Process for the preparation of an aminotadalafil butandioic acid derivative

Abstract

The application discloses a preparation method of an amino tadalafil succinic acid derivative, and comprises the following steps: S1, synthesizing compound 1, i.e. 4-hydrazinyl-4-oxobutanoic acid, by reacting hydrazine with succinic anhydride; S2, synthesizing compound 3, i.e. the amino tadalafil succinic acid derivative, by carrying out a hydrazinolysis cyclization reaction of compound 2 with compound 1. In the amino tadalafil succinic acid derivative prepared by the application, the solubility of the amino tadalafil derivative is greatly improved by introducing succinic acid, and the drug administration mode is expanded; meanwhile, the existence of the carboxyl group as a reactive site can be used to derive other functional groups or to be connected with other active groups to form a synergistic active group, so that more possibilities are provided for preparing other related products based on the amino tadalafil derivative.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing an aminotadalafil succinic acid derivative. Background Technology

[0002] Tadalafil is an effective inhibitor of phosphodiesterase 5 (PED5) and can be used in various conditions, including erectile dysfunction in men, pulmonary hypertension, and lower urinary tract dysfunction. Aminotadalafil is an analogue of tadalafil and has similar efficacy. However, both tadalafil and aminotadalafil suffer from poor solubility. Poor solubility not only affects the drug's in vitro and in vivo activity but also hinders absorption and efficacy.

[0003] Therefore, it is now necessary to improve existing technologies to provide more reliable solutions. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing aminotadalafil succinic acid derivatives, which addresses the shortcomings of the prior art.

[0005] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: a method for preparing an aminotadalafil succinic acid derivative, comprising the following steps:

[0006] S1. Compound 1 (compound 1), namely 4-hydrazino-4-oxobutyric acid, is synthesized by reacting hydrazine with succinic anhydride.

[0007] S2. Compound 3 (compound 3), namely an aminotadanafil succinic acid derivative, is synthesized by hydrazolytic cyclization reaction between compound 2 (compound 2) and compound 1 (compound 1).

[0008] The chemical structures of compounds 2 and 3 are shown below:

[0009] .

[0010] The synthetic route of this invention is as follows:

[0011] .

[0012] Preferably, the preparation method of the aminotadalafil succinic acid derivative includes the following steps:

[0013] Preferably, step S1 specifically involves adding succinic acid monoester and hydrazine to an alcohol solvent, heating the mixture to react, and synthesizing compound 1.

[0014] Preferably, in step S1, the succinic acid monoester is at least one of monomethyl succinic acid and monoethyl succinic acid, and most preferably monomethyl succinic acid.

[0015] Preferably, the molar ratio of hydrazine to monosuccinic acid is 1.2 to 2:1, for example, a ratio of 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1 or any value formed by any two of them, with the most preferred value being 1.4:1.

[0016] Preferably, in step S1, the alcohol solvent is at least one of methanol, ethanol, n-propanol, isopropanol, and n-butanol, with ethanol being the most preferred.

[0017] Preferably, the ratio of the volume of the alcohol solvent to the mass of the succinate ester is 4 to 12:1, in volume units of mL and mass units of g. For example, the ratio is 4, 6, 8, 10, 12 or any combination thereof. To ensure sufficient stirring of the reaction and no waste of solvent, the most preferred ratio is 6.

[0018] Preferably, in step S1, the reaction temperature is 60~85℃, for example, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃ or any value formed by any two of them, with 75℃ being the most preferred.

[0019] Preferably, in step S1, the reaction time is 1 to 5 hours, for example, 1, 2, 3, 4, 5 or any value formed by any two of them, and the reaction endpoint is confirmed by TLC or HPLC to ensure that the succinic acid monoester reaction is complete.

[0020] Preferably, in step S1, the hydrazine is 80% hydrated hydrazine.

