Preparation method of 20-HETE antagonist key intermediate

Abstract

The invention provides a preparation method of a 20-HETE antagonist key intermediate compound shown in a formula 3, and the reaction is as follows: # imgabs0 # comprises the following steps: step 1): a compound shown in a formula 1 and a compound shown in a formula 2 are subjected to the action of n-butyllithium and DMPU (N, N-dimethylallylurea) to obtain the compound shown in the formula 3; through continuous attempts, the inventor accidentally finds that the reaction yield can be greatly increased by 20% or above compared with the prior art when DMPU is used for replacing HMPA, and the preparation method has the advantages of being high in atom utilization rate, easy to operate and high in yield and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing a key intermediate of a 20-HETE antagonist, and belongs to the technical field of medicine and chemistry. Background Art

[0002] 20-HEDE (WIT 002) is an antagonist of 20-hydroxyeicosatetraenoic acid (20-HETE). Anticancer Res. 2009 Oct; 29 (10): 3819-24. It is pointed out that WIT 002 can inhibit the proliferation of 786-O and 769-P renal adenocarcinoma cells. The tumor growth inhibition rate of 20-HETE antagonist WIT 002 is 84% ​​± 128%. The role of 20-HEDE is to effectively inhibit the growth of tumors without affecting the proliferation of normal cells, so it has important uses in medicine.

[0003] The structure of 20-HEDE is as follows:

[0004]

[0005] The compound of formula 3 is a key intermediate of 20-HEDE, and its structure is as follows:

[0006]

[0007] The preparation route of the key intermediate compound of formula 3 of 20-HEDE disclosed in WO1999043310A3 is as follows:

[0008]

[0009] Under argon atmosphere, n-BuLi was added dropwise to a -40°C solution of the compound of formula 2 in THF and HMPA. After 1 hour, a THF solution of the compound of formula 1 was added, and the reaction was warmed to room temperature within 1 hour. The reaction was carried out at room temperature for 16 hours, and then the reaction was terminated with a saturated aqueous solution of NH4Cl and extracted with Et2O. The organic extracts were combined, washed with water and brine, dried with Na2SO4, and evaporated in vacuo. The residue was purified by SiO2 column chromatography eluting with 5% EtOAc / hexane to obtain a light yellow oily diacetylene compound of formula 3 in a yield of 61%.

[0010] The patented method has low reaction temperature, is difficult to control, has complicated post-processing, and has low yield, and is not suitable for industrial production.

[0011] The compound of formula 3 is a key intermediate of 20-HEDE, and there is no other method for preparing the compound of formula 3 in the prior art. Therefore, there is an urgent need for a method for synthesizing the compound of formula 3 that is economical, fast, easy to operate, simple to post-process, high in yield and high in purity, so as to improve the synthesis yield of 20-HEDE, reduce costs and simplify post-processing. Summary of the invention

[0012] In order to solve the above technical problems, the present invention provides a method for preparing a 20-HETE antagonist and its intermediates, which not only improves the yield of intermediates and products, but also reduces the emission of reaction waste, reduces costs, simplifies operations, and is therefore suitable for industrial production.

[0013] In order to achieve the above-mentioned invention object, the present invention adopts the following technical solutions:

[0014] The first aspect of the present invention provides a method for preparing a 20-HETE antagonist key intermediate compound of formula 3, the reaction is as follows:

[0015]

[0016] The steps include:

[0017] Step 1): The compound of formula 1 and the compound of formula 2 are reacted under the action of n-butyl lithium and DMPU (N,N-dimethylpropylene urea) to obtain a compound of formula 3.

[0018] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 1 to the compound of formula 2 in step 1) is 1:(1-3), preferably 1:(1-2);

[0019] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 1 to n-butyl lithium in step 1) is 1:(1-5), preferably 1:(2-4);

[0020] As a further improvement of the present invention, including but not limited to, the reaction time of step 1) is 12 to 48 hours, preferably 16 to 45 hours;

[0021] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 1) is 0 to -40°C, preferably -5 to -30°C;

[0022] As a further improvement of the present invention, including but not limited to, the step 1) is carried out in an aprotic solvent;

[0023] As a further improvement of the present invention, including but not limited to, the aprotic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, hexane, diethyl ether, 1,4-dioxane, and acetone, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, and acetone;

[0024] As a further improvement of the present invention, including but not limited to, the step 1) is to first drop n-butyl lithium into the aprotic solvent of the compound of formula 1, react at -10 to -20°C for 0.5 to 3h, and then drop the solution into the solution of the compound of formula 2 and DMPU to react to obtain the compound of formula 3;

[0025] As a further improvement of the present invention, including but not limited to, the step 1) is to first drop n-butyl lithium into a THF solution of the compound of formula 1, react at -10 to -20°C for 0.5 to 3h, and then drop the solution into a solution of the compound of formula 2 and DMPU to react to obtain a compound of formula 3.

[0026] As a further improvement of the present invention, in certain embodiments, after the reaction in step 1) is completed, post-treatment can be selectively performed, including quenching with water, extracting with an organic solvent, separating the liquids, drying, spinning, and column chromatography to obtain a compound of formula 3.

