Method for preparing polyamine derivative drug and salt-forming intermediate thereof

Abstract

The present invention belongs to the technical field of pharmaceuticals. Disclosed are a method for preparing a polyamine derivative drug and a salt-forming intermediate thereof. The salt-forming intermediate of the polyamine derivative drug provided by the present invention is a pharmaceutical intermediate salt obtained by means of extensive experimental studies according to the requirements of pharmaceutical production, which is suitable for industrialization, is economically feasible, and is conducive to improving the quality stability of products and the operability of the process. When used in the preparation of the polyamine derivative drug, the salt-forming intermediate achieves significant improvements in both product yield and purity, which is beneficial to industrial-scale production of the polyamine derivative drug and has very promising prospects in the chemical and pharmaceutical fields.

Description

Process for the preparation of a polyamine derivative drug and a salt-forming intermediate thereof TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmacy, in particular to a process for the preparation of a polyamine derivative drug and a salt-forming intermediate thereof. BACKGROUND

[0002] Systemic inflammatory response syndrome and autoimmune disorder related diseases, such as sepsis and autoimmune diseases, are two types of diseases caused by excessive immune response of the body itself, and there is still a lack of effective treatment drugs. The targeted prevention and treatment of these diseases is a focus and hot issue in clinical concern. Among them, sepsis is a systemic inflammatory response syndrome mediated by infectious factors. Although antibiotics and critical care medicine have made great progress, sepsis is still the main factor causing death in infected patients, and there is no ideal treatment drug so far.

[0003] A polyamine derivative pharmaceutical salt, a preparation method and application thereof are disclosed in Chinese patent CN105348137B. The polyamine derivative pharmaceutical salt can be used for preparing a drug for treating sepsis. However, the preparation process comprises the following steps:

[0004] The process does not consider the purity of the intermediate compound 5 (D211-F1) and the final product, and the preparation process needs to be improved.

[0005] Chinese patent application CN116947681A discloses an intermediate of a polyamine derivative pharmaceutical salt, a preparation method and application thereof. The preparation process obtains a new intermediate by protecting the amino group, and the reaction is shown as follows:

[0006] Compared with the patent CN105348137B, although the yield and purity of the product obtained by the process are obviously improved, the obtained intermediate needs to be purified by column chromatography. This method has the defects of difficulty in batch amplification, low production efficiency, high cost and unstable quality in industrial production.

[0007] Therefore, it is necessary to develop a new intermediate or production process to avoid the intermediate column chromatography purification operation, for industrialized mass production, to improve the product quality stability and process operability. SUMMARY

[0008] To overcome the shortcomings of the prior art, the present application provides a process for the preparation of a polyamine derivative drug, which is a pharmaceutical salt of D211-H. The structure of D211-H is shown as follows:

[0009] The method is: after D211-F1 is salified with fumaric acid, D211-H is prepared by taking the fumarate of D211-F1 as raw material, and then D211-H is salified with acid;

[0010] The structure of D211-F1 is as shown below:

[0011] Specifically, the acid is a pharmaceutically acceptable acid, including inorganic acid and organic acid, wherein the inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and the organic acid includes but is not limited to acetic acid, oxalic acid, malonic acid, succinic acid, benzoic acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0012] In a specific embodiment, the polyamine derivative drug is a phosphate of D211-H, and the structure is as shown below:

[0013] In the formula, x is 1.9-2.1, for example, 2.

[0014] In a second aspect of the present application, a preparation method of D211-H is also provided, and the preparation method is: after D211-F1 is salified with fumaric acid, D211-H is prepared by taking the fumarate of D211-F1 as raw material.

[0015] In a third aspect of the present application, a salification intermediate of a polyamine derivative drug is also provided, and the intermediate is D211-F1, and the structure is as shown below:

[0016] The salt is a fumarate.

[0017] Further, in some embodiments of the present application, the salt is a 2-fumarate.

[0018] The salification intermediate of the polyamine derivative drug provided in the present application is a pharmaceutical intermediate salt which is suitable for industrialization, economically feasible, and beneficial to improve product quality stability and process operability, and is obtained through a large number of experimental researches according to the needs of pharmaceutical production.

[0019] In a fourth aspect of the present application, a preparation method of the salification intermediate of the aforementioned polyamine derivative drug is also provided, and the method is: D211-F1 free base is dissolved in a solvent, and then added to a mixed solution of acid and solvent, after addition, stirring is performed, an anti-solvent is added, after addition, solid is precipitated, after stirring, suction filtration is performed, and then drying is performed, and the intermediate is obtained.

