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Preparation method of 7-bit methyl-5-bit oxygen-substituted indole compounds

A technology of methyl indole compound and methoxy, which is applied in the field of preparation of indole compounds, can solve the problems of 5-methoxy 7-methyl indole, the problem that the yield and test conditions cannot meet industrial production, and achieve the method Simple, easy-to-operate, low-cost effects

Active Publication Date: 2014-01-08
重庆德润笙医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008]According to our multiple experiments, according to the two-step method reported in the above two literatures, it is difficult to obtain the 5-methoxy 7-methylindole, which is only applicable Laboratory milligram-level preparation methods, yields and test conditions cannot meet the needs of industrial production

Method used

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  • Preparation method of 7-bit methyl-5-bit oxygen-substituted indole compounds
  • Preparation method of 7-bit methyl-5-bit oxygen-substituted indole compounds
  • Preparation method of 7-bit methyl-5-bit oxygen-substituted indole compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 5-Methoxy-7-methyl-1H-indole

[0023]

[0024] General test procedure:

[0025] Fix the dried 5L flask, install the mechanical stirrer to start stirring, and protect by nitrogen (the flow rate of nitrogen is controlled in an appropriate range by observing the liquid seal tube), so that an anhydrous and oxygen-free reaction flask is always maintained environment of.

[0026] Pour the vinyl Grignard reagent (1000ml, c≈1.3 mol / L) quickly into the reaction flask. If the vinyl Grignard reagent has condensation, it can be dissolved by heating or dissolved in anhydrous tetrahydrofuran (THF). Then add 1000ml of dry tetrahydrofuran (THF). Dissolve 70g of the raw material substrate: 2-nitro-5-methoxytoluene with 250ml of anhydrous tetrahydrofuran (THF), add it to the dropping funnel on the reaction flask, and wait for it to drop. Install a low temperature thermometer.

[0027] Take an acetone bath outside the reaction flask, and slowly add dry ice to the acetone. When the temperature ...

Embodiment 2

[0032] 5-Benzyloxy-7-methyl-1H-indole

[0033]

[0034] Same as the general test procedure of Example 1 above, put in the raw material substrate: 80 grams of 5-benzyloxy-2 nitrotoluene (0.3292 Mol) to obtain the light yellow product of 5-benzyloxy-7-methylindole 10.1 grams. The yield was 13.1%. Identified by HPLC, the purity is 97%. MP: 70~72℃; 1 H NMR (400 MHz, CDCl 3 ), δ 7.996 (1H, bs), δ 7.510 (2H, d, J =7.6 Hz), δ 7.411 (2H, t, J =7.6 Hz), δ 7.338 (1H, t, J =7.6 Hz), δ 7.211 (1H, t, J =2.8 Hz), δ 7.060 (1H, d, J =2.0 Hz), δ 6.813 (1H, d, J =1.2 Hz), δ 6.506 (1H, t, J =2.8 Hz), δ 5.125 (2H, s), δ 2.495 (3H, s); ESI-MS M / Z : [M-H] - 236.1.

Embodiment 3

[0036] 4-Bromo-5-methoxy-7-methyl-1H-indole

[0037]

[0038] Preparation of raw material 2-nitro-4-bromo-5-methoxytoluene:

[0039] Under mechanical stirring, add 1000ml trifluoroacetic acid (CF 3 COOH) was added to a 3L three-necked flask, and 100ml sulfuric acid (H 2 SO 4 ), then slowly add 200g of 2-nitro-5-methoxytoluene, and add 223g of N in batches - Bromosuccinimide (NBS), heated to reflux for 3 hours, after the raw material reaction is complete, the reaction solution is slowly poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate aqueous solution, washed with saturated brine, and the organic phase is concentrated The sample was mixed and recrystallized to obtain 175 g of product, 2-nitro-4-bromo-5-methoxytoluene (60%).

[0040] Same as the general test procedure of Example 1 above, put in the raw material substrate: 70g (0.28mol) of 2-nitro-4-bromo-5-methoxytoluene to obtain 4-bromo-5-methoxy-7- Methyl indole 8g product (11.7%). MP: 82~83℃; 1 ...

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Abstract

The invention relates to a preparation method of 7-bit methyl-5-bit oxygen-substituted indole compounds (II). According to the preparation method, 2-methyl-5-oxonitrobenzene compounds (I) and vinyl Grignard reagents are prepared according to the following reaction formula shown as the accompanying drawing, wherein R1 represents hydrogen, methyl and benzyl, R2 represents hydrogen, fluorine, chlorine, bromine or iodine, reaction solvent is tetrahydrofuran (THF), and the reaction temperature is -50 DEG C to 20 DEG C. The preparation method has the advantages that raw materials are cheap and are easy to obtain, the method is simple, the operation is easy, the cost is low, the reaction yield is high, and the preparation method is suitable for larger-scale industrial production implementation.

Description

technical field [0001] The invention belongs to the technical field of a method for preparing indole compounds, and in particular relates to a method for preparing indole at the 7-position and at the 5-position by using a 2-methyl-5-oxonitrobenzene compound as a raw material using the Bartoli indole synthesis method. Oxygen substituted indole compounds. Background technique [0002] Indole compounds have many uses, have biological activity, and are used in medicine, chemical industry, pesticide and other fields. The 7-methyl-5-oxygen substituted indole compound can at least be used as a variety of pharmaceutical intermediates, for example, for the preparation of serotonin receptor affinity agents for the treatment of nervous system diseases (Journal of Medicinal Chemistry, 23(11), 1222-6; 1980 [0003] So far, there are mainly two methods reported in the literature for the preparation of 7-methyl-5-oxo-substituted indole compounds. [0004] 1. Leimgruber-Batcho indole syn...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08
Inventor 胡建兵李嘉和
Owner 重庆德润笙医药有限公司