Preparation method of aminotadalafil succinic acid derivative

Abstract

The invention discloses a preparation method of an aminotadalafil succinic acid derivative, which comprises the following steps: S1, reacting hydrazine with succinic anhydride to synthesize a compound 1, namely 4-hydrazino-4-oxobutyric acid; and S2, carrying out hydrazinolysis cyclization reaction on the compound 2 and the compound 1 to synthesize a compound 3, namely the aminotadalafil succinic acid derivative. According to the amino tadalafil succinic acid derivative prepared by the invention, the solubility of the amino tadalafil derivative is greatly improved through introduction of succinic acid, and the medicine application mode of the amino tadalafil derivative is expanded; meanwhile, the carboxyl is used as a reaction active site and can be derived into other functional groups or 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] The invention relates to the technical field of pharmaceutical chemistry, and in particular to a method for preparing an aminotadalafil succinic acid derivative. Background Art

[0002] Tadalafil is an effective inhibitor of phosphodiesterase 5 (PED5) and can be used in a variety of conditions, including male erectile dysfunction, pulmonary hypertension, and lower urinary tract dysfunction. Amino-tadalafil is an analog of tadalafil and has similar efficacy to tadalafil. However, both tadalafil and amino-tadalafil have the disadvantage of poor solubility, which not only affects the in vitro and in vivo activity of the drug, but also is not conducive to drug absorption and affects the efficacy.

[0003] Therefore, it is necessary to improve the existing technology to provide a more reliable solution. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing an amino tadalafil succinic acid derivative in view of the deficiencies in the above-mentioned prior art.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is: a method for preparing an amino tadalafil succinic acid derivative, comprising the following steps: S1. synthesizing compound 1 (Compound 1), i.e., 4-hydrazino-4-oxobutyric acid, by reacting hydrazine with succinic anhydride; S2, synthesizing compound 3 (Compound 3), i.e., an amino tadalafil succinic acid derivative, by reacting compound 2 (Compound 2) with compound 1 (Compound 1) through hydrazinolysis and cyclization reaction; Among them, the chemical structures of compound 2 and compound 3 are shown below: .

[0006] The synthetic route of the present invention is as follows: .

[0007] Preferably, the preparation method of the amino tadalafil succinic acid derivative comprises the following steps: Preferably, step S1 specifically comprises: adding succinic acid monoester and hydrazine into an alcohol solvent, heating for reaction, and synthesizing compound 1.

[0008] Preferably, in step S1, the succinic acid monoester is at least one of monomethyl succinate and monoethyl succinate, and most preferably is monomethyl succinate.

[0009] Preferably, the molar ratio of hydrazine to succinic acid monoester 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 between them, and most preferably is 1.4:1.

[0010] Preferably, in step S1, the alcohol solvent is at least one of methanol, ethanol, n-propanol, isopropanol and n-butanol, and ethanol is most preferred.

[0011] Preferably, the ratio of the volume of the alcohol solvent to the mass of the succinate ester is 4 to 12:1, measured in units of volume, mL, and mass, g. For example, the ratio is 4, 6, 8, 10, 12, or any value between them. To ensure that the reaction is stirred sufficiently and the solvent is not wasted, 6 is most preferred.

[0012] Preferably, in step S1, the reaction temperature is 60-85°C, for example, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C or any value therebetween, most preferably 75°C.

[0013] Preferably, in step S1, the reaction time is 1 to 5 h, for example, 1, 2, 3, 4, 5 or any value between any two of them, and the reaction endpoint is confirmed by TLC or HPLC that the succinic acid monoester reaction is complete.

[0014] Preferably, in step S1, the hydrazine is 80% hydrazine hydrate.

[0015] Preferably, step S1 specifically comprises: Succinic acid monoester and 80% hydrazine hydrate were added to an alcohol solvent, heated under reflux at 60-85°C for 1-5h. After the reaction was complete, the reaction solution was concentrated, cooled to 5-10°C, filtered, the filter cake was rinsed with water, the filter cake was collected, and dried to obtain compound 1.

[0016] Preferably, step S2 specifically comprises: adding compound 2, compound 1 and an inorganic base into an alcohol solvent, heating for reaction, and synthesizing compound 3.

[0017] Preferably, in step S2, the molar ratio of compound 1 to compound 2 is 1.2-2:1, for example, the ratio is 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1 or any value between them, most preferably 1.4:1.

[0018] Preferably, in step S2, the inorganic base is at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, and most preferably is sodium carbonate.

