Process method for synthesizing N, N-dimethylamino ethyl boronic acid pinacol ester
By reacting N,N-dimethylaminoethyl ethanol with substituted sulfonyl chloride and coupling with pennadol tetraborate under light conditions, it is solved that it is difficult to synthesize N,N-dimethylaminoethyl boronic acid in the prior art. The problem of pinna alcohol ester has achieved efficient and simple synthesis methods and provided a new way to prepare drug intermediates.
Patent Information
- Application Number
- CN202411429432.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-14
- Publication Date
- 2025-01-14
AI Technical Summary
The prior art is difficult to effectively synthesize N,N-dimethylaminoethylborate. It is mainly due to the strong alkalinity of the raw materials, which leads to the elimination of halogenated hydrocarbons, and cannot be prepared through conventional format reactions or metal lithium reactions.
N,N-dimethylaminoethyl ethanol reacts with substituted sulfonyl chloride, and then coupling with Pinnaol tetraborate under light conditions, and N,N-dimethylaminoethylborate is prepared by one pot method. Ester, organic solvent, cuprous bromide dimethylsulfide, ligand and lithium alkyl alcohol are used as auxiliary agents.
The synthesis of Pinnaol esters of N,N-dimethylaminoethylborate with high yield, simple steps and convenient operation is achieved, and a new synthesis method is provided, with easy-to-get raw materials and cheap prices.
Smart Images
Figure BDA0005083193600000021 
Figure HDA0005083193610000011
Abstract
Description
Technical Field
[0001] The invention relates to a process for synthesizing N,N-dimethylaminoethylboronic acid pinacol ester, and belongs to the field of drug intermediate synthesis. Background Art
[0002] N,N-Dimethylaminoethylboronic acid pinacol ester is an organic borate ester compound, which is widely used in Suzuki reaction to construct various CC single bonds.
[0003] In recent years, the synthesis of organic borate compounds has received more and more attention. However, there is no suitable method for the synthesis of N,N-dimethylaminoethyl boric acid pinacol ester. Usually, the synthesis of alkane borate esters uses halogenated alkanes as raw materials, generates Grignard intermediates or organic lithium intermediates through Grignard reaction or metal lithium reaction, and then reacts with alkoxy boric acid pinacol ester to obtain organic borate esters.
[0004] According to the usual method, the raw material for the synthesis of N,N-dimethylaminoethyl boronic acid pinacol ester is N,N-dimethylaminoethyl halogenated hydrocarbon. This type of compound has a strong alkalinity and is very easy to undergo halogenated hydrocarbon elimination to generate olefins, but it is impossible to prepare N,N-dimethylaminoethyl boronic acid pinacol ester through Grignard reaction or metal lithium reaction. Therefore, it is difficult to synthesize N,N-dimethylaminoethyl boronic acid pinacol ester using conventional methods.
[0005] Therefore, it is urgent to find a new method for synthesizing N,N-dimethylaminoethylboronic acid pinacol ester. Summary of the invention
[0006] In order to overcome the above technical defects, the present invention uses N,N-dimethylaminoethanol as a raw material, first reacts with substituted sulfonyl chloride, and then couples with diboric acid pinacol ester under light conditions to prepare N,N-dimethylaminoethyl boric acid pinacol ester in one pot. The method has the advantages of originality, short steps and high yield.
[0007] A process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester comprises the following steps: mixing N,N-dimethylaminoethanol and an organic solvent, controlling the temperature at -5°C to 5°C, adding substituted sulfonyl chloride in batches, and adding biboric acid pinacol ester, cuprous bromide dimethyl sulfide, a ligand and hexafluoroisopropanol after the reaction is finished, controlling the temperature at 45-55°C, adding alkyl alcohol lithium, and reacting under light to obtain N,N-dimethylaminoethyl boric acid pinacol ester.
[0008] The present invention adopts reaction equation to be briefly expressed as follows:
[0009]
[0010] Further, under preferred conditions, the organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.