[0027] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane or a combination thereof.

[0028] As a further improvement of the present invention, in certain embodiments, the present invention uses a combination of n-butyl lithium and DMPU, and by adjusting the order of adding materials, the yield of the compound of formula 3 is increased by more than 20% compared with the prior art, and does not require a very low temperature to react, which is conducive to temperature control, greatly reduces production costs, and is conducive to industrial production.

[0029] The second aspect of the present invention provides a method for preparing 20-HEDE, which includes the method for preparing a 20-HETE antagonist key intermediate compound of formula 3 described in the first aspect above.

[0030] Beneficial technical effects of the present invention:

[0031] 1. Through continuous attempts, the inventors unexpectedly discovered that using DMPU instead of HMPA can greatly improve the reaction yield by more than 20% compared with the prior art. The preparation method provided by the present invention has the advantages of high atomic utilization, simple operation and high yield, and is suitable for industrial production.

[0032] 2. The prior art is to react the compound of formula 2 with n-butyl lithium in a mixed solution of HMPA and THF below -40°C for a period of time, and then add the compound of formula 1 to react. The inventors repeat the method of the prior art but cannot obtain the target product. The inventors find that the compound of formula 1 is first reacted with n-butyl lithium at -20 to -10°C for a period of time, and then the solution is added to the solution of the compound of formula 2 and DMPU for reaction. There is no residual raw material, less impurities, and the effect is unexpectedly very good, and the reproducibility is also very good. In addition, the temperature of the present invention is better controlled, which is conducive to the further preparation of 20-HEDE compounds.

[0033] 3. Compared with the use of trimethylsilyl (TMS) and triethylsilyl (TES), the present invention uses tert-butyldiphenylsilyl (TBDPS) for protection, which not only has a good reaction effect, but also has fewer impurities, is conducive to purification, and has good reproducibility.

[0034] 4. The method of the present invention not only has high yield and high purity, but also has low energy consumption, good reproducibility, effectively reduces costs, and is suitable for industrial production. DETAILED DESCRIPTION

[0035] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0036] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0037] Embodiment 1:

[0038]

[0039] Compound 1 (25 g, 48.7 mmol) was dissolved in tetrahydrofuran (65 ml), cooled to -15-20°C, and 2.5 M n-butyl lithium (58 ml) was added dropwise. The temperature was maintained for 45 minutes, and the solution was added dropwise to a mixture of DMPU (12 mL) and compound 2 (10.7 g, 54.5 mmol, 1.1 eq) at -20°C, and reacted at room temperature for 36 hours. Water was added to quench, and the mixture was extracted with dichloromethane. The organic phases were combined, dried, concentrated, and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 30:1) to obtain compound 3A (25 g, 81.7%), with an HPLC purity of 95%).

[0040] Comparative Example 1:

[0041]

[0042] Compound 2 (1 g, 5.4 mmol) was dissolved in tetrahydrofuran (10 ml) and HMPA (1 ml), cooled to -40°C, and n-butyl lithium (3 ml) was added dropwise. The temperature was maintained for 45 minutes. The solution of formula 1 (2.8 g, 5.4 mmol) was added dropwise to the mixture and reacted for 24 hours. TLC detection showed that the reaction was complicated and no compound of formula 3 was generated.

[0043] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a 20-HETE antagonist key intermediate compound of formula 3, characterized in that: The reaction looks like this: The steps include: Step 1): The compound of formula 1 and the compound of formula 2 are reacted under the action of n-butyl lithium and N,N-dimethylpropylene urea to obtain a compound of formula 3.

2. The preparation method according to claim 1, characterized in that: The step 1) is carried out in an aprotic solvent.

3. The preparation method according to claim 1, characterized in that: In the step 1), n-butyl lithium is first dripped into the aprotic solvent of the compound of formula 1, and reacted at -10 to -20°C for 0.5 to 3 hours, and then the solution is dripped into the solution of the compound of formula 2 and DMPU to react to obtain the compound of formula 3.

4. The preparation method according to claim 2 or 3, characterized in that: The aprotic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, hexane, diethyl ether, 1,4-dioxane, and acetone, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, and acetone.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the compound of formula 1 to the compound of formula 2 in step 1) is 1:(1-3), preferably 1:(1-2).

6. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the compound of formula 1 in step 1) to n-butyl lithium is 1:(1-5), preferably 1:(2-4).

7. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction time of step 1) is 12 to 48 hours, preferably 16 to 45 hours.

8. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction temperature of step 1) is 0 to -40°C, preferably -5 to -30°C.

9. The preparation method according to any one of claims 1 to 3, characterized in that: After the reaction in step 1), post-treatment may be optionally performed, including quenching with water, extracting with an organic solvent, separating the liquids, drying, spin drying, and column chromatography to obtain a compound of formula 3; And / or, preferably, the organic solvent comprises one of ethyl acetate, dichloromethane or a combination thereof.

10. A method for preparing 20-HEDE, comprising preparing a 20-HEDE intermediate 3 using the preparation method according to any one of claims 1 to 3, and further preparing a 20-HEDE compound from the 20-HEDE intermediate 3.

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