Preparation process of enrofen group

Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a preparation process of an enrofen group. According to the method, 9, 10-dimethoxy-2-(2, 4, 6-trimethyl phenyl imino)-3-(2-aminoethyl)-3, 4, 6, 7-tetrahydro-2H-pyrimido [6, 1-a] isoquinoline-4-ketone, N, N '-carbonyldiimidazole and a methanol solution of ammonia are taken as raw materials, 2-methyltetrahydrofuran is taken as a reaction solvent, and enoxine is prepared through a condensation reaction. According to the process, use of a strong acid solution is avoided, acid-containing wastewater is not generated, the environmental pollution is small, the reaction efficiency and the reaction selectivity are high, the production efficiency and the yield of the enoxine group are effectively improved, the enoxine group with the total yield of 85% or above and the purity of 99.5% or above is finally prepared, large-scale production of the enoxine group is facilitated, and the method is suitable for industrial production. And the method has very important significance for expanding the application range of the enrolfen group.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation process of ensifentrine. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by airflow limitation, with a high prevalence rate, high disability and mortality rates, and a long course of disease and treatment cycle. Its three main symptoms are dyspnea, chronic cough, and expectoration. Currently, the treatment of COPD mainly adopts the combined use of bronchodilators and anti-inflammatory drugs. However, due to the adverse drug reactions caused by the combined use of drugs, the safety is worrying.

[0003] Ensifentrine, with the chemical name of 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one, is a dual-target inhibitor targeting phosphodiesterase-3 (PDE3) and phosphodiesterase-4 (PDE4). The affinity for PDE3 is 3440 times that of PDE4. As a dual PDE3 / 4 inhibitor, ensifentrine can provide dual effects of bronchodilation and anti-inflammation, significantly improving the respiratory function and quality of life of patients. Moreover, as a nebulized inhalation preparation, ensifentrine helps to avoid gastrointestinal-related side effects. In addition, ensifentrine has potential application prospects in non-cystic fibrosis, bronchiectasis, cystic fibrosis, asthma, and other respiratory diseases.

[0004] Currently, the synthetic methods of ensifentrine reported in the literature are mainly as follows: An aqueous solution of sodium cyanate is dropped into an aqueous hydrochloric acid solution of 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one for reaction. Ether is also required in the post-treatment process. The reaction rate is slow, hydrochloric acid is required during the reaction process, and the waste liquid has a great impact on the environment. Moreover, the yield of the ensifentrine product obtained by this route is relatively low, which is not suitable for industrial production applications. Therefore, it is necessary to develop a new synthetic process of ensifentrine with high reaction efficiency, environmental friendliness, and high yield. Summary of the Invention

[0005] Aiming at the problems existing in the prior art in the process of preparing ensifentrine, such as slow reaction rate, low product yield, and the generation of acid-containing waste liquid polluting the environment, the present invention provides a preparation process of ensifentrine. This process does not use acid solution and ether, effectively improving the safety and environmental friendliness of the process, and significantly enhancing the reaction efficiency and product yield, which is beneficial to the industrial production of ensifentrine and has high application value.

[0006] To solve the above technical problems, the technical solution provided by the present invention is as follows:

[0007] A preparation process of ensifentrine, comprising the following steps:

[0008] Using a methanolic solution of a parent nucleus precursor, N,N'-carbonyldiimidazole, and ammonia as raw materials, and 2-methyltetrahydrofuran as the reaction solvent, a condensation reaction is carried out at 40°C to 60°C to obtain ensifentrine; wherein, the parent nucleus precursor is 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one.

[0009] Compared with the prior art, the present invention provides a new synthesis method of ensifentrine by designing a new synthetic route. This method uses 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one, N,N'-carbonyldiimidazole, and a methanolic solution of ammonia as raw materials, and 2-methyltetrahydrofuran as the reaction solvent, and prepares ensifentrine through a condensation reaction. This process avoids the use of strong acid solutions, does not produce acid-containing wastewater, has little environmental pollution, and has high reaction efficiency and reaction selectivity, effectively improving the production efficiency and yield of ensifentrine. Finally, ensifentrine with a total yield of more than 85% and a purity of more than 99.5% is prepared. The present invention has the advantages of reasonable process design, high product yield and purity, high production efficiency, and high process safety, which is conducive to the large-scale production of ensifentrine and is of great significance for expanding the application range of ensifentrine.