[0011] Further, under preferred conditions, the substituted sulfonyl chloride is selected from trifluoromethanesulfonyl chloride or methanesulfonyl chloride.
[0012] Further, under preferred conditions, the ligand is selected from 1,3-bis(diphenylphosphino)propane, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or bis(2-diphenylphosphinophenyl)ether.
[0013] Furthermore, under preferred conditions, the illumination wavelength is selected from 370-525 nanometers.
[0014] Further, under preferred conditions, the alkyl lithium alcoholate is selected from lithium methoxide or lithium tert-butoxide.
[0015] Furthermore, under preferred conditions, the weight ratio of the N,N-dimethylaminoethanol, the organic solvent and the hexafluoroisopropanol is 1:3-5:10-30.
[0016] Further, under preferred conditions, the molar ratio of N,N-dimethylaminoethanol to substituted sulfonyl chloride, bipyraclostrobin, cuprous bromide dimethyl sulfide, ligand to alkyl lithium alcohol is 1:1:1-1.5:0.05-0.15:0.05-0.2:2-2.5.
[0017] Advantageous Effects of the Invention
[0018] 1. The present invention uses N,N-dimethylaminoethanol as a raw material, first reacts with substituted sulfonyl chloride, and then couples with diboric acid pinacol ester under light conditions to prepare N,N-dimethylaminoethyl boric acid pinacol ester in one pot. This method is original and has no literature reports.
[0019] 2. The raw material N,N-dimethylaminoethanol used in this method is easily available and cheap, 14,500 yuan / ton. The other raw materials are all bulk chemicals and are relatively easy to prepare.
[0020] 3. The method of the present invention has potential technical advantages, short steps, and simple operation, and provides a new synthesis method for N,N-dimethylaminoethylboronic acid pinacol ester. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 This is the HNMR spectrum of N,N-dimethylaminoethyl boric acid pinacol ester obtained in Example 1. Specific embodiments
[0022] Example 1
[0023] Add 5.35g (60.0mmol) of N,N-dimethylaminoethanol and 27g of N,N-dimethylformamide to the reaction bottle, stir, control the temperature from -5℃ to 5℃, add 6.87g (60.0mmol) of methylsulfonyl chloride dropwise, and keep warm for 1 hour. Sampling GC control, N,N-dimethylaminoethanol is completely converted, add 18.28g (72.0mmol) of biboric acid pinacol ester, 1.23g (6.0mmol) of cuprous bromide dimethyl sulfide, 4.95g (12.0mmol) of 1,3-bis(diphenylphosphino)propane and 107g of hexafluoroisopropanol to the bottle, use KessilPR160L light source for illumination, select wavelength 525nm, the light source is about 4cm away from the reaction bottle, heat to 45-55℃, add 4.78g (126.0mmol) of lithium methoxide in batches, add the materials, and keep warm for 5 hours. The reaction was controlled complete during sampling GC, 107 g of n-heptane was added into the bottle, 107 g of water was added dropwise, the layers were separated, and the organic layer was distilled under reduced pressure. After the solvent was evaporated, the temperature was raised, and the 85-95°C fraction was collected to obtain 10.51 g of light yellow liquid product N,N-dimethylaminoethylboronic acid pinacol ester, GC: 98.8%, yield: 88%.
