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Method for preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane

A -2-boc-2, diazabicyclo technology, applied in the field of medicinal chemistry, can solve the problems of low yield, difficult impurity removal in the synthesis process, etc., and achieve the effects of high purity, few impurities, easy purification and scale-up production

Inactive Publication Date: 2019-02-22
成都福尔斯特医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Aiming at the above-mentioned deficiencies in the prior art, the present invention provides a preparation method of (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane, which can effectively solve the problem of the existing synthesis process Difficult to remove impurities and low yield

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  • Method for preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane

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Embodiment 1

[0035] A preparation method of (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane, comprising the following steps:

[0036] (1) Dissolve 1kg of N-Boc-trans-4-hydroxy-L-proline methyl ester in 5L of methanol, cool in an ice bath to 35°C, then add 465g of sodium borohydride, and add it in 6 hours. And control the temperature during the addition process not to exceed 35°C, react at room temperature for 12 hours, and monitor the completion of the reaction with TLC. After the complete reaction, slowly pour the reaction solution into 10L of water, stir for 30min, filter, and wash the filter cake with 2L of methanol. The filtrate was concentrated under reduced pressure to about 10L, and then extracted three times with 2L of dichloromethane, and then the organic phases obtained from the extraction were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 850 g of a light yellow oily substance, namely Intermediate I;

[0037] (2) Dissolve Inte...

Embodiment 2

[0042] A preparation method of (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane, comprising the following steps:

[0043] (1) Dissolve 800g of N-Boc-trans-4-hydroxy-L-proline methyl ester in 5L of absolute ethanol, cool in an ice bath to 30°C, then add 300g of sodium borohydride, add 6 hours Complete, and control the temperature during the addition process not to exceed 35°C, react at room temperature for 12 hours, and monitor the complete reaction with TLC, after the complete reaction, slowly pour the reaction solution into 10L of water, stir for 30min, filter, and filter the cake with 2L ethanol After washing, the filtrate was concentrated under reduced pressure to about 10L, and then extracted three times with 2L of dichloromethane, and then the organic phases obtained from the extraction were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a light yellow oily substance, namely intermediate I;

[0044](2) Dissolve 800g of in...

Embodiment 3

[0049] A preparation method of (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane, comprising the following steps:

[0050] (1) Dissolve 900g of N-Boc-trans-4-hydroxy-L-proline methyl ester in 5L of absolute ethanol, cool in an ice bath to 35°C, then add 500g of sodium borohydride, add 6 hours Complete, and control the temperature during the addition process not to exceed 35°C, react at room temperature for 12 hours, and monitor the complete reaction with TLC, after the complete reaction, slowly pour the reaction solution into 10L of water, stir for 30min, filter, and filter the cake with 2L ethanol After washing, the filtrate was concentrated under reduced pressure to about 10L, and then extracted three times with 2L of dichloromethane, and then the organic phases obtained from the extraction were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a light yellow oily substance, namely intermediate I;

[0051] (2) Dissolve 1kg of in...

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Abstract

The invention discloses a method for preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane. The method comprises the following steps: (1) preparing an intermediate I by using N-Boc-trans-4-hydroxy-L-proline methyl ester as a raw material; (2) preparing an intermediate II by reacting the intermediate I with an organic base and a sulfonylating reagent; (3) preparing an intermediate III from the intermediate II and benzylamine; and (4) finally preparing (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane by debenzylating the intermediate III. The method provided by the invention simplifies reaction steps, reduces raw material cost and time cost, has high product yield, tends to purify and amplify production, and can reduce waste discharge.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane. Background technique [0002] (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane, CAS No.: 113451-59-5. It has a novel structure and is a very promising pharmaceutical intermediate. [0003] The two existing commonly used preparation methods are as follows: one requires a total of seven steps of reaction, and the total yield is 32.5%. In the last step, triphenylphosphine needs to be used to reduce azide and ring closure, which requires silica gel column purification to remove A large amount of triphenoxyphos by-product is not suitable for industrial production. [0004] Another method is to use N-Boc-trans-4-hydroxy-L-proline methyl ester as a raw material and obtain it through a four-step reaction, but this route requires the use of sodium azide, which is a highly toxic drug , explosive an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/12C07D487/04
CPCC07B2200/07C07D207/12C07D487/04
Inventor 程真勇
Owner 成都福尔斯特医药技术有限公司