Uromostat hydrogen sulfate intermediate I and preparation method thereof

Abstract

The invention discloses a umostat hydrogen sulfate intermediate I and a preparation method thereof, and the method comprises the following steps: (1) uniformly mixing dichloromethane, 4-[(2S)-2-amino-3-(3-cyanophenyl) propionyl] piperazine ethyl formate and 2, 4, 6-triisopropyl benzene sulfonyl chloride in a reaction container; (2) triethylamine is dropwise added into the reaction container, and a temperature-controlled stirring reaction is carried out; (3) adding a diluted hydrochloric acid solution into the reaction container, stirring, standing, separating liquid, and retaining a lower organic layer; (4) adding a diluted hydrochloric acid solution into the organic layer, stirring, standing, separating liquid, and retaining the lower organic layer; (5) adding purified water into the organic layer in the step (4), stirring, standing, separating liquid, retaining the lower organic layer, and concentrating under reduced pressure until the organic layer is dry to obtain a concentrate; and (6) adding absolute ethyl alcohol into the concentrate, and continuously concentrating under reduced pressure until the concentrate is dry, so as to obtain the umostat hydrogen sulfate intermediate I. The synthesis route is simple, the operation is simple, and the reaction conditions are mild.

Description

Technical Field

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

[0002] Upamostat (LH011) is an orally administered serine protease inhibitor. Serine proteases are a class of catalytically active enzymes that participate in a variety of 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 also 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 application. Developing oral drugs can improve patients' treatment compliance and quality of life.

[0003] As an orally administered 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 source is unstable, resulting in poor stability of the extraction process. Therefore, a chemical synthesis method is needed to prepare upamostat, and compound is the key intermediate for preparing upamostat. There are few reports on the synthesis of the intermediate compound at home and abroad. Therefore, it is of great research significance to provide a simple synthesis method for umostast maleate intermediate I. Summary of the Invention

[0004] The purpose of the present invention is to provide umostast maleate intermediate I and a preparation method thereof. It is the main structural fragment of the umostast maleate raw drug, and the subsequent product is the umostast maleate preparation, and its mechanism is an inhibitor of urokinase-type plasminogen activator.

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

[0006] (1) Stir and mix dichloromethane (DCM), ethyl 4-[(2S)-2-amino-3-(3-cyanophenyl)propanoyl]piperazinecarboxylate, and 2,4,6-triisopropylbenzenesulfonyl chloride (TIPPS-Cl) evenly in a reaction vessel;

[0007] (2) Slowly add triethylamine dropwise to the above reaction vessel, control the temperature and stir for reaction;

[0008] (3) Add dilute hydrochloric acid solution to the above reaction vessel, stir, then let it stand and separate the layers, and retain the lower organic layer;

[0009] (4) Add dilute hydrochloric acid solution to the organic layer, stir, then let it stand and separate the layers, and retain the lower organic layer;

[0010] (5) Add purified water to the organic layer in step (4), stir, then let it stand and separate the layers, retain the lower organic layer, and concentrate it under reduced pressure to dryness to obtain a concentrate;

[0011] (6) Add absolute ethanol to the concentrate, continue to concentrate it under reduced pressure to dryness, and thus obtain the ulinastatin hemisulfate intermediate Ⅰ.

[0012] The chemical reaction formula for the preparation of ulinastatin hemisulfate intermediate Ⅰ is as follows:

[0013]

[0014] In addition, according to the preparation method of ulinastatin hemisulfate intermediate Ⅰ in the above embodiments of the present invention, the following additional technical features may also be possessed:

[0015] In some embodiments of the present invention, in step (1), the mass ratio of ethyl 4-[(2S)-2-amino-3-(3-cyanophenyl)propanoyl]piperazinecarboxylate, 2,4,6-triisopropylbenzenesulfonyl chloride, and dichloromethane is 1:0.8 - 1:8 - 9, and the molar ratio of ethyl 4-[(2S)-2-amino-3-(3-cyanophenyl)propanoyl]piperazinecarboxylate and 2,4,6-triisopropylbenzenesulfonyl chloride is 1:1.