[0024] Example 2
[0025] Add 5.35g (60.0mmol) of N,N-dimethylaminoethanol and 27g of N,N-dimethylacetamide to the reaction bottle, control the temperature from -5℃ to 5℃, add 10.11g (60.0mmol) of trifluoromethanesulfonyl chloride dropwise under stirring, and keep warm for 1 hour. Sampling GC control, N,N-dimethylaminoethanol is completely converted, add 18.28g of biboric acid pinacol ester, 0.62g (3.0mmol) of cuprous bromide dimethyl sulfide, 2.47g (6.0mmol) of 1,3-bis(diphenylphosphino)propane and 107g of hexafluoroisopropanol to the bottle, use KessilPR160L light source for illumination, select wavelength 525nm, the light source is about 4cm away from the reaction bottle, heat to 45-55℃, add 4.78g (126.0mmol) of lithium methoxide in batches, add the materials, and keep warm for 5 hours. The reaction was controlled complete during sampling GC, 107 g of n-heptane was added into the bottle, 107 g of water was added dropwise, the layers were separated, and the organic layer was distilled under reduced pressure. After the solvent was evaporated, the temperature was raised, and the 85-95°C fraction was collected to obtain 9.68 g of light yellow liquid product N,N-dimethylaminoethylboronic acid pinacol ester, GC: 98.1%, yield: 81%.
[0026] Example 3
[0027] Add 5.35g (60.0mmol) of N,N-dimethylaminoethanol and 27g of N,N-dimethylformamide to the reaction bottle, control the temperature from -5℃ to 5℃, add 6.87g (60.0mmol) of methylsulfonyl chloride dropwise under stirring, and keep warm for 1 hour. Sampling GC control, N,N-dimethylaminoethanol is completely converted, add 18.28g (72.0mmol) of biboric acid pinacol ester, 1.23g (6.0mmol) of cuprous bromide dimethyl sulfide, 4.95g (12.0mmol) of 1,3-bis(diphenylphosphino)propane and 107g of hexafluoroisopropanol to the bottle, use KessilPR160L light source for illumination, select wavelength 370nm, the light source is about 4cm away from the reaction bottle, heat to 45-55℃, add 4.78g (126.0mmol) of lithium methoxide in batches, add the materials, and keep warm for 8 hours. The reaction was basically completed during the sampling GC control. 107 g of n-heptane was added to the bottle, 107 g of water was added dropwise, the layers were separated, and the organic layer was distilled under reduced pressure. After the solvent was evaporated, the temperature was raised and the 85-95°C fraction was collected to obtain 9.26 g of light yellow liquid product N,N-dimethylaminoethylboronic acid pinacol ester, GC: 98.8%, yield: 77.5%.
[0028] Example 4
[0029] Add 5.35 g (60.0 mmol) of N,N-dimethylaminoethanol and 27 g of N,N-dimethylformamide into the reaction bottle, control the temperature from -5°C to 5°C, add 6.87 g (60.0 mmol) of methylsulfonyl chloride dropwise with stirring, and keep warm for 1 hour. Sampling was controlled in the GC, and the conversion of N,N-dimethylaminoethanol was complete. 22.85 g (90.0 mmol) of bipyraclostrobin, 1.85 g (9.0 mmol) of cuprous bromide dimethyl sulfide, 10.42 g (18.00 mmol) of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene and 160 g of hexafluoroisopropanol were added into the bottle. The light source was used for illumination with a wavelength of 467 nm. The light source was about 4 cm away from the reaction bottle. The temperature was raised to 45-55°C, and 5.70 g (150.0 mmol) of lithium methoxide were added in batches. After the addition was completed, the reaction was kept warm for 5 hours. The reaction was controlled complete during sampling GC, 150 g of n-heptane was added into the bottle, 150 g of water was added dropwise, the layers were separated, and the organic layer was distilled under reduced pressure. After the solvent was evaporated, the temperature was raised, and the 85-95°C fraction was collected to obtain 10.40 g of light yellow liquid product N,N-dimethylaminoethylboronic acid pinacol ester, GC: 98.5%, yield: 87%.
