A process for the preparation of trans-1-ethoxyvinyl-2-boronic acid pinacol ester

Abstract

This invention discloses a method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester, belonging to the field of pharmaceutical intermediates. The process includes the following steps: reacting vinyl ethyl ether with bromine to generate 1,2-dibromoethoxyethane; then eliminating it under organic alkaline conditions to obtain 1-bromo-2-ethoxyethylene; subsequently eliminating it under inorganic alkaline conditions to obtain ethoxyacetylene; finally, coupling ethoxyacetylene with pinacolborane to obtain trans-1-ethoxyvinyl-2-boronic acid pinacol ester. The synthesis process of this invention can be continuously operated, and it also improves the method of obtaining ethoxyacetylene through a one-step elimination of 1,2-dibromoethoxyethane, providing a method for industrial-scale synthesis of this product.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis and relates to a method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester. Background Technology

[0002] Trans-1-ethoxyvinyl-2-boronic acid pinacol ester is a borate pinacol ester containing ethoxyvinyl as an organic building block. As a pharmaceutical intermediate, it is used to conjugate a series of anticancer or antitumor drugs, such as for the prevention or treatment of Mps1 kinase-interaction-induced proliferative diseases (WO2014 / 37750,2014,A1), MAP4K1 inhibitors (WO2021 / 146370,2021,A1), or for the degradation of E3 ubiquitin ligases recruited by target proteins (WO2022 / 12622,2022,A1). It can also be used in pesticides, fragrances, and other fields.

[0003] Currently, patent records regarding the synthesis of trans-1-ethoxyvinyl-2-boronic acid pinacol esters generally fall into two categories:

[0004] The first method, WO2012 / 162129,2012,A1, is obtained by coupling ethoxyacetylene with pinacolborane; the reaction pathway is shown below:

[0005]

[0006] The main problem with this method is that ethoxyacetylene is not readily available and has a high market price (which is also the key problem that this invention addresses). Ethoxyacetylene is prepared from starting materials and then obtained via a coupling reaction to produce trans-1-ethoxyvinyl-2-boronic acid pinacol ester.

[0007] The second type, WO2021 / 66873,2021,A1, is obtained by coupling vinyl diethyl ether with pinacol borane; the reaction pathway is shown below:

[0008]

[0009] The raw materials for this method are readily available, but the method also produces cis-1-ethoxyvinyl-2-boronic acid pinacol ester, making it difficult to separate the product into a single configuration compound. Summary of the Invention

[0010] To overcome the above-mentioned technical defects, the present invention provides a method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester. Using vinyl ethyl ether as a raw material, an important intermediate ethoxyacetylene is obtained through a relatively simple method, and then trans-1-ethoxyvinyl-2-boronic acid pinacol ester is obtained through a coupling reaction. This method uses readily available raw materials, is simple to operate, and has low cost.

[0011] The preparation method of trans-1-ethoxyvinyl-2-boronic acid pinacol ester according to the present invention includes the following steps:

[0012]

[0013] Step 1: Preparation of 1,2-dibromoethoxyethane: Vinyl ethyl ether is reacted with bromine in an organic solvent, and the resulting product is 1,2-dibromoethoxyethane.

[0014] The second step is the preparation of 1-bromo-2-ethoxyethylene: an organic base is added to the reaction system and the temperature is raised to 80-100℃. 1,2-Dibromoethoxyethane is slowly added, and 1-bromo-2-ethoxyethylene is obtained by vacuum distillation while reacting.

[0015] The third step is the preparation of ethoxyacetylene: 1-bromo-2-ethoxyethylene, n-hexane and sulfolane are mixed, heated to 70-75℃, and inorganic base is added in batches. The reaction is carried out while distilling at atmospheric pressure to obtain a n-hexane solution of ethoxyacetylene.

[0016] Step 4, Preparation of trans-1-ethoxyvinyl-2-boronic acid pinacol ester: Mix an ethoxyacetylene n-hexane solution with an organic solvent, add pinacolborane and zirconium hydride to react, and then obtain trans-1-ethoxyvinyl-2-boronic acid pinacol ester.

[0017] In a further preferred embodiment of the present invention, the organic solvent in the preparation of 1,2-dibromoethoxyethane in the first step is selected from dichloromethane or 1,2-dichloroethane; dichloromethane is preferred; and the molar ratio of vinyl ethyl ether to bromine is 1:0.95-1.02.

[0018] In a further preferred embodiment of the present invention, the organic base used in the preparation of 1-bromo-2-ethoxyethylene in the second step is selected from triethylamine, pyridine, N,N-dimethyllauroylamine, N,N-dimethylaniline, or N,N-diethylaniline, preferably N,N-dimethyllauroylamine. The intermediate is collected at a distillation pressure of 20 mmHg and a temperature of 44-48°C. The molar ratio of 1,2-dibromoethoxyethane to the organic base is 1:2.5-3.5.

