Preparation method of ubiquitin ligase huwe1 specific antagonist BI8626

Abstract

This invention discloses a method for preparing BI8626, a specific antagonist of the ubiquitin ligase HUWE1, comprising the following steps: deprotecting compound G to obtain compound BI8626; obtaining compound G through the preparation method of the intermediate G; this invention reduces the difficulty of obtaining raw materials, simplifies purification, and increases yield, thereby reducing production costs; and finally, the production steps are simple and easy to produce and promote.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and in particular to a method for preparing BI8626, a specific antagonist of the ubiquitin ligase HUWE1. Background Technology

[0002] The HUWE1 antagonist BI8626 is a small molecule compound that induces ectopic expression of HUWE1 to eliminate MCL1 ubiquitination in HeLa cells. BI8626 inhibits Ls174T cell colony formation, and treatment can delay Ls174T cells through all stages of the cell cycle, with the strongest effect on the G1 phase.

[0003] The main problems with current methods for synthesizing BI8626 are high raw material costs and a lack of relevant preparation literature reports. Therefore, it is necessary to develop a new synthetic route to obtain the target product. Summary of the Invention

[0004] This invention provides a method for preparing BI8626, a specific antagonist of the ubiquitin ligase HUWE1, to solve the problems mentioned in the background art.

[0005] The solution of the present invention is:

[0006] A method for preparing intermediate D in the preparation of the ubiquitin ligase HUWE1 inhibitor BI8626 includes the following steps:

[0007] 1) Compound B and compound C are reacted in a solvent under the action of a base to obtain compound D; compound D is intermediate D; the chemical reaction structure of compound D is as follows:

[0008]

[0009] The molar ratio of compound B to compound C is 1:1 to 1.5.

[0010] This invention discloses a method for preparing intermediate F in the preparation of the ubiquitin ligase HUWE1 inhibitor BI8626, comprising the following steps:

[0011] 2) Compound D and compound E are reacted under the action of a base to obtain compound F; compound F is an intermediate F; the chemical reaction structure of compound F is as follows:

[0012]

[0013] Wherein, Ra is an amino protecting group; wherein, the molar ratio of compound D to compound E is 1:1 to 1.5;

[0014] Or it may include the following steps:

[0015] 1) Compound B and compound C are reacted in a solvent under the action of a base to obtain compound D;

[0016] 2) Compound D and compound E are reacted under the action of a base to obtain compound F; compound F is an intermediate F; the chemical reaction structure of compound F is as follows:

[0017]

[0018] Wherein, Ra is an amino protecting group; the molar ratio of compound D to compound E is 1:1 to 1.5.

[0019] This invention discloses a method for preparing intermediate G in the preparation of the ubiquitin ligase HUWE1 inhibitor BI8626, comprising the following steps:

[0020] 3) Compound F undergoes a dehalogenation reaction with hydrogen in a solvent under the action of a catalyst to obtain compound G; compound G is an intermediate G; the chemical reaction structure of compound G is as follows:

[0021]

[0022] Or it may include the following steps:

[0023] 1) Compound B and compound C are reacted in a solvent under the action of a base to obtain compound D;

[0024] 2) Compound D and compound E are reacted under the action of a base to obtain compound F;

[0025] 3) Compound F undergoes a dehalogenation reaction with hydrogen in a solvent under the action of a catalyst to obtain compound G; compound G is an intermediate G; the chemical reaction structure of compound G is as follows:

[0026]

[0027] Wherein, Ra is an amino protecting group;

[0028] The catalyst is selected from one or more of palladium on carbon, platinum on carbon, or Raney nickel; the solvent is selected from alcohols, ethers, and haloalkanes.

[0029] As a preferred technical solution, the alcohols, ethers, and haloalkanes are methanol, ethanol, tetrahydrofuran, and dichloromethane.

[0030] A method for preparing intermediate D, intermediate F, and intermediate G for preparing ubiquitin ligase HUWE1 inhibitor BI8626, wherein in the above three preparation methods, the molar ratio of compound B to compound C in step 1) is 1:1.05 to 1.15.

[0031] As a preferred technical solution, the solvent in 1) is selected from tetrahydrofuran, acetone, and 1,4-dioxane.

[0032] As a preferred technical solution, the solvent in 1) is tetrahydrofuran.

[0033] As a preferred technical solution, the alkali in 1) is selected from potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydroxide.

[0034] As a preferred technical solution, the alkali in 1) is potassium carbonate.

[0035] As a preferred technical solution, the reaction temperature in step 1) is ≤10℃.

