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Synthesis method of 6-methoxy-1-tetralone

A synthesis method and tetralinone technology are applied in the field of preparation of substituted tetralinone, and can solve the problems of difficult separation and removal, high safety risk, low total yield and the like

Active Publication Date: 2022-05-06
ZHEJIANG XIANJU JUNYE PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The traditional synthesis method of 6-methoxy-1-tetralone is prepared by using 2-methoxynaphthalene through hydrogenation and oxidation steps, but the hydrogenation step needs to adopt a dangerous process of high-pressure catalytic hydrogenation, which requires high equipment requirements , high safety risk; chromium trioxide is used as an oxidant in the oxidation step, heavy metal pollution is serious, and the three wastes are difficult to meet regulatory requirements; and the total yield is lower than 35%
Oxidation is prone to produce 4-keto impurities as by-products, which are difficult to separate and remove

Method used

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  • Synthesis method of 6-methoxy-1-tetralone
  • Synthesis method of 6-methoxy-1-tetralone
  • Synthesis method of 6-methoxy-1-tetralone

Examples

Experimental program
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Effect test

Embodiment 1

[0019] The synthesis of embodiment 1 compound (2):

[0020] In the reaction bottle A, add 400g of toluene and 12.7g of magnesium flakes, fully replace with nitrogen, raise the temperature to 80°C, add 0.5mL of methyl iodide, after the reaction is initiated, dropwise add 3-bromoanisole (1) (100g) of toluene ( 1600g) solution, temperature control 60~100°C, dropwise addition is completed in about 2 hours; keep warm for 4 hours until the magnesium flakes disappear completely; cool to 0°C to obtain 3-methoxyphenylmagnesium bromide solution;

[0021] In the reaction bottle B, add 1000 g of toluene and 200 g of ethyl succinate monoacyl chloride, stir to dissolve, and cool to -50 ° C; dropwise add the 3-methoxyphenyl magnesium bromide solution obtained above, about 2 hours, control Temperature below -40°C; after adding, keep warm for 2 hours; quench the reaction solution into dilute sulfuric acid, separate layers, wash with water, wash with saturated sodium bicarbonate, wash with satu...

Embodiment 2

[0022] The synthesis of embodiment 2 compound (3):

[0023] In the reaction flask C, add all the crude compound (2) prepared in Example 1 and 600 g of dichloromethane to prepare a dichloromethane solution of compound 2;

[0024] In the reaction flask D, add 800g of dichloromethane and 200g of triethylsilane, cool down to 0°C, add 150g of trifluoroacetic acid dropwise; raise the temperature to 15~20°C, add the dichloromethane solution of compound 2 dropwise for about 1 hour, Control the temperature at 10-30°C; keep warm for 3 hours after addition; add 800 g of water dropwise, and stir for 2 hours; let stand to separate layers, wash with water, wash with saturated saline, and dry over anhydrous sodium sulfate; concentrate the organic phase to obtain the oily compound (3).

Embodiment 3

[0025] Synthesis of Example 3 Compound 4

[0026] In the reaction flask, add all the crude compound (3) obtained in Example 2 and 800 g of methanol, stir and dissolve; add 30 g of sodium hydroxide and 800 g of water; heat up to reflux, and reflux for 4 hours; after the reaction solution is concentrated to remove methanol, use Washed twice with ethyl acetate, then adjusted the pH to 2 with 4M hydrochloric acid, extracted three times with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 83 g of a yellow solid, namely compound (4)); The total mass yield of the first step reaction was 83%, and the HPLC purity was 92%.

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Abstract

The invention relates to a synthesis method of 6-methoxy-1-tetralone, which comprises the following steps: 1) adding magnesium metal into toluene, adding iodomethane for initiation, and dropwise adding a toluene solution of 3-bromoanisole to prepare a 3-methoxyphenyl magnesium bromide solution; dissolving ethyl succinate monoacyl chloride in toluene, cooling to-45 DEG C to-55 DEG C, adding a 3-methoxyphenyl magnesium bromide solution, and reacting to prepare a crude product of a compound (2); 2) dropwise adding trifluoroacetic acid (TFA) into the compound (2) and triethyl silane in dichloromethane, and dropwise adding water to obtain an oily compound (3) crude product; 3) dissolving the compound (3) in methanol, adding sodium hydroxide and water, and carrying out a reflux reaction for 3-5 h to obtain a compound (4), and 4) dissolving the compound (4) in dichloromethane, dropwise adding thionyl chloride, and after the reaction is completed, adding anhydrous aluminum trichloride, and after the reaction is completed, carrying out a reaction to obtain the 6-methoxy-1-tetralone.

Description

technical field [0001] The invention relates to a preparation method of an oxo-condensed ring compound, in particular to a preparation method of a substituted tetralone. Background technique [0002] Many steroid drugs, such as: mifepristone, norethindrone, drospirenone, levonorgestrel, desogestrel, etonogestrel, levonorgestrel, dydrogesterone, etc., can be produced by 6-methoxy-1-tetralone as the basic raw material and methyl D ring or ethyl D ring can be obtained through a series of synthetic strategies. Therefore, 6-methoxy-1-tetralone (compound 5) is a vital basic raw material in the field of total synthesis of steroid drugs. [0003] Its structural formula is as follows: [0004] [0005] The traditional synthesis method of 6-methoxy-1-tetralone is prepared by using 2-methoxynaphthalene through hydrogenation and oxidation steps, but the hydrogenation step needs to adopt a dangerous process of high-pressure catalytic hydrogenation, which requires high equipment requ...

Claims

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Application Information

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IPC IPC(8): C07C45/46C07C49/755
CPCC07C67/343C07C67/317C07C51/09C07C45/46C07C2602/10C07C69/738C07C69/734C07C59/64C07C49/755
Inventor 张峥斌李纯尹金玉何成胜吴静周海亮
Owner ZHEJIANG XIANJU JUNYE PHARM CO LTD
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