Asymmetric synthesis of 1-aryl-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester derivatives

A technology of methyl carboxylate and aryl group, which is applied in the field of synthesis of 1H-pyridine[3,4-b]indole compounds, can solve the problems of activity difference and achieve good economic and social benefits

Active Publication Date: 2018-01-09
北京华素制药股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As described in the aforementioned invention patent CN201610804063.1, Example 9, MIPO-6-1 and MIPO-6-2 are a pair of diastereoisomers with 6-fold difference in activity

Method used

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  • Asymmetric synthesis of 1-aryl-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester derivatives
  • Asymmetric synthesis of 1-aryl-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester derivatives
  • Asymmetric synthesis of 1-aryl-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: synthetic compound F (reaction formula 9): ( R )-tryptophan methyl ester (compound F English name: ( R )-methyl-2-amino-3-(1H-indol-3-yl) propanoate)

[0032]

[0033] In a three-necked flask equipped with mechanical stirring, add 600 mL of anhydrous methanol and D-tryptophan (102.1 g, 500 mmol), stir at room temperature, use an ice-salt bath to lower the temperature of the reaction system to 0 ° C, drop After the dropwise addition of thionyl chloride (71.4 g, 600 mmol), the temperature was raised to room temperature to react for about 12 hours. TLC monitoring, when the raw material reaction is complete, stop the reaction. After most of the remaining thionyl chloride and methanol are evaporated under normal pressure, the thionyl chloride and methanol are removed under reduced pressure, and cooled to obtain solid tryptophan methyl ester hydrochloride (separate from air, and can be stored at low temperature for a long time) . When using free tryptopha...

Embodiment 2

[0035] Embodiment 2: synthetic compound L (l R ,2 S )-2-( N -2'-Hydroxy-3'-isopropyl-5'-methoxybenzyl)amino-1,2-diphenylethanol

[0036] Add ((l R ,2 S )-1,2-diphenylaminoethanol 853 mg (4 mmol) and a magnetic stirrer, then add 12 mL of absolute ethanol to dissolve it, and then add 2-hydroxy-3-isopropyl-5-methoxy 777 mg (4 mmol) of benzaldehyde. The reaction was stirred at 25°C and monitored by thin layer chromatography (TLC) until the starting material was completely reacted. Add NaBH directly to the system 4 460mg (12 mmol, 3eq.), stirred at 25°C for 6 hours, and quenched by adding 25 mL of water. Extracted with 25mL×3 dichloromethane, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, distilled off the solvent under reduced pressure, and purified by column chromatography to obtain a white solid, 1.22 g, yield 78%.

Embodiment 3

[0037] Example 3: Synthesis of (1R, 3R)-1-(3,5-difluorophenyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3- Methyl carboxylate (E-6-1)

[0038] Add a magnetic stirrer and 9.8 mg (0.025 mmoL) chiral tridentate ligand (compound L, whose structural formula is shown in formula 8) to the dry reaction test tube, vacuum dry, replace with nitrogen three times, and add in sequence under nitrogen protection Anhydrous 0.4 mL dichloromethane, 25 uL Ti(O- i Pr) 4 (0.025 mmoL) of 1M toluene solution, 20 mg 4A molecular sieve, stirred at 30°C for 2 hours. Then, the solvent (dichloromethane, toluene) and the newly formed isopropanol were exhausted with a vacuum pump, and the reaction system was cooled to 0°C under the protection of nitrogen, and set aside. Then, add a magnetic stir bar, 35.6 mg (0.25 mmoL) 3,5-difluorobenzaldehyde and 54.6 mg (0.25 mmoL) ( R )-Tryptophan methyl ester, vacuum-dried, replaced with nitrogen three times, then added 0.5 mL of anhydrous THF under nitrogen pro...

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Abstract

The invention discloses an asymmetric synthesis method for synthesizing 1-aryl-1H-pyridine[3,4-4]indole-3-carboxylic acid methyl ester derivatives containing two chiral centers from (R)methyl-2-amino-3-(1H-indol-3-yl)propanoate and aldehyde as main starting materials under catalysis of a catalyst, namely, chiral Lewis acid formed by a chiral tridentate ligand compound L and Ti(O-iPr)4. Compared with the prior art, the method has the advantages that the reaction yield is increased and the reaction non-correspondence selectivity is remarkably improved.

Description

technical field [0001] The present invention relates to the synthesis of 1H-pyridine[3,4-b]indole compounds, especially a class of 1-aryl-1H-pyridine[3,4-b]indole-3- The invention relates to the synthesis of carboxylate derivatives, belonging to the field of asymmetric synthesis. Background technique [0002] Chirality is a basic feature of nature. If a molecule cannot coincide with its mirror image, the molecule is called a chiral molecule. Many bioactive molecules in nature are chiral molecules. When the atomic composition of two molecules is the same, but the spatial structure is different, and the relationship between them is a real object and a mirror image, which can also be compared to the relationship between left and right hands, these two molecules are enantiomers of each other. Almost all biomolecules that play a key role in the generation and evolution of life are chiral, such as naturally occurring sugars ( D )-configuration, the amino acid is ( L )-configur...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 杨维清杨梓轩杨宗伟张燕谢川曹永静周婷婷吴静邱妮
Owner 北京华素制药股份有限公司
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