[0016] In some embodiments of the present invention, in step (2), the temperature for temperature control is 30 - 50 °C, and the time for the stirring reaction is 10 - 30 h.

[0017] In some embodiments of the present invention, in steps (3) and (4), the mass concentration percentage of the dilute hydrochloric acid is 3.0% - 4.0%.

[0018] In some embodiments of the present invention, in step (3), the stirring time is 15 - 25 h, and the stirring frequency is 30 - 40 Hz.

[0019] In some embodiments of the present invention, in step (5), the mass ratio of the organic layer to purified water is 3.5 - 4:1.

[0020] In some embodiments of the present invention, in step (6), the mass ratio of the concentrate to absolute ethanol is 1:1 - 1.5.

[0021] In another aspect of the present invention, there is provided ulimorelin hydrogen sulfate intermediate I prepared by the method for preparing ulimorelin hydrogen sulfate intermediate I.

[0022] In addition, ulimorelin hydrogen sulfate intermediate I according to the above embodiments of the present invention may further have the following additional technical features:

[0023] In some embodiments of the present invention, its chemical formula is as follows:

[0024]

[0025] In another aspect of the present invention, there is provided the use of ulimorelin hydrogen sulfate intermediate I for preparing ulimorelin hydrogen sulfate.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] The present invention provides a method for preparing ulimorelin hydrogen sulfate intermediate I, which has a simple synthesis route, simple operation, mild reaction conditions, high product purity and high yield. Detailed Embodiments

[0028] 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 them. 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.

[0029] Example 1

[0030] A method for preparing ulimorelin hydrogen sulfate intermediate I, comprising the following steps:

[0031] (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.

[0032] (2) Slowly add 1616.8 g of triethylamine to the reactor, control the temperature at 30 °C, and stir and react for 20 hours.

[0033] (3) Prepare two portions of dilute hydrochloric acid solution: Mix 786.7 g of hydrochloric acid and 7333.0 g of purified water.

[0034] (4) Add one of the prepared portions of dilute hydrochloric acid solution to the reaction kettle, stir, then turn off the stirring, let it stand, separate the liquid, and retain the lower organic layer.

[0035] (5) Add the other prepared portion of 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.

[0036] (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.

[0037] (7) Add 6.40 kg of absolute ethanol to the concentrate, continue to concentrate it under reduced pressure to dryness to obtain the intermediate Ⅰ of ulimorelin hydrogen sulfate, and its chemical formula is as follows:

[0038]

[0039] Example 2

[0040] A preparation method of the intermediate Ⅰ of ulimorelin hydrogen sulfate, comprising the following steps:

[0041] (1) Add 24.80 kg of dichloromethane to a 50 L glass-lined reaction kettle, start stirring, and sequentially add 2933.3 g of ethyl 4-[(2S)-2-amino-3-(3-cyanophenyl)propionyl]piperazinecarboxylate and 2416.0 g of 2,4,6-triisopropylbenzenesulfonyl chloride.

[0042] (2) Slowly drop 1616.8 g of triethylamine into the reaction kettle, control the temperature at 40 °C, and stir and react for 15 hours.

[0043] (3) Prepare two portions of dilute hydrochloric acid solution: Mix 786.7 g of hydrochloric acid and 7333.0 g of purified water.

[0044] (4) Add one of the prepared portions of dilute hydrochloric acid solution to the reaction kettle, stir, then turn off the stirring, let it stand, separate the liquid, and retain the lower organic layer.

[0045] (5) Add the other prepared portion of 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.

[0046] (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.

[0047] (7) Add 6.40 kg of absolute ethanol to the concentrate, and continue to concentrate it under reduced pressure until dry to obtain Umonastatin Hydrogensulfate Intermediate I, whose chemical formula is as follows:

[0048]

[0049] Example 3

[0050] A preparation method of Umonastatin Hydrogensulfate Intermediate I, comprising the following steps:

[0051] (1) Add 24.80 kg of dichloromethane to a 50 L enamel reaction kettle, 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.

