Water-soluble amino tadalafil derivative and preparation method thereof

Abstract

The invention discloses a water-soluble aminotadalafil derivative and a preparation method thereof, and the method comprises the following steps: S1, taking a tadalafil intermediate as a raw material, carrying out heating reflux on the tadalafil intermediate and hydrazine in an alcohol solvent, and carrying out hydrazinolysis cyclization reaction to generate aminotadalafil; and S2, taking aminotadalafil as a raw material, and carrying out amide condensation reaction on the aminotadalafil and a succinic acid derivative in an organic solvent to synthesize the water-soluble aminotadalafil derivative. The invention provides a method for synthesizing the water-soluble amino tadalafil derivative with high yield, high specificity and selectivity, in the prepared amino tadalafil derivative, the solubility of the amino tadalafil derivative is greatly improved due to 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.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a water-soluble amino tadalafil derivative and a preparation method thereof. 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 water-soluble amino tadalafil derivative and a preparation method thereof 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: In the first aspect of the present invention, a water-soluble amino tadalafil derivative is provided, which has a chemical structure shown in the following formula III: .

[0006] The synthetic route of the water-soluble amino tadalafil derivative is as follows: .

[0007] The second aspect of the present invention provides a method for preparing the water-soluble amino tadalafil derivative as described above, comprising the following steps: S1. Using a tadalafil intermediate having a structure shown in the following formula Ⅰ as a raw material, heating and refluxing with hydrazine in an alcohol solvent to generate amino tadalafil by hydrazine cyclization reaction. The structure of amino tadalafil is shown in the following formula Ⅱ; S2, using amino tadalafil as a raw material, and reacting it with a succinic acid derivative in an organic solvent to undergo an amide condensation reaction to synthesize a water-soluble amino tadalafil derivative; .

[0008] Preferably, the hydrazine is selected from at least one of 80% hydrazine hydrate, hydrazine hydrochloride and hydrazine sulfate. Considering factors such as the volatilization loss of hydrazine and the effective content of hydrazine under the reaction conditions, hydrazine hydrochloride is most preferred.

[0009] Preferably, the molar ratio of hydrazine to tadalafil intermediate is 1.5 to 3.5:1, for example, the ratio is 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1 or any value between them. To ensure that the tadalafil intermediate reacts completely and the hydrazine is not excessive, the most preferred ratio is 2:1.

[0010] Preferably, the alcohol solvent is selected from at least one of methanol, ethanol, n-propanol and isopropanol, and ethanol is most preferred.

[0011] Preferably, the ratio of the volume of the alcohol solvent to the mass of the tadalafil intermediate is 4 to 9:1, measured in units of volume, mL, and mass, g. For example, the ratio is 4, 5, 6, 7, 8, 9, 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, the reaction time in step S1 is 6 to 16 hours, for example, 6, 8, 10, 12, 14, 16 or any value between any two of them, and the reaction endpoint is confirmed by TLC or HPLC that the tadalafil intermediate is completely reacted.

[0013] Preferably, step S1 specifically comprises: The tadalafil intermediate and hydrazine are added to an alcohol solvent, heated under reflux at 65-95°C for 6-16 hours, cooled to room temperature after the reaction is completed, the pH value of the product is adjusted to greater than 9, filtered, the filter cake is rinsed with deionized water, the filter cake is collected, and dried to obtain amino tadalafil.

[0014] Preferably, in step S2, the reaction temperature is 40-100°C, for example, 40, 60, 80, 100°C or any value therebetween. To ensure a faster reaction and reduce side reactions, 60°C is most preferred.

[0015] Preferably, in step S2, the reaction time is 4 to 10 hours, for example, 4, 5, 6, 7, 8, 9, 10 or any value between any two of them, and the reaction endpoint is confirmed by TLC or HPLC aminotadalafil reaction completion.

[0016] Preferably, an organic base may or may not be added in step S2.

[0017] Preferably, when no organic base is added, step S2 is specifically as follows: Add amino tadalafil to an organic solvent, then add a succinic acid derivative, react at 40-100°C for 4-10 hours, cool to room temperature after the reaction is completed, stir for 1-2 hours, filter with suction, slurry the filter cake with a mixed solvent of acetone and water, filter with suction, collect the filter cake, and dry to obtain a water-soluble amino tadalafil derivative.

