to a mixed solution containing Tween 80, benzyltriethylammonium chloride, hydrazine hydrate and zinc powder, obtains N-amino-2-methylindoline through a reduction reaction, and obtains a target compound, N-amino-2-methylindoline hydrochloride, after acidification with a hydrogen chloride proton solution. The method has a simple synthesis process, a mild and controllable reaction process, can improve the purity and yield of the target compound, and is conducive to industrial application.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation methods for drug synthesis, and specifically relates to a method for synthesizing an indapamide intermediate, N-amino-2-methylindoline hydrochloride. Background Art

[0002] There are three main methods for preparing this intermediate reported in the literature:

[0003] Method 1

[0004]

[0005] Patent US5110946 reports that 2-methylindoline is used as a raw material, which reacts with hydroxylamine sulfonic acid to generate N-amino-2-methylindoline, which is then salified with hydrochloric acid in toluene to form N-amino-2-methylindoline hydrochloride.

[0006] Method 2

[0007]

[0008] Patent EP0462016A1 reports that the target compound is prepared using the Raschig method, sodium hypochlorite reacts with ammonia at -10°C to generate monochloramine, then an alcohol solution of 2-methylindoline is added to the reaction solution, and then a sodium hydroxide solution is added to react to generate N-amino-2-methylindoline, and finally acidified to form N-amino-2-methylindoline hydrochloride.

[0009] Method 3

[0010]

[0011] This method is divided into two processes: nitrification and reduction. The main reaction process is:

[0012] 1. Using 2-methylindoline as raw material, firstly use sodium nitrite solution to carry out nitrosation reaction in an acidic system;

[0013] 2. Add zinc powder to the nitrosating solution to reduce the nitroso group to the amino group, and then acidify to obtain the product N-amino-2-methylindoline hydrochloride.

[0014] There are three preparation methods in the literature for comparison. Method 1, compared with the other two methods, has high raw material cost, long reaction time, which takes 24 hours, and low yield, with a total yield of about 60%, so it has not been used in large-scale industrial applications.

[0015] Method 2 has strict requirements on the reaction temperature, and needs to react at -10°C. In addition, the Raschig method has many side reactions in the synthesis of such compounds, and the pH and reaction solution concentration are greatly affected, resulting in many reaction impurities and low yield. Therefore, this method is not suitable for large-scale industrial production.

[0016] Method three is the most widely used method in current industrial production.

[0017] However, this method currently has the following disadvantages in practical applications:

[0018] 1. During the reduction process of nitrite, as zinc powder is added to the nitrite, the reaction temperature rises sharply. The zinc powder is added for a long time, causing some nitrite to be oxidized and decomposed before being reduced, affecting the reaction yield. The reaction yield of this step is low.

[0019] 2. In the process of adding zinc powder to the nitrite solution, heat is released violently and the adding speed needs to be strictly controlled. The safety factor is low and the operation is difficult.

[0020] 3. The impurities produced by the reduction reaction are tar-like substances that are easy to adhere to the solid surface and are difficult to remove, resulting in the poor appearance of the product, which is a brown to light brown solid.

[0021] 4. The nitrosation-reduction reaction is a solid-liquid two-phase reaction with a slow reaction rate and incomplete reaction. The incompletely reduced nitrosamine compounds are genotoxic impurities, which can be transferred to the finished indapamide product, creating the risk of exceeding the limit of genotoxic impurities and causing the quality of the finished indapamide product to be unqualified. Summary of the invention

[0022] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a novel method for synthesizing N-amino-2-methylindoline hydrochloride.

[0023] The present invention is achieved through the following technical scheme, and the synthesis steps include:

[0024] Dissolve 2-methylindoline in methanol, and when the temperature drops to 0-15°C, add hydrochloric acid to the reaction system, and add sodium nitrite solution dropwise at a temperature of 0-15°C. After the addition, maintain the internal temperature at 0-15°C and stir for 10 minutes to obtain a nitrosation reaction solution for standby use.