[0020] Further, in some embodiments of the present application, the method for preparing the salted intermediate of the polyamine derivative drug further comprises a purification step, i.e. dissolving the obtained product in a solvent, adding an anti-solvent at 10-30°C, after the addition, solid precipitates, after stirring, suction filtration, and drying, to obtain the product.

[0021] Further, in some embodiments of the present application, the D211-F1 free base is dissolved in a solvent and then added to a mixed solution of acid and solvent at 10-30°C.

[0022] Further, in some embodiments of the present application, the anti-solvent is added at 10-30°C in the method for preparing the salted intermediate.

[0023] Further, in some embodiments of the present application, the solvent in the method for preparing the salted intermediate is an alcohol solvent, such as methanol or ethanol.

[0024] Further, in some embodiments of the present application, the anti-solvent in the method for preparing the salted intermediate is a non-alcohol organic solvent, such as ethyl acetate.

[0025] Specifically, the reagents, solvents, anti-solvents and reaction conditions in the above preparation method have the corresponding definitions described above in the present application, and if not specified, the skilled person in the art can select the conventional reagents, solvents, anti-solvents and reaction conditions according to the needs based on the specific embodiments of the present application to achieve all the technical solutions of the present application.

[0026] The salted intermediate of the polyamine derivative drug provided by the present application is easy to prepare and purify, and when used for the preparation of the polyamine derivative drug, the yield and purity of the obtained product are significantly improved, the operation is simple and fast, which is conducive to improving the industrialized production of the polyamine derivative drug described in the present application, and has a very good application prospect in the field of chemical industry and medicine. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 is the nuclear magnetic resonance hydrogen spectrum detection result of the D211-F1 fumarate salt obtained in Example 1 of the present application;

[0028] Figure 2 is the mass spectrum detection result of the D211-F1 fumarate salt obtained in Example 1 of the present application. DETAILED DESCRIPTION

[0029] Unless otherwise defined, all scientific and technical terms used in the present application have the same meanings as generally understood by those skilled in the art to which the present application relates.

[0030] The disclosures of various publications and published patent specifications cited herein are hereby incorporated by reference in their entireties.

[0031] The technical solutions of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0032] In actual production, the starting material D211-F1 free base crude described in Examples 1-2 of the present application can be prepared in any way, which does not affect the preparation of the salt of D211-F1 and the polyamine derivative drug described in the present application. In the specific embodiments of the present application, for the purpose of more intuitive comparison, the D211-F1 free base crude used in Examples 1-2 and Comparative Examples of the present application is obtained by the following method:

[0033] As shown in the above reaction formula, according to the method of Comparative Example 1 of Chinese Patent Application CN116947681A, compound 1, ethanol and Raney nickel were added to an autoclave, hydrogen was filled, and the reaction was stirred at 45℃, 1.0-2.0 MPa for 48 h. Concentrated to dryness under reduced pressure to obtain compound 5 (D211-F1) free base crude (purity 68.9%, yield 66.5%).

[0034] Example 1: Salting and purification of D211-F1

[0035] Example 1

[0036] The 19.1 g of starting material D211-F1 free base crude (purity 68.9%) was dissolved in 114.6 g of methanol, and slowly added to a mixture of 6.11 g of fumaric acid and 76.4 g of methanol at room temperature. After the addition was completed, the mixture was stirred at room temperature for 1 h, and then 649.4 g of ethyl acetate was added dropwise. After the addition was completed, solid precipitated, and the stirring was continued for 3 h. The mixture was filtered and dried to obtain a white powder solid, which was the crude fumarate salt of D211-F1, 16.5 g (purity 89.9%, yield 85.4%).

[0037] Dissolve 16.5 g of D211-F1 fumarate crude product in 247.5 g of methanol, slowly drop 742.5 g of ethyl acetate at room temperature, after dropping, solid precipitates, continue stirring at room temperature for 3 h, filter and dry, to obtain 14.6 g of white powder, which is D211-F1 fumarate (purity 96.2%, yield 88.5%). MS: [M+H]+m / z=730.8, 1H NMR (DMSO-d6): δ 6.672-6.799 (m, 6H), δ 6.441 (s, 4H), δ 3.663-3.692 (m, 12H), δ 3.279-3.280 (m, 12H), δ 2.694-2.734 (m, 8H), δ 2.521-2.525 (m, 4H), δ 1.730 (m, 4H), δ 1.745 (m, 4H), δ 1.224-1.349 (m, 9H).