[0036] As a preferred technical solution, the reaction temperature in step 1) is preferably ≤0℃.

[0037] As a preferred technical solution, the reaction temperature in step 1) is -30 to -10℃.

[0038] As a preferred technical solution, the reaction time in step 1) is 10 to 120 minutes.

[0039] As a preferred technical solution, the reaction time in step 1) is 20 to 30 minutes.

[0040] As a preferred technical solution, the molar ratio of compound D to compound E in step 2) is 1:1 to 1.5.

[0041] As a preferred technical solution, the molar ratio of compound D to compound E in step 2) is 1:1.05 to 1.15.

[0042] As a preferred technical solution, the molar ratio of compound D to compound E in step 2) is 1:1.1.

[0043] As a preferred technical solution, the alkali in 2) is selected from potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydroxide.

[0044] As a preferred technical solution, the solvent used in 2) is the same as the solvent used in 1).

[0045] As a preferred technical solution, the reaction temperature in step 2) is 0–30°C.

[0046] As a preferred technical solution, the reaction temperature in step 2) is 15-25℃.

[0047] As a preferred technical solution, the reaction time in step 2) is 0.5 to 3 hours.

[0048] As a preferred technical solution, the reaction time in step 2) is 1 to 2 hours.

[0049] This invention also discloses a method for preparing the ubiquitin ligase HUWE1 inhibitor BI8626, comprising the following steps:

[0050] Compound G was deprotected to obtain compound BI8626; compound G was obtained using the preparation method of intermediate G in the preparation process of BI8626, a ubiquitin ligase HUWE1 inhibitor according to the present invention; the chemical reaction structure of compound BI8626 is as follows:

[0051]

[0052] The present invention also discloses an intermediate compound I, the structure of which is shown below:

[0053]

[0054] Among them, R1, R2, R3, and R4 are independently selected from hydrogen, halogens,

[0055] Ra is an amino protecting group, and R1, R2, R3, and R4 are either hydrogen or Cl at the same time.

[0056] As a preferred technical solution, compound I comprises the following structure:

[0057]

[0058] The preparation method of a ubiquitin ligase HUWE1 specific antagonist BI8626 using the above-mentioned technical solution includes the following steps: deprotecting compound G to obtain compound BI8626; wherein compound G is obtained by preparing intermediate G according to a preparation method of ubiquitin ligase HUWE1 inhibitor BI8626.

[0059] Advantages of this invention:

[0060] This preparation method is simple and quick to prepare the required ubiquitin ligase HUWE1 specific antagonist BI8626. First, the raw materials are readily available, reducing the difficulty of obtaining them. Second, the purification is simple and the yield is high, thereby reducing the production cost. Finally, the production steps are simple and easy to produce and promote. Attached Figure Description

[0061] Figure 1 This is a flowchart of the compound preparation process in Example 1 of the present invention;

[0062] Figure 2 The 1H NMR spectrum of compound F-1 in Example 1 of this invention;

[0063] Figure 3 This is the 1H NMR spectrum of compound G-1 from Example 1 of the present invention. Detailed Implementation

[0064] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments.

[0065] Example 1:

[0066] Step 1

[0067]

[0068] Procedure: Under argon protection, mix 20g of compound A, 104g of phosphorus pentachloride, and 500ml of phosphorus oxychloride, heat to 120℃ and stir for 12h.

[0069] Post-processing: Direct concentration was performed, and the filtrate was slowly added to 1000 ml of ice water, resulting in the precipitation of a large amount of pale yellow solid. The solid was filtered and dried to obtain 24 g of pale yellow solid compound B, with a yield of 90%.

[0070] Step Two

[0071]

[0072] Procedure: Under argon protection, mix 24g of compound B, 25g of potassium carbonate, and 0.5L of THF, and cool to below -25℃. Add dropwise a mixture of 18g of compound C and 0.5L of THF, and stir for 30 minutes while maintaining the temperature below -20℃. (To monitor the completion of the reaction: Take 0.2ml of the stirred reaction solution, add 1ml of water and 0.3ml of EA, shake, and let stand. Spot the supernatant onto a TLC plate. If the reactants disappear and new spots form, the reaction has been quenched and post-processing is required.)

[0073] Post-processing: The mixture of compound D after the reaction was completed was directly used for the next reaction, and 36.5 g of compound D was obtained based on a 100% yield.

[0074] Step 3

[0075]

[0076] Procedure: Under argon protection, mix the previous compound D solution, 25g of potassium carbonate, and 124g of compound E-12 and react at room temperature for 2 hours.