[0021] Preferably, step S1 specifically includes:

[0022] Succinic acid monoester and 80% hydrazine hydrate were added to an alcohol solvent and heated under reflux at 60-85°C for 1-5 hours. After the reaction was complete, the reaction solution was concentrated, cooled to 5-10°C, filtered, the filter cake was washed with water, collected, and dried to obtain compound 1.

[0023] Preferably, step S2 specifically involves adding compound 2, compound 1, and an inorganic base to an alcohol solvent, heating the mixture to react, and synthesizing compound 3.

[0024] Preferably, in step S2, the molar ratio of compound 1 to compound 2 is 1.2 to 2:1, for example, the ratio is 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1 or any value formed by any two of them, with the most preferred value being 1.4:1.

[0025] Preferably, in step S2, the inorganic base is at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate, with sodium carbonate being the most preferred.

[0026] Preferably, the molar ratio of the inorganic base to compound 2 is 0.6 to 1.6:1, for example, the ratio is 0.6:1, 0.8:1, 1.0:1, 1.2:1, 1.4:1, 1.6:1 or any value formed by any two of them, with the most preferred value being 1.2:1.

[0027] Preferably, in step S2, the alcohol solvent is at least one of methanol, ethanol, n-propanol, isopropanol, and n-butanol, with ethanol being the most preferred.

[0028] Preferably, the ratio of the volume of the alcohol solvent to the mass of compound 2, expressed in mL or g, is 4 to 10:1. For example, the ratio can be 4, 5, 6, 7, 8, 9, 10, or any combination thereof. To ensure thorough stirring and no waste of solvent, a ratio of 5 is preferred.

[0029] Preferably, in step S2, the reaction temperature is 60~85℃, for example, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃ or any value formed by any two of them, with 75℃ being the most preferred.

[0030] Preferably, in step S2, the reaction time is 1 to 5 hours, for example, 1, 2, 3, 4, 5 or any value formed by any two of them, and the reaction endpoint is confirmed by TLC or HPLC to indicate that compound 2 has reacted completely.

[0031] Preferably, step S2 specifically includes:

[0032] Compound 2, Compound 1, and an inorganic base were added to an alcohol solvent and heated at 60-85°C for 1-5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the pH was adjusted to 2-3, and the mixture was filtered. The filter cake was slurried with a mixture of acetone and water, filtered under vacuum, and the filter cake was collected and dried to obtain product compound 3.

[0033] The beneficial effects of this invention are:

[0034] This invention provides a method for preparing aminotadalafil succinic acid derivatives. The method uses tadalafil intermediates as raw materials, and condenses 4-hydrazine-4-oxobutyric acid with succinic acid derivatives via hydrazine condensation to generate 4-hydrazine-4-oxobutyric acid. Then, the tadalafil intermediates undergo hydrazine decyclization and cyclization reaction to synthesize aminotadalafil succinic acid derivatives. This process has the advantages of high yield, high specificity and high selectivity.

[0035] The aminotadalafil succinic acid derivative prepared by this invention significantly improves the solubility of the aminotadalafil derivative by introducing succinic acid (it can be diluted with commercially available soda water to form a 100mg / 100mL aqueous solution), expanding its drug application methods; at the same time, the presence of the carboxyl group as a reactive site can be used to derive other functional groups or connect with other active groups to form synergistic active groups, providing more possibilities for the preparation of other related products based on aminotadalafil derivatives.

[0036] The preparation process provided by this invention is simple, low-cost, and easy to operate, and can achieve large-scale production. Attached Figure Description

[0037] Figure 1 The 1H NMR spectrum of the aminotadanafil succinic acid derivative prepared in Example 1;

[0038] Figure 2 The images show the solubility test results of the aminotadalafil succinic acid derivative prepared in Example 1 and commercially available aminotadalafil in soda water. Detailed Implementation

[0039] The present invention will be further described in detail below with reference to embodiments, so that those skilled in the art can implement it based on the description.

[0040] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

[0041] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available. For examples where specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer are followed. For reagents or instruments whose manufacturers are not specified, they are all commercially available products.

