Preparation method of 3-hydroxy-1-amantadine transition state intermediate

A technology of amantadine and amantadine hydrochloride, which is applied in the preparation of amino hydroxyl compounds, the preparation of organic compounds, and the preparation of amino compounds from amines, etc. It can solve the problems of high risk level and failure to meet the requirements, and speed up the reaction The effect of increasing the speed and gap and reducing the reaction temperature

Inactive Publication Date: 2020-12-01
江苏泰洁智邦检测技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The existing 3-hydroxyl-1-adamantanamine intermediate is prepared from amantadine hydrochloride, 98% concentrated sulfuric acid reagent grade, and 98% concentrated nitric acid reagent grade. The existing conventional preparation method is to add Amantadine hydrochloride, then slowly add concentrate...

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0031] A kind of preparation method of 3-hydroxyl-1-adamantanamine transition state intermediate, comprises the following steps:

[0032] SS1: Preparation of amantadine sulfate-sulfuric acid mixture: Add 3.68 mol of 96% concentrated sulfuric acid dropwise to 0.76 mol amantadine hydrochloride at a rate of 1.5 g / min under ice water under stirring at 50 rpm , stirred and reacted for 0.5 h for later use;

[0033] SS2: Add 1.81 mol of 98% nitric acid into a 1000mL reactor, and then add 4.12 mol of 96% concentrated sulfuric acid dropwise into the reactor while stirring at 150rpm. h;

[0034] SS3: heat up the reactor to 30°C, drop the mixed solution configured in step SS1, the molar ratio of fuming nitric acid in SS2 to amantadine hydrochloride in SS1 is 2.38:1, and the dropping rate is 1g / min, The dropping time was 10 h. After the dropping, the reaction was continued for 2 h to obtain the transition state intermediate of 3-hydroxy-1-adamantanamine.

[0035] The parameters of the ...

Embodiment 2

[0040] A kind of preparation method of 3-hydroxyl-1-adamantanamine transition state intermediate, comprises the following steps:

[0041] SS1: Preparation of amantadine sulfate-sulfuric acid mixture: Add 3.68 mol of 96% concentrated sulfuric acid dropwise to 0.76 mol amantadine hydrochloride at a rate of 1.5 g / min under ice water under stirring at 50 rpm , stirred and reacted for 0.5 h for later use;

[0042] SS2: Add 1.81 mol of 98% nitric acid into a 1000mL reactor, and then add 4.12 mol of 96% concentrated sulfuric acid dropwise into the reactor while stirring at 150rpm. h;

[0043]SS3: heat up the reaction kettle to 50°C, drop the mixed solution configured in step SS1, the molar ratio of fuming nitric acid in SS2 to amantadine hydrochloride in SS1 is 2.38:1, and the dropping rate is 1g / min, The dropping time was 12 h. After the dropping, the reaction was continued for 2 h to obtain the transition state intermediate of 3-hydroxy-1-adamantanamine.

[0044] The parameters ...

Embodiment 3

[0049] A kind of preparation method of 3-hydroxyl-1-adamantanamine transition state intermediate, comprises the following steps:

[0050] SS1: Preparation of amantadine sulfate-sulfuric acid mixture: Add 1.91 mol of 96% concentrated sulfuric acid dropwise to 0.26 mol amantadine hydrochloride at a rate of 1.5 g / min under ice water under stirring at 50 rpm , stirred and reacted for 0.5 h for later use;

[0051] SS2: Add 0.61 mol of 98% nitric acid into the 1000mL reactor, and then add 5.6mol of 96% concentrated sulfuric acid dropwise into the reactor while stirring at 150rpm. h;

[0052] SS3: heat up the reactor to 30°C, drop the mixed solution configured in step SS1, the molar ratio of fuming nitric acid in SS2 to amantadine hydrochloride in SS1 is 2.35:1, and the dropping rate is 1g / min, The dropping time was 10 h. After the dropping, the reaction was continued for 2 h to obtain the transition state intermediate of 3-hydroxy-1-adamantanamine.

[0053] The parameters of this...

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Abstract

The invention discloses a preparation method of a 3-hydroxy-1-amantadine transition state intermediate. The method comprises the following steps: preparing an amantadine sulfate and sulfuric acid mixed solution, dropwise adding nitric acid into the reaction kettle, dropwise adding concentrated sulfuric acid, heating a reaction kettle, and dropwise adding the prepared amantadine sulfate and sulfuric acid mixed solution to obtain the 3-hydroxy-1-amantadine transition state intermediate. By changing the drop-by-drop adding mode of concentrated sulfuric acid and concentrated nitric acid, the nitric acid ratio is always in a high-proportion state, the reaction speed is increased, the material accumulation degree is reduced, meanwhile, the reaction temperature is reduced, the difference betweenthe reaction temperature and the secondary decomposition temperature is increased, and the reaction safety is guaranteed.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a preparation method of a transition state intermediate of 3-hydroxy-1-adamantanamine. Background technique [0002] Vildagliptin is a DPP-4 inhibitor developed by Novartis, which is suitable for the treatment of type 2 diabetes and was officially approved by the CFDA for marketing in August 2011. [0003] Regarding the patent application of the original research company Novartis, the vildagliptin compound was first disclosed in the patent application CN1160330C with the filing date of December 9, 1999. This application has been authorized to protect the vildagliptin compound or its pharmaceutically acceptable salt and They are used to inhibit DPP-IV, diabetes, and obesity. The expiration date of the patent is December 9, 2019. [0004] 3-Hydroxy-1-amantadine is an important intermediate. After the patent is opened and it enters the medical insurance catalog, the demand for thi...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/44C07C209/68C07C211/38
CPCC07C213/00C07C209/68C07C2603/74C07C211/38C07C215/44
Inventor 俞晓明闻飞肖前进姜钧元
Owner 江苏泰洁智邦检测技术有限公司
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