[0038] Example 2

[0039] Dissolve 16.5 g of D211-F1 fumarate crude product in 247.5 g of methanol, slowly drop 742.5 g of ethyl acetate at room temperature, after dropping, solid precipitates, continue stirring at room temperature for 3 h, filter and dry, to obtain 14.6 g of white powder, which is D211-F1 fumarate (purity 96.2%, yield 88.5%). MS: [M+H]+m / z=730.8, 1H NMR (DMSO-d6): δ 6.672-6.799 (m, 6H), δ 6.441 (s, 4H), δ 3.663-3.692 (m, 12H), δ 3.279-3.280 (m, 12H), δ 2.694-2.734 (m, 8H), δ 2.521-2.525 (m, 4H), δ 1.730 (m, 4H), δ 1.745 (m, 4H), δ 1.224-1.349 (m, 9H).

[0040] Dissolve 16.5 g of D211-F1 fumarate crude product in 247.5 g of methanol, slowly drop 742.5 g of ethyl acetate at room temperature, after dropping, solid precipitates, continue stirring at room temperature for 3 h, filter and dry, to obtain 14.6 g of white powder, which is D211-F1 fumarate (purity 96.2%, yield 88.5%). MS: [M+H]+m / z=730.8, 1H NMR (DMSO-d6): δ 6.672-6.799 (m, 6H), δ 6.441 (s, 4H), δ 3.663-3.692 (m, 12H), δ 3.279-3.280 (m, 12H), δ 2.694-2.734 (m, 8H), δ 2.521-2.525 (m, 4H), δ 1.730 (m, 4H), δ 1.745 (m, 4H), δ 1.224-1.349 (m, 9H).

[0041] Example 2: Test of the influence of the kind of acid on salt formation

[0042] In the salt screening experiment, 18 common organic or inorganic acids were tried. However, the acids with strong acidity such as hydrochloric acid, sulfuric acid and trifluoroacetic acid were not considered because the risk of removing BOC group during the reaction of these acids with D211-F1 was extremely high.

[0043] In the specific experiment, the method of Example 1 Example 2 was used, and the acid was replaced under the same reaction scale and conditions to explore the influence of phosphoric acid, oxalic acid, D-tartaric acid, fumaric acid, succinic acid, maleic acid and gentisic acid on salt formation. That is, the crude product of D211-F1 free base (purity 68.9%) was dissolved in ethanol, slowly added to the mixed solution of acid and ethanol at room temperature, and stirred at room temperature after the addition was completed.

[0044] The results are shown in Table 1.

[0045] Table 1 Influence of acid type on salt formation Note: *Green sticky material appeared on the bottom of the bottle before the addition of anti-solvent, which could not be filtered. After centrifugation, the supernatant was poured off, and the remaining solid was vacuum dried. The sticky material was still sticky and had poor properties, which was not suitable for further development. & The slightly turbid solution had almost no product on the filter paper after filtration, and the yield was extremely low. Slowly adding anti-solvent ethyl acetate to the filtrate did not precipitate solid, which was not suitable for further development. # White suspension could be filtered to obtain white solid powder. ￠ Clear, no solid was obtained after adding anti-solvent.

[0046] After salt screening, fumaric acid was finally selected as the acid with solid precipitation and good product properties. The results were similar when the acid equivalent was adjusted to 1-5, and the conclusion was the same.

[0047] Example 3: Influence of salt formation solvent on salt formation of various acids

[0048] According to the experimental results of Example 2, oxalic acid, D-tartaric acid, fumaric acid, malic acid and citric acid were selected to investigate the salt formation of these acids with D211-F1 in methanol or ethyl acetate solvent. The results are shown in Table 2.

[0049] Table 2 Influence of salt formation solvent on salt formation of various acids

[0050] From the salt formation properties, fumaric acid salt can obtain solid powder in alcohol solvent, and the purification method is simple. The purity of D211-F1 fumaric acid salt is high, and column chromatography is not required before preparing polyamine derivative drugs. Considering comprehensively, fumaric acid is finally selected to form salt with D211-F1.

[0051] From Table 2, it can be seen that the solvent can have an effect on the salt formation properties. The acids excluded in Example 2 were prepared using methanol or ethyl acetate as the solvent to further investigate the salt formation properties. It was found that the solvent had little effect on the salt formation properties in general, and the results obtained by adjusting the acid equivalent to between 1 and 5 were similar, and the same conclusion was reached that fumaric acid was the better acid. For example, when phosphoric acid was used, the solution was slightly turbid when methanol was used as the solvent, and the solution was first turbid and then became a green viscous substance at the bottom when ethyl acetate was used as the solvent. When the acid equivalent was 3, 4 or 5, the solution was only slightly turbid or a green viscous substance was formed at the bottom.