[0052] (2) Slowly add 1616.8 g of triethylamine to the reaction kettle, control the temperature at 50 °C, and stir and react for 20 hours.

[0053] (3) Prepare two portions of dilute hydrochloric acid solution: Mix 786.7 g of hydrochloric acid and 7333.0 g of purified water.

[0054] (4) Add one portion of the prepared dilute hydrochloric acid solution to the reaction kettle, stir, then turn off the stirring, let it stand, separate the liquid, and retain the lower organic layer.

[0055] (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.

[0056] (6) Add 8.00 kg of purified water to the organic layer, stir, then turn off the stirring, let it stand, separate the liquid, and retain the lower organic layer. Concentrate it under reduced pressure until dry.

[0057] (7) Add 6.40 kg of absolute ethanol to the concentrate, and continue to concentrate it under reduced pressure until dry to obtain Umonastatin Hydrogensulfate Intermediate I, whose chemical formula is as follows:

[0058]

[0059] The above content is only an example and illustration of the present invention. Those skilled in the art of this technology can make various modifications or supplements to the described specific embodiments or use similar methods for substitution. 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. A method for preparing ulimorelin hydrogen sulfate intermediate I, characterized in that, It includes the following steps: (1) Stir and mix dichloromethane, ethyl 4-[(2S)-2-amino-3-(3-cyanophenyl)propanoyl]piperazinecarboxylate, and 2,4,6-triisopropylbenzenesulfonyl chloride evenly in a reaction vessel; (2) Slowly drip triethylamine into the above reaction vessel, control the temperature and stir for reaction; (3) Add dilute hydrochloric acid solution into the above reaction vessel, stir, then let it stand and separate the liquid, retain the lower organic layer; (4) Add dilute hydrochloric acid solution into the organic layer, stir, then let it stand and separate the liquid, retain the lower organic layer; (5) Add purified water into the organic layer in step (4), stir, then let it stand and separate the liquid, retain the lower organic layer, and concentrate it under reduced pressure until dry to obtain a concentrate; (6) Add absolute ethanol to the concentrate, continue to concentrate it under reduced pressure until dry to obtain the umostatin mesylate intermediate Ⅰ.

2. The preparation method of umostastin mesylate intermediate I according to claim 1, characterized in that: In step (1), the mass ratio of ethyl 4-[(2S)-2-amino-3-(3-cyanophenyl)propanoyl]piperazinecarboxylate, 2,4,6-triisopropylbenzenesulfonyl chloride, and dichloromethane is 1:0.8 - 1:8 - 9.

3. The preparation method of umostastin hydrogensulfate intermediate I according to claim 1, characterized in that: In step (2), the temperature for temperature control is 30 - 50 °C, and the time for the stirring reaction is 10 - 30 h.

4. The preparation method of ulinastatin intermediate I bisulfate according to claim 1, characterized in that: In steps (3) and (4), the mass concentration percentage of the dilute hydrochloric acid is 3.0% - 4.0%.

5. The preparation method of umostastin mesylate intermediate I according to claim 1, characterized in that: In step (3), the time for stirring is 15 - 25 h, and the stirring frequency is 30 - 40 Hz.

6. The preparation method of umostatin hydrogensulfate intermediate I according to claim 1, characterized in that: In step (5), the mass ratio of the organic layer to purified water is 3.5 - 4:

1.

7. The preparation method of umostatin hydrogensulfate intermediate I according to claim 1, characterized in that: In step (6), the mass ratio of the concentrate to absolute ethanol is 1:1 - 1.

5.

8. The umostatin mesylate intermediate Ⅰ prepared by the preparation method of the umostatin mesylate intermediate Ⅰ according to any one of claims 1 - 7.

9. The ulimoreastatin hydrogensulfate intermediate I according to claim 8, characterized in that, The chemical formula is as follows:

10. The umostatin mesylate intermediate Ⅰ described in claim 8 is used for preparing umostatin mesylate.

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