[0010] As a specific embodiment of the present invention, the preparation process of ensifentrine specifically comprises the following steps:

[0011] S1, adding the parent nucleus precursor into 2-methyltetrahydrofuran, cooling down, and adding N,N'-carbonyldiimidazole to obtain a mixed solution a;

[0012] S2, adding the methanolic solution of ammonia into 2-methyltetrahydrofuran, mixing evenly to obtain a mixed solution b;

[0013] S3, adding the mixed solution a into the mixed solution b, heating to 40°C to 60°C for a condensation reaction to obtain ensifentrine.

[0014] The reaction equation of the above preparation process is as follows:

[0015]

[0016] The synthetic process of ensifentrine provided by the present invention uses N,N'-carbonyldiimidazole as the reaction raw material and condensing agent. Its reaction activity is moderate, which can not only ensure the smooth progress of the reaction, but also prevent uncontrollable side reactions caused by excessive activity. The methanol solution of ammonia is used as the nucleophile. Among them, the activity of ammonia in methanol is relatively high, and the reaction selectivity of ammonia in this reaction system is relatively high, which can effectively improve the conversion rate of the parent nucleus precursor. Using 2-methyltetrahydrofuran as the reaction raw material can improve the reaction rate and the uniformity of the reaction, and its boiling point is moderate, which is convenient for recovery and recycling by distillation and other methods after the reaction, reducing production costs. By selecting specific reaction raw materials and reaction conditions, the occurrence of side reactions is effectively reduced, and thus a high-yield and high-purity ensifentrine product is obtained, providing a new process route for the preparation of ensifentrine, which has broad prospects in the field of drug research and development and industrial production.

[0017] Preferably, in S1, the temperature for cooling is 0°C to 10°C.

[0018] Preferably, in S1, the molar ratio of N,N'-carbonyldiimidazole to the parent nucleus precursor is (1 to 5):1.

[0019] Preferably, in S1, the volume-mass ratio of 2-methyltetrahydrofuran to the parent nucleus precursor is (10 to 30) mL:1 g.

[0020] Preferably, in S2, the concentration of ammonia in the methanol solution of ammonia is 6 mol / L to 8 mol / L.

[0021] Preferably, in S2, the volume ratio of 2-methyltetrahydrofuran to the methanol solution of ammonia is (1 to 3):1.

[0022] Preferably, calculated by NH3, the molar ratio of the methanol solution of ammonia to the parent nucleus precursor is (10 to 30):1.

[0023] Preferably, in S3, the time for the condensation reaction is 2 h to 3 h.

[0024] The preferred reaction conditions can promote the full progress of the condensation reaction. At the same time, it is also beneficial to improve the reaction rate of the condensation reaction.

[0025] Preferably, after the condensation reaction in S3, there is also a post-treatment process, specifically: adding water to quench the reaction solution, concentrating, recrystallizing the concentrate with absolute ethanol, filtering by suction, and drying to obtain ensifentrine.

[0026] Specifically, in S3, the specific steps of the recrystallization are: heating to reflux, holding for 0.5 h to 2 h, and then cooling to 10°C to 30°C for crystal precipitation for 1 h to 4 h.

[0027] Preferably, in S3, the specific steps of the recrystallization are as follows: heating to reflux, holding for 1 h, then cooling to 20 °C, and crystallizing for 2 h.

[0028] Specifically, in S3, the volume-to-mass ratio of the absolute ethanol to the concentrate is (5 - 15) mL:1 g. Preferably 10 mL:1 g.

[0029] The synthesis method of ensifentrine provided by the present invention does not require the use of highly toxic sodium cyanate and strong acid solutions, and ether is not introduced during the post-treatment process. The process is safer and more environmentally friendly. At the same time, the reaction conditions are mild, the reaction efficiency is high, the total yield of ensifentrine can reach more than 85%, and the purity can reach more than 99.5%. It provides a new process route for the preparation of ensifentrine. The development of this method provides strong support for the wide application of ensifentrine and has high popularization and application value. Detailed implementation manners

[0030] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0031] In the following examples and comparative examples, the parent nucleus precursor is 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one.