[0025] A certain amount of Tween 80, benzyltriethylammonium chloride, hydrazine hydrate and ammonium acetate are added to a protic solvent, wherein the amount of Tween 80 added is such that the mass ratio of Tween 80 to 2-methylindoline is 0.01-0.1:1, the amount of benzyltriethylammonium chloride added is such that the mass ratio of benzyltriethylammonium chloride to 2-methylindoline is 0.01-0.1:1, the amount of hydrazine hydrate added is such that the mass ratio of hydrazine hydrate to 2-methylindoline is 0.01-0.1:1, and the amount of ammonium acetate added is such that the mass ratio of ammonium acetate to 2-methylindoline is 1-5:1. Under stirring, zinc powder is added to the reaction system, wherein the mass ratio of zinc powder to 2-methylindoline is 0.5-2:1. The temperature is controlled at 0-40° C., and the above-mentioned nitrosation reaction solution is added to the reaction system. After the addition is completed, the temperature is controlled at 10-40° C. and stirred for 1-4 hours. The reaction solution is extracted with toluene, the temperature of the reaction system is controlled at 0-40°C, a proton solution of hydrogen chloride is added to the toluene layer, the mass ratio of the proton solution of hydrogen chloride to 2-methylindoline is 0.5-2:1, after the solution is added, the temperature is 0-40°C, crystallization is carried out, and N-amino-2-methylindoline hydrochloride is obtained by filtration.

[0026] The protonic solvent of hydrogen chloride in the reduction reaction is water, methanol, ethanol, isopropanol or a mixture thereof, preferably water; the protonic solution of hydrogen chloride in the salt formation is a saturated hydrogen chloride isopropanol solution or a hydrogen chloride aqueous solution (i.e., hydrochloric acid), preferably a hydrogen chloride isopropanol solution.

[0027] In order to obtain better results, a large number of experiments were carried out to optimize the conditions and screen them. The preferred raw material ratios were as follows: the amount of Tween 80 added was a mass ratio of Tween 80 to 2-methylindoline of 0.01-0.05:1, the amount of benzyltriethylammonium chloride added was a mass ratio of benzyltriethylammonium chloride to 2-methylindoline of 0.01-0.05:1, the amount of hydrazine hydrate added was a mass ratio of hydrazine hydrate to 2-methylindoline of 0.01-0.05:1, and the amount of ammonium acetate added was a mass ratio of ammonium acetate to 2-methylindoline of 1-3:1. The mass ratio of zinc powder to 2-methylindoline is 1-2:1, the mass ratio of the proton solution of hydrogen chloride to 2-methylindoline during salt formation is 0.5-1.2:1, the temperature of the nitrosation reaction solution is preferably 10-30°C, after the addition is completed, the temperature of the temperature-controlled reaction is preferably 10-30°C, the reaction time is preferably 2-4 hours, the temperature of the proton solution of hydrogen chloride added to the toluene layer is preferably 10-30°C, the mass ratio of the proton solution of hydrogen chloride to 2-methylindoline is 0.5-1.2:1, and the temperature of the crystallization after the addition is preferably 0-20°C.

[0028] More preferably, the amount of Tween 80 added is such that the mass ratio of Tween 80 to 2-methylindoline is 0.03:1, the amount of benzyltriethylammonium chloride added is such that the mass ratio of benzyltriethylammonium chloride to 2-methylindoline is 0.03:1, the amount of hydrazine hydrate added is such that the mass ratio of hydrazine hydrate to 2-methylindoline is 0.03:1, the amount of ammonium acetate added is such that the mass ratio of ammonium acetate to 2-methylindoline is 2:1, the mass ratio of zinc powder to 2-methylindoline is 1.5:1, the mass ratio of the proton solution of hydrogen chloride to 2-methylindoline during salt formation is 1:1, the temperature of the nitrosation reaction solution added is 15-20°C, after the addition is completed, the temperature of the temperature-controlled reaction is 20-30°C, the reaction time is 3 hours, the temperature when the proton solution of hydrogen chloride is added to the toluene layer is preferably 20-30°C, the mass ratio of the proton solution of hydrogen chloride to 2-methylindoline is 1:1, and the temperature of the cooling and crystallization after the addition is preferably 0-10°C.

