Synthesis method of O-benzotriazole-tetramethylurea tetrafluoroborate

Abstract

The invention relates to a synthesis method of O-benzotriazole-tetramethylurea tetrafluoroborate, and belongs to the technical field of chemical synthesis, and the synthesis method comprises the following steps: S1, in a 1000L glass kettle, dissolving HOBT in water, dropwise adding a potassium hydroxide solution while stirring, and reacting to generate potassium salt of 1-hydroxybenzotriazole; and S2, adding dichloromethane and tetramethyl chloroformamidine tetrafluoroborate into a 2000L glass-lined kettle, transferring a KOBT solution at room temperature, after the reaction is finished, standing for layering, extracting a water layer once by using dichloromethane, combining dichloromethane layers, concentrating under reduced pressure, adding petroleum ether for crystallization, centrifuging by using a centrifugal machine, and performing double-cone vacuum drying to obtain the TBTU. According to the synthesis method of the O-benzotriazole-tetramethylurea tetrafluoroborate, phosphorus oxychloride is used for replacing oxalyl chloride, so that the reaction conversion rate is increased, the raw material cost is greatly reduced, the core competitiveness of enterprises is improved, large-scale industrial processing is promoted, and the synthesis method has a good application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate. Background Art

[0002] O-Benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate is a highly efficient amidation reagent, often referred to as TBTU, which can promote the condensation reaction between carboxylic acid and amine to form an amide bond. TBTU has a certain selectivity for substrates and can effectively promote specific types of chemical reactions while reducing the generation of by-products. This reaction can be carried out under mild conditions with a high yield, so it is widely used in the fields of peptide synthesis, drug synthesis, and biomolecule labeling.

[0003] In the process of preparing TBTU, oxalyl chloride is the key intermediate required for preparing TBTU. Oxalyl chloride has high reactivity, especially in organic synthesis. It is easy to react with various functional groups, such as hydroxyl and amino groups, to generate corresponding acyl chloride derivatives. At present, the price of oxalyl chloride in the market is 31,000-39,000 yuan / ton, which leads to the current high cost of TBTU preparation and difficulty in large-scale industrial processing.

[0004] Based on this, a synthesis method of O-benzotriazole-tetramethyluronium tetrafluoroborate is proposed to solve the above problems. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate, which has the advantages of high conversion rate and reduced raw material cost, and solves the problem that the current TBTU preparation cost is too high and it is difficult to process it on a large scale in an industrial manner.

[0006] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate, comprising the following steps:

[0007] S1, in a 1000L glass kettle, HOBT is dissolved in water, and potassium hydroxide solution is added dropwise under stirring to react and generate potassium salt of 1-hydroxybenzotriazole;

[0008] S2, add dichloromethane and tetramethylchloroformamidine tetrafluoroborate to a 2000L glass-lined reactor, transfer the KOBT solution at room temperature, and after the reaction is completed, let it stand for stratification, extract the water layer once with dichloromethane, combine the dichloromethane layers, concentrate under reduced pressure, add petroleum ether for crystallization, centrifuge, and dry in a double cone vacuum to obtain TBTU;

[0009] The tetramethylchloroformamidine tetrafluoroborate is prepared from tetramethylchloroformamidine dichlorophosphate, and the tetramethylchloroformamidine dichlorophosphate is prepared from phosphorus oxychloride.

[0010] Further, the synthesis method of tetramethylchloroformamidine tetrafluoroborate comprises the following steps:

[0011] S2-1, add dichloromethane to the tetramethylchloroformamidine dichlorophosphate reaction solution, cool it down and dropwise add an aqueous solution of potassium tetrafluoroborate for 30 minutes. After the dropwise addition is completed, continue to stir vigorously for 30 minutes;

[0012] S2-2, separate the liquids, wash the organic phase with tap water twice, separate the liquids again, dry the organic phase with magnesium sulfate and filter, wash the magnesium sulfate with dichloromethane, distill the dichloromethane under reduced pressure at 50°C, and obtain the desired tetramethylchloroformamidine tetrafluoroborate after crystallization, centrifugation and drying.