[0019] In a further preferred embodiment of the present invention, the inorganic base used in the preparation of the third step of ethoxyacetylene is selected from potassium tert-butoxide or sodium tert-butoxide, preferably potassium tert-butoxide; the molar ratio of 1-bromo-2-ethoxyethylene to the inorganic base is 1:1.4-1.8.

[0020] In a further preferred embodiment of the present invention, in the preparation of the product in the fourth step, the organic solvent is selected from dichloromethane.

[0021] In a further preferred embodiment of the present invention, in the preparation of the product in the fourth step, the molar ratio of ethoxyacetylene, pinacolborane and zirconium chlorohydride is 1:1.1-1.2:0.05-0.06.

[0022] In a further preferred embodiment of the present invention, the preparation of ethoxyacetylene preferably combines the second and third steps into one step, obtaining ethoxyacetylene from 1,2-dibromoethoxyethane via a one-step elimination reaction. The specific steps are as follows: n-hexane, sulfolane, DBU, and potassium tert-butoxide are heated to 70-80°C, and 1,2-dibromoethoxyethane is added dropwise. The reaction is carried out simultaneously with atmospheric distillation to obtain a hexane solution of ethoxyacetylene. The reaction pathway is shown below:

[0023]

[0024] In a further preferred embodiment, the molar ratio of 1,2-dibromoethoxyethane, DBU, and potassium tert-butoxide in the preparation of ethoxyacetylene is 1:1.1-1.2:1.3-1.5.

[0025] Beneficial effects of the invention

[0026] The raw material vinyl ether is readily available. The stepwise elimination process optimizes the selection of suitable base and reaction conditions, and further optimizes the merging of the two-step elimination process. This not only reduces labor steps but also improves the yield. The combined application of DBU and potassium tert-butoxide greatly improves the conversion rate and reduces the reaction cost. Attached Figure Description

[0027] Figure 1 The image shows the HNMR spectrum of trans-1-ethoxyvinyl-2-boronic acid pinacol ester obtained in Example 5. Detailed Implementation

[0028] The technical solution of the present invention will be described in more detail through the following embodiments.

[0029] Example 11, Preparation of 2-dibromoethoxyethane

[0030]

[0031] 72 g of vinyl ethyl ether (1.0 mol) and 300 mL of dichloromethane were added to a 1000 mL reaction flask and mixed. The mixture was cooled to 0 °C, and a mixture of 168 g of bromine (1.05 mol) and 100 mL of dichloromethane was added dropwise. After the addition was complete, the reaction was carried out for 3 hours. GC analysis confirmed that the reaction was complete. The reaction was quenched with 100 mL of sodium bisulfite aqueous solution, and the mixture was separated into layers. The organic phase was washed with sodium bicarbonate aqueous solution and water, respectively. The organic phase was dried over anhydrous sodium sulfate. The organic phase was first concentrated under reduced pressure at room temperature to remove dichloromethane, and then distilled under reduced pressure to obtain 218.8 g of pale yellow oily 1,2-dibromoethoxyethane, with a yield of 94.3% and a GC positivity of 95.7%. 1 HNMR(400MHz, CDCl3):6.01-5.99(m,1H),3.89-3.87(m,2H),3.71-3.69(m,2H),1.35-1.32(m,3H).

[0032] Example 2: Preparation of cis / trans-1-bromo-2-ethoxyethylene

[0033]

[0034] 288.1 g of N,N-dimethyllaurylamine (1.35 mol) was added to a reaction flask equipped with a vacuum distillation device. The temperature was raised to 90-100 °C, and 116 g of 1,2-dibromoethoxyethane (0.5 mol) was slowly added dropwise. After the addition was complete, the reaction was carried out under micro-vacuum while distilling under reduced pressure to obtain crude (cis / trans)-1-bromo-2-ethoxyethylene. The crude product was then subjected to rectification under a vacuum of 18-22 mmHg, a reflux ratio of 5:1, and a mainstream receiving temperature of 44-48 °C to obtain 58.3 g of cis / trans-1-bromo-2-ethoxyethylene. Yield: 77.2%, GC: trans 84.2% + cis 13.4% = 97.6%, GC-MS: m / z 151.9 (M + ).

