Process for the preparation of tebufelone

Abstract

The present application provides a preparation method of Tebufelone. Specifically, the method of the present application comprises the following steps: (a) amidation reaction of a compound of formula VIII with a compound of formula VII in a first solvent in the presence of a condensing agent to obtain a compound of formula VI; (b) conversion of the compound of formula VI into a Grignard reagent of formula VI in a second solvent, and then reaction with a boronating agent to obtain a compound of formula V; (c) reaction of the compound of formula V with a compound of formula IV in a third solvent in the presence of a basic reagent and a catalyst to obtain a compound of formula III; and (d) reaction of the compound of formula III with a compound of formula II in a fourth solvent in the presence of a basic acid-binding agent to obtain a compound of formula I.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a method for preparing tibanibulin. Background Technology

[0002] Tirbanibulin is a microtubule inhibitor with the structure shown in Formula I.

[0003]

[0004] It promotes apoptosis in proliferating cells by inhibiting microtubule polymerization and is suitable for topical treatment of actinic keratosis on the face or scalp. Actinic keratosis is a precancerous skin lesion caused by skin exposure to ultraviolet radiation. If left untreated, 10-15% of AK lesions will develop into skin cancer.

[0005] Athenex and Almirall entered into a research and development collaboration in 2017 to jointly develop tirbanibulin in the United States and Europe. On December 15, 2020, Athenex and Almirall jointly announced that the U.S. FDA had approved Klisyri (tirbanibulin) for the topical treatment of actinic keratosis (AK) of the face or scalp. This approval was based on data from two randomized, double-blind, excipient-controlled, pivotal Phase 3 clinical trials evaluating the efficacy and safety of Klisyri (tirbanibulin) 1% ointment in 702 adult patients with actinic keratosis of the face or scalp. Compared to excipient-based treatments, the number of patients receiving tirbanibulin who achieved complete clearance of facial or scalp lesions was significantly higher at day 57.

[0006] The applications of tembambarin still have room for expansion, and the requirements for its compound preparation are constantly increasing. Several synthetic methods for tembambarin are already available, as detailed below:

[0007] The method for synthesizing tembambarin described in patent US2006 / 160800A1 is as follows:

[0008]

[0009] The two fragments in the final step of this method need to be synthesized separately. The boric acid reagent has a low synthesis yield, and the final product contains excessive levels of heavy metals, which is difficult to handle.

[0010] The synthetic route for tebanbulin described in patent EP2558085B1 is as follows:

[0011]

[0012] The original synthesis route has four steps, while this route has six steps, and the third step is more difficult to achieve. This synthesis route is longer and the overall yield is lower.

[0013] Patent CN113354575A provides the following synthetic route for tebanbulin:

[0014]

[0015] In this reaction route, some reaction steps require harsh conditions, resulting in low yields and purity. There is also the issue of the Suzuki reaction occurring in the final step.

[0016] Although there are existing processes for synthesizing terbambulin, they involve numerous reaction steps and are difficult to handle heavy metals. Therefore, there is an urgent need in this field to develop new methods for preparing terbambulin that are highly reactive, environmentally friendly, easy to operate, low in cost, have mild reaction conditions, produce easily purified products, have high yields, and are suitable for large-scale industrial production. Summary of the Invention

[0017] The purpose of this invention is to provide a method for preparing terbambulin that is highly reactive, environmentally friendly, easy to operate, low in cost, has mild reaction conditions, is easy to purify, has a high yield, and is suitable for large-scale industrial production.

[0018] A first aspect of the present invention provides a method for preparing a compound of formula I, comprising the steps of:

[0019] (a) In a first solvent, under the action of a condensing agent, compound VIII and compound VII undergo an amidation reaction to give compound VI:

[0020]

[0021] (b) In a second solvent, compound VI is converted into a Grignard reagent of compound VI, which then reacts with a borate reagent to give compound V:

[0022]

[0023] (c) In a third solvent, under the action of a basic reagent and a catalyst, compound V and compound IV react to form compound III:

[0024]

[0025] (d) In a fourth solvent, in the presence of a basic acid-binding agent, compound III reacts with compound II to form compound I:

[0026]

[0027] In another preferred embodiment, step (a) is carried out under the catalysis of 4-dimethylaminopyridine.

