Environmentally friendly synthesis method of 4,4'-dimethoxytriphenylmethane

Abstract

The present invention relates to the field of chemical industry, and in particular to an environmentally friendly synthesis method for 4,4'-dimethoxytriphenylmethane. The synthesis route is as follows: #imgabs0# comprising the following steps: step 1, reacting anisole and trichlorotoluene in a polyethylene glycol solvent; step 2, recrystallizing the crude product to obtain pure 4,4'-dimethoxytriphenylmethane chloride. The present invention has the following beneficial effects: a one-pot synthesis of 4,4'-dimethoxytriphenylmethane is successful in a PEG-600 medium with high yield and good purity, which has significant advantages over previous methods; aluminum chloride produces more wastewater, causing environmental pollution. The use of PEG-600 avoids the use of aluminum chloride, thereby making the method environmentally friendly; treating aluminum chloride wastewater causes the production cost of 4,4'-dimethoxytriphenylmethane to increase. The use of PEG-600 and its ability to be reused at least five times significantly reduce the production cost of 4,4'-dimethoxytriphenylmethane.

Description

Technical Field

[0001] The present invention relates to the field of chemical industry, and in particular to an environmentally friendly synthesis method of 4,4'-dimethoxytriphenylmethane. Background Art

[0002] The structure of 4,4'-dimethoxytriphenylmethane (DMTr-Cl) is as follows:

[0003]

[0004] DMTr-Cl plays a crucial role in the field of nucleotides and nucleotide chemistry, often serving as a hydroxyl-protecting agent in the synthesis of these important biochemicals. This technical field encompasses precise and specialized chemical syntheses, where precise control of reactants, conditions, and purification processes is crucial. The synthesis of DMTr-Cl is particularly important because its quality directly impacts the quality and efficacy of downstream nucleotides and nucleotide analogs, which have a wide range of applications in pharmaceuticals, diagnostics, and molecular biology. Therefore, the efficient and reliable production of DMTr-Cl is crucial.

[0005] As technology advances, those skilled in the art have explored various methods for synthesizing DMTr-Cl in the past. These prior art methods are important references for understanding the challenges and limitations involved in traditional DMTr-Cl production. The following are some notable prior art methods:

[0006] Grignard Reagent Synthesis: Historically, the synthesis of DMTr-Cl began with the formation of 4,4'-dimethoxytrityl alcohol via the reaction of p-methoxymagnesium bromide Grignard reagent and p-methoxyphenylphenone. While effective in principle, this approach requires the use of highly volatile and potentially explosive solvents, such as ether or tetrahydrofuran, as Grignard reagents. The safety risks associated with these solvents limit their practicality for large-scale production. (References: Journal of the American Chemical Society, Vol. 111, No. 11, 1989; Chemical Society, Perkin Transformations 2: Physical Organic Chemistry, 1989).

[0007] Anisole and trichlorotoluene method: An alternative method has been developed using anisole and trichlorotoluene as the primary raw materials for 4,4'-dimethoxytrityl alcohol. However, this method has issues, including low reaction yields, purification difficulties, and challenges in industrial-scale application. (Reference: Indian Journal of Chemistry, B: Organic Chemistry including Medicinal Chemistry, 1995; CN1432553A).

[0008] These prior art methods have played an important role in advancing our understanding of DMTr-Cl synthesis. However, they suffer from significant limitations, including safety concerns, low yields, and complex purification processes. These shortcomings of traditional methods highlight the need for innovative and improved methods for DMTr-Cl synthesis, which the present invention addresses. Summary of the Invention

[0009] In view of the problems existing in the prior art, the present invention provides a method for synthesizing DMTr-Cl. This method is environmentally friendly and easy to operate, has a high product yield and high purity, and is suitable for the industrial production of DMTr-Cl.

[0010] To this end, the present invention provides a method for synthesizing 4,4'-dimethoxytriphenylmethane (DMTr-Cl), and the synthetic route thereof is as follows.

[0011]

[0012] Scheme 1: Synthesis of DMTr-Cl

[0013] The following steps are involved:

[0014] Anisole and trichlorotoluene were reacted in polyethylene glycol solvent.