[0029] The present invention discloses a method for synthesizing an indapamide intermediate, N-amino-2-methylindoline hydrochloride. Compared with the prior art, this process has the following advantages:

[0030] 1. During the reduction process, the antioxidant hydrazine hydrate is added to inhibit the occurrence of nitrite oxidation and decomposition side reactions to the greatest extent, thereby achieving the effect of improving the reaction yield and quality.

[0031] 2. The order of adding materials in the traditional process is changed, and the nitrite reaction liquid is added to the solution containing zinc powder, which makes the reaction process more gentle and controllable, increases the safety factor of the reaction, and is more suitable for large-scale industrial production.

[0032] 3. Adding Tween 80 and benzyltriethylammonium chloride to the reaction system can increase the contact area between zinc powder and liquid during the reaction, thereby playing a catalytic role in the reaction, making the reaction more complete, thereby achieving the purpose of improving the reaction yield and product quality.

[0033] Compared with the traditional process, the invention adds antioxidant hydrazine hydrate, Tween 80 and benzyltriethylammonium chloride to play a synergistic catalytic role, and changes the order of adding materials. The process yield can be improved by more than 10% compared with the traditional process yield, reaching more than 90%, the product purity is improved from 90%-95% to about 99%, the product appearance is improved from light brown solid to off-white solid, the subsequent quality and yield of indapamide are promoted, the total yield is high, and the problems of high cost, low safety factor, unsuitability for industrial production and the like of the prior art are solved. DETAILED DESCRIPTION

[0034] For the purpose of simplicity and clarity, the description of the known technology is appropriately omitted below to avoid those unnecessary details affecting the description of the technical solution. In conjunction with the preferred embodiments below, a method for producing N-amino-2-methylindoline hydrochloride of the present invention is further described, and the 2-methylindoline, Tween 80, benzyltriethylammonium chloride, hydrazine hydrate, sodium nitrite, zinc powder, etc. used are particularly described and are all commercially available. The present invention is further described below in conjunction with the examples, but the present invention is not limited thereto. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Liquid phase chromatogram of N-amino-2-methylindoline hydrochloride in Example 1

[0036] Figure 2 Liquid phase chromatogram of N-amino-2-methylindoline hydrochloride in Example 2

[0037] Figure 3 Liquid phase chromatogram of N-amino-2-methylindoline hydrochloride in Example 3

[0038] Figure 4 Liquid phase chromatogram of N-amino-2-methylindoline hydrochloride in Example 4

[0039] Figure 5 Comparative Example 1 N-amino-2-methylindoline hydrochloride liquid chromatogram

[0040] Figure 6 Comparative Example 2 N-amino-2-methylindoline hydrochloride liquid chromatogram Figure 7 The NMR of N-amino-2-methylindoline hydrochloride obtained in Example 1

[0041] Example 1

[0042] Dissolve 20g of 2-methylindoline in 40g of methanol, and when the temperature drops to 0-15°C, add 20g of hydrochloric acid to the reaction system, and add sodium nitrite solution (15g of sodium nitrite is dissolved in 30g of water) dropwise at a temperature of 0-15°C. After the addition, maintain the internal temperature at 0-15°C and stir for 10 minutes to obtain a nitrosation reaction solution for standby use.

[0043] Add 40g of ammonium acetate, 50mL of water, 0.6g of Tween 80, 0.6g of benzyltriethylammonium chloride, and 0.6g of hydrazine hydrate to a reaction flask, add 30g of zinc powder under stirring, control the temperature at 15-20°C, start adding the above nitrosation reaction solution, control the temperature at 20-25°C for 3 hours, and the reaction is complete. Use 180g of toluene to extract the reaction solution, discard the aqueous phase and unreacted zinc powder, leave the organic phase, control the temperature in the reaction flask at 20-30°C, add 20g of hydrogen chloride isopropanol solution to the organic phase, cool to 0-10°C after addition, and stir for 4 hours. Filter, rinse the filter cake with 20.0g of toluene, and obtain 26.5g of N-amino-2-methylindoline hydrochloride, with a yield of 95.5% and a purity of 99.40%.

