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Piperidine sulfamide spiro-compound and preparation method thereof

A technology for sulfonamide spiro and cyclic compounds, which is applied in the field of piperidine sulfonamide spiro compounds and their preparation, can solve the problems such as undiscovered sulfonamide spiro compounds, and achieve the effects of increasing diversity and improving polarity.

Inactive Publication Date: 2012-11-28
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no research report on the special synthesis of sulfonamide spiro compounds in the literature

Method used

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  • Piperidine sulfamide spiro-compound and preparation method thereof
  • Piperidine sulfamide spiro-compound and preparation method thereof
  • Piperidine sulfamide spiro-compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 : 8-Benzyl-2-thio-1,3,8-triazolespiro[4,5]decane-2,2-dioxide-4-one 1-a preparation of

[0042]

[0043] Steps:

[0044] N-Benzylpiperidone 1 (189 grams, 1 mole), 576 grams of ammonium carbonate (6 moles), 133 grams of potassium cyanide (2 moles) and 1.5 liters of ammonium formate were added to the autoclave. The mixture was stirred at 100°C for 48 hours, then cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate and the resulting organic phase was concentrated to 170 g of white 8-benzyl-1,3,8-triazolspiro[4.5]decane-2,4-dione 2 . Yield: 66%.

[0045] HNMR (DMSO) δ:10.63 (br s, 1H), 8.44 (s, 1H), 7.33-7.20 (m, 5H), 3.47 (s, 2H), 2.69-2.66 (m, 2H), 2.30-2.24 ( m, 2H), 1.18-1.17 (m, 2H), 1.52-1.48 (m, 2H).

[0046]100 grams of 8-benzyl-1,3,8-triazole spiro[4.5]decane-2,4-dione 2 (0.39 moles), 300 grams of sodium hydroxide (7.5 moles) were added to 2 liters of water, the mixture was heated to 100 ° C and stir...

Embodiment 2

[0054] Example 2 : 3-Methyl-8-benzyl-2-thio-1,3,8-triazolespiro[4,5]decane-2,2-dioxide-4-one 1-b preparation of

[0055]

[0056] Steps:

[0057] 295 mg of 8-benzyl-2-thio-1,3,8-triazolespiro[4,5]decane-2,2-dioxide-4 1-a (1 mmol), was added to 50 ml of tetrahydrofuran solution, and then 60 mg of sodium hydride (60% in mineral oil) was added. The mixture was stirred at room temperature 25°C for 0.5 hours, then 142 mg of methyl iodide was added to the mixture, the reaction solution was stirred at room temperature for 16 hours and concentrated, and the resulting crude product was separated by column chromatography to obtain 500 mg of 3-methyl-8-benzyl -2-Sulfur-1,3,8-triazolespiro[4,5]decane-2,2-dioxide-4-one 1-b . Yield: 82%.

[0058] HNMR (DMSO) δ: 7.33-7.27 (m, 5H), 7.15 (s, 1H), 3.57 (s, 2H), 2.85 (s, 3H), 2.62-2.60 (m, 2H), 2.42-2.30 (m , 2H), 1.98-1.95 (m, 2H), 1.82-1.80 (m, 2H).

Embodiment 3

[0059] Example 3 : 3,8-Dibenzyl-2-thio-1,3,8-triazolespiro[4,5]decane-2,2-dioxide-4-one 1-c preparation of

[0060]

[0061] Steps:

[0062] 295 mg of 8-benzyl-2-thio-1,3,8-triazolespiro[4,5]decane-2,2-dioxide-4 1-a (1 mmol), was added to 50 ml of tetrahydrofuran solution, and then 60 mg of sodium hydride (60% in mineral oil) was added. The mixture was stirred at room temperature 25°C for 0.5 hours, and then 126 mg of benzyl chloride was added to the mixture. The reaction solution was stirred at room temperature for 16 hours and then concentrated. The obtained crude product was separated by column chromatography to obtain 390 mg of 3,8-dibenzyl-2 -Sulfur-1,3,8-triazolespiro[4,5]decane-2,2-dioxide-4-one 1-c . Yield: 96%.

[0063] HNMR (DMSO) δ: 7.43-7.20 (m, 10H), 7.15 (s, 1H), 4.67 (s, 2H), 3.57 (s, 2H), 2.62-2.60 (m, 2H), 2.42-2.30 (m , 2H), 1.98-1.95 (m, 2H), 1.82-1.80 (m, 2H).

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Abstract

The invention relates to a piperidine sulfamide spiro-compound and a preparation method thereof, and mainly solves the technical problems that the synthesis method of the piperidine sulfamide spiro-compound has not been reported in any literature, and the medical structure-activity relationship thereof can not be screened in the prior art. The structural general formula is shown in the specification, wherein R1 and R2 are hydrogen, alkyl or aryl; and preferably, alkyl or aryl is one of C1-C4 straight-chain alkyl, alkyl containing substituent branch chains and substituent aryl.

Description

technical field [0001] The invention relates to a piperidine sulfonamide spiro compound and a preparation method. Background technique [0002] As early as the 1970s, spirocyclic compounds were found to have biological activity. After more than 30 years of research and development, a variety of spirocyclic derivatives have been proven to have promising therapeutic effects, such as anti-depression, inhibition of angiogenesis (anti-tumor), anti-platelet aggregation (anti-thrombosis), and anti-alheian Merz disease (senile dementia), etc. The structure of the sulfonamide spiro compound contains both hydrogen bond acceptors and donors (R 2 = H). The simultaneous presence of hydrogen bond acceptors and donors can increase the chance of interaction between the substrate and the target, and thus may increase the degree of binding between the substrate and the protein target to increase the activity of the substrate. It has been widely proven that it has various Such biological a...

Claims

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Application Information

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IPC IPC(8): C07D513/10A61P1/14
Inventor 肖贻崧张培权周凯柏祝贺海鹰陈曙辉
Owner 上海药明康德新药开发有限公司