[0028] In another preferred embodiment, the molar ratio of the 4-dimethylaminopyridine to formula VIII is 0.005-0.02:1.

[0029] In another preferred embodiment, in step (a), the condensing agent is selected from the group consisting of DCC, DIC, EDCI, or combinations thereof.

[0030] In another preferred embodiment, the molar ratio of the condensing agent to formula VIII is 0.8-1.2:1.

[0031] In another preferred embodiment, the first solvent is selected from the group consisting of dichloromethane, trichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, or combinations thereof.

[0032] In another preferred embodiment, in step (a), the reaction temperature is 10-50°C, more preferably 15-45°C, and most preferably 20-25°C.

[0033] In another preferred embodiment, in step (a), tetrahydrofuran is used as the reaction solvent; and / or DCC is used as the reaction condensing agent.

[0034] In another preferred embodiment, in step (a), ethyl acetate is used as the reaction solvent; and / or the reaction is carried out at 20-25°C.

[0035] In another preferred embodiment, in step (b), the compound of formula VI undergoes a Grignard exchange reaction with a Grignard reagent to obtain a Grignard reagent of the compound of formula VI; preferably, the Grignard reagent is a tetrahydrofuran solution of isopropyl magnesium chloride or a tetrahydrofuran solution of isopropyl magnesium chloride-lithium chloride.

[0036] In another preferred embodiment, in step (b), the compound of formula VI reacts with magnesium powder, iodine, and iodoethane in a second solvent to obtain the Grignard reagent of the compound of formula VI.

[0037] In another preferred embodiment, in step (b), the borate reagent is selected from the group consisting of trimethyl borate, triethyl borate, or combinations thereof.

[0038] In another preferred embodiment, the molar ratio of the borate reagent to the Grignard reagent of the compound of formula VI is 0.8-1.2:1.

[0039] In another preferred embodiment, step (b) further includes treating the reaction product with an acidic reagent after the borylation reaction; preferably, the acidic reagent is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof.

[0040] In another preferred embodiment, the Grignard reagent of the compound of formula VI does not need to be separated and can proceed directly to the next reaction step.

[0041] In another preferred embodiment, the second solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, diethoxymethane, or combinations thereof.

[0042] In another preferred embodiment, in step (b), the reaction temperature of the Grignard exchange reaction is preferably 0-30°C, more preferably 10-30°C, and most preferably 20-30°C.

[0043] In another preferred embodiment, in step (b), the reaction temperature of the borate reaction is preferably 10-40°C, more preferably 20-45°C, and most preferably 20-25°C.

[0044] In another preferred embodiment, in step (b), the reaction solvent is tetrahydrofuran; the Grignard reagent is a tetrahydrofuran solution of isopropyl magnesium chloride; the borate reagent is trimethyl borate; and / or the reaction is carried out at 0-30°C.

[0045] In another preferred embodiment, in step (c), the catalyst is selected from the group consisting of: bis(triphenylphosphine)palladium dichloride, palladium acetate, tetratriphenylphosphine palladium, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, palladium chloride, or combinations thereof.

[0046] In another preferred embodiment, the molar ratio of the catalyst to the compound of formula V is 0.005-0.1:1.

[0047] In another preferred embodiment, in step (c), the alkaline reagent is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, or combinations thereof.

[0048] In another preferred embodiment, the molar ratio of the compound of formula V to the basic reagent is 0.8-1.2:1-2.

[0049] In another preferred embodiment, the third solvent is selected from the group consisting of tetrahydrofuran, 1,2-dichloroethane, ethyl acetate, toluene, methanol, ethanol, water, or combinations thereof.

[0050] In another preferred embodiment, in step (c), the reaction temperature is preferably 50-70°C, more preferably 55-65°C.

[0051] In another preferred embodiment, in step (c), the reaction solvent is a mixture of toluene and water; the alkaline reagent is sodium carbonate; the catalyst is bis(triphenylphosphine)palladium dichloride; and / or the reaction is carried out at 60-65°C.

