Process for the preparation of the starting material for the synthesis of the antioxidants 1010, 1076, 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester

Abstract

This invention relates to a method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, a raw material for synthesizing antioxidants 1010 and 1076. Specifically, this invention uses 2,6-di-tert-butylphenol and methyl 3-bromopropionate as reactants, adds an organic solvent, and reacts them in a reaction system under light and in the presence of a palladium catalyst to obtain methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate; furthermore, the reaction system also includes an alkaline additive. This invention provides a novel method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. By activating the C-H bond at the 4-position of the benzene ring of 2,6-di-tert-butylphenol, a methyl propionate group is directly attached to the 4-position of the benzene ring. Compared to existing technologies, this method does not require strong bases or highly toxic reagents and has a lower reaction temperature. This method has the potential to be an alternative to existing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate preparation processes and a new route for obtaining synthetic raw materials for antioxidants 1010 and 1076.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to the preparation method of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, a raw material for the synthesis of antioxidants 1010 and 1076. Background Technology

[0002] Antioxidants 1010 and 1076 are both hindered phenolic antioxidants, possessing excellent heat resistance and water extraction resistance. They are widely used in polyethylene, polypropylene, polyoxymethylene, ABS resin, P resin, PVC, engineering plastics, polystyrene, polyvinyl chloride, rubber, and petroleum products, exhibiting outstanding antioxidant properties that can effectively extend the service life of products.

[0003]

[0004] Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate is a key raw material for the synthesis of the above-mentioned hindered phenolic antioxidants 1010 and 1076. Antioxidant 1010 is prepared by transesterification of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and pentaerythritol, while antioxidant 1076 is prepared by transesterification of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and n-octadecyl alcohol.

[0005] The existing methods for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate mainly involve reacting 2,6-di-tert-butylphenol with a strong base, followed by the addition of methyl acrylate. For example, patent CN108358781A discloses the preparation of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate by reacting a mixture of zinc carbonate and tributyltin acetate with 2,6-di-tert-butylphenol, followed by the dropwise addition of methyl acrylate. Patent CN114456072A, in addition to using a strong base such as potassium tert-butoxide, also adds an auxiliary agent to modify the metal oxide to reduce side reactions.

[0006]

[0007] The existing preparation of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate requires the use of highly toxic or basic reagents at high temperatures, which is highly corrosive to equipment and raises concerns about operator safety. Furthermore, current techniques for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate are largely fixed in terms of the reaction substrates and reaction types, resulting in a lack of alternative methods.

[0008] The direct introduction of alkyl groups through transition metal-catalyzed activation of the CH bonds in aromatic rings to form C-C bonds has become a research hotspot in recent years. This type of reaction can be carried out under relatively mild conditions and exhibits good site and stereoselectivity through condition optimization. However, the structural types of substrates used in this type of reaction are currently limited, resulting in poor universality. Introducing groups onto the benzene ring often requires the presence of activating and directing groups on the benzene ring. No such reactions have been reported in the synthesis of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. Summary of the Invention

[0009] The technical problem to be solved by the present invention is that the existing technology for preparing antioxidants 1010 and 1076 has problems such as the single reaction type of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, which has strong toxicity or alkalinity of the reagents used, corrosiveness of equipment, high reaction temperature, and low safety. Therefore, a new method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate is provided.

[0010] Specifically, the present invention uses 2,6-di-tert-butylphenol and methyl 3-bromopropionate as reaction raw materials, adds an organic solvent, and reacts in a reaction system under light and in the presence of a palladium catalyst to obtain methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate.

[0011]

[0012] Furthermore, the reaction system also includes alkaline additives.

[0013] Furthermore, the reaction solvent is a non-benzene organic solvent, selected from one or more of DMF, DMA, tetrahydrofuran, tetrachloromethane, chloroform, dichloromethane, DMSO, acetone, and diethyl ether, with DMF being preferred.

[0014] Furthermore, the illumination conditions are provided by using a 30-80W LED blue light lamp, preferably a 60W LED blue light lamp.

[0015] Furthermore, the palladium catalyst is selected from one or more of Pd(OAc)2, PdCl2, Pd(TFA)2, Pd(PPh3)4, and Pd(PPh3)2Cl2, with Pd(OAc)2 being preferred.

[0016] Furthermore, the molar amount of the palladium catalyst is 3-20% relative to the reaction substrate 2,6-di-tert-butylphenol, preferably 10%.

