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3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride and preparation method thereof

A technology of octane hydrochloride and azabicyclo, applied in the field of preparation of 3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride, achieving high overall yield, safe operation, The effect of easy access to raw materials

Active Publication Date: 2022-01-14
PTG ADVANCED CATALYST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The Grignard reaction is economical and convenient, and compared with metal lithium reagents, the operation is also safer. However, there is no public report on the addition reaction of the carbonyl group on the 3-quinine ketone to make the Grignard reagent with bromochloromethane. A new way of preparing CMAO.HCl

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  • 3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride and preparation method thereof
  • 3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride and preparation method thereof
  • 3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride and preparation method thereof

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preparation example Construction

[0036] According to the present invention, a kind of preparation method of 3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride is provided, the method comprises the following steps:

[0037] Step 1, the Grignard reagent is reacted with 3-quininone to obtain the product I.

[0038] According to the present invention, in step 1, the Grignard reagent is prepared by the following method: iodine is used to initiate a reaction, magnesium powder is added into a container, and a solution containing a chloromethylation reagent is slowly added dropwise for reaction to obtain a Grignard reagent.

[0039] According to the present invention, in step 1, the chloromethylation reagent is halochloromethane, preferably one or both of bromochloromethane and iodochloromethane.

[0040] According to the present invention, in step 1, the Grignard reagent is prepared by the following method: at 20-30°C (such as a room temperature of 25°C), under a protective gas atmosphere, Mg powder is added to ...

Embodiment 1

[0080] (1) Under the protection of nitrogen at room temperature, add 1.5g of freshly polished magnesium chips into a three-necked flask, add a grain of iodine as an initiator, and slowly add 15ml of dissolved 4.32g of ClCH 2 Br dry tetrahydrofuran solution, after the reaction is complete, slowly add dropwise to 10ml of dry tetrahydrofuran solution dissolved with 5g 3-quininone at 0°C, naturally rise to room temperature and stir for 0.5h, heat to reflux for 2h, cool to room temperature Quench the reaction with saturated ammonium chloride aqueous solution, add 30ml of water, extract with 30ml*2 ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and spin the mother liquor to obtain crude yellow-green oily product 3-chloromethyl-1-aza Bicyclo[2.2.2]octan-2-ol 5.77g, yield 82.3%;

[0081] (2) Add 5.7g of the above oil 3-chloromethyl-1-azabicyclo[2.2.2]octan-2-ol and 9.4ml of thionyl chloride to 12ml of toluene, and react at 85-90°C for 14 After cooling to room tem...

Embodiment 2

[0088] (1) Under the protection of nitrogen at room temperature, add 1.5g of freshly polished magnesium chips into the three-necked flask, iodine triggers the reaction, slowly add 15ml of ClCH dissolved in 8.5g 2 I solution in tetrahydrofuran. After the reaction is complete, slowly add dropwise at 0°C into 10ml of tetrahydrofuran solution in which 5g of 3-quininone is dissolved, naturally rise to room temperature and stir for 0.5 hours, heat and reflux for 2 hours, cool to room temperature and quench with saturated ammonium chloride aqueous solution To quench the reaction, add 30ml of water, extract with 30ml*2 ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and spin the mother liquor to obtain the crude product 3-chloromethyl-1-azabicyclo[2.2.2]octane -2-alcohol 6.06g, yield 86.3%;

[0089] (2) Add 6.0g of the above oil 3-chloromethyl-1-azabicyclo[2.2.2]octan-2-ol and 10ml of thionyl chloride to 12ml of toluene, and react at 85-90°C for 14 hours After co...

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Abstract

The invention discloses 3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride and a preparation method thereof. The method comprises the following steps of 1, subjecting a Grignard reagent and 3-quininone to a reaction to obtain a product I; 2, reacting the product I with thionyl chloride to obtain a product II; and 3, carrying out hydrogenation reaction on the product II in the presence of a catalyst to obtain CMAO, and treating the CMAO to obtain CMAO.HCl. The invention provides a new method for synthesizing CMAO.HCl, and provides a thought for performing chloromethylation on alkane containing ketone and aldehyde carbonyl groups and an aromatic hydrocarbon compound at the alpha position of the carbonyl groups by using halochloromethane, and the method provided by the invention has the advantages of simple synthetic route, easily available raw materials, economy, safety and high total yield, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of 3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride. Background technique [0002] CMAO is an important pharmaceutical intermediate, the molecular structure is as follows figure 1 shown. In 1954, C.A.Gro (Helvetica Chemica Acta, 1954, 37, 1689-1698) reported for the first time the method of using 3-quininone as the starting material and obtaining the target product through 7 steps of reaction. The synthetic route is as follows figure 2 Shown, this method route is longer, although the yield of each step is all more than 60%, but total yield is no more than 3%. Jean et al. (US4546185) improved the above-mentioned method, using 3-methylene quinine as the starting material and replacing it with chlorine, liquid bromine or concentrated hydrochloric acid. The advantage of this route is that the target product can be obtained in one step reaction, and the disadvantage Because the starting materials are n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
CPCC07D471/08Y02P20/584
Inventor 付强高建勋肖贺廷王丽颖
Owner PTG ADVANCED CATALYST CO LTD