[0035] Example 3: Preparation of ethoxyacetylene

[0036]

[0037] 45.3 g (cis / trans)-1-bromo-2-ethoxyethylene (0.3 mol), 200 mL n-hexane, and 50 mL sulfolane were added to a reaction flask equipped with an atmospheric distillation apparatus. The mixture was heated to 70-75 °C with stirring. 50.5 g of potassium tert-butoxide solid (0.45 mol) was added in portions. Stirring was stopped when the solid was added, and stirring was continued after the addition was complete. 113.6 g of an ethoxyacetylene n-hexane solution was obtained by atmospheric distillation while reacting. The yield was 70.1% according to QNMR (12.96%) and GC (94.3%). 1HNMR(400MHz, CDCl3):4.14-4.12(m,2H),1.56(s,1H),1.40-1.38(m,3H).

[0038] Example 4: Preparation of ethoxyacetylene

[0039]

[0040] 250 mL of n-hexane and 70 mL of sulfolane were added to a reaction flask equipped with an atmospheric distillation apparatus. 83.7 g of DBU (0.55 mol) and 78.5 g of potassium tert-butoxide (0.7 mol) were added at room temperature. The mixture was stirred at room temperature for 10 min, then heated to 70 °C. 116 g of 1,2-dibromoethoxyethane (0.5 mol) was added dropwise. After the addition was complete, the temperature was raised to 75-80 °C, and the mixture was distilled at atmospheric pressure while reacting to obtain 151.9 g of an ethoxyacetylene / n-hexane solution. The QNMR was 18.69%, yield 81.1%, GC: 95.8%.

[0041] Example 5: Preparation of trans-1-ethoxyvinyl-2-boronic acid pinacol ester

[0042]

[0043] 150 g of ethoxyacetylene / n-hexane solution (0.4 mol) obtained in Example 4 was mixed with 300 mL of dichloromethane, cooled to 0 °C, and 57.6 g of pinacolborane (0.45 mol) and 5.2 g of zirconium chlorohydrogen bis(chlorodichlorohexene) (0.02 mol) were added. The mixture was then reacted overnight at room temperature. 5 g of activated carbon was added, and the mixture was quickly passed through silica gel and filtered. The filter cake was washed with 50 mL of dichloromethane. The filtrate was concentrated under reduced pressure to remove the dichlorodi ... 1 HNMR(400MHz, CDCl3):7.06-7.03(m,1H),4.45-4.41(m,1H),3.85-3.83(m,2H),1.30-1.26(m,15H).

[0044] The above embodiments describe 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 present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester, characterized in that, It includes the following four steps: Step 1: React vinyl ethyl ether with bromine in an organic solvent to obtain 1,2-dibromoethoxyethane; the organic solvent used in this step is selected from dichloromethane or 1,2-dichloroethane. Step 2: Add an organic base to the reaction system and heat to 80-100℃. Slowly add 1,2-dibromoethoxyethane and distill under reduced pressure while reacting to obtain crude 1-bromo-2-ethoxyethylene. The organic base is selected from N,N-dimethyllaurylamine. The molar ratio of 1,2-dibromoethoxyethane to the organic base is 1:2.5-3.

5. Step 3: Mix 1-bromo-2-ethoxyethylene, n-hexane, and sulfolane, heat to 70-75℃, add an inorganic base in batches, and distill at atmospheric pressure while reacting to obtain an ethoxyacetylene / n-hexane solution; the inorganic base is selected from potassium tert-butoxide or sodium tert-butoxide; the molar ratio of 1-bromo-2-ethoxyethylene to the inorganic base is 1:1.4-1.8; Step 4: Mix ethoxyacetylene / n-hexane solution with an organic solvent, add pinacolborane and zirconium hydrochloride to react, and then obtain trans-1-ethoxyvinyl-2-boronic acid pinacol ester.

2. The method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester according to claim 1, characterized in that: In the fourth step, the organic solvent is selected from dichloromethane.

3. The method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester according to claim 1, characterized in that: In the first step, the molar ratio of vinyl ethyl ether to bromine is 1:0.95-1.

02.

4. The method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester according to claim 1, characterized in that: In the fourth step, the molar ratio of ethoxyacetylene, pinacolborane and zirconium hydroxide is 1:1.1-1.2:0.05-0.

06.

5. A method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester, characterized in that, The reaction circuit is shown below: ； The second step of the reaction involves heating n-hexane, sulfolane, DBU, and potassium tert-butoxide to 70-80°C, adding 1,2-dibromoethoxyethane dropwise, and distilling at atmospheric pressure while reacting to obtain a n-hexane solution of ethoxyacetylene.

6. The method for preparing trans-1-ethoxyvinyl-2-boronic acid pinacol ester according to claim 5, characterized in that: The molar ratio of 1,2-dibromoethoxyethane, DBU, and potassium tert-butoxide is 1:1.1-1.2:1.3-1.5.

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