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Preparation method of 10-oxononadecanedioic acid

A technology of oxononadecane and diacid, which is applied in the field of preparation of 10-oxononadecanedioic acid, can solve the problems of difficult control of the reaction process, harsh reaction conditions and high equipment requirements, and achieves easy operation and control, The effect of mild reaction conditions and great economic potential

Pending Publication Date: 2022-07-29
SHENZHEN SHENXIN BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But find in practical application, this method has following shortcoming: the first, the price of 8-bromooctanoic acid ethyl ester is expensive, and every molecule product needs two molecule 8-bromooctanoic acid ethyl esters at least, and production cost is high; : There are many side reactions, and 1,3 diethyl acetone dicarboxylate and intermediates can undergo enol interconversion, which makes it difficult to control and monitor the reaction, and the reaction process is difficult to control; in addition, in the hydrolysis decarboxylation step, two carboxyl groups need to be removed at the same time , complex reaction, many side reactions, low product purity, therefore, this method is not an ideal preparation method
However, in this method, monomethyl sebacic acid is chlorinated first, and then reacted with aqueous dimethylamine to obtain monomethyl sebacate amide, which has many side reactions and takes a long time to purify; and the subsequent steps use sodium metal to be dissolved in methanol to newly prepare Sodium methylate is used as alkali, and heating under vacuum condition carries out Claisen condensation of sebacic acid monomethyl ester amide itself, and reaction condition is harsh, and safety is poor, and reaction time is long, and equipment requirement is high, is unfavorable for industrial production, therefore, this method is not an ideal method of preparation

Method used

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  • Preparation method of 10-oxononadecanedioic acid
  • Preparation method of 10-oxononadecanedioic acid
  • Preparation method of 10-oxononadecanedioic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Dimethyl sebacate (compound (III)) (1.0 equiv, 170 g, 738.2 mmol) was weighed in a 2000 mL round-bottom flask, dissolved in N,N-dimethylformamide (850 mL, 5 times the volume), cooled To -10°C, potassium hydroxide powder (1.1 equiv) was added and the reaction was allowed to proceed overnight at -10°C, the solution gradually turned from clear to white cloudy. After the reaction is completed, add 2 L of water to dilute, extract three times with 500 mL of ethyl acetate, and recover the unconverted raw material dimethyl sebacate. The aqueous phase was adjusted to pH=3 with dilute hydrochloric acid, extracted three times with 500 mL of ethyl acetate, and the solvent was removed by rotary evaporation to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5, V / V) to obtain Monomethyl sebacate (compound (IV)) 121 g, yield 76%, white solid, purity detected by HPLC normalization method was 99%.

[0095] LC-MS (ESI): Calculated ...

Embodiment 2

[0099]In a 500 mL round-bottomed flask were weighed monomethyl sebacate (compound (IV)) (1.0 equiv, 5.1 g, 23.57 mmol), dimethylamine hydrochloride (1.3 equiv, 2.5 g, 30.64 mmol), EDCI (1.5 equiv. , 6.78 g, 35.36 mmol), DMAP (0.1 equiv, 288 mg, 2.36 mmol), dissolved in 50 mL of dichloromethane, finally added pyridine (2.8 equiv, 5.22 g, 66 mmol), and stirred at room temperature overnight. After the reaction, 50 mL of water was added to dilute, adjusted to pH=3 with dilute hydrochloric acid, the organic phase was separated, the aqueous phase was extracted twice with 70 mL of dichloromethane, the organic phases were combined, washed with water, washed with saturated sodium chloride solution, and washed with anhydrous sulfuric acid. It was dried over sodium and concentrated to obtain 4.8 g of methyl 10-(dimethylamino)-10-oxodecanoate (compound (V)), with a yield of 84%, as a brownish yellow oil, which was directly used in the next step without further purification. step.

[0100...

Embodiment 3

[0104] In a 250mL three-necked flask equipped with two 100mL constant pressure dropping funnels and three-way nitrogen balloons, weigh 10-(dimethylamino)-10-oxodecanoic acid methyl ester (compound (V)) (1.0 equiv., 10 g, 41.09 mmol), dissolved in 50 mL of dichloromethane, replaced with nitrogen protection, cooled the device to 0 °C, weighed titanium tetrachloride (1.2 equiv, 9.35 g, 49.31 mmol) and injected it into a constant pressure dropping funnel with a syringe It was added dropwise to the reaction solution, and the solution was kept for 5 minutes after the dropwise addition was completed. At this time, the solution was orange. Then, triethylamine (1.4 equivalents, 5.82 g, 57.53 mmol) was weighed and injected into a constant pressure dropping funnel with a syringe for dropwise addition. In the reaction solution, the reaction solution turned black and white smoke was generated. After the dropwise addition was completed, the reaction was kept at a temperature for 1 hour. Aft...

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Abstract

The invention relates to a preparation method of 10-oxononadecanedioic acid. Compared with a corresponding synthesis method in the prior art, the preparation method disclosed by the invention is high in conversion rate, few in side reaction, simple in process, easy to control, high in safety, low in equipment requirement and suitable for industrial application, and has huge economic potential.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and in particular relates to a preparation method of 10-oxononadecanedioic acid. Background technique [0002] Gene medicine is to deliver genes with specific genetic information to target cells by artificial means. The expressed target protein has the effect of regulating, treating or even curing diseases caused by congenital or acquired gene defects, or gene series can interfere or regulate related genes. expression to achieve clinical therapeutic effect. [0003] WO2013086322A1 discloses a low toxicity cationic lipid compound (compound I) suitable for gene delivery into cells, which is widely used in gene delivery, and its structural formula is shown in formula (I): [0004] [0005] In the prior art, WO2013086322A1 reported the preparation method of compound (I), the method uses 10-oxonadecanedioic acid (10-Oxononadecanedioic Acid in English) represented by the structural formula (II) as...

Claims

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Application Information

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IPC IPC(8): C07C51/06C07C59/347
CPCC07C51/06C07C67/313C07C231/02C07C231/12C07C59/347C07C69/50C07C233/05C07C235/74
Inventor 陈永好张再伟陈明洪
Owner SHENZHEN SHENXIN BIOTECHNOLOGY CO LTD
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