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Method for preparing 1,2,3,4-tetrahydro-1-naphthoic acid by using superstrong alkali method

A super base and naphthoic acid technology, which is applied in the preparation of carboxylate, carboxylate, and carbon-based compounds, etc., can solve the problems of long route, non-reaction, and low yield, and achieve high operability, Convenient for industrialization and good repeatability

Active Publication Date: 2020-04-17
安庆博曼生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Method 1, although the starting materials are cheap, but the steps are long, the equipment used in thionyl chloride is highly corrosive, and the most fatal is the use of cyano groups on sodium cyanide. Sodium cyanide is highly toxic, and its use is strictly restricted. Although we I also tried other cyanation methods, either the yield was low, or there was no reaction, and the steps were long and the yield was low. This route does not have industrial value
[0012] Method 2, raw materials are cheap and easy to obtain, but using high-pressure hydrogenation, Raney nickel has a huge safety risk. We found in the actual preparation process that the product contains the following impurities: , , etc. These impurities are similar in nature and difficult to separate, so this route has no industrial value
[0013] Method 3, the route is long, the raw materials are expensive, the witting reaction yield is only 50%, the hydrolysis reaction yield is 20%, the oxidation reaction is 60%, the total yield is 6%, the cost is not advantageous, and the witting reaction produces a lot of worthless Pollutants, three wastes treatment costs are high

Method used

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  • Method for preparing 1,2,3,4-tetrahydro-1-naphthoic acid by using superstrong alkali method
  • Method for preparing 1,2,3,4-tetrahydro-1-naphthoic acid by using superstrong alkali method
  • Method for preparing 1,2,3,4-tetrahydro-1-naphthoic acid by using superstrong alkali method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] In a 1000ML three-neck flask, equipped with a thermometer and a nitrogen-protected mouthpiece, put 19.8g of tetrahydronaphthalene under nitrogen protection, add 200ml of n-hexane, add 59.6g of potassium tert-butoxide, control the temperature at 0°C, and add dropwise 2.5M n-butyllithium 72ml, release heat, control the temperature below 10°C, after dripping, react at 10-20°C for 1 hour, set aside.

[0058] The temperature of the system was lowered to -70°C, and dry carbon dioxide was introduced for 30 minutes. The system released heat, and the temperature was raised to -30°C. The temperature was controlled at -30 to -70°C, and the reaction was carried out for 1 hour. Followed by HPLC, until the residual material remained below 10%.

[0059] Cool down to -70°C, extract the reaction solution with 25% dilute sulfuric acid until the pH is less than 1, raise it to room temperature, stir for 30 minutes, and the extraction is complete.

[0060] Then use 50% liquid caustic soda t...

Embodiment 2

[0062] In a 500ML three-necked flask, equipped with a thermometer and a nitrogen protection mouthpiece, put 19.8g tetralin under nitrogen protection, add 200ml n-hexane, add 59.6g potassium tert-butoxide, control the temperature at 0°C, and add dropwise 2.5M n-butyllithium 72ml, release heat, control the temperature below 10°C, after dripping, react at 10-20°C for 1 hour, set aside.

[0063] A 1000ml three-neck flask was equipped with a thermometer and a nitrogen-protected mouthpiece. Under nitrogen protection, 100g of dry ice was added, and the spare solution was added dropwise to the system, stirred and reacted for 30 minutes, followed by HPLC until the remaining raw materials were less than 5%.

[0064] Cool down to -70°C, extract the reaction solution with 25% dilute sulfuric acid until the pH is less than 1, raise it to room temperature, stir for 30 minutes, and the extraction is complete.

[0065] Then use 50% liquid caustic soda to adjust the pH to be greater than 11, s...

Embodiment 3

[0067] In a 50L reaction kettle, equipped with a thermometer and a mouthpiece protected by nitrogen gas, put 3000g of tetralin under nitrogen protection, add 10kg of n-hexane, add 9.05kg of potassium tert-butoxide, control the temperature at 0°C, and add dropwise 2.5M n-butyllithium 10.9 L, exothermic, control the temperature below 10°C, after dropping, react at 10-20°C for 1 hour, set aside.

[0068] In a 100L reaction kettle, equipped with a thermometer and a mouthpiece protected by nitrogen gas, under nitrogen protection, add 20Kg of dry ice, press the spare liquid into the dry ice system with nitrogen, start without stirring, wait until the temperature of the system rises to -50°C, start stirring, and react 60 minutes, HPLC tracking, until the raw material remains below 5%.

[0069] The reaction solution was extracted with 10 liters of water, raised to room temperature, stirred for 30 minutes, and the extraction was completed.

[0070] Layering, standing for layering, dis...

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Abstract

The invention discloses a method for preparing 1,2,3,4-tetrahydro-1-naphthoic acid by using a superstrong alkali method. The method comprises the following steps: (1) under the protection of nitrogen,preparing a hydrogen drawing product by using tetrahydronaphthalene as a raw material, adding potassium tert-butoxide, using n-hexane as a solvent and dropwisely adding n-butyllithium; and (2) underthe protection of nitrogen, introducing dry carbon dioxide into the system, and acidifying to obtain the target product, wherein in the step (1), a molar ratio of potassium tert-butoxide to n-butyllithium is 1:(0.5-1.5), preferably 1:1.0, and preferably in the step (1), a molar ratio of the superstrong alkali to the tetrahydronaphthalene is 1:(0.5-2), preferably 1:(1.2-1.5). Compared with the method in the prior art, the method of the invention has the advantages of short steps, cheap raw materials, high yield, high operability, good repeatability and convenience in industrialization.

Description

technical field [0001] The invention relates to the technical field of compound preparation, and more specifically relates to a method for preparing 1,2,3,4-tetrahydro-1-naphthoic acid in one step. Background technique [0002] Palonosetron hydrochloride, trade name Alexi, developed by Helsinn Healthcare SA in Switzerland, is the second generation 5-HT3 receptor antagonist. Palonosetron hydrochloride was approved by FDA in July 2003. Very few developed countries such as the United States and Japan have achieved listing. It is a 5-HT3 receptor selective antagonist with strong affinity. The 5-HT3 receptor is located in the center of the emetic chemoreceptor area of ​​the medullary postrema and the vagus nerve endings around it. Chemotherapy drugs release 5-HT by stimulating the chromaffin cells of the small intestine. -HT reactivates the 5-HT3 receptor of the vagus afferent nerve to produce a vomiting reflex, and palonosetron hydrochloride achieves an antiemetic effect by inh...

Claims

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Application Information

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IPC IPC(8): C07C51/15C07C61/39C07C67/00C07C69/753C07C45/00C07C47/445
CPCC07C51/15C07F1/06C07C67/00C07C45/00C07C2602/10C07C61/39C07C69/753C07C47/445
Inventor 陈佳何雪垠刘文涛
Owner 安庆博曼生物技术有限公司
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