Method for preparing methylenequinone compounds by deamination of Mannich base

Abstract

The present invention relates to a method for preparing methylenequinone compounds by deamination of Mannich bases. This method involves reacting an amino acid with a Mannich base, and the organic amine on the Mannich base forms a water-soluble amide compound with the amino acid. After the reaction, it is separated from the product by washing with water. The method of the present invention avoids the problems of environmental pollution and high energy consumption caused by the traditional use of inorganic acids or acid anhydrides and distillation methods for deamination, has high reaction efficiency, is green and environmentally friendly, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and relates to a method for deamination, which is particularly suitable for the process of preparing methylenequinone compounds from Mannich bases. Background Art

[0002] Methylenequinone compounds are important intermediates in organic synthesis and can be used in the synthesis of biologically active compounds such as natural melanin, lignin, anticancer drugs, and antibacterial drugs. Methylenequinone compounds can be divided into ortho-methylenequinone and para-methylenequinone. Compared with ortho-methylenequinone, para-methylenequinone compounds are relatively stable. Among them, 2,6-di-tert-butyl-7-substituted methylenequinone compounds can be used as intermediates for a variety of organic compounds and biologically active compounds, and can also be used as inhibitors of unsaturated hydrocarbons.

[0003] Currently reported synthesis methods for 2,6-di-tert-butyl-7-substituted methylenequinone compounds mainly include three categories. Among them, the methylene oxidation method uses a highly toxic solvent benzene and an oxidant potassium ferricyanide. The phenyl lithium method or the Grignard reagent method requires the use of expensive phenyl lithium or Grignard reagent, and the reaction needs to be carried out under anhydrous and anaerobic conditions. These two methods are not suitable for large-scale industrial production. The Mannich method has cheap and easily available raw materials, low requirements for equipment and operation, and is an ideal synthesis method.

[0004] The Mannich method uses 2,6-di-tert-butylphenol, benzaldehyde, and secondary amine as raw materials, first generates Mannich base, and then deaminates to obtain the product. EP0744392A1 and CN109354571 reported the use of hydrochloric acid and sulfuric acid for deamination to generate amine hydrochloride and sulfate. This method has problems such as difficult control of the acid addition amount, easy corrosion of equipment, and violent reaction with high danger. EP0744392A1 also reported a method using acid anhydride for deamination, but the amide generated by the reaction is difficult to completely distill and separate from the system, affecting the product purity. Wang reported a method of vacuum distillation for deamination, but this method has high requirements for equipment and high reaction energy consumption. Summary of the Invention

[0005] The purpose of the present invention is to solve the problems of low efficiency and high danger in the existing deamination reaction of Mannich base, and provide a method for preparing methylenequinone compounds by deamination of Mannich base with high efficiency, low toxicity, easy separation of products, and suitable for industrial production.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] A method for preparing methylenequinone compounds by deamination of Mannich base, the method comprising:

[0008] React amino acids, Mannich bases, and solvents at a reaction temperature of 70-110 °C. After the reaction is completed, wash the reaction system with water to obtain an organic phase, and then obtain the product through crystallization;

[0009] Among them, the Mannich base compound has the following structural formula:

[0010]

[0011] In the formula: R1 is one of methyl, ethyl, isopropyl, tert-butyl, phenyl, hydroxyl, nitrile, methoxy, ethoxy, isopropoxy, butoxy, phenoxy, carboxyl, nitro, halogen, acetyl; R2 is one of methyl, hydroxyl, nitrile, methoxy, halogen; R3 is one of hydroxyl, nitrile, methoxy, nitro, halogen; In the nitrogen-containing six-membered ring, the X element is one of carbon, oxygen, and nitrogen.

[0012] In the above method of the present invention, preferably, the molar ratio of the amino acid to the Mannich base is 1.8-1.1:1, and more preferably the molar ratio is 1.5-1.2:1.

[0013] In the above method of the present invention, the reaction temperature is preferably 80-90 °C; the reaction time is preferably 1.5-3.5 h, and more preferably 2-3 h.

[0014] The amino acid compound is one of lysine, serine, glycine, glutamic acid, and alanine.

[0015] The method of the present invention uses amino acids to react with Mannich bases to deaminate. The carboxyl group on the amino acid reacts with the amine to form an amide. Since the amino acid has a hydrophilic group, the generated amide can be easily separated from the reaction system by washing with water. The reaction conditions are mild, the selectivity is good, and at the same time, the by-product amide can also be recycled as an organic synthesis intermediate, having good industrial prospects. Specific Embodiments

[0016] To better understand the present invention, the content of the present invention will be further clarified below in conjunction with examples, but the content of the present invention is not limited to the following examples.

