Uromostat hydrogen sulfate intermediate II and preparation method thereof

Abstract

The method comprises the following steps: (1) mixing and stirring an intermediate I and absolute ethyl alcohol, (2) introducing nitrogen for protection, adding a hydroxylamine solution into the solution obtained in the step (1), heating to 60-80 DEG C, stirring and reacting for 10-30 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure until the reaction solution is dry, then adding ethyl acetate, and reacting for 1-2 hours at the temperature of 60-80 DEG C to obtain the umostat hydrogen sulfate intermediate II. Concentrating under reduced pressure to be dry to obtain a concentrate; (3) adding acetone into the concentrate, and stirring until the solution is clear; (4) dissolving 1, 5-naphthalene disulfonic acid tetrahydrate in acetone, then adding into the solution obtained in the step (3), heating to 25-45 DEG C, carrying out heat preservation and stirring reaction for 1-5 hours, then stopping heating, cooling to 0-20 DEG C, continuing to carry out stirring reaction for 10-18 hours, and then discharging and centrifuging to obtain a wet product; and (5) stirring and mixing the wet product and propyl alcohol, discharging, centrifuging to obtain a wet product of an intermediate II, and drying to obtain the umostat hydrogen sulfate intermediate II. The method is simple to operate and mild in reaction condition.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceuticals, and particularly to umostast maleate intermediate II and a preparation method thereof. Background Art

[0002] Upamostat (LH011) is an oral serine protease inhibitor. Serine proteases are a class of enzymes with catalytic activity and are involved in various physiological and pathological processes. In tumors, abnormally activated proteases can promote extracellular matrix degradation, cell migration, and angiogenesis, thereby accelerating tumor progression. By specifically inhibiting serine proteases, it may block the key signaling pathways of tumor growth and metastasis, providing new molecular targets for cancer treatment. Traditional chemotherapy drugs can damage normal cells while killing tumor cells, resulting in serious side effects. Some targeted drugs may develop drug resistance after long-term use, limiting their clinical applications. Developing oral drugs can improve patients' treatment compliance and quality of life.

[0003] As an oral serine protease inhibitor, upamostat can specifically inhibit related proteases in the tumor microenvironment and block tumor progression. By optimizing the drug structure and administration route, upamostat aims to reduce toxic side effects and improve patients' tolerance. In addition to cancer treatment, the abnormal activation of serine proteases is also associated with various diseases (such as inflammation, fibrosis), and upamostat may have a wider range of indications. Currently, the preparation process of upamostat involves biological extraction and purification techniques, and the raw material sources are unstable, resulting in poor stability of the extraction process. Therefore, a chemical synthesis method is needed to prepare upamostat, and compound is a key intermediate for preparing upamostat. There are few reports on the synthesis of the intermediate compound at home and abroad. Therefore, providing a simple synthesis method for umostast maleate intermediate is of great research significance. Summary of the Invention

[0004] The purpose of the present invention is to provide umostast maleate intermediate II and a preparation method thereof. It is the main structural fragment of the upamostat API and can be successfully used to prepare upamostat subsequently.

[0005] In one aspect of the present invention, a preparation method of umostast maleate intermediate II is proposed. According to an embodiment of the present invention, the method includes the following steps:

[0006] (1) Mix and stir intermediate I with absolute ethanol, wherein the chemical formula of intermediate I is as follows:

[0007]

[0008] (2) Under nitrogen protection, add hydroxylamine solution to the solution in step (1), heat up to 60 - 80 °C, stir and react for 10 - 30 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to dryness, then add ethyl acetate, and concentrate to dryness under reduced pressure to obtain a concentrate;

[0009] (3) Add acetone to the concentrate and stir until it becomes clear;

[0010] (4) Dissolve 1,5-naphthalenedisulfonic acid tetrahydrate in acetone, then add it to the solution in step (3), heat up to 25 - 45 °C, keep warm and stir for 1 - 5 h, then turn off the heating, cool to 0 - 20 °C, continue to stir and react for 10 - 18 h, then discharge the material and centrifuge to obtain a wet product;

[0011] (5) Stir and mix the wet product and propanol, then discharge the material and centrifuge to obtain the wet intermediate II, and dry it to obtain the umbrastatin mesylate intermediate II.

