A kind of preparation method of amino-substituted compound

Abstract

A method for preparing a novel spiro compound substituted with an amino group, which is prepared by using a special reaction kettle, the reaction kettle has a glass body (1), the body is equipped with a kettle cover (11), a lower flange (12), a barrel Body (13), the reactor also includes inlet combination (2), gas outlet combination (3), fixture (4), stirring part (5); Methyl)bicyclo[2.2.2]decane-1-carboxylic acid is dissolved in THF, add NEt3, isobutyl chloroformate, obtain ((4-carbonamidobicyclo[2.2.2]decane-1-base) Methyl) benzyl carbonate, thus prepared ((4-cyano bicyclo [2.2.2] decane-1-yl) methyl) benzyl carbonate; add anhydrous methanol, nickel chloride hexahydrate, B ℃ acid anhydride to obtain ((4-((((benzyloxy)carbonyl)amino)methyl)bicyclo[2.2.2]decane-1-yl)methyl)benzyl carbonate; adding 1,4-dioxy In the hexacyclic solution and the dioxane hydrochloride solution, MTBE was added to obtain ((4-(aminomethyl)bicyclo[2.2.2]decyl-1-yl)methyl)benzyl carbonate.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a method for synthesizing pharmaceutical intermediates ((4-(aminomethyl)bicyclo[2.2.2]oct-1-yl)methyl)benzyl carbonate. Background technique [0002] Benzyl carbonate and its derivatives are an important class of compounds with strong biological activity and are widely used in medicine, pesticides and other fields. Therefore, the synthesis of benzyl carbonate derivatives has received extensive attention, especially among pharmaceutical intermediates. are widely used in. CN201410087799.2 provides a bactericidal composition containing benzyl carbonate-2,3,8-trimethyl-6-heptafluoroisopropyl-4-quinoline ester, which is the application of benzyl carbonate derivatives and Synthetic example, but ((4-(aminomethyl)bicyclo[2.2.2]oct-1-yl)methyl)benzyl carbonate mentioned in the application rarely has the application or preparation method as a pharmaceutical intermediate , or h...

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Problems solved by technology

CN201410087799.2 provides a bactericidal composition containing benzyl carbonate-2,3,8-trimethyl-6-heptafluoroisopropyl-4-quinoline ester, which is the application of benzyl carbonate derivatives and Synthetic example, but ((4-(aminomethyl)bicyclo[2.2.2]oct-1-yl)methyl)benzyl carbonate mentioned in the application rarely has the application or preparation method as a pharmaceutical intermediate , or there are documents or information published

[0003] Due to the properties of this molecule, the method cannot be extended to the synthesis of other similar structures

This is determined by the ingenuity of the preparation method, the higher yield and the non-reproducibility of the shorter reaction time obtained from numerous experiments. Other routes basically cannot have higher yield or acceptable reaction time.

[0004] In addition, there is also such a problem in the prior art, that is, the existing four-necked bottle has a significant deficiency as a reaction vessel. Generally, this type of laboratory preparation uses a four-necked bottle as a reaction vessel, and several disadvantages are prominent: one. Insufficient performance, when the mixture in the four-necked bottle needs to be stirred, because the four-necked bottle generally clamps the main bottleneck to achieve high-speed stirring, but the bottom of the four-necked bottle is uneven, so that the stirring rod cannot go deep, and it is difficult to achieve high-speed stirring. The most stable stirring speed is 350-400 rpm. If it is higher, the overall vibration of the device is too severe, and there is a risk of damage to the whole bottle. Due to the uneven bottom of the bottle, the material In many cases, it is also difficult to obtain effective and sufficient stirring, which affects the full progress of the reaction; 2. The deficiency of the existing nitrogen protection method, the existing nitrogen protection is to feed nitrogen from one mouth of the four-necked bottle, and lead the bottle from the other mouth. However, due to the limitation of the shape of the four-necked bottle in this way, a large dead volume or a volume that does not participate in convection will be generated in the bottle. According to infrared video detection, the occurrence of such a dead volume is a high probability event. And the current simple way of nitrogen ventilation is difficult to overcome; 3. The problem of large loss of the reaction mixture, the multiple ports of the four-necked bottle, and the small problem of the main port make it difficult for the reaction mixture to be properly processed during each step. In practice, a large amount or most of them are lost, and often each step will reduce the product quantity by 1-20% due to operational problems, which not only affects the actual product quantity obtained, but also makes the yield of each step The calculation deviates from the actual situation, which cannot be overcome by using the four-necked bottle system

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