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Method for mass preparation of formamide phenol compound

A large-scale preparation technology of retinoic acid, applied in the direction of organic chemistry, etc., can solve the problems of increasing the protection and deprotection process, high requirements for reaction equipment, cumbersome routes, etc., and achieve cheap reaction reagents and short reaction steps , good effect of reaction selectivity

Inactive Publication Date: 2008-03-12
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The feature of this method is that the pure target product can be obtained through recrystallization, and the yield is high, and it can be produced on a large scale; The reaction is a high-temperature reaction, which requires high reaction equipment and increases the cost

Method used

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  • Method for mass preparation of formamide phenol compound
  • Method for mass preparation of formamide phenol compound
  • Method for mass preparation of formamide phenol compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 47.3ml of thionyl chloride (SOCl 2 , 0.666mol) and 51.3ml of anhydrous N,N-dimethylformamide (DMF, 0.666mol), stirred under nitrogen protection for 1h. Add 500 ml of anhydrous DMF containing 100 g of all-trans retinoic acid (0.333 mol) and react for 3 h at 0° C. in the dark to obtain a red acid chloride solution. Then add 92.3ml triethylamine (Et 3 N, 0.666mol), and continued to react for 1 h to obtain a deep red acyl ammonium salt solution.

[0030] Add 108.0g p-aminophenol (0.99mol) in 2 liters of three-necked flask equipped with thermometer, dropping funnel and drying tube, dissolve with 500ml anhydrous DMF, then add dropwise the above-mentioned acid chloride solution, the temperature is controlled at Below 20°C, after the dropwise addition, continue to stir until the reaction is complete as monitored by thin layer chromatography (TLC). Pour the reaction solution into 5 L of NH 4 Cl saturated aqueous solution, extracted with ethyl acetate, and then the organi...

Embodiment 2

[0034] Add 61.2ml of phosphorus oxychloride (POCl 3 , 0.666mol) and 51.3ml DMF (0.666mol), stirred under nitrogen protection for 1h. Add 500 ml of anhydrous DMF containing 100 g of all-trans retinoic acid (0.333 mol) and react for 3 h at 0° C. in the dark to obtain a red acid chloride solution. Then add 92.3ml Et 3 N (, 0.666mol), the reaction was continued for 1h to obtain a deep red acyl ammonium salt solution.

[0035] Add 108.0g p-aminophenol (0.99mol) in 2 liters of three-necked flask equipped with thermometer, dropping funnel and drying tube, dissolve with 500ml anhydrous DMF, then add dropwise the above-mentioned acid chloride solution, the temperature is controlled at Below 20°C, after the dropwise addition, continue to stir until the reaction is complete as monitored by TLC. Pour the reaction solution into 5 L of NH 4 Cl saturated aqueous solution, extracted with ethyl acetate, and then the organic layer was washed with water, saturated brine, Na 2 SO 4 Dry over...

Embodiment 3

[0037] Add 47.3ml SOCl to a 1-liter eggplant-shaped bottle 2 (0.666mol) and 51.3ml DMF (0.666mol), stirred under nitrogen protection for 1h. Add 500 ml of anhydrous DMF containing 100 g of all-trans retinoic acid (0.333 mol) and react for 3 h at 0° C. in the dark to obtain a red acid chloride solution. Then 53.8 ml of pyridine (Py, 0.666 mol) was added, and the reaction was continued for 1 h to obtain a deep red acyl ammonium salt solution.

[0038]Add 108.0g p-aminophenol (0.99mol) in 2 liters of three-necked flask equipped with thermometer, dropping funnel and drying tube, dissolve with 500ml anhydrous DMF, then add dropwise the above-mentioned acid chloride solution, the temperature is controlled at Below 20°C, after the dropwise addition, continue to stir until the reaction is complete as monitored by TLC. Pour the reaction solution into 5 L of NH 4 Cl saturated aqueous solution, extracted with ethyl acetate, and then the organic layer was washed with water, saturated b...

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Abstract

A method of the large-scale preparation of the dimensional formyl phenol amine compound provides a method of the large-scale preparation of the dimensional formyl phenol amine compound; the method is simple, low in cost, high in collection rate, and simple in the post processing. In the method, the wholly inversed dimensional formic acid is used as the starting material to react with the chlorination agent to produce the acyl chloride; then the acyl chloride reacts with the organic alkali to form the salt; the acyl ammonium salt and the substituted amino phenol do the amidation reaction to produce the dimensional formyl phenol amine compound. The substituted amino phenol is the compound as shown in the formula (I), wherein R is H, NO2, CO2R1, OR1, NHCOR1, SO2R1; R1 is the alkyl of C1 to C4. The chlorination agent is the dichloro sulfoxide, phosphorus trichloride, phosphorus oxychloride and so on; the organic alkali is the triethylamine, pyridine and the derivative, and so on. The molar ration between the used chlorination agent and the wholly inversed dimensional formic acid is 1.0 to 5.0; the molar ration between the used substituted amino phenol and the wholly inversed dimensional formic acid is 1.0 to 10.0.

Description

technical field [0001] The invention relates to a method for large-scale preparation of retinoid amine compounds, and belongs to the technical field of synthesis of amide compounds in organic chemistry. Background technique [0002] Fenretinide, also known as fenretinide, is a synthetic all-trans retinoic acid derivative, which was first developed by Johnson & Johnson for the prevention and treatment of breast cancer. Studies have shown that retinoylamine can also induce apoptosis in various tumor cells such as neuroblastoma, malignant liver cancer, prostate cancer, ovarian cancer, and cervical cancer; Amines have the characteristics of low toxicity and low adverse reactions, and have gradually become one of the best substitutes for retinoic acid drugs. In addition to its anti-tumor efficacy, Italy's Sirion company also uses it for ophthalmic diseases such as age-related macular degeneration, recessive (hereditary) macular dystrophy, etc., and is currently in phase II clini...

Claims

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Application Information

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IPC IPC(8): C07C403/20
Inventor 吉民吴晓晴余佳
Owner SOUTHEAST UNIV
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