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Tetrahydro-gamma-carboline derivative synthesis method

A synthetic method and derivative technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of limited application range, indispensable ortho-fluorine substituents, etc., and achieve the effect of simple operation and high yield

Active Publication Date: 2015-05-13
BIRDO (SHANGHAI) PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] Tetrahydro-γ-carbolines obtained by Kudzma using 2-fluorophenylimine at reflux in THF in the presence of lithium diisopropylamide [10] , the disadvantage is that the ortho-fluorine substituent in the substrate is indispensable, which limits the scope of application of this method

Method used

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  • Tetrahydro-gamma-carboline derivative synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of 3-(methylamino)methyl propionate (VIII)

[0043] Methylamine ethanol solution (33% methylamine mass fraction, 320mmol) was placed in a 100mL round bottom flask, methyl acrylate (VII) (6.9g, 80mmol) was dissolved in ethanol (15mL) and placed in a constant pressure dropping funnel Slowly add the ethanol solution of methyl acrylate (VII) dropwise to the methylamine ethanol solution at minus 20°C. After the dropwise addition, continue the reaction at minus 20°C for 8 hours, return to normal temperature after the reaction, and remove the solvent under reduced pressure and unreacted methylamine, and the residue was separated and purified by vacuum distillation to obtain 8.0 g of a colorless oily liquid, yield: 86%.

[0044] Experiments have proved that when the reaction temperature is selected at minus 10°C, the preparation of methyl 3-(methylamino)propionate (VIII) can also be completed in the same manner as in this example.

Embodiment 2

[0046] Preparation of 3-[(tert-butoxycarbonyl)(methyl)amino]propionic acid methyl ester (IX)

[0047] Methyl 3-(methylamino)propionate (VIII) (9.4 g, 80 mmol) was dissolved in dichloromethane (200 mL), and triethylamine (22 mL, 160 mmol) and di-tert-butyl dicarbonate were added to the solution (19g, 88mmol). Stir the reaction at room temperature for 5 hours, and when the reaction is complete, add a saturated solution of ammonium chloride (100 mL) to the reaction solution and stir for half an hour, collect the organic layer in a separatory funnel, wash with water (150 mL), and wash the organic phase with anhydrous After drying over sodium sulfate and concentrating under reduced pressure, a crude product was obtained. The crude product was separated and purified by column chromatography to obtain 17.4 g of a colorless oily liquid, yield: 94%.

[0048] 1 H NMR (400MHz, CDCl 3 ): δ3.69(s,3H),3.51(t,J=6.8Hz,2H),2.87(s,3H),2.55(t,J=6.8Hz,2H),1.46(s,9H). 13 C NMR (101MHz, CDCl 3...

Embodiment 3

[0050] Preparation of 3-[(tert-butoxycarbonyl)(methyl)amino]propionic acid (X)

[0051] 3-[(tert-butoxycarbonyl)(methyl)amino]propionic acid methyl ester (IX) (6.5g, 30mmol) was dissolved in ethanol (150mL), and an aqueous solution of sodium hydroxide (1.8 g, 45mmol, 50mL), stirred and reacted at room temperature for 6 hours, removed ethanol under reduced pressure, adjusted the pH of the solution to 3 with hydrochloric acid (2N), placed the resulting aqueous solution in a separatory funnel, extracted with ethyl acetate (150mL), collected And the organic phase was concentrated to obtain 5.8 g of colorless viscous liquid, yield: 95%.

[0052] 1 H NMR (400MHz, CDCl 3 ):δ3.53(t,J=6.9Hz,2H),2.89(s,3H),2.61(t,J=6.8Hz,2H),1.47(s,9H).

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Abstract

The invention discloses a tetrahydro-gamma-carboline derivative synthesis method which comprises the following steps: substituted aniline (II) is used as a raw material, acetic acid is used as a catalytic agent, and the substituted aniline (II) reacts with 5-amino-3-oxo-ethyl valerate (III) to form N-aryl enamine (IV); the compound (IV) reacts under the action of palladium acetate and copper acetate to form an indole-3-carboxylic acid ethyl ester derivative (V); and the compound (V) is subjected to deprotection of tertiary-butoxyocarbonyl (Boc) protecting groups under the action of trifluoroacetic acid in methylene dichloride and then subjected to a reflux reaction in methanol in sodium hydroxide to form a 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4, 3-b] indol-1-keton derivative (VI); and the compound (VI) is subjected to a reflux reaction in tetrahydrofuran under the action of lithium aluminum hydride to form a tetrahydro-gamma-carboline derivative (1). The tetrahydro-gamma-carboline derivative synthesis method has the advantages that the operation is simple, the reaction raw materials and the reaction agents are easy to obtain, the yield is high, and the like.

Description

technical field [0001] The invention relates to a synthesis method of tetrahydro-γ-carboline derivatives. Background technique [0002] The tetrahydro-γ-carboline structure exists in a variety of medicinal molecules or important intermediates in the synthesis of some natural products, such as the experimental drug Dimebon for Alzheimer's disease [1] (A), second-generation histone deacetylase inhibitors [2] (B), new antipsychotic drug Pyridoindolebenzodiazepien [3] (C), c-Met kinase small molecule inhibitor [4] (D), 5-HT 6 and H 1 receptor antagonist [5] (E) Neuroprotective factor pseudo-nitric oxide [6] (F) et al., the natural product Horsfline [7] (G) Important intermediates in synthesis also contain such structures. Therefore, pharmaceutical molecules or natural products containing such structures can be prepared from such tetrahydro-γ-carboline compounds. [0003] [0004] The relevant literature is as follows: [0005] [1] Gao, M.; Wang, M. Bioorg. Med. Chem...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCY02P20/55
Inventor 杜云飞吕晶磊尚巳耘赵康
Owner BIRDO (SHANGHAI) PHARMATECH CO LTD
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