[0019] Preferably, the molar ratio of the inorganic base to the 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 between them, most preferably 1.2:1.

[0020] Preferably, in step S2, the alcohol solvent is at least one of methanol, ethanol, n-propanol, isopropanol and n-butanol, and ethanol is most preferred.

[0021] Preferably, the ratio of the volume of the alcohol solvent to the mass of compound 2 is 4 to 10:1, with the volume unit being mL and the mass unit being g. For example, the ratio is 4, 5, 6, 7, 8, 9, 10 or any value between them. To ensure that the reaction is sufficiently stirred and the solvent is not wasted, 5 is most preferred.

[0022] Preferably, in step S2, the reaction temperature is 60-85°C, for example, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C or any value therebetween, most preferably 75°C.

[0023] Preferably, in step S2, the reaction time is 1 to 5 h, for example, 1, 2, 3, 4, 5 or any value between any two of them, and the reaction endpoint is confirmed by TLC or HPLC that compound 2 is completely reacted.

[0024] Preferably, step S2 specifically comprises: Compound 2, compound 1 and an inorganic base are added to an alcohol solvent, heated at 60-85°C for 1-5 hours. After the reaction is complete, the reaction solution is cooled to room temperature, the pH is adjusted to 2-3, filtered, the filter cake is slurried with a mixed solvent of acetone and water, filtered, the filter cake is collected, and dried to obtain the product compound 3.

[0025] The beneficial effects of the present invention are: The present invention provides a method for preparing an amino tadalafil succinic acid derivative. The method uses a tadalafil intermediate as a raw material, condenses hydrazine with a succinic acid derivative to generate 4-hydrazine-4-oxobutyric acid, and then undergoes a hydrazine cyclization reaction with the tadalafil intermediate to synthesize the amino tadalafil succinic acid derivative. The process has the advantages of high yield, high specificity and high selectivity. In the amino tadalafil succinic acid derivative prepared by the present invention, the solubility of the amino tadalafil derivative is greatly improved by the introduction of succinic acid (it can be prepared into a 100 mg / 100 mL aqueous solution with commercially available soda water), thereby expanding its medicinal application method; at the same time, the presence of the carboxyl group as a reaction active site can be derived into other functional groups or connected with other active groups to form a synergistic active group, providing more possibilities for the preparation of other related products based on the amino tadalafil derivative; The preparation process provided by the invention is simple, low in cost, easy to operate, and can realize large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The hydrogen nuclear magnetic resonance spectrum of the amino tadalafil succinic acid derivative prepared in Example 1; Figure 2 This is a physical picture of the solubility test of the amino tadalafil succinic acid derivative prepared in Example 1 and commercially available amino tadalafil in soda water. DETAILED DESCRIPTION

[0027] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0028] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0029] The test methods used in the following examples are conventional methods unless otherwise specified. The materials and reagents used in the following examples are all commercially available unless otherwise specified. In the following examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be purchased commercially.

[0030] In the following examples, the compound 2 (tadalafil intermediate) used is a commercially available product, the chemical structure of which is shown below, and the source is as follows: tadalafil methyl chloride, CAS: 171489-59-1, purchased from Maanshan Dehong Biotechnology Co., Ltd.

[0031] . Example 1

[0032] A method for preparing an aminotadalafil succinic acid derivative comprises the following steps: S1. In a 1L three-necked flask, 100 g (1.0 eq, 0.757 mol) of monomethyl succinate, 66.31 g (1.4 eq, 1.060 mol) of 80% hydrazine hydrate and 600 mL of ethanol were added, and then heated to 75°C for reaction for 3 h. The reaction of monomethyl succinate was completed by TLC monitoring. The reaction solution was concentrated to about 100 mL, and then cooled to 5°C, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried at 60°C to obtain 77.3 g of solid compound 1, i.e., 4-hydrazino-4-oxobutyric acid, with a yield of 77.3%.

[0033] S2. 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 to a 1 L three-necked flask, and then heat to 75°C for reaction for 3 h; TLC monitors the complete reaction of the raw materials, the reaction solution is cooled to room temperature, and the pH is adjusted to 2 with 2N hydrochloric acid, filtered, and the filter cake is slurried with a mixed solvent of acetone: deionized water in a volume ratio of 7:3, filtered, and the filter cake is collected and dried at 60°C to obtain 103.3 g of compound 3, i.e., aminotadalafil succinic acid derivative, with a yield of 89.9%.

[0034] The chemical structures of compound 2 and compound 3 are shown below: .