[0012] In addition, according to the preparation method of the umbrastatin mesylate intermediate II in the above embodiments of the present invention, the following additional technical features may also be included:

[0013] In some embodiments of the present invention, in step (1), the mass ratio of the intermediate I to absolute ethanol is 1:1.5 - 2.

[0014] In some embodiments of the present invention, in step (2), the mass ratio of the intermediate I, hydroxylamine, and ethyl acetate is 1:(0.1 - 0.2):(1 - 1.1).

[0015] In some embodiments of the present invention, in step (2), the mass percentage of the hydroxylamine solution is 40% - 60%.

[0016] In some embodiments of the present invention, in step (3), the mass ratio of acetone to the intermediate I is 1:7.6 - 8.

[0017] In some embodiments of the present invention, in step (4), the mass ratio of the intermediate I to 1,5-naphthalenedisulfonic acid tetrahydrate is 1:0.03 - 0.04.

[0018] In some embodiments of the present invention, in step (5), the drying is carried out using a vacuum dryer.

[0019] In some embodiments of the present invention, the vacuum dryer controls the temperature at 30 - 50 °C and reduces the pressure for drying for 5 - 10 h.

[0020] On the other hand, the present invention provides an umbrastatin mesylate intermediate II prepared by the preparation method of the umbrastatin mesylate intermediate II described above, and its chemical formula is as follows:

[0021]

[0022] In another aspect of the present invention, the present invention provides that the umostatin mesylate intermediate II is used for preparing umostatin mesylate.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] The present invention provides a brand-new preparation route for synthesizing umostatin mesylate intermediate II, which has simple operation, mild reaction conditions, high product purity and high yield. Specific Embodiments

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Apparently, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0026] Example 1

[0027] A preparation method of umostatin mesylate intermediate I, comprising the following steps:

[0028] (1) Add 24.80 kg of dichloromethane to a 50 L glass-lined reactor, start stirring, and sequentially add 2933.3 g of ethyl 4-[(2S)-2-amino-3-(3-cyanophenyl)propanoyl]piperazinecarboxylate and 2416.0 g of 2,4,6-triisopropylbenzenesulfonyl chloride.

[0029] (2) Slowly add 1616.8 g of triethylamine to the reactor, control the temperature at 30 °C, and stir for 20 hours.

[0030] (3) Prepare two portions of dilute hydrochloric acid solution: Mix 786.7 g of hydrochloric acid and 7333.0 g of purified water.

[0031] (4) Add one portion of the prepared dilute hydrochloric acid solution to the reactor, stir, then turn off the stirring, let it stand, separate the liquid, and retain the lower organic layer.

[0032] (5) Add the other portion of the prepared dilute hydrochloric acid solution to the organic layer, stir, then turn off the stirring, let it stand, separate the liquid, and retain the lower organic layer.

[0033] (6) Add 8.00 kg of purified water to the organic layer, stir, then turn off the stirring, let it stand, separate the liquid, retain the lower organic layer, and concentrate it under reduced pressure to dryness.

[0034] (7) Add 6.40 kg of absolute ethanol to the concentrate, and continue to concentrate it under reduced pressure to dryness to obtain umostatin mesylate intermediate I, the chemical formula of which is as follows:

[0035]

[0036] Example 2

[0037] The preparation method of umomostat hydrogen sulfate intermediate II comprises the following steps:

[0038] (1) The anhydrous ethanol solution of Intermediate I prepared in Example 1 was added to a 50 L glass-lined reactor, stirring was started, and 11.05 kg of anhydrous ethanol was added.

[0039] (2) Under nitrogen protection, add 726.6 g of 50% hydroxylamine solution, raise the temperature to 60° C., and stir to react for 10 hours.