[0015] The crude product was recrystallized to obtain pure 4,4'-dimethoxytriphenylphosphine chloride.

[0016] Polyethylene glycol (PEG) is a polyether compound, commonly referred to as a polymer. It is synthesized from ethylene glycol monomers, hence the name. Chemically, PEG is represented by the formula HO(CH2CH2O)nH. Due to its unique properties, PEG is widely used in a variety of applications. PEG is a water-soluble, biocompatible, and non-toxic compound. Its physical state varies depending on its molecular weight. Typically, low-molecular-weight PEG is a viscous liquid, while high-molecular-weight PEG is a waxy solid. In the pharmaceutical industry, PEG plays a variety of roles, including as a solvent, catalyst, plasticizer, surfactant, and ointment base.

[0017] In the present invention, PEG is used as a catalyst and reaction solvent, which simplifies the operation, improves the utilization rate of raw materials, avoids the use of metal salts, reduces wastewater discharge, and makes the method environmentally friendly. PEG increases the conversion rate of the reaction, thereby increasing the yield and purity of 4,4'-dimethoxytriphenyl chloride.

[0018] The mechanism for the synthesis of 4,4'-dimethoxybenzyl alcohol using PEG as a catalyst involves the following steps: PEG-600 initiates the reaction by forming a complex with the starting material and accepting an electron pair from it. Once the complex is formed, PEG-600 facilitates the departure of the leaving group from the starting material. This step results in the formation of a triphenyl cation. The triphenyl cation is highly reactive and can react with another molecule. This step results in the formation of 4,4'-dimethoxybenzyl alcohol through a nucleophilic attack on the triphenyl cation.

[0019] Regeneration of PEG-600: After the reaction is complete, PEG-600, as a Lewis acid catalyst, should be restored to its original state to prepare for another round of reaction. This regeneration step may involve transferring negative electrons from the nucleophilic molecule back to PEG-600.

[0020] The best choice is to choose PEG-600 in a series of reactions using PEG-100, PEG-600, and PEG-1000.

[0021] In summary, the present invention has the following beneficial effects:

[0022] The one-pot synthesis of 4,4'-dimethoxytriphenylmethane in PEG-600 medium was successful with high yield and good purity, which has significant advantages over previous methods.

[0023] Aluminum chloride produces more wastewater, causing environmental pollution. The use of PEG-600 avoids the use of aluminum chloride, making the method environmentally friendly.

[0024] Treatment of aluminum chloride wastewater will lead to an increase in the production cost of 4,4'-dimethoxytriphenylmethane.

[0025] The use of PEG-600 and its ability to be reused at least five times significantly reduces the production cost of 4,4'-dimethoxytriphenylmethane. DETAILED DESCRIPTION

[0026] The present invention is described in further detail below.

[0027] This specific embodiment is merely an explanation of the present invention and is not intended to limit the present invention. After reading this specification, those skilled in the art may make non-creative modifications to this embodiment as needed. However, as long as such modifications are within the scope of the claims of the present invention, they are protected by patent law.

[0028] Example 1: Synthesis of 4,4'-dimethoxytriphenyl chloride using PEG-100:

[0029] Place 225 g of PEG-100 and 150 g of trichlorotoluene in a 1-liter round-bottom flask and cool to 5-10°C. Then, slowly add 174.3 g of anisole dropwise at 5-10°C. Raise the temperature to 25°C and then further to 40°C. Maintain the reaction mixture at 40°C for 3 hours. Cool the reaction mixture to 25°C, add 1 L of water, and stir for 1 hour. Filter the solid and rinse thoroughly with water.

[0030] Recrystallization of crude product:

[0031] The crude product was dissolved in 500 g of dichloromethane and stirred at 25°C for 1 hour. 1000 g of hexane was then slowly added over a 3-hour period until all the product had recrystallized. The product was filtered and washed with ice-cold dichloromethane. Yield: 168.6 g (64.85%). High-performance liquid chromatography (HPLC) purity: 99.79%.