[0018] Preferably, when an organic base is added, step S2 is specifically: Add amino tadalafil to an organic solvent, then add an organic base, add a succinic acid derivative after stirring, react at 40-100°C for 4-10 hours, cool to room temperature after the reaction is completed, stir for 1-2 hours, adjust pH to 2-3, filter, slurry the filter cake with a mixed solvent of acetone and water, filter, collect the filter cake, and dry to obtain a water-soluble amino tadalafil derivative.

[0019] Preferably, in step S2, the succinic acid derivative is selected from at least one of succinic anhydride, dimethyl succinate, diethyl succinate, monomethyl succinate, and monoethyl succinate, and is most preferably succinic anhydride.

[0020] Preferably, the molar ratio of the succinic acid derivative to aminotadalafil 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. To ensure that the aminotadalafil reaction is complete and the amount of succinic acid derivative used is minimal, the most preferred ratio is 1.4:1.

[0021] Preferably, the organic base is selected from at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, and sodium hydrogen hydride, and most preferably is potassium tert-butoxide.

[0022] In step S2, the molar ratio of the organic base to amino tadalafil is 1.5 to 3:1, for example, the ratio is 1.5:1, 2:1, 2.5:1, 3:1 or any value between them. The amount of the organic base also needs to consider the type and amount of the succinic acid derivative.

[0023] Preferably, the organic solvent is selected from tetrahydrofuran, N , N -dimethylformamide, N , N - At least one of dimethylacetamide and 1,4-dioxane, and most preferably tetrahydrofuran.

[0024] Preferably, the ratio of the volume of the organic solvent to the mass of aminotadalafil 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 sufficiently stirred and the solvent is not wasted, 6 is most preferred.

[0025] The beneficial effects of the present invention are: The present invention provides a water-soluble amino tadalafil derivative and a preparation method thereof. The present invention uses a tadalafil intermediate as a raw material, generates amino tadalafil through a hydrazine cyclization reaction, and then undergoes an amide condensation reaction with a succinic acid derivative to synthesize a water-soluble amino tadalafil derivative with high yield, high specificity and selectivity. In the amino tadalafil derivatives prepared by the present invention, the introduction of succinic acid greatly improves the solubility of the amino tadalafil derivatives (can be prepared into a 100 mg / 100 mL aqueous solution with commercially available soda water), expanding its medicinal application method; at the same time, the presence of the carboxyl group as a reactive 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 amino tadalafil derivatives; The preparation method provided by the invention is simple and easy to implement, is conducive to large-scale production, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The hydrogen nuclear magnetic resonance spectrum of the water-soluble amino tadalafil derivative prepared in Example 1; Figure 2 This is a physical picture of the water-soluble amino tadalafil derivative prepared in Example 1 and the solubility test of 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 tadalafil intermediate used is a commercially available product, the chemical structure of which is shown in Formula I 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 a water-soluble amino tadalafil derivative comprises the following steps: S1. Add 100 g (1.0 eq, 0.234 mol) of tadalafil intermediate, 32.13 g (2.0 eq, 0.469 mol) of hydrazine hydrochloride (hydrazine hydrochloride) and 600 mL of ethanol into a 1 L three-necked flask, and then heat and reflux at 78°C for 6 h. The reaction of the raw materials is complete as monitored by TLC. The reaction solution is cooled to room temperature, and the pH value of the product is adjusted to greater than 9 with a 10 wt % sodium hydroxide solution. Filter by suction, rinse the filter cake with deionized water, collect the filter cake, and dry it at 60°C to obtain 85.2 g of amino tadalafil with a yield of 93.2%.

[0033] S2. Add 85.2 g (1.0 eq, 0.218 mol) of amino tadalafil and 511 mL of tetrahydrofuran into a 1 L three-necked flask, add 30.57 g (1.4 eq, 0.306 mol) of succinic anhydride in batches, and then heat to 60 ° C for 8 h. The reaction of the raw materials is complete after monitoring by TLC. The reaction solution is cooled to room temperature, stirred for 2 h, and filtered. 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 100.3 g of a water-soluble amino tadalafil derivative with a yield of 93.7%.

