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Method for synthesizing 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine

A synthesis method, tetramethyl technology, applied in the field of synthesis of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine, can solve the problem of high pollution and safety Poor performance, high cost and other problems, to achieve the effect of high reaction yield, high safety, simple operation

Active Publication Date: 2009-07-22
重庆莱美隆宇药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the preparation of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine is reported in this document by 2,6-dichlorohexane and benzene through ring 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene is prepared by combining, and then nitrated, and then catalytic hydrogenation reduction is obtained. The total yield of the three steps is only about 15%, especially It is the following two steps, and the yield of each step is only 20%. In these three steps, benzene with high toxicity is used for cyclization, which causes great pollution in the nitration process, high cost of catalytic hydrogenation, poor safety, environmental protection, and high cost. Not suitable for industrial production

Method used

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  • Method for synthesizing 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine
  • Method for synthesizing 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine

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Embodiment 1

[0014] 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthamide, its structural formula is as follows:

[0015]

[0016] Put 20g into a three-necked flask, add 200ml ethylene glycol and 5.8g potassium hydroxide, heat to 100°C, stir for 2 hours, cool, pour the reaction solution into a large amount of water, let it stand overnight, filter, and recrystallize the solid with methanol / water , Get yellow solid 14.2g, yield 85.7%, mp: 71-74, 1H-NMR (300MZ, CHCl3) 1.24 (6H) 1.27 (6H) 1.69 (4H) 3.5-3.9 (2H) 6.56 (1H) 6.68 ( 1H) 7.13 (1H).

[0017] Among them, the preparation method of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthamide can be referred to the description in EP0478787.

Embodiment 2

[0019] Put 20g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthamide into a three-necked flask, add 200ml glycerol and 7.0g sodium hydroxide, and heat to 150℃ After stirring for 2 hours, cooling, the reaction solution was poured into a large amount of water, placed overnight, filtered, and the solid was recrystallized with methanol / water to obtain 14.5 g of a yellow solid with a yield of 87.5%.

Embodiment 3

[0021] Put 18g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthamide into a three-necked flask, add 100ml of 1,2-propanediol and 6.5g of sodium hydroxide, and heat up After stirring at 130°C for 2 hours, cooling, the reaction solution was poured into a large amount of water, placed overnight, filtered, and the solid was recrystallized with methanol / water to obtain 12.1 g of a yellow solid with a yield of 83.0%.

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Abstract

The invention discloses a synthesis method of 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthylamine. The synthesis method comprises the following steps: the 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthoamide reacts with sodium hydroxide in a high boiling point solvent; a protective group of the amino group is removed at temperature between 100 DEG C and 200 DEG C; a reaction solution is deposited with water and filtered; a solid product obtained is recrystallized to obtain the 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthylamine. The method is environmentally friendly,has little pollution, low cost, simple operation, high safety, high reaction yield and high transformation rate reaching more than 80 percent and requires no adoption of expensive Pd-C catalysts and no catalytic hydrogenation. If necessary, the obtained 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthylamine can be condensed and hydrolyzed to obtain tamibarotene.

Description

Technical field [0001] The invention relates to a synthesis method of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine. Background technique [0002] 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine, with the following formula (I), is the main raw material for the synthesis of tamibarotene (tamibarotene). The molecular structure of mibarotene is shown in formula (II). [0003] [0004] Tamibarotene is a tretinoin agonist. Its preparation and efficacy are described in J.med.chem.1988, 31, 2182-2192. Tamibarotene has valuable pharmacological value and has been marketed as a therapeutic drug for acute promyelocytic leukemia in Japan. [0005] J.med.chem.1988, 31, 2182-2192 also describes the synthesis method of Tamibarotene, using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-Naphthylamine is condensed with methyl p-formate benzoyl chloride and then prepared by hydrolysis. The method has high yield and is suitable for industrial production. However, it is reported in this ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/58C07C209/62
CPCY02P20/55
Inventor 彭建坤安林
Owner 重庆莱美隆宇药业有限公司
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