[0035] The nuclear magnetic resonance hydrogen spectrum of the amino tadalafil succinic acid derivative prepared in this example is as follows Figure 1 As shown, the NMR data are as follows: 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

[0036] A method for preparing an aminotadalafil succinic acid derivative comprises the following steps: S1. In a 1L three-necked flask, 100 g (1.0 eq, 0.684 mol) of monoethyl succinate, 66.5 g (1.6 eq, 1.095 mol) of 80% hydrazine hydrate and 500 mL of ethanol were added, and then heated to 80°C for reaction for 3.5 h. The reaction of monoethyl succinate was completed as monitored by TLC. The reaction solution was concentrated to about 100 mL, then cooled to 5°C, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried at 60°C to obtain 68.5 g of solid compound 1 with a yield of 75.8%.

[0037] S2. 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 (1.4eq, 0.327 mol) of potassium carbonate and 600 mL of isopropanol into a 1 L three-necked flask, and then heat to 80°C for reaction for 2.5 h; TLC monitors the complete reaction of the raw materials, the reaction solution is cooled to room temperature, and the pH is adjusted to 2 with 2N hydrochloric acid, filtered, and the filter cake is slurried with a mixed solvent of acetone: deionized water in a volume ratio of 7:3, filtered, and the filter cake is collected and dried at 60°C to obtain 101.9 g of compound 3, i.e., aminotadalafil succinic acid derivative, with a yield of 88.7%.

[0038] The chemical structures of compound 2 and compound 3 are shown below: . Solubility test:

[0039] After testing, the aminotadalafil succinic acid derivatives prepared in Examples 1-2 all have good solubility properties and can be prepared into a 100 mg / 100 mL aqueous solution with commercially available soda water. Under the same conditions, commercially available aminotadalafil (purchased from Xi'an Laina Biotechnology Co., Ltd., CAS: 385769-84-6) is almost insoluble, and tadalafil is similar to aminotadalafil and is also almost insoluble.

[0040] Reference Figure 2 , which is a physical diagram of the solubility of the same mass of the amino tadalafil succinic acid derivative prepared in Example 1 and the commercially available amino tadalafil added to the same volume of soda water. When the amino tadalafil 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 amino tadalafil solution is turbid and almost insoluble.

[0041] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for preparing an aminotadalafil succinic acid derivative, characterized in that: The following steps are involved: S1, synthesizing compound 1, i.e. 4-hydrazino-4-oxobutyric acid, by reacting hydrazine with succinic anhydride; S2, compound 2 and compound 1 undergo hydrazinolysis and cyclization reaction to synthesize compound 3, i.e., an amino tadalafil succinic acid derivative; Among them, the chemical structures of compound 2 and compound 3 are shown below: 。 2. The method for preparing the amino tadalafil succinic acid derivative according to claim 1, characterized in that: The following steps are involved: S1, adding succinic acid monoester and hydrazine to an alcohol solvent, heating for reaction, and synthesizing compound 1; S2. Add compound 2, compound 1 and an inorganic base into an alcohol solvent, heat to react, and synthesize compound 3.

3. The method for preparing the amino tadalafil succinic acid derivative according to claim 2, characterized in that: In step S1, the succinic acid monoester is at least one of methyl succinate and ethyl succinate; and the molar ratio of hydrazine to the succinic acid monoester is 1.2-2:

1.

4. The method for preparing the amino tadalafil succinic acid derivative according to claim 2, characterized in that: In step S1, the alcohol solvent is at least one of methanol, ethanol, n-propanol, isopropanol, and n-butanol; and the ratio of the volume of the alcohol solvent to the mass of the succinate ester is 4-12:1, measured in units of volume (mL) and mass (g).

5. The method for preparing the amino tadalafil succinic acid derivative according to claim 2, characterized in that: In step S1, hydrazine is 80% hydrazine hydrate.

6. The method for preparing the amino tadalafil succinic acid derivative according to claim 2, characterized in that: Step S1 is specifically as follows: Succinic acid monoester and 80% hydrazine hydrate were added to an alcohol solvent, heated under reflux at 60-85°C for 1-5h. After the reaction was complete, the reaction solution was concentrated, cooled to 5-10°C, filtered, the filter cake was rinsed with water, the filter cake was collected, and dried to obtain compound 1.

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

1.

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

1.

9. The method for preparing the amino tadalafil succinic acid derivative according to claim 2, 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, with the volume unit being mL and the mass unit being g.

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

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