[0034] The H NMR spectrum of the water-soluble amino tadalafil 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 12.18 (s, 1H), 11.11 (s, 1H), 10.46 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.10-7.04 (m, 1H), 7.03-6.97(m, 1H), δ 6.87 (s, 1H), 6.82-6.77 (m, 2H), 6.20 (s, 1H), 5.93 (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), 3.32 (s, 1H), 2.96 (dd, J= 15.6, 11.7 Hz, 1H), 2.51-2.48 (m, 2H), 2.44-2.41 (m, 2H). Example 2

[0035] A method for preparing a water-soluble amino tadalafil derivative comprises the following steps: S1. Add 100 g (1.0 eq, 0.234 mol) of compound, 43.98 g (3.0 eq, 0.703 mol) of 80% hydrazine hydrate and 500 mL of ethanol into a 1 L three-necked flask, and then heat under reflux at 78°C for 7 h. TLC monitors the complete reaction of the raw materials. The reaction solution is cooled to room temperature, and the pH value of the product is adjusted to greater than 9 with 10 wt % sodium hydroxide solution. Filter by suction, rinse the filter cake with deionized water, collect the filter cake, and dry it at 60°C to obtain 83.4 g of amino tadalafil with a yield of 91.2%.

[0036] S2. Add 83.4 g (1.0 eq, 0.214 mol) of aminotadalafil and 500 mL of 1,4-dioxane into a 1L three-necked flask, add 35.96 g (1.5 eq, 0.320 mol) of potassium tert-butoxide in batches, stir for 30 min, add 37.46 g (1.2 eq, 0.256 mol) of dimethyl succinate, and then heat to 70°C for reaction for 5 h; TLC monitors the complete reaction of the raw materials, the reaction solution is cooled to room temperature, 300 mL of water is added, and stirred for 2 h, the pH is adjusted to 3 with 2N hydrochloric acid, and the filter cake is slurried with a mixed solvent of acetone: deionized water in a volume ratio of 7:3, filtered, the filter cake is collected, and dried at 60°C to obtain 95.6 g of a water-soluble aminotadalafil derivative product with a yield of 91.2%. Example 3

[0037] A method for preparing a water-soluble amino tadalafil derivative comprises the following steps: S1. Add 100 g (1.0 eq, 0.234 mol) of tadalafil intermediate, 76.2 g (2.5 eq, 0.586 mol) of hydrazine sulfate and 650 mL of isopropanol into a 1 L three-necked flask, and then heat to 83°C for reflux reaction for 7 h. The reaction of the raw materials was monitored by TLC to complete the reaction. The reaction solution was cooled to room temperature, and the pH value of the product was adjusted to greater than 9 with 10 wt% sodium hydroxide solution. The filter cake was filtered, rinsed with deionized water, collected, and dried at 60°C to obtain 82.1 g of amino tadalafil with a yield of 89.8%.

[0038] S2. Add 82.1 g (1.0 eq, 0.210 mol) of amino tadalafil and 410 mL of methanol into a 1 L three-necked flask, add 24.99 g (2.2 eq, 0.463 mol) of sodium methoxide in batches, stir for 30 min, add 30.56 g (1.1 eq, 0.231 mol) of monomethyl succinate, and then heat to 65 ° C for 7 h; TLC monitors the complete reaction of the raw materials, the reaction solution is cooled to room temperature, 300 mL of water is added, and stirred for 2 h, the pH is adjusted to 3 with 2N hydrochloric acid, and filtered with suction. The filter cake is slurried with a mixed solvent of methanol: deionized water in a volume ratio of 7:3, filtered with suction, the filter cake is collected, and dried at 60 ° C to obtain 92.5 g of a water-soluble amino tadalafil derivative product with a yield of 89.7%. Solubility test:

[0039] After testing, the water-soluble aminotadalafil derivatives prepared in Examples 1-3 all have good solubility and can be prepared into a 100 mg / 100 mL aqueous solution with commercially available soda water. Under the same conditions, the intermediate product aminotadalafil in each example 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 water-soluble amino-tadalafil derivative prepared in Example 1 and amino-tadalafil added to the same volume of soda water. When the water-soluble amino-tadalafil 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 water-soluble amino tadalafil derivative, characterized in that: It has the chemical structure shown in the following formula III: 。 2. A method for preparing a water-soluble amino tadalafil derivative as claimed in claim 1, characterized in that: The following steps are involved: S1. Using a tadalafil intermediate having a structure shown in the following formula Ⅰ as a raw material, heating and refluxing with hydrazine in an alcohol solvent to generate amino tadalafil by hydrazine cyclization reaction. The structure of amino tadalafil is shown in the following formula Ⅱ; S2, using amino tadalafil as a raw material, and reacting it with a succinic acid derivative in an organic solvent to undergo an amide condensation reaction to synthesize a water-soluble amino tadalafil derivative; 。 3. The method for preparing a water-soluble amino tadalafil derivative according to claim 2, characterized in that: The hydrazine is selected from at least one of 80% hydrazine hydrate, hydrazine hydrochloride and hydrazine sulfate, and the molar ratio of hydrazine to the tadalafil intermediate is 1.5-3.5:

1.

4. The method for preparing a water-soluble amino tadalafil derivative according to claim 2, characterized in that: The alcohol solvent is selected from at least one of methanol, ethanol, n-propanol and isopropanol; Measured in units of volume (mL) and mass (g), the ratio of the volume of the alcohol solvent to the mass of the tadalafil intermediate is 4 to 9:

1.

5. The method for preparing a water-soluble amino tadalafil derivative according to claim 2, characterized in that: The steps in S1 are specifically: The tadalafil intermediate and hydrazine are added to an alcohol solvent, heated under reflux at 65-95°C for 6-16 hours, cooled to room temperature after the reaction is completed, the pH value of the product is adjusted to greater than 9, filtered, the filter cake is rinsed with deionized water, the filter cake is collected, and dried to obtain amino tadalafil.

6. The method for preparing a water-soluble amino tadalafil derivative according to claim 2, characterized in that: The steps in S2 are specifically: Add amino tadalafil to an organic solvent, then add a succinic acid derivative, react at 40-100°C for 4-10 hours, cool to room temperature after the reaction is completed, stir for 1-2 hours, filter with suction, slurry the filter cake with a mixed solvent of acetone and water, filter with suction, collect the filter cake, and dry to obtain a water-soluble amino tadalafil derivative.

7. The method for preparing a water-soluble amino tadalafil derivative according to claim 2, characterized in that: The steps in S2 are specifically: Add amino tadalafil to an organic solvent, add an organic base, add a succinic acid derivative after stirring, react at 40-100°C for 4-10 hours, cool to room temperature after the reaction is completed, stir for 1-2 hours, adjust the pH to 2-3, filter, slurry the filter cake with a mixed solvent of acetone and water, filter, collect the filter cake, and dry to obtain a water-soluble amino tadalafil derivative.

8. The method for preparing a water-soluble amino tadalafil derivative according to claim 6 or 7, characterized in that: In step S2, the succinic acid derivative is selected from at least one of succinic anhydride, dimethyl succinate, diethyl succinate, monomethyl succinate, and monoethyl succinate; The molar ratio of the succinic acid derivative to amino tadalafil is 1.2-2:

1.

9. The method for preparing a water-soluble amino tadalafil derivative according to claim 7, characterized in that: The organic base is selected from at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, and sodium hydrogen; In step S2, the molar ratio of the organic base to amino tadalafil is 1.5-3:

1.

10. The method for preparing a water-soluble amino tadalafil derivative according to claim 6 or 7, characterized in that: The organic solvent is selected from tetrahydrofuran, N , N -dimethylformamide, N , N - At least one of dimethylacetamide and 1,4-dioxane; The ratio of the volume of the organic solvent to the mass of aminotadalafil is 4-12:1, with the volume unit being mL and the mass unit being g.

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