A method for preparing Sabizabulin

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of Sabizabulin. The preparation method of Sabizabulin uses the compound of formula I and the compound of formula II as raw materials for cyclization reaction to obtain Sabizabulin, wherein the compound of formula II is 1H-indole-3-carboximidamide or its salt, and the reaction equation is as follows: wherein, X is selected from F, Cl, Br or I.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of Sabizabulin. Background Art

[0002] Sabizabulin (the chemical structural formula is shown below) is a clinical candidate drug for cancer treatment developed by the American biopharmaceutical company Veru. It can inhibit tubulin, block the intracellular transport of the new coronavirus along microtubules, and exert anti-tumor activity in vivo and in vitro. Currently, its clinical trial for prostate cancer is in Phase II. At the same time, research shows that Sabizabulin also has significant anti-inflammatory activity and can prevent cytokine storms caused by new coronavirus infection.

[0003]

[0004] On April 11, 2022, the Phase III clinical trial data of the new coronavirus oral drug Sabizabulin developed by the American biopharmaceutical company Veru showed that the drug was effective in a double-blind, randomized, placebo-controlled clinical trial. Compared with the placebo, the mortality rate of Sabizabulin (9 mg, orally once a day) in the treatment of moderately and severely hospitalized patients was reduced by 55%, which was statistically significant and clinically significant. On May 11, the new coronavirus oral drug Sabizabulin submitted an Emergency Use Authorization (EUA) application and has great prospects for listing.

[0005] Chinese Patent CN102883607 provides a synthesis method of Sabizabulin, which involves a key reaction as shown below:

[0006]

[0007] This step of the reaction requires the use of flammable and explosive dangerous reagent such as n-butyllithium, and needs to be carried out at an ultra-low temperature of -78 °C. The reaction conditions are relatively harsh, and the yield is low (30%). In addition, because this step of the reaction requires adding multiple steps of protection and deprotection, even if it has no impact on the total yield, the impact on the extension of the synthesis process and the increase in cost is inevitable. At the same time, the preparation process of the imidazole raw material is complex, with large pollution, and finally involves the process of removing benzenesulfonyl under harsh conditions. Summary of the Invention

[0008] The present invention provides a preparation method of Sabizabulin to solve the problems of harsh reaction conditions, low yield, and high cost in the current synthesis route.

[0009] In order to solve the above technical problems, the technical solution of the present invention is: the preparation method of Sabizabulin, which uses the compound of formula I and the compound of formula II as raw materials for cyclization reaction to obtain Sabizabulin, and the reaction equation is as follows:

[0010]

[0011] wherein X is selected from F, Cl, Br or I.

[0012] Optionally, in the compound of formula I, X is Br.

[0013] Optionally, the compound of formula I is obtained by halogenation reaction using the compound of formula III as a raw material, and the reaction equation is as follows:

[0014]

[0015] Alternatively, when X in the compound of formula I is Br, the brominating agent is copper bromide.

[0016] Optionally, in the preparation of Sabizabulin using the compound of formula III as a raw material, after the bromination reaction of the compound of formula III is completed, the bromination reaction is completed, the filtrate is filtered, and the filtrate is concentrated, and the concentrated solution is used as a raw material for the cyclization reaction.

[0017] Alternatively, the reaction process for preparing Sabizabulin using the compound of formula III as a raw material is as follows: copper bromide and the compound of formula III are mixed in a solvent, heated under reflux until the reaction is completed, cooled and filtered, and the filtrate is concentrated; the concentrate is dissolved in a solvent, and then the compound of formula II is added to the reaction system, heated under reflux until the reaction is completed, and post-processed and purified to obtain Sabizabulin.

[0018] Optionally, in the cyclization reaction system of the compound of formula I and the compound of formula II, the solvent is ethanol, methanol or N,N-dimethylformamide (DMF), preferably N,N-dimethylformamide.

[0019] Optionally, the molar ratio of the compound of formula III to copper bromide is 1:1-3; the molar ratio of the compound of formula III to the compound of formula II is 1:1-3.