[0032] Example 1

[0033] This example provides a preparation process of ensifentrine, including the following steps:

[0034] Add 100 mL of 2-methyltetrahydrofuran and 10.0 g (23.00 mmol) of the parent nucleus precursor to a reaction flask, cool to 0 - 10 °C, and add 3.73 g (23.00 mmol) of N,N'-carbonyldiimidazole to obtain a mixed solution a;

[0035] Add 100 mL of 2-methyltetrahydrofuran and 32.9 mL of a methanol solution of ammonia (7N) to the reaction flask, add the above mixed solution a. After adding, heat to 50 °C and react for 3 h, add 100 mL of purified water to quench the reaction, concentrate, and add the concentrate to absolute ethanol according to the ratio of 1 g:10 mL. Heat to reflux, hold for 1 h, cool to 20 °C to crystallize for 2 h, filter by suction, and dry in vacuo at 50 °C to obtain ensifentrine, with a yield of 87.2% and a purity of 99.6%.

[0036] ESI-MS: m / z = 478.2.

[0037] 1 HNMR (400 MHz; DMSO-d6) δ 6.970 (1H, s), 6.863 (2H, s), 6.677 (1H, s), 5.483 (2H, brs), 5.342 (1H, s), 4.219 - 4.185 (2H, t), 3.950 - 3.920 (2H, t), 3.813 (3H, s), 3.626 (3H, s), 3.397 - 3.349 (2H, m), 2.929 - 2.898 (2H, t), 2.226 (3H, s), 1.987 (6H, s), 1.891 (1H, brs).

[0038] 13 C NMR (400 MHz; DMSO-d6) δ 160.4, 158.4, 149.3, 146.6, 146.1, 142.2, 129.3, 129.2, 128.7, 126.4, 120.2, 111.4, 109.5, 87.6, 56.3, 53.5, 45.8, 38.6, 26.7, 21.6, 18.9.

[0039] Example 2

[0040] This example provides a preparation process for ensifentrine, which includes the following steps:

[0041] Add 200 mL of 2-methyltetrahydrofuran and 10.0 g (23.00 mmol) of the parent nucleus precursor to a reaction flask, cool down to 0 - 10 °C, and add 11.91 g (69.00 mmol) of N,N'-carbonyldiimidazole to obtain a mixed solution a;

[0042] Add 100 mL of 2-methyltetrahydrofuran and 65.6 mL of a methanol solution of ammonia (7N) to a reaction flask, add the above mixed solution a. After adding, heat up to 60 °C and react for 2 h, add 100 mL of purified water to quench the reaction, concentrate, add the concentrate to anhydrous ethanol according to the ratio of 1 g:15 mL, heat up to reflux, keep warm for 0.5 h, cool down to 10 °C for crystallization for 1 h, filter by suction, and dry in vacuo at 50 °C to obtain ensifentrine, with a yield of 86.4% and a purity of 99.5%.

[0043] ESI-MS: m / z = 478.2.

[0044] 1HNMR (400 MHz; CDCl3) δ 6.910 (2H, s), 6.725 - 6.698 (2H, d), 5.581 (2H, brs), 5.472 (1H, s), 4.440 - 4.410 (2H, t), 4.081 - 4.056 (2H, t), 3.923 (3H, s), 3.792 (3H, s), 3.561 - 3.546 (2H, m), 2.954 - 2.925 (2H, t), 2.307 (3H, s), 2.084 (6H, s), 1.939 (1H, brs).

[0045] 13 C NMR (400 MHz; CDCl3) δ 160.6, 158.5, 149.5, 146.7, 146.0, 142.6, 129.7, 129.5, 128.9, 126.6, 120.3, 111.4, 109.6, 87.6, 56.5, 53.8, 45.8, 38.5, 26.7, 21.9, 18.5.