[0030] Example 5
[0031] Add 5.35g (60.00mmol) of N,N-dimethylaminoethanol and 27g of N,N-dimethylformamide to the reaction bottle, control the temperature from -5℃ to 5℃, add 6.87g (60.0mmol) of methylsulfonyl chloride dropwise under stirring, and keep warm for 1 hour. Sampling GC control, N,N-dimethylaminoethanol is completely converted, add 22.85g (90.0mmol) of biboric acid pinacol ester, 1.23g (6.0mmol) of cuprous bromide dimethyl sulfide, 4.95g (12.0mmol) of 1,3-bis(diphenylphosphino)propane and 107g of hexafluoroisopropanol to the bottle, use KessilPR160L light source for illumination, select wavelength 427nm, the light source is about 4cm away from the reaction bottle, heat to 45-55℃, add 5.70g (150.0mmol) of lithium methoxide in batches, add the materials, and keep warm for 5 hours. The reaction was controlled complete during sampling GC, 107 g of n-heptane was added into the bottle, 107 g of water was added dropwise, the layers were separated, and the organic layer was distilled under reduced pressure. After the solvent was evaporated, the temperature was raised, and the 85-95°C fraction was collected to obtain 9.92 g of light yellow liquid product N,N-dimethylaminoethylboronic acid pinacol ester, GC: 98.6%, yield: 83%.
[0032] Comparative Example 1: No Light Condition
[0033] Add 5.35g (60.0mmol) of N,N-dimethylaminoethanol and 27g of N,N-dimethylformamide to the reaction bottle, control the temperature from -5℃ to 5℃, add 6.87g (60.0mmol) of methylsulfonyl chloride dropwise under stirring, and keep warm for 1 hour. Sampling GC control, N,N-dimethylaminoethanol is completely converted, add 18.28g (72.0mmol) of biboric acid pinacol ester, 1.23g (6.0mmol) of cuprous bromide dimethyl sulfide, 4.95g (12.00mmol) of 1,3-bis(diphenylphosphino)propane and 107g of hexafluoroisopropanol to the bottle, heat to 45-55℃, add 4.78g (126.00mmol) of lithium methoxide in batches, add the materials, and keep warm for reaction. The reaction in the sampling GC control was no longer carried out. 107 g of n-heptane was added into the bottle, 107 g of water was added dropwise, the layers were separated, and the organic layer was distilled under reduced pressure. After the solvent was evaporated, the temperature was raised and the 85-95°C fraction was collected to obtain 6.56 g of light yellow liquid product N,N-dimethylaminoethylboronic acid pinacol ester, GC: 97.8%, yield: 55%.
[0034] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.
Claims
1. A process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester, characterized in that: The following steps are involved: N,N-dimethylaminoethanol and an organic solvent are mixed, the temperature is controlled at -5°C to 5°C, substituted sulfonyl chloride is added in batches, and after the reaction is completed, diboric acid pinacol ester, cuprous bromide dimethyl sulfide, ligand and hexafluoroisopropanol are added, the temperature is controlled at 45-55°C, alkyl alcohol lithium is added, and the reaction is carried out under light to obtain N,N-dimethylaminoethylboric acid pinacol ester.
2. The process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester according to claim 1, characterized in that: The organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.
3. The process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester according to claim 1, characterized in that: The substituted sulfonyl chloride is selected from trifluoromethanesulfonyl chloride or methanesulfonyl chloride.
4. The process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester according to claim 1, characterized in that: The ligand is selected from 1,3-bis(diphenylphosphino)propane, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or bis(2-diphenylphosphinophenyl)ether.
5. The process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester according to claim 1, characterized in that: The wavelength of light is selected from 370-525 nanometers.
6. The process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester according to claim 1, characterized in that: The lithium alkyl alcoholate is selected from lithium methoxide or lithium tert-butoxide.
7. The process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester according to claim 1, characterized in that: The weight ratio of N,N-dimethylaminoethanol, organic solvent and hexafluoroisopropanol is 1:3-5:10-30.
8. The process for synthesizing N,N-dimethylaminoethyl boric acid pinacol ester according to claim 1, characterized in that: The molar ratio of N,N-dimethylaminoethanol to substituted sulfonyl chloride, bipyraclostrobin, cuprous bromide dimethyl sulfide, ligand and alkyl alcohol lithium is 1:1:1-1.5:0.05-0.15:0.05-0.2:2-2.5.