[0052] In addition, experiments were conducted using other anti-solvents such as acetone, tetrahydrofuran, acetonitrile, n-heptane, etc. It was found that among the 18 commonly used organic acids or inorganic acids, the acid that produced the best product properties (solid powder can be obtained without using column chromatography for purification) was still fumaric acid.

[0053] Example 4:

[0054] D211-F1 fumarate salt de-Boc (tert-butyloxycarbonyl)

[0055] Into a three-necked flask was added 70 g of D211-F1 fumarate salt obtained after purification in Example 1, Example 1, and 210 g of water was added to dissolve it. Then, 10% sodium hydroxide was used to adjust the pH value to 14, and the aqueous phase was extracted with 200 ml of dichloromethane four times. The dichloromethane phases were combined and concentrated to dryness under reduced pressure to obtain 55.0 g of D211-F1 free base with a purity of 96.4% and a yield of 100%.

[0056] The above 55.0 g of D211-F1 free base was dissolved in 550 g of dichloromethane, and the temperature was lowered to 5°C. Then, 15% (mass fraction) hydrochloric acid ethyl acetate solution was slowly added dropwise. After the addition was completed, the reaction was continued at 0-5°C for 1.5 h. Then, 275 g of water was added to the reaction liquid, and the liquid was allowed to stand to separate. The aqueous phase was adjusted to a pH value of 14 using 10% sodium hydroxide, and then the aqueous phase was extracted with 200 ml of dichloromethane four times. The dichloromethane phases were combined and concentrated to dryness under reduced pressure to obtain 44.1 g of colorless oil D211-H with a purity of 98.5% and a yield of 96.0%.

[0057] Preparation of D211-H phosphate salt

[0058] The above 44.1 g of D211-H was dissolved in 352 g of methanol, and then the solution was poured into a three-necked flask. Phosphoric acid methanol solution was slowly added dropwise at 0-5°C. After the addition was completed, the reaction was continued at 0-5°C for 2 h, and white solids were precipitated. The stirring was continued for 4 h to allow the crystals to precipitate, and then the mixture was filtered under suction and dried under vacuum to obtain 49.4 g of white powder D211-H phosphate salt with a yield of 85.6% and a purity of 99.6%.

[0059] Comparative Example 1

[0060] Referring to Comparative Example 1 of Chinese Patent Application CN116947681A, compound 1, ethanol and Raney nickel were added to an autoclave, hydrogen was filled, and stirring was performed at 45°C, 1.0-2.0 MPa for 48 h. After being concentrated to dryness under reduced pressure, the purity of the crude D211-F1 was only 69.2%, and the yield was 65.9%, which was not conducive to obtaining high-purity drug raw materials in subsequent production. Therefore, two purification methods were used to try to improve the purity of D211-F1.

[0061] The first purification method was as follows: the crude D211-F1 was passed through a column (200-300 mesh silica gel chromatography column), eluted with acetone: n-heptane = 4:1 (v / v), and the purity of D211-F1 was 72.4%, and the total yield was 30.5%. After trying column purification, the purity and yield were still very low.

[0062] The second purification method was as follows: the crude D211-F1 was added to dichloromethane (DCM) and stirred to dissolve, the temperature was controlled at 0-10°C, 1M hydrochloric acid was extracted twice, the water phase was combined, 1M sodium hydroxide was added to adjust the pH to above 10, DCM was added for extraction three times, 10% sodium chloride was washed twice, and concentrated to dryness. The above operation was repeated three times, the purity of D211-F1 was 96.1%, and the yield was 6.4%. This purification method had a certain effect of removing impurities, but there was serious emulsification during the alkaline extraction process, and the process was complex, which was not conducive to scale-up production.

[0063] The D211-F1 fumarate prepared by using the present patent can be a solid powder, and does not need to be purified by column chromatography. Both the D211-F1 fumarate and the D211-F1 obtained after Boc removal have high purity. Compared with CN116947681A, since column chromatography purification operation is not needed, the production cost, production cycle and three waste generation of a single step of preparing D211-F1 are greatly reduced, among which the material cost is reduced from 113,000 yuan to 17,000 yuan; the operation cycle of producing a batch is reduced from 40 days to 2 days; and the three waste generation is reduced from 11 tons to 0.7 tons. In addition, the salt formation purification is more operable, the batch difference is smaller, and the quality is more controllable.