[0044] Example 2

[0045] The preparation method of nitrosation reaction solution is the same as that of Example 1

[0046] Add 60g of ammonium acetate, 25g of water, 25g of ethanol, 1g of Tween 80, 1g of benzyltriethylammonium chloride, and 1g of hydrazine hydrate to a reaction flask, add 40g of zinc powder under stirring, control the temperature at 10-15°C, start adding the nitrosation reaction solution, control the temperature at 15-20°C for 4 hours, and the reaction is complete. Use 180g of toluene to extract the reaction solution, discard the aqueous phase and unreacted zinc powder, and leave the organic phase. Control the temperature in the reaction flask at 10-20°C, add 24g of hydrochloric acid to the organic phase, cool to 10-15°C after addition, and stir for 4 hours. Filter, rinse the filter cake with 20.0g of toluene to obtain 25.7g of N-amino-2-methylindoline hydrochloride, with a yield of 92.6% and a purity of 99.23%.

[0047] Example 3

[0048] The preparation method of nitrosation reaction solution is the same as that of Example 1

[0049] Add 20g of ammonium acetate, 25g of water, 25g of methanol, 0.5g of Tween 80, 0.2g of benzyltriethylammonium chloride, and 0.5g of hydrazine hydrate to a reaction flask, add 20g of zinc powder under stirring, control the temperature at 20-30°C, start adding the nitrosation reaction solution, and after the addition, control the temperature at 25-30°C to react for 3 hours, and the reaction is complete. Use 180g of toluene to extract the reaction solution, discard the aqueous phase and unreacted zinc powder, and leave the organic phase. Control the temperature in the reaction flask at 30-40°C, add 10g of hydrogen chloride isopropanol solution to the organic phase, cool to 15-20°C after the addition, and stir for 4 hours. Filter, rinse the filter cake with 20.0g of toluene, and obtain 25.2g of N-amino-2-methylindoline hydrochloride, with a yield of 90.8% and a purity of 99.01%.

[0050] Example 4

[0051] The preparation method of nitrosation reaction solution is the same as that of Example 1

[0052] Add 50g of ammonium acetate, 25g of water, 25g of isopropanol, 0.2g of Tween 80, 0.5g of benzyltriethylammonium chloride, and 0.2g of hydrazine hydrate to a reaction flask, add 30g of zinc powder under stirring, control the temperature at 30-40°C, start adding the nitrosation reaction solution, control the temperature at 30-40°C for 2 hours, and the reaction is complete. Use 180g of toluene to extract the reaction solution, discard the aqueous phase and unreacted zinc powder, leave the organic phase, control the temperature in the reaction flask at 20-40°C, add 15g of hydrogen chloride isopropanol solution to the organic phase, control the temperature at 20-40°C after addition, and stir for 4 hours. Filter, rinse the filter cake with 20.0g of toluene, and obtain 24.8g of N-amino-2-methylindoline hydrochloride, with a yield of 89.4% and a purity of 99.03%.

[0053] Example 5

[0054] Preparation of indapamide using N-amino-2-methylindoline hydrochloride prepared in Example 1

[0055] Add 200 ml of tetrahydrofuran and 9.3 g of N-amino-2-methylindoline hydrochloride to the reaction bottle, add 8.5 ml of triethylamine dropwise under stirring, cool to 10°C, add 10.8 g of N, N'-dicyclohexylcarbodiimide and 11.0 g of 4-chloro-3-sulfonylaminobenzoic acid, control the reaction temperature at 0-20°C, and react for 10 hours. After the reaction is completed, filter out the insoluble matter, evaporate the tetrahydrofuran in the filtrate, add isopropanol-water solution for recrystallization, and obtain 16.5 g of indapamide with a yield of 90.4%.

[0056] Comparative Example 1

[0057] Dissolve 20g of 2-methylindoline in 40g of methanol, and when the temperature drops to 0-15°C, add 20g of hydrochloric acid to the reaction system, and add sodium nitrite solution (15g of sodium nitrite dissolved in 30g of water) dropwise at a temperature of 0-15°C. After the addition, maintain the internal temperature at 0-15°C and stir for 10 minutes to obtain a nitrosation reaction solution.