[0040] (3) After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure. 4.93 kg of ethyl acetate is added and the mixture is concentrated to dryness under reduced pressure.

[0041] (4) Add 37.70 kg of acetone to the concentrate and stir until it dissolves.

[0042] (5) 1785.4 g of 1,5-naphthalene disulfonic acid tetrahydrate was dissolved in 4.26 kg of acetone.

[0043] (6) The acetone solution of 1,5-naphthalene disulfonic acid tetrahydrate was slowly added dropwise to the reaction kettle. After the addition was complete, the temperature was raised to 20°C and the mixture was stirred and reacted for 2 hours.

[0044] (7) Turn off the heating, reduce the temperature to 0°C, and continue stirring the reaction for 10 hours.

[0045] (8) Discharge the material, centrifuge, and obtain the wet product.

[0046] (9) Add 20.92 kg of acetone to a 50 L glass-lined reactor, start stirring, add the wet product, and stir.

[0047] (10) Discharge the material and centrifuge to obtain the wet product of intermediate II.

[0048] (11) The wet product was placed in a vacuum dryer, controlled at 30°C, and dried under reduced pressure for 10 h. A white solid intermediate II was obtained, whose chemical formula is as follows:

[0049]

[0050] The chemical reaction formula for the preparation of umomostat hydrogen sulfate intermediate II is as follows:

[0051]

[0052] Example 3

[0053] The preparation method of umomostat hydrogen sulfate intermediate II comprises the following steps:

[0054] (1) Add the anhydrous ethanol solution of Intermediate Ⅰ prepared in Example 1 to a 50 L glass-lined reactor, start stirring, and then add 11.05 kg of anhydrous ethanol.

[0055] (2) Under nitrogen protection, add 726.6 g of 50% hydroxylamine solution, heat up to 70 °C, and stir and react for 20 hours.

[0056] (3) After the reaction is completed, concentrate the reaction solution under reduced pressure until dry. Then add 4.93 kg of ethyl acetate and concentrate to dryness under reduced pressure.

[0057] (4) Add 37.70 kg of acetone to the concentrate and stir until it is clear.

[0058] (5) Dissolve 1785.4 g of 1,5-naphthalenedisulfonic acid tetrahydrate in 4.26 kg of acetone.

[0059] (6) Slowly drip the acetone solution of 1,5-naphthalenedisulfonic acid tetrahydrate into the reactor. After the dripping is completed, heat up to 35 °C and keep stirring and reacting for 4 hours.

[0060] (7) Turn off the heating, cool down to 10 °C, and continue stirring and reacting for 15 hours.

[0061] (8) Discharge the material, centrifuge to obtain the wet product.

[0062] (9) Add 20.92 kg of acetone to a 50 L glass-lined reactor, start stirring, add the wet product, and stir.

[0063] (10) Discharge the material, centrifuge to obtain the wet product of Intermediate Ⅱ.

[0064] (11) Feed the wet product into a vacuum dryer, control the temperature at 40 °C, and dry under reduced pressure for 8 h. Obtain the white solid Intermediate Ⅱ, and its chemical formula is as follows:

[0065]

[0066] Example 4

[0067] A method for preparing the intermediate Ⅱ of ulinastatin hydrogen sulfate, comprising the following steps:

[0068] (1) Add the anhydrous ethanol solution of Intermediate Ⅰ prepared in Example 1 to a 50 L glass-lined reactor, start stirring, and then add 11.05 kg of anhydrous ethanol.

[0069] (2) Under nitrogen protection, add 726.6 g of 50% hydroxylamine solution, heat up to 80 °C, and stir and react for 25 hours.

[0070] (3) After the reaction is completed, concentrate the reaction solution under reduced pressure until dry. Then add 4.93 kg of ethyl acetate and concentrate to dryness under reduced pressure.

[0071] (4) Add 37.70 kg of acetone to the concentrate and stir until it becomes clear.

[0072] (5) Dissolve 1785.4 g of 1,5-naphthalenedisulfonic acid tetrahydrate in 4.26 kg of acetone.