[0020] Optionally, the copper bromide and the compound of formula III are mixed by adding a chloroform solution of the compound of formula III to a copper bromide dispersion system in ethyl acetate.

[0021] Optionally, the compound of formula III is prepared using 3,4,5-trimethoxyaniline as a starting material.

[0022] Optionally, the preparation process of the compound of formula III specifically includes diazotization-iodination reaction, propyne coupling reaction and oxidation reaction process, and the reaction equation is as follows:

[0023]

[0024] The technical solution provided by the present invention has the following advantages compared with the prior art: the reagents used in the reaction system are of low cost, the reaction conditions are mild and the safety is high. In addition, the overall yield of Sabizabulin is high, which is particularly suitable for industrial production. Detailed implementation manners

[0025] For the convenience of understanding, the preparation method of Sabizabulin is described below in conjunction with embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0026] Unless otherwise specified, the raw materials, reagents or equipment used in the embodiments are all commercially available products.

[0027] Example 1 Preparation of Sabizabulin

[0028]

[0029] To a solution of CuBr2 (22.5 g, 0.10 mol) in ethyl acetate, a solution of the compound of formula III (12.0 g, 0.05 mol) in chloroform was added dropwise, and the mixture was refluxed for about 8 h until the raw materials reacted completely. The reaction system was cooled and filtered, and the filtrate was carefully evaporated on a rotary evaporator to obtain a transparent yellow-green oil, i.e., the unpurified compound of formula I.

[0030] The unpurified compound of formula I was dissolved in DMF at room temperature, and then slowly added dropwise to a DMF solution of the compound of formula II (9.0 g, 56.8 mmol). The mixture was refluxed for about 8 h, and after the raw materials reacted completely, it was cooled to room temperature.

[0031] [[ID=**28**]]It should be noted that if the compound of formula II purchased is a salt of 1H-indole-3-carboxamidine such as 1H-indole-3-carboxamidine hydrochloride, it can be free-based and then added to the reaction, or directly added to the reaction system, and then a base such as triethylamine or sodium bicarbonate is added to the reaction system to participate in the reaction.

[0032] Post-treatment: The solvent was removed under reduced pressure, the residue was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. After purification of the crude product, 14 g of the final product Sabizabulin was obtained, and the two-step yield was about 75%). Characterization data: 1H-NMR (400 MHz, DMSO) δ. 11.86 (s, 1H), 11.53 (s, 1H), 8.37 (s, 1H), 8.02 (s, 1H), 7.50 (m, 2H), 7.21 (m, 2H), 7.06 (s, 2H), 3.95 (s, 6H), 3.74 (s, 3H), HRMS (ESI-Q-TOF) m / z: [M+H] + calculated for C 21 H 20 N3O4: 378.1446, found: 378.1451。

[0033] Example 2 Preparation of Compound of Formula III

[0034]

[0035] 1) Diazotization-iodination reaction

[0036] Add 4M HCl solution to the tetrahydrofuran solution of Compound of Formula IV (20.5 g), stir to form a salt in an ice-water bath, and gradually add an aqueous solution of 0.1 L of NaNO2 (9.3 g) dropwise to the above mixture. After 20 minutes, gradually add an aqueous solution of KI (46.4 g) dropwise to the above mixture. After detecting that the raw material reaction is complete, add 1M aqueous Na2S2O3 solution to the reaction system until the color of the mixture turns white. After post-treatment and purification, a yellow liquid is obtained, which is Compound of Formula V (31.8 g, yield about 96%).

[0037] 2) Propargyl coupling reaction

[0038] Prepare a DMF solution of Compound of Formula V (30 g). Under a nitrogen atmosphere, add triethylamine (31.2 g), PdCl2(PPh3)2 (3.6 g) and CuI (2.0 g) to the above reaction system, then add a DMF solution of propyne (5.0 g), keep the temperature at about 90 °C and stir for about 12 h. After the reaction is complete, cool, and after post-treatment such as extraction, filtration, drying and concentration, finally purify to obtain 26.4 g of white powder and Compound of Formula VI, with a yield of about 86%.

