Process of synthesizing 3-methyl amino indole compound

A methylaminoindole compound and a technology for the indole compound are applied in the field of synthesizing optically active 3-methylaminoindole compounds, and the effects of mild reaction conditions and easy operation are achieved

Inactive Publication Date: 2007-07-18
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are few reports on the asymmetric addition reaction of sulfonylimide and indole in the literature. Most of the reactions take several days of reaction time, and most of them have metals to participate in the reaction. The enantioselective method of synthesizing 3-methylaminoindole compounds is the focus and difficulty in this respect

Method used

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  • Process of synthesizing 3-methyl amino indole compound
  • Process of synthesizing 3-methyl amino indole compound
  • Process of synthesizing 3-methyl amino indole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1: the preparation of chiral phosphoric acid

[0021] Under the protection of argon at room temperature, dissolve diphenol or dihydroxy derivatives (0.5mmol) in 1mL dry pyridine in a dry reaction tube, and dissolve (1.0mmol) phosphorus oxychloride Slowly added dropwise to the system, stirred at room temperature for 3 hours. 1 mL of water was slowly added dropwise to the system, and stirred at room temperature for 30 minutes. Dichloromethane was added to dissolve, washed with 1N hydrochloric acid aqueous solution (10mL×3), the organic layer was dried over anhydrous sodium sulfate, the solvent was spun off under reduced pressure, and the residue was separated by column chromatography to obtain the product.

[0022] C1: (S)-3,3'-[3,5-bis(trifluoromethyl)phenyl]2-1,1'-binaphthol phosphate

[0023] (S)-3,3′-[3,5-Bis(trifluoromethyl)phenyl]2-1,1′-binaphthyl phosphate

[0024] (or its enantiomers)

[0025] Solid, 89% yield. IR (CHCl 3 ) 1620, 1501, 1474, 137...

Embodiment 2

[0057] Example 2: Chiral phosphoric acid catalyzed addition reaction of indoles to sulfonimides

[0058] Add (chiral) phosphoric acid compound (0.025mmol), sulfonimide compound (0.25mmol), and toluene 1mL in sequence to a dry reaction tube, stir at room temperature for 10 minutes, then put it in a -60°C bath and stir for 5 minutes , add indole compound (0.75mmol), react under -60 ℃, the reaction finishes, add 10%NaHCO 3 aqueous solution (3mL), separated, the organic layer was washed once with 5mL water, once with saturated brine 5mL, and the organic layer was washed with anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure and the residue was separated by column chromatography to obtain the product.

[0059] P1: (R)-N-((3-(1H-indol-3-yl)(phenylmethyl)-4-methylphenylsulfonamide (R)-N-((1H-indol-3- yl)(phenyl)methyl)-4-methylbenzenesulfonamide

[0060] (or its enantiomers)

[0061] Catalyst is C7 (10mol%),-60 ℃; R f =0.40 (ethyl acetate / petrol...

Embodiment 3

[0142] Embodiment 3: removal and conversion (application example) of sulfonyl group in the product

[0143] P22: (R)-N-((3-(1H-indol)yl)(phenylmethyl)-benzylcarbonamide

[0144] (R)-Benzyl(1H-indol-3-yl)(phenyl)methylcarbamate

[0145]

[0146] In a dry reaction tube was added P2 (1.10 g, 2.5 mmol) followed by dry THF (10 mL). This solution was cooled to -78°C and liquid ammonia (50 mL) was added, then excess sodium metal (500 mg) was added in portions until the dark blue color was maintained for 5 minutes. Ammonium chloride solid (5 g) was added to quench at -78°C, the system slowly rose to room temperature, and the liquid ammonia volatilized. The resulting residue was partitioned with water (50 mL) and dichloromethane (50 mL), the organic phase was collected, and the aqueous phase was extracted with dichloromethane (4×50 mL). The organic layers were combined, dried and concentrated. The resulting white solid was dissolved in THF (30 mL), and water (15 mL) was added. ...

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PUM

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Abstract

The present invention takes chiral phosphate as catalyst, uses sulfonyl imide and indole compounds synthesize 3-methylamino-indole compound of high-efficiency and high enantioselectivity. Compared with the existing method, it can be applied to many different types of indole and sulfonyl imide compounds, mild reaction conditions, simple operation. In addition, the reaction without joining any metal salts compounds, so useful for drug production and processing. And the reaction yields are better, high enantioselectivity.

Description

technical field [0001] The invention relates to a method for synthesizing 3-methylaminoindole compounds, in particular to a method for synthesizing optically active 3-methylaminoindole compounds. The method is a Friedel-Crafts reaction of sulfonimide and indole compound catalyzed by chiral phosphoric acid, and the reaction can realize high-efficiency and high-enantioselectivity synthesis of 3-methylaminoindole compound. Background technique [0002] In recent years, organic small molecule catalysis has attracted widespread attention from academia and industry all over the world due to its advantages of easy synthesis, convenient structure modification, and no heavy metal residue [(a) Seayad, J.; List, B.Org .Biomol.Chem.2005,3,719-724.(b) Dalko, P.I.; Moisan, L.Angew.Chem.Int.Ed.2004,43,5138-5175.], wherein by chiral phosphoric acid as catalyst The achieved asymmetric catalysis has achieved rapid development in the past three years [(a) Akiyama, T.; Itoh, J.; Yokota, K.; Fu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/14B01J31/24
Inventor 游书力康强赵卓安
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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