[0013] Further, the synthetic structural formula of the tetramethylchloroformamidine tetrafluoroborate is:

[0014]

[0015] Further, the synthesis method of tetramethylchloroformamidine dichlorophosphate comprises the following steps:

[0016] S2-1-1, add tetramethylurea liquid into the reaction kettle to cool down, and when the system temperature reaches 0°C, add phosphorus oxychloride liquid dropwise for 30 minutes;

[0017] S2-1-2, after the dropwise addition is completed, the temperature is raised to 100°C, the reaction is carried out for 60 minutes, and the mixture is cooled to room temperature to obtain a transparent yellow liquid, that is, the desired tetramethylchloroformamidine dichlorophosphate.

[0018] Further, the synthetic structural formula of the tetramethylchloroformamidine dichlorophosphate is:

[0019]

[0020] Further, the synthetic structural formula of the O-benzotriazole-tetramethyluronium tetrafluoroborate is:

[0021]

[0022] Compared with the prior art, the present invention provides a method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate, which has the following beneficial effects:

[0023] The synthesis method of O-benzotriazole-tetramethyluronium tetrafluoroborate uses phosphorus oxychloride instead of oxalyl chloride, improves the reaction conversion rate, greatly reduces the cost of raw materials, improves the core competitiveness of the enterprise, helps to promote large-scale industrial processing, has good application prospects, and solves the current problem of high preparation cost of TBTU and difficulty in large-scale industrial processing. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The figure is a flow chart of the synthesis method of O-benzotriazole-tetramethyluronium tetrafluoroborate of the present invention;

[0025] Figure 2 The present invention is a flow chart of the synthesis method of tetramethylchloroformamidine tetrafluoroborate;

[0026] Figure 3 The present invention is a flow chart of the synthesis method of tetramethylchloroformamidine dichlorophosphate. DETAILED DESCRIPTION

[0027] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] See also Figures 1 to 3 , a method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate in this embodiment comprises the following steps:

[0029] 1) In a 1000L glass kettle, HOBT is dissolved in water, and potassium hydroxide solution is added dropwise under stirring to react and generate potassium salt of 1-hydroxybenzotriazole;

[0030] 2) Add dichloromethane and tetramethylchloroformamidine tetrafluoroborate to a 2000L glass-lined kettle, transfer the KOBT solution at room temperature, and after the reaction is completed, let it stand to separate the layers. Extract the aqueous layer once with dichloromethane, combine the dichloromethane layers, concentrate under reduced pressure, add petroleum ether for crystallization, centrifuge, and dry in a double cone vacuum to obtain TBTU.

[0031] Among them, the synthetic structural formula of O-benzotriazole-tetramethyluronium tetrafluoroborate is:

[0032]

[0033] In this embodiment, tetramethylchloroformamidine tetrafluoroborate is prepared from tetramethylchloroformamidine dichlorophosphate, and tetramethylchloroformamidine dichlorophosphate is prepared from phosphorus oxychloride.

[0034] It should be noted that the synthesis method of tetramethylchloroformamidine tetrafluoroborate comprises the following steps:

[0035] 2-1), add dichloromethane to the tetramethylchloroformamidine dichlorophosphate reaction solution, cool and dropwise add potassium tetrafluoroborate aqueous solution for 30 minutes. After the addition is completed, continue to stir vigorously for 30 minutes;

[0036] 2-2), separate the liquids, wash the organic phase with tap water twice, separate the liquids again, dry the organic phase with magnesium sulfate and filter, wash the magnesium sulfate with dichloromethane, distill the dichloromethane under reduced pressure at 50°C, crystallize, centrifuge and dry to obtain the desired tetramethylchloroformamidine tetrafluoroborate.