[0064] Comparative Example 2: using un-salted and purified D211-F1 to prepare D211-H and its phosphate salt

[0065] Into a three-necked flask, 5.5 g of the crude starting material D211-F1 free base (self-made according to the counterexample 1 of Chinese patent application CN116947681A, purity 68.9%) without salification and purification was dissolved in 55 g of dichloromethane, and then slowly added with 15% (mass fraction) hydrochloric acid ethyl acetate solution at 5°C. After the addition was completed, the reaction was continued at 0-5°C for 1.5 h. Then 28 g of water was added to the reaction solution, and then the liquid was allowed to stand and separate. The water phase was adjusted to pH 14 with 10% sodium hydroxide, and then extracted with 200 ml of dichloromethane four times. The dichloromethane phase was combined and concentrated under reduced pressure to dryness, to obtain 3.3 g of light yellow oil D211-H, with a purity of 75.2% and a yield of 69.5%.

[0066] After 3.3 g of D211-H was dissolved in 26.5 g of methanol, it was put into a three-necked flask, and then slowly added with phosphoric acid methanol solution at 0-5°C. After the addition was completed, the reaction was continued at 0-5°C for 2 h. White solid was precipitated, and then the stirring was continued for 4 h. Filtration and vacuum drying were performed, to obtain 3.4 g of white powder compound D211-H phosphate, with a yield of 78.5% and a purity of 85.6%. The product had a low purity, and many impurities could not be removed.

[0067] Conclusion: Compared with the prior art, in the production process disclosed by the application, the purity of the key intermediate D211-F1 can be increased from less than 70% to 96.2% through salification. The purity of the product obtained through subsequent reactions is greatly improved. The process does not use column chromatography for purification during preparation, and is simple to operate, suitable for industrial large-scale production, and has low production cycle and cost, and achieves the expected effect.

[0068] The steps of the method in the application do not constitute any limitation on the order of the steps of the method, and the foregoing examples and methods can be different based on the ability, experience and preference of the person skilled in the art.

[0069] The above description of the application is only the preferred embodiment of the application, and is not intended to limit the application. Any modification, equivalent replacement, etc. made within the spirit and principle of the application shall be included in the protection scope of the application.

Claims

1. A method for preparing a polyamine derivative drug, wherein the polyamine derivative drug is a pharmaceutically acceptable salt of D211-H, and the structure of D211-H is as follows: It is characterized by: The preparation method comprises the following steps: D211-F1 is reacted with fumaric acid to form a salt, the fumarate of D211-F1 is used as a raw material to prepare D211-H, and then D211-H is reacted with acid to form a salt; The structure of D211-F1 is as follows:

2. The method for preparing a polyamine derivative drug according to claim 1, wherein: The polyamine derivative drug is the phosphate salt of D211-H, and its structure is shown below: Here, x is 1.9 to 2.1, for example, 2.

3. A method for preparing D211-H, wherein the structure of D211-H is as follows: It is characterized by: The preparation method is to form a salt of D211-F1 with fumaric acid, and then use the fumarate of D211-F1 as a raw material to prepare D211-H; The structure of D211-F1 is as follows:

4. A salt-forming intermediate of a polyamine derivative drug, characterized in that: The intermediate is D211-F1, and its structure is shown below: The salt is a fumarate.

5. The salt-forming intermediate of polyamine derivative drugs according to claim 4, characterized in that: The molar ratio of compound D211-F1 to fumaric acid in the salt is 1:

2.

6. A method for preparing a salt-forming intermediate of a polyamine derivative drug according to any one of claims 4 to 5, characterized in that: The method comprises the following steps: dissolving D211-F1 free base in a solvent, adding the solution to a mixed solution of an acid and a solvent, stirring the solution after the addition is completed, adding an anti-solvent, allowing solid to precipitate after the addition is completed, filtering the solution after stirring, and drying the solution to obtain the product.

7. The method for preparing the salt-forming intermediate of the polyamine derivative drug according to claim 6, characterized in that: The preparation method of the salt-forming intermediate of the polyamine derivative drug also includes a purification step, that is, dissolving the dried product in a solvent, adding an anti-solvent at 10-30° C., and after the addition, solids precipitate, stirring, filtering, and drying to obtain the product.

8. The method for preparing the salt-forming intermediate of the polyamine derivative drug according to claim 6, characterized in that: The D211-F1 free base is dissolved in a solvent and then added into a mixed solution of acid and solvent at 10-30°C.

9. The method for preparing the salt-forming intermediate of the polyamine derivative drug according to claim 6, characterized in that: In the preparation method of the salt-forming intermediate, the anti-solvent is added at 10-30°C.

10. The method for preparing the salt-forming intermediate of the polyamine derivative drug according to claim 6, characterized in that: The solvent in the method for preparing the salt-forming intermediate is an alcohol solvent, such as methanol or ethanol; preferably, the anti-solvent in the method for preparing the salt-forming intermediate is a non-alcohol organic solvent, such as ethyl acetate.

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