[0073] (6) Slowly add the acetone solution of 1,5-naphthalenedisulfonic acid tetrahydrate to the reaction kettle. After the addition is complete, raise the temperature to 45 °C and keep stirring and reacting for 3 hours.

[0074] (7) Turn off the heating, cool down to 20 °C, and continue stirring and reacting for 16 hours.

[0075] (8) Discharge the material and centrifuge to obtain the wet product.

[0076] (9) Add 20.92 kg of acetone to a 50 L glass-lined reaction kettle, start stirring, add the wet product, and stir.

[0077] (10) Discharge the material and centrifuge to obtain the wet product of Intermediate II.

[0078] (11) Feed the wet product into a vacuum dryer, control the temperature at 50 °C, and dry under reduced pressure for 5 h. Obtain the white solid Intermediate II, and its chemical formula is as follows:

[0079]

[0080] The above content is only an example and explanation of the present invention. Those skilled in the art of this technology can make various modifications, supplements, or use similar methods to replace the specific embodiments described. As long as they do not deviate from the structure of the present invention or exceed the scope defined by this claim book, they should fall within the protection scope of the present invention.

Claims

1. Preparation method of ulinastatin intermediate II bisulfate, characterized in that, It includes the following steps: (1) Mix and stir intermediate Ⅰ with absolute ethanol. The chemical formula of intermediate Ⅰ is as follows: (2) Under nitrogen protection, add hydroxylamine solution to the solution in step (1), heat up to 60 - 80 °C, stir and react for 10 - 30 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to dryness, then add ethyl acetate and concentrate to dryness under reduced pressure to obtain a concentrate; (3) Add acetone to the concentrate and stir until it becomes clear; (4) Dissolve 1,5 - naphthalenedisulfonic acid tetrahydrate in acetone, then add it to the solution in step (3), heat up to 25 - 45 °C, keep warm and stir for 1 - 5 h, then turn off the heating, cool down to 0 - 20 °C, continue to stir and react for 10 - 18 h, then discharge the material and centrifuge to obtain a wet product; (5) Stir and mix the wet product with propanol, then discharge the material and centrifuge to obtain a wet product of intermediate Ⅱ, and dry it to obtain the umostatin bisulfate intermediate Ⅱ.

2. The preparation method of umostastin bisulfate intermediate II according to claim 1, characterized in that: In step (1), the mass ratio of intermediate Ⅰ to absolute ethanol is 1:1.5 - 2.

3. The preparation method of ulinastatin intermediate II bisulfate according to claim 1, characterized in that: In step (2), the mass ratio of intermediate Ⅰ, hydroxylamine, and ethyl acetate is 1:(0.1 - 0.2):(1 - 1.1).

4. The preparation method of ulimorelin hydrogen sulfate intermediate II according to claim 1, wherein: In step (2), the mass percentage of the hydroxylamine solution is 40% - 60%.

5. The preparation method of umbrastatin II bisulfate intermediate II according to claim 1, characterized in that: In step (3), the mass ratio of acetone to intermediate Ⅰ is 1:7.6 - 8.

6. The preparation method of umostastin bisulfate intermediate II according to claim 1, characterized in that: In step (4), the mass ratio of intermediate Ⅰ to 1,5 - naphthalenedisulfonic acid tetrahydrate is 1:0.03 - 0.

04.

7. The preparation method of umostatin intermediate II hydrogen sulfate according to claim 1, characterized in that: In step (5), the drying is carried out using a vacuum dryer.

8. The preparation method of umostastin mesylate intermediate II according to claim 7, characterized in that: The vacuum dryer controls the temperature at 30 - 50 °C and reduces the pressure for drying for 5 - 10 h.

9. The ulimoreastatin hydrogen sulfate intermediate II prepared by the preparation method of the ulimoreastatin hydrogen sulfate intermediate II according to any one of claims 1-8, characterized in that, The chemical formula is as follows:

10. The umostatin bisulfate intermediate Ⅱ described in claim 9 is used for preparing umostatin bisulfate.

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