[0042] In the following examples, compound 2 (tadalafil intermediate) is a commercially available product with the following chemical structure and source: tadalafil methyl chloride, CAS: 171489-59-1, purchased from Ma'anshan Dehong Biotechnology Co., Ltd.

[0043] . Example 1

[0044] A method for preparing an aminotadalafil succinic acid derivative includes the following steps:

[0045] S1. In a 1L three-necked flask, add 100g (1.0 eq, 0.757 mol) of monomethyl succinate, 66.31g (1.4 eq, 1.060 mol) of 80% hydrazine hydrate, and 600mL of ethanol. Then heat to 75℃ and react for 3h. TLC monitoring shows that the reaction of monomethyl succinate is complete. The reaction solution is concentrated to about 100mL, then cooled to 5℃, filtered, the filter cake is washed with water, collected, and dried at 60℃ to give 77.3g of solid compound 1, namely 4-hydrazino-4-oxobutyric acid, with a yield of 77.3%.

[0046] S2. In a 1 L three-necked flask, add 100 g (1.0 eq, 0.234 mol) of compound 2, 43.34 g (1.4 eq, 0.328 mol) of compound 1, 29.76 g (1.2 eq, 0.281 mol) of sodium carbonate, and 500 mL of ethanol. Then heat to 75 °C and react for 3 h. Monitor the reaction of the starting materials by TLC until complete. Cool the reaction solution to room temperature and adjust the pH to 2 with 2N hydrochloric acid. Filter the solution and slurry the filter cake with a mixed solvent of acetone:deionized water in a volume ratio of 7:3. Filter the solution and collect the filter cake. Dry the filter cake at 60 °C to obtain 103.3 g of compound 3, i.e., aminotadalafil succinic acid derivative, with a yield of 89.9%.

[0047] The chemical structures of compounds 2 and 3 are shown below:

[0048] .

[0049] The 1H NMR spectrum of the aminotadanafil succinic acid derivative prepared in this embodiment is as follows: Figure 1 As shown, the NMR data are as follows:

[0050] 1 H NMR (400 MHz, DMSO): δ 12.21 (s, 1H), 11.13 (s, 1H), 10.48 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.09-7.05 (m, 1H), 7.02-6.98 (m, 1H), δ 6.87 (s, 1H), 6.80-6.78 (m, 2H), 6.20 (s, 1H), 5.94 (s, 2H), 4.59 (dd, J = 11.6, 4.7 Hz, 1H), 4.51 (dd, J = 16.4, 1.2 Hz, 1H), 3.86 (d, J= 16.5 Hz, 1H), 3.50 (dd, J = 15.8, 4.8 Hz, 1H), 3.35 (s, 1H), 2.96 (dd, J = 15.6, 11.7 Hz, 1H), 2.52-2.48 (m, 2H), 2.44-2.41 (m, 2H). Example 2

[0051] A method for preparing an aminotadalafil succinic acid derivative includes the following steps:

[0052] S1. In a 1L three-necked flask, add 100g (1.0 eq, 0.684 mol) of monoethyl succinate, 66.5g (1.6 eq, 1.095 mol) of 80% hydrazine hydrate, and 500mL of ethanol. Then heat to 80℃ and react for 3.5h. TLC monitoring shows that the reaction of monoethyl succinate is complete. The reaction solution is concentrated to about 100mL, then cooled to 5℃, filtered, the filter cake is washed with water, collected, and dried at 60℃ to give 68.5g of solid compound 1, with a yield of 75.8%.

[0053] S2. In a 1 L three-necked flask, add 100 g (1.0 eq, 0.234 mol) of compound 2, 46.44 g (1.5 eq, 0.351 mol) of compound 1, 45.21 g (1.4 eq, 0.327 mol) of potassium carbonate, and 600 mL of isopropanol. Then heat to 80 °C and react for 2.5 h. Monitor the reaction of the starting materials by TLC until complete. Cool the reaction solution to room temperature and adjust the pH to 2 with 2N hydrochloric acid. Filter the solution and slurry the filter cake with a mixed solvent of acetone:deionized water in a volume ratio of 7:3. Filter the solution and collect the filter cake. Dry the filter cake at 60 °C to obtain 101.9 g of compound 3, i.e., aminotadalafil succinic acid derivative, with a yield of 88.7%.