[0046] Example 3

[0047] This example provides a preparation process for ensifentrine, including the following steps:

[0048] Add 300 mL of 2 - methyltetrahydrofuran and 10.0 g (23.00 mmol) of the parent nucleus precursor to the reaction flask, cool down to 0 - 10 °C, and add 18.65 g (115.00 mmol) of N,N'-carbonyldiimidazole to obtain a mixed solution a;

[0049] Add 100 mL of 2 - methyltetrahydrofuran and 98.7 mL of methanol solution of ammonia (6N) to the reaction flask, add the above - mentioned mixed solution a, after adding, warm up to 40 °C and react for 3 h, add 100 mL of purified water to quench the reaction, concentrate, and add the concentrate to anhydrous ethanol according to the ratio of 1 g:5 mL, warm up to reflux, keep warm for 2 h, cool down to 30 °C for crystallization for 4 h, filter by suction, and dry in vacuum at 50 °C to obtain ensifentrine, with a yield of 85.6% and a purity of 99.7%.

[0050] ESI - MS: m / z = 478.2.

[0051] 1HNMR (400 MHz; CDCl3) δ 6.912 (2H, s), 6.726 - 6.700 (2H, d), 5.581 (2H, brs), 5.475 (1H, s), 4.443 - 4.408 (2H, t), 4.085 - 4.055 (2H, t), 3.933 (3H, s), 3.790 (3H, s), 3.562 - 3.544 (2H, m), 2.955 - 2.924 (2H, t), 2.309 (3H, s), 2.085 (6H, s), 1.942 (1H, brs).

[0052] 13 C NMR (400 MHz; CDCl3) δ 160.6, 158.7, 149.4, 146.9, 146.4, 142.3, 129.6, 129.3, 128.7, 126.4, 120.5, 111.4, 109.5, 87.6, 56.4, 53.6, 45.7, 38.6, 26.7, 21.9, 19.1.

[0053] Comparative Example 1

[0054] This comparative example provides a preparation process of ensifentrine, including the following steps:

[0055] Under stirring at 80 °C, an aqueous solution of sodium cyanate (6.0 g, 0.092 mmol) was added dropwise to a solution of 9,10 - dimethoxy - 2 - (2,4,6 - trimethylphenylimino) - 3 - (2 - aminoethyl) - 3,4,6,7 - tetrahydro - 2H - pyrimido[6,1 - a]isoquinolin - 4 - one (20.0 g, 0.046 mol) in water (600 mL) and 1N HCl (92 mL). The mixture was stirred at 80 °C for 2 h, and the reaction solution was cooled in an ice bath and alkalized with 2N NaOH solution. It was extracted with dichloromethane (3 × 200 mL), the extraction solutions were combined, dried over anhydrous magnesium sulfate, and distilled under vacuum. The obtained yellow foam was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (97:3), and developed with ether to obtain a yellow solid, namely 11.9 g of ensifentrine, with a yield of 54%.

[0056] Comparative Example 2

[0057] This comparative example provides a preparation process of ensifentrine, including the following steps:

[0058] 100 mL of 2 - methyltetrahydrofuran and 10.0 g (23.00 mmol) of the parent nucleus precursor were added to a reaction flask. The temperature was lowered to 0 - 10 °C, and 3.73 g (23.00 mmol) of N,N'-carbonyldiimidazole was added to obtain a mixed solution a;

[0059] Add 100 mL of 2-methyltetrahydrofuran and 32.9 mL of a methanol solution of ammonia (7N) to a reaction flask. Add the above mixed solution a. After adding, heat up to 30 °C and react for 3 h. Add 100 mL of purified water to quench the reaction. Concentrate, and according to the ratio of 1 g:10 mL, add the concentrate to absolute ethanol. Heat up to reflux, keep warm for 1 h, cool down to 20 °C and crystallize for 2 h. Filter by suction and dry in vacuo at 50 °C to obtain ensifentrine, with a yield of 20.6% and a purity of 98.5%.

