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(S)1-phenyl-1,2,3,4-tetrahydroisoquinoline synthesis method

A technology of tetrahydroisoquinoline and a synthesis method is applied in the field of synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline, and can solve the problems of poor optical purity and low yield of the product, To achieve the effect of simple and safe reaction operation, easy access to raw materials and simple equipment

Active Publication Date: 2020-01-14
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)1-phenyl-1,2,3,4-tetrahydroisoquinoline synthesis method

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[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 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 Yi Antai Pharmaceutical Technology Co., Ltd.), add 12g of 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 analys...

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 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 reaction...

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Abstract

The invention relates to a (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline synthesis method, wherein the reaction route is defined in the specification. The synthesis method comprises: 1) dissolving a rawmaterial 1 in a solvent, and adding an alkali and a catalyst; and (2) carrying out gas replacement by using hydrogen to form a hydrogen atmosphere, and carrying out an pressurization reaction 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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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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