[0052] In another preferred embodiment, in step (c), the reaction solvent is a mixture of toluene and water, preferably, the volume ratio of toluene to water is 1-3:1.

[0053] In another preferred embodiment, in step (d), the alkaline acid-binding agent is selected from the group consisting of morpholine, triethylamine, pyridine, piperidine, imidazole, potassium carbonate, sodium carbonate, or combinations thereof.

[0054] In another preferred embodiment, the molar ratio of the compound of formula III to the compound of formula II is 0.8-1.2:1.

[0055] In another preferred embodiment, the molar ratio of the compound of formula III to the basic acid-binding agent is 0.8-1.2:1-2.

[0056] In another preferred embodiment, the fourth solvent is selected from the group consisting of acetone, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, DMF, DMAC, or combinations thereof.

[0057] In another preferred embodiment, in step (d), the reaction temperature is preferably 40-60°C, more preferably 50-55°C.

[0058] In another preferred embodiment, in step (d), catalysis is performed using a catalyst.

[0059] In another preferred embodiment, the catalyst comprises 4-dimethylaminopyridine.

[0060] In another preferred embodiment, in step (d), the reaction solvent is acetone; the basic acid-binding agent is potassium carbonate; and / or the reaction is carried out at 50-55°C.

[0061] A second aspect of the present invention provides a compound of formula III having the structure shown in formula III:

[0062]

[0063] A third aspect of the present invention provides a method for preparing the compound of formula III as described in the second aspect of the present invention, comprising the steps of:

[0064] (a) In a first solvent, under the action of a condensing agent, compound VIII and compound VII undergo an amidation reaction to give compound VI:

[0065]

[0066] (b) In a second solvent, compound VI is converted into a Grignard reagent of compound VI, which then reacts with a borate reagent to give compound V:

[0067]

[0068] (c) In a third solvent, under the action of a basic reagent and a catalyst, compound V and compound IV react to form compound III:

[0069]

[0070] A fourth aspect of the present invention provides a method for preparing a compound of formula I, comprising the steps of:

[0071] In the fourth solvent, in the presence of a basic acid-binding agent, compound III reacts with compound II to form compound I:

[0072]

[0073] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0074] Through extensive and in-depth research and numerous screenings, the inventors have developed a novel method for synthesizing tembambarin. This method involves reacting compounds VIII and VII, which have unique structures, to obtain compound VI. Further, compound V is obtained through a Grignard reaction and a boronization reaction. Compounds V and IV are then coupled via Suzuki coupling to obtain compound III, which is then reacted with compound II to efficiently produce high-purity compound I (i.e., tembambarin). This invention is based on this foundation.

[0075] Tebanbulin

[0076] In this invention, the structure of Tebanbulin is shown in Formula I.

[0077]

[0078] Preparation method

[0079] The preparation method of the compound of Formula I of the present invention is described in more detail below.

[0080] This invention provides a novel method for preparing terbanolol, comprising the steps of:

[0081] Using compounds of formula VIII and formula VII as raw materials, an amidation reaction is performed to obtain compound VI; further, a Grignard reaction and a borate reaction are performed to obtain compound V; compound V and compound IV are coupled via Suzuki coupling to obtain compound III; and reacted with compound II to obtain compound I.

[0082] In this invention, during the preparation process, each reaction is typically carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 80°C, preferably 0°C to 50°C). The reaction time is typically 0.1 h to 60 h, preferably 0.5 h to 48 h. Furthermore, the reactants, such as compounds of formula VIII, formula VII, formula IV, and formula II, are commercially available or prepared by conventional methods.

[0083] Typically, the preparation method of the compound of formula I of the present invention includes:

[0084] Step (a): In a first solvent, under the action of a condensing agent, compound VIII and compound VII undergo an amidation reaction to yield compound VI:

[0085]

[0086] Step (b): In a second solvent, compound VI is reacted with a borate reagent via a Grignard reagent that converts it to compound VI to yield compound V:

[0087]

[0088] Step (c): In a third solvent, under the action of a basic reagent and a catalyst, compound V and compound IV react to form compound III:

[0089]

[0090] Step (d): In a fourth solvent, in the presence of a basic acid-binding agent, compound III reacts with compound II to form compound I:

[0091]

[0092] The main advantages of this invention include:

[0093] (1) This invention prepositions the Suzuki reaction, which solves the problem of excessive heavy metals and reduces costs.