[0058] Add 40g of ammonium acetate, 0.6g of Tween 80, 0.6g of benzyltriethylammonium chloride, and 0.6g of hydrazine hydrate to the nitrosation reaction solution, control the temperature at 15-20°C while stirring, add 30g of zinc powder in portions, and control the temperature at 20-25°C to react for 3 hours. Extract the reaction solution with 180g of toluene, discard the aqueous phase and unreacted zinc powder, and leave the organic phase. Control the temperature in the reaction bottle at 20-30°C, add 20g of hydrogen chloride isopropanol solution to the organic phase, cool to 0-10°C after addition, and stir for 4 hours. Filter, rinse the filter cake with 20.0g of toluene, and obtain 21.8g of N-amino-2-methylindoline hydrochloride, with a yield of 78.6% and a purity of 91.01%.

[0059] Comparative Example 2

[0060] Dissolve 20g of 2-methylindoline in 40g of methanol, and when the temperature drops to 0-15°C, add 20g of hydrochloric acid to the reaction system, and add sodium nitrite solution (15g of sodium nitrite dissolved in 30g of water) dropwise at a temperature of 0-15°C. After the addition, maintain the internal temperature at 0-15°C and stir for 10 minutes to obtain a nitrosation reaction solution.

[0061] Add 40g of ammonium acetate to the nitrosation reaction solution, control the temperature at 15-20°C while stirring, add 30g of zinc powder in portions, control the temperature at 20-25°C and react for 3 hours. Extract the reaction solution with 180g of toluene, discard the aqueous phase and unreacted zinc powder, leave the organic phase, control the temperature in the reaction bottle at 20-30°C, add 20g of hydrogen chloride isopropanol solution to the organic phase, cool to 0-10°C after addition, and stir for 4 hours. Filter, rinse the filter cake with 20.0g of toluene, and obtain 21.3g of N-amino-2-methylindoline hydrochloride, with a yield of 76.8% and a purity of 90.38%.

Claims

1. A method for synthesizing an indapamide intermediate, N-amino-2-methylindoline hydrochloride, characterized in that The synthesis steps include: 1) Dissolve 2-methylindoline in methanol, and when the temperature drops to 0-15°C, add hydrochloric acid to the reaction system, and add sodium nitrite solution dropwise at a temperature of 0-15°C. After the addition, maintain the internal temperature at 0-15°C and stir for 10 minutes to obtain a nitrosation reaction solution for standby use. 2) Add a certain amount of Tween 80, benzyltriethylammonium chloride, hydrazine hydrate, and ammonium acetate to the protic solvent, add zinc powder to the reaction system under stirring, control the temperature at 0-40°C, add the nitrosation reaction solution of step 1 to the reaction system, control the temperature at 10-40°C and stir for 1-4 hours. Extract the reaction solution with toluene. 3) Control the temperature of the reaction system to 0-40° C., add the proton solution of hydrogen chloride to the organic phase, keep the temperature at 0-40° C. for crystallization, and filter to obtain N-amino-2-methylindoline hydrochloride.

2. The method for synthesizing the indapamide intermediate N-amino-2-methylindoline hydrochloride according to claim 1, characterized in that The ratio of each reactant is as follows: the mass ratio of Tween 80 to 2-methylindoline is 0.01-0.1:1, the mass ratio of benzyltriethylammonium chloride to 2-methylindoline is 0.01-0.1:1, the added amount of hydrazine hydrate is 0.01-0.1:1, the added amount of ammonium acetate is 1-5:1, and under stirring, the added amount of zinc powder is 0.5-2:

1.

3. The synthetic method of N-amino-2-methylindoline hydrochloride according to claim 1, characterized in that The protic solvent of hydrogen chloride in step 3) is water, methanol aqueous solution, ethanol aqueous solution or isopropanol aqueous solution.

4. The method for synthesizing the indapamide intermediate N-amino-2-methylindoline hydrochloride according to claim 1, characterized in that The proton solution of hydrogen chloride described in step 3) is hydrochloric acid or isopropanol solution of hydrogen chloride, and the mass ratio of the proton solution of hydrogen chloride to 2-methylindoline is 0.5-2:1.

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