[0017] Example 1

[0018] Add 0.394 g (1 mmol) of 2,6 - di - tert - butyl - 4 - [(4 - methylphenyl)-1 - piperidinylmethyl]phenol and 50 ml of toluene into a three - necked flask, stir and heat to 80 °C, add 20 ml of an aqueous solution containing 0.09 g (1.2 mmol) of glycine, after stirring for 2 hours, stop the reaction, separate the aqueous phase, wash the organic phase three times with 100 ml of water, remove toluene, and crystallize with ethanol to obtain 0.286 g of the product 4 - p - tolylmethylene - 2,6 - di - tert - butyl - 2,5 - cyclohexadiene - 1 - one, with a yield of 93%.

[0019] Example 2

[0020] Add 0.396 g (1 mmol) of 2,6 - di - tert - butyl - 4 - [(2 - hydroxyphenyl)-1 - piperidinylmethyl]phenol and 50 ml of toluene into a three - necked flask, stir and heat to 85 °C, add 20 ml of an aqueous solution containing 0.116 g (1.3 mmol) of alanine, after stirring for 2 hours, stop the reaction, separate the aqueous phase, wash the organic phase three times with 100 ml of water, remove toluene, and crystallize with ethanol to obtain 0.295 g of the product 4 - o - hydroxyphenylmethylene - 2,6 - di - tert - butyl - 2,5 - cyclohexadiene - 1 - one, with a yield of 95%.

[0021] Example 3

[0022] Add 0.425 g (1 mmol) of 2,6 - di - tert - butyl - 4 - [(3 - nitrophenyl)-1 - piperidinylmethyl]phenol and 50 ml of toluene into a three - necked flask, stir and heat to 90 °C, add 20 ml of an aqueous solution containing 0.206 g (1.4 mmol) of glutamic acid, after stirring for 2 hours, stop the reaction, separate the aqueous phase, wash the organic phase three times with 100 ml of water, remove toluene, and crystallize with ethanol to obtain 0.316 g of the product 4 - m - nitrophenylmethylene - 2,6 - di - tert - butyl - 2,5 - cyclohexadiene - 1 - one, with a yield of 93%.

[0023] Comparative Example 1

[0024] Add 0.394 g (1 mmol) of 2,6 - di - tert - butyl - 4 - [(4 - methylphenyl)-1 - piperidinylmethyl]phenol and 50 ml of toluene into a three - necked flask, stir and heat to 80 °C, continuously introduce HCl gas into the system, after stirring for 5 hours, stop the reaction, wash the organic phase three times with 100 ml of water, remove toluene, and crystallize with ethanol to obtain 0.268 g of the product 4 - p - tolylmethylene - 2,6 - di - tert - butyl - 2,5 - cyclohexadiene - 1 - one, with a yield of 87%.

[0025] Comparative Example 2

[0026] 0.394 g (1 mmol) of 2,6-di-tert-butyl-4-[(4-methylphenyl)-1-piperidinylmethyl]phenol was added to a three-necked flask, and vacuum distillation was carried out at a vacuum of 1000 Pa and 200 °C. After 6 hours, the reaction was stopped, and the residue was crystallized with ethanol to obtain 0.246 g of the product 4-p-methylbenzylidene-2,6-di-tert-butyl-2,5-cyclohexadien-1-one, with a yield of 80%.

Claims

1. A method for preparing methylenequinone compounds by deamination of Mannich bases, characterized in that, Comprising: React amino acid, Mannich base, and solvent at a reaction temperature of 80 - 90 °C for 1.5 - 3.5 h. After the reaction is completed, wash the reaction system with water to obtain an organic phase, and then obtain the product through crystallization. Among them, the Mannich base compound has the following structural formula: or or ; In the formula: R1 is one of methyl, ethyl, isopropyl, tert-butyl, phenyl, hydroxyl, nitrile, methoxy, ethoxy, isopropoxy, butoxy, phenoxy, carboxyl, nitro, halogen, acetyl; R2 is one of methyl, hydroxyl, nitrile, methoxy, halogen; R3 is one of hydroxyl, nitrile, methoxy, nitro, halogen; in the nitrogen-containing six-membered ring, the X element is carbon. The molar ratio of the amino acid to the Mannich base is 1.1 - 1.8:1, and the amino acid is one of aqueous glycine solution, aqueous glutamic acid solution, and aqueous alanine solution.

2. The method according to claim 1, characterized in that The molar ratio of the amino acid to the Mannich base is 1.2 - 1.5:1.

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