[0094] (2) The reaction routes of this invention are all conventional reactions, with high yield and low requirements for industrial equipment.

[0095] (3) The present invention uses conventional reaction reagents, which reduces material costs.

[0096] (4) The present invention is easy to operate and is suitable for large-scale industrial production.

[0097] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0098] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0099] Example 1

[0100] Preparation of Compound VI

[0101] Add 21.6 g (0.1 mol) of compound VIII and 300 ml of ethyl acetate to a 1 L reaction flask, stir to dissolve, add 22.7 g of DCC (0.11 mol) and 0.2 g of DMAP, and add 11.8 g (0.11 mol) of compound VII in portions while maintaining the temperature at 20-25 °C. React for about 3 hours, take a sample to determine if compound VIII has been consumed, add 1.8 g of water dropwise, stir for 0.5 hours, filter, add 20 ml of 5% dilute hydrochloric acid to the resulting reaction solution, stir and separate the liquid, wash the ethyl acetate phase with water, concentrate the ethyl acetate, add 50 ml of petroleum ether, stir and filter, the resulting filter cake is compound VI, which is dried under vacuum to obtain 29.0 g, with a molar yield of 95% and an HPLC purity of ≥98.5%.

[0102] MS (m / z): 306.1 (M+H).

[0103] Example 2

[0104] Preparation of Compound V

[0105] Under nitrogen protection, 30.6 g (0.1 mol) of compound VI and 300 ml of tetrahydrofuran were added to a 500 ml reaction flask. 60 ml of 2M isopropyl magnesium chloride tetrahydrofuran solution (0.12 mol) was added, and the reaction was carried out at 20-30 °C for 3 hours. The temperature was then lowered to 0-10 °C, and 12.5 g (0.12 mol) of trimethyl borate was added dropwise. The temperature was slowly raised to 20-25 °C, and the mixture was stirred for 6 hours. 50 ml of 4M hydrochloric acid was added dropwise. The reaction solution was filtered, and the resulting solid was recrystallized from water. After filtration and vacuum drying, 24.1 g of solid was obtained, with a molar yield of 89% and HPLC ≥ 98.0%.

[0106] MS (m / z): 270.1 (M).

[0107] Example 3

[0108] Preparation of Compound III

[0109] Under nitrogen protection, 29.7 g (0.11 mol) of compound V, 17.3 g (0.1 mol) of compound IV, 200 ml of toluene, 100 ml of water, and 15.9 g (0.15 mol) of sodium carbonate were added to a 500 ml reaction flask. The mixture was stirred, and 0.7 g of bis(triphenylphosphine)palladium dichloride was added. The temperature was raised to 60-65 °C, and the reaction was carried out for 4 hours. Observations were made, and samples were taken for analysis. Compound IV was completely consumed. The pH was adjusted to acidic with 10% hydrochloric acid, and the mixture was cooled to room temperature. The mixture was separated into liquid and liquid phases. 1.2 g of cysteine ​​was added to the toluene phase, and the temperature was raised to 60-65 °C. The reaction was carried out for 1 hour, cooled, and filtered. The toluene was concentrated to near dryness, and 50 ml of petroleum ether was added. The mixture was stirred and filtered to obtain a solid powder of compound I. Vacuum drying yielded 28.6 g of the powder, with a molar yield of 90% and HPLC accuracy ≥ 99.0%.

[0110] MS (m / z): 318.30 (M).

[0111] Example 4

[0112] Preparation of Compound I

[0113] Under nitrogen protection, 200 ml of acetone, 31.8 g (0.1 mol) of compound III, 16.4 g (0.11 mol) of compound II, and 20.7 g (0.15 mol) of potassium carbonate were added to a 500 ml reaction flask. The mixture was stirred, heated to 50-55 °C, and reacted for 4 hours. Samples were taken for analysis, and compound III was found to be completely consumed. The mixture was filtered, rotary evaporated, and recrystallized from ethanol to give 36.2 g of the compound, with a molar yield of 84% and HPLC accuracy ≥ 99.5%.