[0017] Furthermore, the alkaline additive is selected from one or more of K2CO3, KHCO3, KOAc, KOH, Na2CO3, NaHCO3, NaOAc, and NaOH, preferably K2CO3.

[0018] Furthermore, the molar amount of the alkaline additive is 2-4 equivalents relative to the reaction substrate 2,6-di-tert-butylphenol, preferably 3 equivalents.

[0019] Furthermore, the reaction is carried out under the protection of an inert gas, such as nitrogen or argon.

[0020] Furthermore, the reaction is carried out at 40-100°C, preferably 60°C; the reaction time is 48-96 hours, preferably 72 hours.

[0021] This invention provides a novel method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, which differs from existing technologies in both its reaction substrate and reaction type. Instead of reacting methyl acrylate with 2,6-di-tert-butylphenol, it uses methyl 3-bromopropionate with 2,6-di-tert-butylphenol under mild conditions of light and palladium catalysis. The methyl propionate group is directly attached to the 4-position of the benzene ring of 2,6-di-tert-butylphenol by activating the CH bond at the 4-position. Compared to existing technologies, this invention eliminates the need for strong bases and highly toxic reagents, and operates at a lower reaction temperature. This method has the potential to serve as an alternative to existing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate preparation processes and as a new route for obtaining synthetic raw materials for antioxidants 1010 and 1076. Implementation

[0022] The present invention will be described in more detail below with reference to specific embodiments.

[0023] Example 1: Screening of Reaction Conditions

[0024] 206.3 mg (1 mmol) of 2,6-di-tert-butylphenol and 183.7 mg (1.1 mmol) of methyl 3-bromopropionate were added to a glass-sealed tube, along with a catalyst, a basic additive, and finally 20 mL of reaction solvent and a magnetic stir bar. After argon protection, the glass tube was quickly sealed and the mixture was directly irradiated with a 40W LED blue light while stirring in an oil bath. Specific reaction conditions for each parallel experiment are shown in Table 1 below. After the reaction, a suitable amount of dilute hydrochloric acid solution was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The ethyl acetate fraction was concentrated under reduced pressure and separated by silica gel column chromatography to obtain the target product, methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. The yield of the target product was calculated.

[0025] Table 1 Screening of Reaction Conditions

[0026] catalyst Alkali additive (3eq) solvent Reaction temperature and time Yield <![CDATA[10% Pd(PPh3)4]]> <![CDATA[K2CO3]]> DMF 60℃，72h 62% <![CDATA[10%PdCl2]]> <![CDATA[K2CO3]]> DMF 60℃，72h 39% <![CDATA[10%Pd(TFA)2]]> <![CDATA[K2CO3]]> DMF 60℃，72h 43% <![CDATA[10% Pd(OAc)2]]> <![CDATA[K2CO3]]> DMF 60℃，72h 86% <![CDATA[10%Pd(PPh3)2Cl2]]> <![CDATA[K2CO3]]> DMF 60℃，72h 51% <![CDATA[5%Pd(OAc)2]]> <![CDATA[K2CO3]]> DMF 60℃，72h 75% <![CDATA[10%Pd(OAc)2]]> <![CDATA[2eq K2CO3]]> DMF 60℃，72h 67% <![CDATA[10%Pd(OAc)2]]> KOAc DMF 60℃，72h 26% <![CDATA[10%Pd(OAc)2]]> KOH DMF 60℃，72h 17% <![CDATA[10%Pd(OAc)2]]> <![CDATA[KHCO3]]> DMF 60℃，72h 59% <![CDATA[10%Pd(OAc)2]]> <![CDATA[Na2CO3]]> DMF 60℃，72h 72% <![CDATA[10%Pd(OAc)2]]> <![CDATA[K2CO3]]> DMA 60℃，72h 69% <![CDATA[10%Pd(OAc)2]]> <![CDATA[K2CO3]]> THF 60℃，72h 43% <![CDATA[10%Pd(OAc)2]]> <![CDATA[K2CO3]]> <![CDATA[CHCl3]]> 60℃，72h 32% <![CDATA[10%Pd(OAc)2]]> <![CDATA[K2CO3]]> DMSO 60℃，72h 42% <![CDATA[10%Pd(OAc)2]]> <![CDATA[K2CO3]]> acetone 60℃，72h Trace <![CDATA[10%Pd(OAc)2]]> <![CDATA[K2CO3]]> DMF 100℃，72h 71% <![CDATA[10%Pd(OAc)2]]> <![CDATA[K2CO3]]> DMF 100℃，48h 75% <![CDATA[10%Pd(OAc)2]]> None DMF 100℃，48h NR None <![CDATA[K2CO3]]> DMF 100℃，48h NR <![CDATA[10% Pd(OAc)2 without light illumination]]> <![CDATA[K2CO3]]> DMF 100℃，48h Trace

