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Preparation method of azelaic acid

A technology of azelaic acid and alkyl malonate, applied in the field of medicinal compounds, can solve the problems of difficult separation of ring-closing impurities, affecting product purity and yield, etc., and achieves low impurity content, easy acquisition, and easy large-scale production. The effect of promotion

Pending Publication Date: 2022-05-13
武汉华尔生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But in medicine field, the method commonly used at present is exactly dibromohydrocarbon and malonic acid or derivative thereof in strong base (sodium ethylate or sodium tert-butoxide etc.), takes alcohols as the condition of solvent to take place substitution reaction, and then It is prepared by hydrolysis under alkaline conditions, and then decarboxylation. In this method, by-products (ring-closing products) are easily produced. This ring-closing impurity is very difficult to separate, which seriously affects the purity and yield of the product.

Method used

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  • Preparation method of azelaic acid
  • Preparation method of azelaic acid
  • Preparation method of azelaic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Add 19g (0.12mol) diethyl malonate, 22.2g (0.12mol) 1-bromo-5 chloropentane, 39.1g (0.12mol) cesium carbonate, 3.8g (0.012mol) tetrabutyl Ammonium bromide and 200ml dimethyl sulfoxide, control the temperature to 20°C, keep the temperature for 5h, after the gas chromatography detects that the reaction is complete, filter, add 200ml ethyl acetate to the filtrate for extraction, take the upper organic phase, add to the organic phase Dry over anhydrous sodium sulfate and filter. After drying the organic phase of the filtrate under reduced pressure, 29.6 g of a yellow oily substance (Compound I) was obtained, the purity of which was detected by gas chromatography was 98.3%, and the calculated yellow oily substance (Compound I) was 0.11 mol.

[0048] Mix 29.6g of yellow oil (compound I) with 17.9g (0.11mol) of diethyl malonate, 35.8g (0.11mol) of cesium carbonate, 3.6g (0.011mol) of tetrabutylammonium bromide, 18.3g (0.11mol) mol) potassium iodide and 200ml dimethyl sulfoxid...

Embodiment 2

[0052] Add 15.8g (0.12mol) dimethyl malonate, 44.4g (0.24mol) 1-bromo-5 chloropentane, 25.4g (0.24mol) sodium carbonate, 16.6g (0.06mol) tetrabutyl Hydroxyl ammonium chloride and 200ml toluene, control the temperature to 30°C, keep the temperature for 6h, after the gas chromatography detects that the reaction is complete, filter, add 200ml ethyl acetate to the filtrate for extraction, take the upper organic phase, add anhydrous sulfuric acid to the organic phase Dry over sodium and filter. After the filtrate dried the organic phase under reduced pressure, 26 g of a yellow oil was obtained, the purity of which was detected by gas chromatography was 98.4%, and the yellow oil was calculated to be 0.11 mol.

[0053] Mix 26g of yellow oil with 29g (0.22mol) of dimethyl malonate, 23.3g (0.22mol) of sodium carbonate, 15.3g (0.055mol) of tetrabutylammonium chloride, 33g (0.22mol) of sodium iodide and 200ml After mixing the toluene, control the temperature to 30°C, heat and stir the r...

Embodiment 3

[0057] Add 22.6g (0.12mol) dipropyl malonate, 22.2g (0.12mol) 1-bromo-5 chloropentane, 19.3g (0.14mol) potassium carbonate, 3.9g (0.012mol) tetrabutyl ammonium bromide and 200ml N,N-dimethylformamide, control the temperature to 30°C, and keep it warm for 5h. After the gas chromatography detects that the reaction is complete, filter it, add 200ml ethyl acetate to the filtrate for extraction, take the upper organic phase, and pour it into Anhydrous sodium sulfate was added to the organic phase, dried and filtered. After drying the organic phase of the filtrate under reduced pressure, 32.2 g of a yellow oily substance was obtained. The gas chromatography detection purity was 98.9%, and the yellow oily substance was calculated to be 0.11 mol.

[0058] Combine 32.2g of yellow oil with 20.7g (0.11mol) of dipropyl malonate, 19.7g (0.143mol) of potassium carbonate, 3.6g (0.011mol) of tetrabutylammonium bromide, 22.1g (0.165mol) of iodide After mixing lithium and 200ml N,N-dimethylfor...

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Abstract

The invention provides a preparation method of azelaic acid, which comprises the following steps: carrying out reaction on alkyl malonate, 1-bromo-5-chloropentane, alkali, a first catalyst and a first solvent to obtain a compound I, carrying out reaction on the compound I, alkyl malonate, alkali, a second catalyst, a third catalyst and a second solvent to obtain a compound II, reacting the compound II with strong base to obtain a compound III; reacting the compound III with water, inorganic salt and a fourth solvent to obtain azelaic acid through concentration and crystallization. The raw materials used in the method for preparing azelaic acid are easy to obtain, reaction conditions are mild, generated impurities are few, and the method has good application prospects.

Description

technical field [0001] The invention relates to the technical field of medical compounds, in particular to a preparation method of azelaic acid. Background technique [0002] Azelaic acid is a saturated aliphatic dicarboxylic acid with the molecular formula HOOC-(CH)9-COOH. It is also known as 1,9-azelaic acid and is an important chemical raw material. Meanwhile, azelaic acid is also a component of hair and skin care products. For example, azelaic acid cream (20%, Allergan Inc) is very effective in the treatment of acne. In industry, azelaic acid is usually prepared from unsaturated fatty acids, such as oleic acid, linoleic acid, castor oil, etc., and obtained by oxidative cleavage with ozone, potassium permanganate, hydrogen peroxide, etc. But in medicine field, the method commonly used at present is exactly dibromohydrocarbon and malonic acid or derivative thereof in strong base (sodium ethylate or sodium tert-butoxide etc.), takes alcohols as the condition of solvent t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/38C07C55/18C07C51/09C07C55/24C07C67/343C07C69/63C07C69/34
CPCC07C51/38C07C51/09C07C67/343C07C69/63C07C69/34C07C55/24C07C55/18
Inventor 张宇鹏余熙文程冲
Owner 武汉华尔生物科技有限公司