[0077] Post-processing: Extract three times with 1000ml of brine and 150ml of EA. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate.

[0078] Purification: DCM:MeOH = 100:1 yielded 35g of pale yellow solid compound F-1, yield: 64% (see details). Figure 2 ).

[0079] Step Four:

[0080]

[0081] Procedure: Under argon protection, mix 35g of compound F-1, 3.5g of 10% Pd / C, and 500ml of methanol at a pressure of approximately 3-5 atm, purge with hydrogen four times, and stir at room temperature for 6 hours.

[0082] Post-processing: Direct filtration was performed. The solid was washed once with 10 ml of methanol. The filtrate was concentrated to give 22 g of a pale yellow solid compound G-1 (see details). Figure 3 Yield: 71%, directly used for the next step.

[0083] Step 5:

[0084]

[0085] Procedure: Under argon protection, mix 22g of compound G-1, 46ml of 4M HCl / dioxane, and 400ml of methanol, and stir at room temperature for 6 hours.

[0086] Post-processing: 200 ml of methanol was concentrated, 500 ml of water was added, and the pH was adjusted to 8 by adding 1 M sodium hydroxide aqueous solution. A large amount of yellow solid precipitated. The solid was filtered, washed twice with 100 ml of water, and dried to obtain 3 g of pale yellow solid compound H1. Yield: 73%.

[0087] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing intermediate D in the preparation of the ubiquitin ligase HUWE1 inhibitor BI8626, characterized in that, Includes the following steps: 1) Compound B and compound C are reacted in a solvent under the action of a base to obtain compound D; compound D is intermediate D; the chemical reaction structure of compound D is as follows: ； The molar ratio of compound B to compound C is 1:1 to 1.

5.

2. A method for preparing intermediate F in the preparation of the ubiquitin ligase HUWE1 inhibitor BI8626, characterized in that, Includes the following steps: 2) Compound D reacts with compound E under the action of a base to obtain compound F; compound F is intermediate F; the chemical reaction structure of compound F is as follows: ； Wherein, Ra is an amino protecting group; wherein, the molar ratio of compound D to compound E is 1:1 to 1.

5.

3. The method for preparing intermediate F in the preparation process of the ubiquitin ligase HUWE1 inhibitor BI8626 as described in claim 2, characterized in that: The preparation method of compound D is as follows: 1) Compound B and compound C react in a solvent under the action of a base to give compound D; the chemical reaction structure is as follows: 。 4. The method for preparing intermediate F in the preparation process of the ubiquitin ligase HUWE1 inhibitor BI8626 as described in claim 3, characterized in that: The alkali in 2) is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydroxide; The solvent used in 2) is the same as the solvent used in 1); The reaction temperature in step 2) is 0–30°C; The reaction time in 2) is 0.5 to 3 hours.

5. The method for preparing intermediate F in the preparation process of the ubiquitin ligase HUWE1 inhibitor BI8626 as described in claim 3, characterized in that: The molar ratio of compound B to compound C is 1:1.05 to 1.

15.

6. The method for preparing intermediate F in the preparation process of the ubiquitin ligase HUWE1 inhibitor BI8626 as described in claim 3, characterized in that: The solvent in 1) is selected from tetrahydrofuran, acetone, and 1,4-dioxane; The alkali in 1) is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydroxide; The reaction temperature in 1) is ≤10℃; The reaction time in 1) is 10 to 120 min.

7. The method for preparing intermediate F in the preparation process of the ubiquitin ligase HUWE1 inhibitor BI8626 as described in claim 2, characterized in that: The molar ratio of compound D to compound E is 1:1.05 to 1.

15.

8. A method for preparing intermediate G in the preparation of the ubiquitin ligase HUWE1 inhibitor BI8626, characterized in that, Includes the following steps: 3) Compound F undergoes a dehalogenation reaction with hydrogen in a solvent under the action of a catalyst to obtain compound G; compound G is an intermediate G; the chemical reaction structure of compound G is as follows: ； Wherein, Ra is an amino protecting group; The catalyst is selected from one or more of palladium on carbon, platinum on carbon, or Raney nickel; the solvent is selected from alcohols, ethers, and haloalkanes.

9. A method for preparing BI8626, an inhibitor of the ubiquitin ligase HUWE1, characterized in that, Includes the following steps: Compound G is prepared by the method for preparing intermediate G according to claim 8; compound G is deprotected to obtain compound BI8626; the chemical reaction structure of compound BI8626 is as follows: 。 10. An intermediate compound I, characterized in that, Compound I has the following structure: 、 。

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