[0054] The chemical structures of compounds 2 and 3 are shown below:

[0055] .

[0056] Solubility test:

[0057] Tests showed that the aminotadalafil succinic acid derivatives prepared in Examples 1-2 all had good solubility and could be dissolved in commercially available soda water to form a 100 mg / 100 mL aqueous solution. Under the same conditions, commercially available aminotadalafil (purchased from Xi'an Lina Biotechnology Co., Ltd., CAS: 385769-84-6) was almost insoluble, and tadalafil was similar to aminotadalafil and was also almost insoluble.

[0058] Reference Figure 2The figures show the solubility of the aminotadalafil succinic acid derivative prepared in Example 1 and commercially available aminotadalafil in the same volume of soda water. When the aminotadalafil succinic acid derivative is prepared into an aqueous solution with a concentration of 100 mg / 100 mL, the solution is clear and completely dissolved; while the aminotadalafil solution is turbid and almost insoluble.

[0059] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details.

Claims

1. A process for preparing an aminotadalafil butandioic acid derivative, characterized by, Includes the following steps: S1. Add succinic acid monoester and hydrazine to an alcohol solvent and heat to react, thereby synthesizing compound 1; S2. Compound 2, Compound 1, and inorganic base are added to an alcohol solvent and heated to react, thereby synthesizing Compound 3, namely, an aminotadalafil succinic acid derivative. The chemical structures of compounds 1, 2, and 3 are shown below: ； In step S1, the succinic acid monoester is at least one of monomethyl succinic acid and monoethyl succinic acid; the molar ratio of hydrazine to succinic acid monoester is 1.2~2:

1.

2. The process for preparing aminotadalafil succinate derivative according to claim 1, characterized by, In step S1, the alcohol solvent is at least one of methanol, ethanol, n-propanol, isopropanol, and n-butanol; the ratio of the volume of the alcohol solvent to the mass of the succinate is 4~12:1, measured in mL and g respectively.

3. The method for preparing the aminotadalafil succinic acid derivative according to claim 1, characterized in that, In step S1, the hydrazine is 80% hydrated hydrazine.

4. The method for preparing the aminotadalafil succinic acid derivative according to claim 1, characterized in that, Step S1 is as follows: Succinic acid monoester and 80% hydrazine hydrate were added to an alcohol solvent and heated under reflux at 60-85°C for 1-5 hours. After the reaction was complete, the reaction solution was concentrated, cooled to 5-10°C, filtered, the filter cake was washed with water, collected, and dried to obtain compound 1.

5. The method for preparing the aminotadalafil succinic acid derivative according to claim 1, characterized in that, In step S2, the molar ratio of compound 1 to compound 2 is 1.2 to 2:

1.

6. The method for preparing the aminotadalafil succinic acid derivative according to claim 1, characterized in that, In step S2, the inorganic base is at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate; the molar ratio of the inorganic base to compound 2 is 0.6 to 1.6:

1.

7. The method for preparing the aminotadalafil succinic acid derivative according to claim 1, characterized in that, In step S2, the alcohol solvent is at least one of methanol, ethanol, n-propanol, isopropanol, and n-butanol; the ratio of the volume of the alcohol solvent to the mass of compound 2 is 4 to 10:1, measured in mL and g respectively.

8. The method for preparing the aminotadalafil succinic acid derivative according to claim 1, characterized in that, Step S2 is as follows: Compound 2, Compound 1, and an inorganic base were added to an alcohol solvent and heated at 60-85°C for 1-5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the pH was adjusted to 2-3, and the mixture was filtered. The filter cake was slurried with a mixture of acetone and water, filtered under vacuum, and the filter cake was collected and dried to obtain product compound 3.

Images