[0114] MS(m / z): 431.5(M).1HNMR(300MHz, CDCl3)δ:8.7(d,1H),7.81(dd,1H),7.65(s,1H),7.49(d,2H),7.37-7.20( m,6H),7.01(d,2H),4.49(d,2H),4.16(t,2H),3.82(s,2H),3.78-3.72(m,4H),2.84(t,2H),2.62-2.58(m,4H).

[0115] Comparative Example 1

[0116] Preparation of Compound I

[0117] Add 150 ml DMF, 31.8 g (0.1 mol) of compound III, 16.4 g (0.11 mol) of compound II, and 20.7 g (0.15 mol) of potassium carbonate to a 500 ml reaction flask. Stir and heat to 50-55 °C. React for 4 hours. Take a sample for analysis; compound III is completely consumed. Add 1 L of water and stir for 0.5 hours. Filter. Add 200 ml ethyl acetate and 100 ml water to the filter cake. Stir and separate the layers. Wash the ethyl acetate layer once with 100 ml of water. Concentrate the ethyl acetate to dryness and recrystallize with ethanol to obtain 24.1 g of product, with a molar yield of 56%. MS(m / z): 431.5(M).1HNMR(300MHz, CDCl3)δ:8.7(d,1H),7.81(dd,1H),7.65(s,1H),7.49(d,2H),7.37-7.20( m,6H),7.01(d,2H),4.49(d,2H),4.16(t,2H),3.82(s,2H),3.78-3.72(m,4H),2.84(t,2H),2.62-2.58(m,4H).

[0118] In summary, this invention exhibits strong reactivity, is environmentally friendly, easy to operate, low in cost, mild reaction conditions, easy product purification, and high yield, making it suitable for large-scale industrial production.

[0119] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a compound of formula I, characterized in that, Including the following steps: (a) In a first solvent, under the action of a condensing agent, compound VIII and compound VII undergo an amidation reaction to give compound VI: (b) In a second solvent, compound VI is converted into a Grignard reagent of compound VI, which then reacts with a borate reagent to give compound V: (c) In a third solvent, under the action of a basic reagent and a catalyst, compound V and compound IV react to form compound III: (d) In a fourth solvent, in the presence of a basic acid-binding agent, compound III reacts with compound II to form compound I: 。 2. The method as described in claim 1, characterized in that, Step (a) is carried out under the catalysis of 4-dimethylaminopyridine.

3. The method as described in claim 1, characterized in that, In step (a), the condensing agent is selected from the group consisting of DCC, DIC, EDCI, or combinations thereof.

4. The method as described in claim 1, characterized in that, In step (b), the compound of formula VI undergoes a Grignard exchange reaction with a Grignard reagent to obtain the Grignard reagent of the compound of formula VI.

5. The method as described in claim 4, characterized in that, The reagent is a tetrahydrofuran solution of isopropyl magnesium chloride or a tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride.

6. The method as described in claim 1, characterized in that, In step (b), compound VI reacts with magnesium powder, iodine, and iodoethane in a second solvent to obtain the Grignard reagent of compound VI.

7. The method as described in claim 1, characterized in that, In step (b), the borate reagent is selected from the group consisting of trimethyl borate, triethyl borate, or a combination thereof.

8. The method as described in claim 1, characterized in that, In step (c), the catalyst is selected from the group consisting of: bis(triphenylphosphine)palladium dichloride, palladium acetate, tetratriphenylphosphine palladium, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, palladium chloride, or combinations thereof.

9. The method as described in claim 1, characterized in that, In step (c), the alkaline reagent is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, or combinations thereof.

10. The method as described in claim 1, characterized in that, In step (d), the alkaline acid-binding agent is selected from the group consisting of morpholine, triethylamine, pyridine, piperidine, imidazole, potassium carbonate, sodium carbonate, or combinations thereof.

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