(s) Synthetic method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline

A technology of tetrahydroisoquinoline and synthetic method, which is applied in the field of synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline, can solve problems such as low yield and poor optical purity of products, Achieve the effects of easy access to raw materials, simple and safe reaction operations, and low production costs

Active Publication Date: 2021-03-23
ENANTIOTECH CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method not only has a low yield, but also has poor optical purity of the product, requiring multiple purifications

Method used

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  • (s) Synthetic method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline
  • (s) Synthetic method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline
  • (s) Synthetic method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline

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preparation example Construction

[0018] The embodiment of the present invention provides a synthesis method of (S) 1-phenyl-1,2,3,4-tetrahydroisoquinoline, the reaction route of the synthesis method includes:

[0019]

[0020] Described synthetic method comprises the steps:

[0021] 1) Dissolving raw material 1 in a solvent, adding alkali and catalyst;

[0022] 2) Using hydrogen for gas replacement to form a hydrogen atmosphere, and performing a pressurized reaction to obtain (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline 2;

[0023] Wherein, the catalyst is a BIAMH system catalyst, a D-BIMAH system catalyst or a P-BIMAH system catalyst.

[0024] In the above-mentioned synthetic method, the structural general formula of the BIAMH system catalyst that adopts is:

[0025]

[0026] The general structural formula of the D-BIMAH system catalyst is:

[0027]

[0028] The general structural formula of the P-BIMAH system catalyst is:

[0029] Among them, R 1 For high molecular polymers.

[0030] Preferab...

Embodiment 1

[0043] In this embodiment, a synthetic method of (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline, the steps are as follows:

[0044] 1) In a 5L autoclave, under an argon atmosphere, add 100g of the raw material reactant 1-phenyl-dihydroquinoline (1) through the feeding port, then add 1L of ethanol to fully dissolve the raw material (1), and continue to pass Inject argon for bubbling degassing, continue bubbling for 1 hour, and degassing is completed;

[0045] 2) Then, under argon atmosphere, add 0.5g catalyst (S)-diopRuCl from the feeding port 2 (R)-P-Me-BIMAH (purchased from Zhongshan Yiantai Pharmaceutical Technology Co., Ltd.), add 12g potassium tert-butoxide, after the feeding is completed, quickly close the feeding port; replace the argon with hydrogen, slowly feed the hydrogen to 30atm, Close the inflation valve and stir the reaction at 25-35°C; when the pressure drops to remain constant, the reaction is considered to be stopped, and the sample is sent for liquid phase analy...

Embodiment 2

[0048] In this embodiment, a synthetic method of (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline, the steps are the same as in Example 1, the difference is that the catalyst used is (S)-diopRuCl 2 (R)-Me-BIMAH (BIAMH system catalyst).

[0049] Specific steps are as follows:

[0050] 1) In a 5L autoclave, under an argon atmosphere, add 100g of the raw material reactant 1-phenyl-dihydroquinoline (1) through the feeding port, then add 1L of ethanol to fully dissolve the raw material (1), and continue to pass Inject argon for bubbling degassing, continue bubbling for 1 hour, and degassing is completed;

[0051] 2) Then, under argon atmosphere, add 0.5g catalyst (S)-diopRuCl from the feeding port 2 (R) -Me-BIMAH (purchased from Zhongshan Yiantai Pharmaceutical Technology Co., Ltd.), finally add 12g of potassium tert-butoxide, after the addition, quickly close the feeding port; replace the argon with hydrogen, slowly introduce hydrogen to 30atm, close Inflate the valve and stir the re...

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Abstract

The present invention relates to a kind of synthetic method of (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline, the reaction route of described synthetic method is as follows; Described synthetic method comprises the following steps: 1) making The raw material 1 is dissolved in a solvent, and a base and a catalyst are added; 2) hydrogen gas is used for gas replacement to form a hydrogen atmosphere, and a pressurized reaction is carried out to obtain (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline 2 ; Wherein, the catalyst is a BIAMH system catalyst, a D-BIMAH system catalyst or a P-BIMAH system catalyst.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a synthesis method of (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline. Background technique [0002] Sophinacin is a selective muscarinic M3 receptor antagonist developed by Japan Astellas Company, mainly used for the treatment of overactive bladder with symptoms of urgency and frequent urination. The chemical name of Sofinaxin is (3R)-1-azabicyclo[2,2,2]octane-3-yl(1S)-1-phenyl-1,4-dihydroisoquinoline- 2-(1H)-carboxylate, the structure is shown in the following formula (1): [0003] [0004] It can be seen from the above structural formula that solifenacin contains two chiral centers, one chiral center is located on the isoquinoline (2) structural unit, and the other chiral center is located on the quinuclidin structural unit. Therefore the synthetic method of solifenacin is usually based on (S) 1-phenyl-1,2,3,4-tetrahydroisoquinoline (formula (2)) and quinuclidinol (f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/02
CPCC07B2200/07C07D217/02
Inventor 李彦雄蒙发明温锦涛李苏泳郭俊毛波徐亮
Owner ENANTIOTECH CORP
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