[0039] 3) Oxidation reaction

[0040] Add a mixed solution of dichloromethane and water (dichloromethane: water volume ratio = 4:1) to the reactor of 15.6 g of Compound of Formula VI, then add 73.1 g of PhI(OAc)2 and 1.6 g of catalyst RuCl3. Stir at room temperature for about 2 h. After the reaction is complete, extract with dichloromethane, then wash, dry and concentrate the organic layer. After purification, 9.2 g of yellow solid is obtained, which is Compound of Formula III, with a yield of about 48%. Characterization data of Compound of Formula III:1 H-NMR (400 MHz, DMSO) δ 7.29 (s, 2H), 3.95 (s, 3H), 3.91 (s, 6H), 2.53 (s, 3H). HRMS (ESI-Q-TOF) m / z: [M+H] + calculated for C 12 H 15 O5: 239.0901, found: 239.0907)

[0041] Example 3 The bromination reaction and cyclization reaction were carried out step by step

[0042]

[0043] To a solution of CuBr2 (13.0 g, 58 mmol) in ethyl acetate, a chloroform solution of Compound III (5 g, 21 mmol) was added dropwise, and the reaction was refluxed for about 8 h until the raw materials were completely reacted; after cooling, it was subjected to post-treatment such as concentration, extraction, and drying, and finally purified by column chromatography to obtain about 6.0 g of a pale yellow liquid and Compound I, with a yield of about 91%.

[0044] The purified Compound I (5.0 g, 15.8 mmol) was dissolved in ethanol at room temperature, and then slowly added dropwise to an ethanol solution of Compound II (5.0 g, 31.5 mmol), and the reaction was refluxed. After the raw materials were completely reacted, it was cooled to room temperature.

[0045] Post-treatment: The solvent was removed under reduced pressure, the residue was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. After purification of the crude product, 3.1 g of the final product Sabizabulin was obtained, with a two-step yield of 40%).

[0046] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing examples, or perform equivalent replacements for some or all of the technical features, and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for preparing Sabizabulin, characterized in that, Sabizabulin is obtained by cyclization reaction using the compound of formula I and the compound of formula II, wherein the compound of formula II is 1H-indole-3-carboximidamide, and the reaction equation is as follows: ， Wherein, X is selected from F, Cl, Br or I.

2. The preparation method according to claim 1, wherein, In the compound of formula I, X is Br.

3. The preparation method according to claim 1, characterized in that, In the cyclization reaction system, the solvent is ethanol, methanol or N,N-dimethylformamide.

4. The preparation method according to claim 3, wherein In the cyclization reaction system, the solvent is N,N-dimethylformamide.

5. The preparation method according to claim 1, wherein The compound of formula I is obtained by halogenation reaction using the compound of formula III as a raw material, and the reaction equation is as follows: 。 6. The preparation method according to claim 5, wherein When X in the compound of formula I is Br, the brominating reagent is copper bromide.

7. According to the preparation method described in claim 6, characterized in that, In the preparation of Sabizabulin using the compound of formula III as a raw material, after the bromination reaction of the compound of formula III is completed, after filtration and concentration of the filtrate, the concentrated solution is used as a raw material for the cyclization reaction.

8. The preparation method according to claim 7, wherein The specific reaction process is as follows: Copper bromide and the compound of formula III are mixed in a solvent, heated to reflux until the reaction is complete, cooled and filtered, and the filtrate is concentrated; the concentrated solution is dissolved in a solvent, then the compound of formula II is added to the reaction system, heated to reflux until the reaction is complete, and Sabizabulin is obtained by post-treatment and purification.

9. The preparation method according to claim 8, wherein The mixing method of copper bromide and the compound of formula III is to add a chloroform solution of the compound of formula III to a system in which copper bromide is dispersed in ethyl acetate.

10. The preparation method according to claim 6, characterized in that, The molar ratio of the compound of formula III to copper bromide is 1:1-3; the molar ratio of the compound of formula III to the compound of formula II is 1:1-3.

11. According to the preparation method described in claim 5, wherein, The compound of formula III is prepared using 3,4,5-trimethoxyaniline as a starting material.

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