[0060] Comparative Example 3

[0061] This comparative example provides a preparation process for ensifentrine, which includes the following steps:

[0062] Add 100 mL of 2-methyltetrahydrofuran and 10.0 g (23.00 mmol) of the parent nucleus precursor to a reaction flask. Cool down to 0 - 10 °C, and add 3.73 g (23.00 mmol) of N,N'-carbonyldiimidazole to obtain a mixed solution a;

[0063] Add 100 mL of 2-methyltetrahydrofuran and 32.9 mL of an ammonia water solution (7N) to a reaction flask. Add the above mixed solution a. After adding, heat up to 50 °C and react for 3 h. Add 100 mL of purified water to quench the reaction. Concentrate, and according to the ratio of 1 g:10 mL, add the concentrate to absolute ethanol. Heat up to reflux, keep warm for 1 h, cool down to 20 °C and crystallize for 2 h. Filter by suction and dry in vacuo at 50 °C to obtain ensifentrine, with a yield of 36.5% and a purity of 95.9%.

[0064] In summary, the preparation process for ensifentrine provided by the embodiments of the present invention uses N,N'-carbonyldiimidazole and a methanol solution of ammonia to replace highly toxic sodium cyanate, and no strong acid solution is added in the preparation process, and ether is not introduced in the post-treatment, significantly improving the safety and environmental protection of the process. Moreover, the reaction conditions are mild, the reaction rate is fast, effectively reducing the reaction energy consumption and production cost. The yield of the obtained ensifentrine can reach 85% - 90%, and the purity can reach more than 99.5%, which is convenient for realizing industrial-scale production and has high application prospects.

[0065] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation process of ensifentrine, characterized in that, It includes the following steps: Using a methanol solution of a parent nucleus precursor, N,N'-carbonyldiimidazole, and ammonia as raw materials, and 2-methyltetrahydrofuran as the reaction solvent, a condensation reaction is carried out at 40 °C to 60 °C to obtain ensifentrine; wherein, the parent nucleus precursor is 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one.

2. The preparation process of ensifentrine according to claim 1, characterized in that, Specifically, it includes the following steps: S1. Add the parent nucleus precursor to 2-methyltetrahydrofuran, cool down, and add N,N'-carbonyldiimidazole to obtain a mixed solution a; S2. Add the methanol solution of ammonia to 2-methyltetrahydrofuran and mix evenly to obtain a mixed solution b; S3. Add the mixed solution a to the mixed solution b, heat up to 40 °C to 60 °C for a condensation reaction to obtain ensifentrine.

3. The preparation process of ensifentrine according to claim 2, characterized in that, In S1, the temperature of the cooling is 0 °C to 10 °C.

4. The preparation process of ensifentrine according to claim 2, characterized in that, In S1, the molar ratio of N,N'-carbonyldiimidazole to the parent nucleus precursor is (1 to 5):1; and / or In S1, the volume-mass ratio of 2-methyltetrahydrofuran to the parent nucleus precursor is (10 to 30) mL:1 g.

5. The preparation process of ensifentrine according to claim 2, wherein, In S2, the concentration of ammonia in the methanol solution of ammonia is 6 mol / L to 8 mol / L.

6. The preparation process of ensifentrine according to claim 5, characterized in that, In S2, the volume ratio of 2-methyltetrahydrofuran to the methanol solution of ammonia is (1 to 3):

1.

7. The preparation process of ensifentrine according to claim 2 or 5, characterized in that, Calculated as NH3, the molar ratio of the methanol solution of ammonia to the parent nucleus precursor is (10 to 30):

1.

8. The preparation process of ensifentrine according to claim 2, characterized in that, In S3, the reaction time of the condensation reaction is 2 h to 3 h.

9. The preparation process of ensifentrine according to claim 2, wherein, In S3, after the condensation reaction, a post-treatment process is also included, specifically: adding water to the reaction solution for quenching, concentrating, recrystallizing the concentrate with anhydrous ethanol, filtering by suction, and drying to obtain ensifentrine.

10. The preparation process of ensifentrine according to claim 2, characterized in that, In S3, the specific steps of the recrystallization are: heating up to reflux, keeping warm for 0.5 h to 2 h, and then cooling down to 10 °C to 30 °C for crystal precipitation for 1 h to 4 h.

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