[0027] In this embodiment, methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate was prepared using 2,6-di-tert-butylphenol and methyl 3-bromopropionate as reaction substrates. The column chromatography separation yield of the target product was used as the evaluation index to screen reaction conditions and determine the preferred catalyst and its dosage, basic additives, reaction solvent, reaction temperature and time, and other condition parameters.

[0028] Example 2: Verification of the repeatability of reaction conditions

[0029] To verify the repeatability and stability of the reaction conditions, six parallel reactions were performed under the highest yield conditions selected in the examples: 206.3 mg (1 mmol) of 2,6-di-tert-butylphenol and 183.7 mg (1.1 mmol) of methyl 3-bromopropionate were added to a glass-sealed tube, followed by 10% Pd(OAc)2 and 3 eq K2CO3. Finally, 20 mL of DMF and a magnetic stir bar were added. After argon protection, the glass-sealed tube was quickly tightened, and the reaction was directly irradiated with a 40W LED blue light. The reaction was stirred in a 60℃ oil bath for 72 h. After the reaction was completed, an appropriate amount of dilute hydrochloric acid solution was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The ethyl acetate fraction was concentrated under reduced pressure and separated by silica gel column chromatography to obtain the target product methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. The yield of the target product was calculated, and the results are shown in Table 2.

[0030] Table 2 Results of repeatability stability verification of reaction conditions

[0031] Parallel reaction 1 Parallel reaction 1 Parallel reaction 1 Parallel reaction 1 Parallel reaction 1 Parallel reaction 1 Yield 83% 88% 81% 83% 86% 85%

[0032] The results in Table 2 show that the optimal results of the reaction methodology obtained by this invention have high repeatability and stability, and have the potential to be applied in actual production.

[0033] While the above description has outlined several specific forms of the present invention, it is clear that various modifications and combinations made to the present invention without departing from its principles and scope should also fall within the scope of the present invention.

Claims

1. A method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, a raw material for the synthesis of antioxidants 1010 and 1076, characterized in that, Using 2,6-di-tert-butylphenol and methyl 3-bromopropionate as reactants, an organic solvent was added, and the reaction was carried out in a reaction system under light, with a palladium catalyst and an alkaline additive to obtain methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. The reaction solvent is selected from one of DMF, DMA, tetrahydrofuran, chloroform, and DMSO; the illumination condition is irradiation with a 30-80W LED blue light lamp; The palladium catalyst is selected from one of Pd(OAc)2, PdCl2, Pd(TFA)2, Pd(PPh3)4, and Pd(PPh3)2Cl2, and the molar amount of the catalyst is 3-20% relative to the reaction substrate 2,6-di-tert-butylphenol; The alkaline additive is selected from one of K2CO3, KHCO3, and Na2CO3, and the molar amount of the alkaline additive is 2-4 equivalents relative to the reaction substrate 2,6-di-tert-butylphenol.

2. The method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, the synthetic raw material for antioxidants 1010 and 1076 as described in claim 1, is characterized in that... The reaction solvent is DMF.

3. The method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, the synthetic raw material for antioxidants 1010 and 1076 as described in claim 1, is characterized in that... The lighting conditions described are achieved by using a 60W LED blue light lamp.

4. The method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, the synthetic raw material for antioxidants 1010 and 1076 as described in claim 1, is characterized in that... The palladium catalyst is selected from Pd(OAc)2, and the molar amount of the catalyst is 10% relative to the reaction substrate 2,6-di-tert-butylphenol.

5. The method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, the synthetic raw material for antioxidants 1010 and 1076 as described in claim 1, is characterized in that... The alkaline additive is K2CO3, and the molar amount of the alkaline additive is 3 equivalents relative to the reaction substrate 2,6-di-tert-butylphenol.

6. The method for preparing methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, a raw material for synthesizing antioxidants 1010 and 1076 as described in any one of claims 1-5, is characterized in that... The reaction was carried out at 40-100°C for 48-96 hours.

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