[0037] Among them, the synthetic structural formula of tetramethylchloroformamidine tetrafluoroborate is:

[0038]

[0039] It should be noted that the synthesis method of tetramethylchloroformamidine dichlorophosphate comprises the following steps:

[0040] 2-1-1), add tetramethylurea liquid into the reaction kettle to cool down, and when the system temperature reaches 0°C, add phosphorus oxychloride liquid dropwise for 30 minutes;

[0041] 2-1-2), after the addition is completed, the temperature is raised to 100°C, the reaction is carried out for 60 minutes, and the mixture is cooled to room temperature to obtain a transparent yellow liquid, that is, the desired tetramethylchloroformamidine dichlorophosphate.

[0042] Among them, the synthetic structural formula of tetramethylchloroformamidine dichlorophosphate is:

[0043]

[0044] The beneficial effects of the present invention are:

[0045] The synthesis method of O-benzotriazole-tetramethyluronium tetrafluoroborate uses phosphorus oxychloride instead of oxalyl chloride, improves the reaction conversion rate, greatly reduces the cost of raw materials, improves the core competitiveness of the enterprise, helps to promote large-scale industrial processing, and has good application prospects.

[0046] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate, characterized in that: The following steps are involved: S1, in a 1000L glass kettle, HOBT is dissolved in water, and potassium hydroxide solution is added dropwise under stirring to react and generate potassium salt of 1-hydroxybenzotriazole; S2, add dichloromethane and tetramethylchloroformamidine tetrafluoroborate to a 2000L glass-lined reactor, transfer the KOBT solution at room temperature, and after the reaction is completed, let it stand for stratification, extract the water layer once with dichloromethane, combine the dichloromethane layers, concentrate under reduced pressure, add petroleum ether for crystallization, centrifuge, and dry in a double cone vacuum to obtain TBTU; The tetramethylchloroformamidine tetrafluoroborate is prepared from tetramethylchloroformamidine dichlorophosphate, and the tetramethylchloroformamidine dichlorophosphate is prepared from phosphorus oxychloride.

2. The method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate according to claim 1, characterized in that: The synthesis method of tetramethylchloroformamidine tetrafluoroborate comprises the following steps: S2-1, add dichloromethane to the tetramethylchloroformamidine dichlorophosphate reaction solution, cool it down and dropwise add an aqueous solution of potassium tetrafluoroborate for 30 minutes. After the dropwise addition is completed, continue to stir vigorously for 30 minutes; S2-2, separate the liquids, wash the organic phase with tap water twice, separate the liquids again, dry the organic phase with magnesium sulfate and filter, wash the magnesium sulfate with dichloromethane, distill the dichloromethane under reduced pressure at 50°C, and obtain the desired tetramethylchloroformamidine tetrafluoroborate after crystallization, centrifugation and drying.

3. The method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate according to claim 1, characterized in that: The synthetic structural formula of the tetramethylchloroformamidine tetrafluoroborate is:

4. The method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate according to claim 1, characterized in that: The synthesis method of tetramethylchloroformamidine dichlorophosphate comprises the following steps: S2-1-1, add tetramethylurea liquid into the reaction kettle to cool down, and when the system temperature reaches 0°C, add phosphorus oxychloride liquid dropwise for 30 minutes; S2-1-2, after the dropwise addition is completed, the temperature is raised to 100°C, the reaction is carried out for 60 minutes, and the mixture is cooled to room temperature to obtain a transparent yellow liquid, that is, the desired tetramethylchloroformamidine dichlorophosphate.

5. The method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate according to claim 1, characterized in that: The synthetic structural formula of the tetramethylchloroformamidine dichlorophosphate is:

6. The method for synthesizing O-benzotriazole-tetramethyluronium tetrafluoroborate according to claim 1, characterized in that: The synthetic structural formula of the O-benzotriazole-tetramethyluronium tetrafluoroborate is:

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