[0032] Example 2: Synthesis of 4,4'-dimethoxytriphenyl chloride using PEG-600

[0033] Place 225 g of PEG-600 and 150 g of trichlorotoluene in a 1-liter round-bottom flask and cool to 5-10°C. Then, slowly add 174.3 g of anisole dropwise at 5-10°C. Raise the temperature to 25°C and then further to 40°C. Maintain the reaction mixture at 40°C for 3 hours. Cool the reaction mixture to 25°C, add 1 L of water, and stir for 1 hour. Filter the solid and rinse thoroughly with water.

[0034] Recrystallization of crude product:

[0035] The crude product was dissolved in 500 g of dichloromethane and stirred at 25°C for 1 hour. 1000 g of hexane was then slowly added over a 3-hour period until all the product had recrystallized. The product was filtered and washed with ice-cold dichloromethane. Yield: 228.78 g (88%). HPLC purity: 99.86%.

[0036] Example 3: Synthesis of 4,4'-dimethoxytriphenyl chloride using PEG-1000

[0037] Place 225 g of PEG-1000 and 150 g of trichlorotoluene in a 1-liter round-bottom flask and cool to 5-10°C. Then, slowly add 174.3 g of anisole dropwise at 5-10°C. Raise the temperature to 25°C and then further to 40°C. Maintain the reaction mixture at 40°C for 3 hours. Cool the reaction mixture to 25°C, add 1 L of water, and stir for 1 hour. Filter the solid and rinse thoroughly with water.

[0038] Recrystallization of crude product:

[0039] The crude product was dissolved in 500 g of dichloromethane and stirred at 25°C for 1 hour. Then, 1000 g of hexane was slowly added over a 3-hour period until all the product had recrystallized. The product was filtered and washed with ice-cold dichloromethane. Yield: 112.5 g (43.27%). HPLC purity: 99.59%.

[0040] Example 4: Recycling of PEG-600:

[0041] To reuse PEG-600, water was distilled off under vacuum at 60°C, and then PEG-600 was washed with ether and dried at 60°C for 3 hours. The procedure in Example 2 was repeated using the recovered PEG-600. Product yield: 221.76 g (85.3%) HPLC purity: 99.81%.

[0042] PEG-600 was successfully reused five times with no significant difference in product yield and quality.

Claims

1. An environmentally friendly synthesis method of 4,4'-dimethoxytriphenylmethane, characterized in that: The synthetic route is as follows: The following steps are involved: Step 1: reacting anisole and trichlorotoluene in a polyethylene glycol solvent; Step 2: Recrystallize the crude product to obtain pure 4,4'-dimethoxytriphenyl chloride; The molecular weight of polyethylene glycol is 600.

2. The environmentally friendly synthesis method of 4,4'-dimethoxytriphenylmethane according to claim 1, characterized in that: Step 1 specifically includes: Polyethylene glycol and trichlorotoluene were added to a container and then cooled to 5-10°C. Anisole was slowly added dropwise at 5-10°C, and the temperature was raised to 25°C and then further raised to 40°C. The reaction mixture was maintained at 40°C for 3 hours. The reaction mixture was cooled to 25°C, water was added and stirred for 1 hour, and the solid was filtered and washed thoroughly with water.

3. The environmentally friendly synthesis method of 4,4'-dimethoxytriphenylmethane according to claim 1, characterized in that: Step 2 specifically includes: The crude product was dissolved in dichloromethane and stirred at 25°C for 1 hour, then hexane was slowly added and maintained for 3 hours until all the product was recrystallized. The product was filtered and washed with ice-cold dichloromethane and the product yield was tested.

4. The environmentally friendly synthesis method of 4,4'-dimethoxytriphenylmethane according to claim 1, characterized in that: After the reaction is finished, the polyethylene glycol, which acts as a catalyst, should be restored to its original state to be ready for another round of reaction.

5. The environmentally friendly synthesis method of 4,4'-dimethoxytriphenylmethane according to claim 4, characterized in that: The steps to restore polyethylene glycol to its original state include: The water was distilled off in vacuo at 60°C, and the polyethylene glycol was then washed with ether and dried at 60°C for 3 hours.

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