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Method for synthesizing 4-(3-iodo-2-pyridinyl) piperazine compound

A synthetic method, pyridyl-based technology, applied in the direction of organic chemistry, can solve the problems of low overall yield, difficult product separation, by-product generation, etc., and achieve cheap starting materials, simple operation and post-treatment, and time-saving short effect

Active Publication Date: 2012-05-09
SHANGHAI SYNTHEALL PHARM CO LTD
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  • Abstract
  • Description
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Problems solved by technology

It mainly solves the technical problems existing in the existing preparation methods, such as harsh reaction conditions, generation of by-products, difficulty in product separation, low total yield and unsuitable for large-scale production

Method used

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  • Method for synthesizing 4-(3-iodo-2-pyridinyl) piperazine compound
  • Method for synthesizing 4-(3-iodo-2-pyridinyl) piperazine compound
  • Method for synthesizing 4-(3-iodo-2-pyridinyl) piperazine compound

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Experimental program
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Effect test

Embodiment 1

[0026]

[0027] Synthesis of 4-(3-nitro-pyridine-2)-piperazine-1-tert-butyl carbonate

[0028] 2-Chloro-3-nitro-pyridine (47.5 g, 0.3 mol), N-tert-butoxy-piperazine (67 g, 0.36 mol), potassium carbonate (125 g, 0.9 mol) were added to dimethylsulfoxide ( 500 mL), stirred at room temperature for 10 minutes, then raised the temperature to 90° C., and reacted for 5 hours. After the system was cooled to room temperature, the reaction solution was poured into water and extracted with ethyl acetate (500 mL×3). The organic layers were combined, dried and concentrated to obtain tert-butyl 4-(3-nitro-pyridine-2)-piperazine-1-carbonate (87.5 g, yield 94.6%), which was used in the next reaction without purification.

[0029] 1 H NMR (300MHz, CDCl 3 ): δ1.41(s, 9H), 3.36-3.41(m, 4H), 3.48-3.51(m, 4H), 6.70-6.74(q, J=8.1Hz, J=4.5Hz, 1H), 8.06- 8.09(dd, J=8.1Hz, J=1.8,1H), 8.26-8.28(dd, J=4.5Hz, J=1.8,1H)

Embodiment 2

[0031]

[0032] Synthesis of 4-(3-nitro-pyridine-2)-piperazine-1-tert-butyl carbonate

[0033]2-Chloro-3-nitro-pyridine (4.75 g, 003 mol), N-tert-butoxy-piperazine (6.7 g, 0.036 mol), potassium carbonate (12.5 g, 0.09 mol) were added to acetonitrile (20 mL) , stirred at room temperature for 10 minutes, and then heated to reflux for 18 hours. After the system was cooled to room temperature, it was filtered, the filtrate was washed with water, and extracted with ethyl acetate (20 mL×3). The organic layers were combined, dried and concentrated to obtain tert-butyl 4-(3-nitro-pyridine-2)-piperazine-1-carbonate (7.5 g, yield 81%), which was used in the next reaction without purification.

[0034] 1 H NMR (300MHz, CDCl 3 ): δ1.41(s, 9H), 3.36-3.41(m, 4H), 3.48-3.51(m, 4H), 6.70-6.74(q, J=8.1Hz, J=4.5Hz, 1H), 8.06- 8.09(dd, J=8.1Hz, J=1.8,1H), 8.26-8.28(dd, J=4.5Hz, J=1.8,1H)

Embodiment 3

[0036]

[0037] Synthesis of 4-(3-nitro-pyridine-2)-piperazine-1-tert-butyl carbonate

[0038] 2-Chloro-3-nitro-pyridine (4.75g, 0.03mol), N-tert-butoxy-piperazine (6.7g, 0.036mol), cesium carbonate (19.5g, 0.06mol) were added to N,N -Dimethylformamide (20 mL), stirred at 60°C for 8 hours. After the system was cooled to room temperature, the reaction solution was poured into water and extracted with ethyl acetate (20 mL×3). The organic layers were combined, dried and concentrated to obtain tert-butyl 4-(3-nitro-pyridine-2)-piperazine-1-carbonate (8.5 g, yield 92%), which was used in the next reaction without purification.

[0039] 1 H NMR (300MHz, CDCl 3 ): δ1.41(s, 9H), 3.36-3.41(m, 4H), 3.48-3.51(m, 4H), 6.70-6.74(q, J=8.1Hz, J=4.5Hz, 1H), 8.06- 8.09(dd, J=8.1Hz, J=1.8,1H), 8.26-8.28(dd, J=4.5Hz, J=1.8,1H)

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Abstract

The invention relates to a method for synthesizing a 4-(3-iodo-2-pyridinyl) piperazine compound, which mainly solves the technical problems that the prior preparation method has harsh reaction conditions, the generation of side reactions, difficult separation, low total yield and difficult large-scale production. The method comprises the following preparation steps: using 2-chloro-3-nitropyridineas an initial raw material to perform N-alkylation reaction with N-tert-butoxycarbonyl-piperazine and alkali in an organic solvent to obtain 1-tert-butoxycarbonyl-4-(3-nitro-2-pyridinyl) piperazine (11); under the action of a reducing agent, reducing the nitryl in the compound (11) to obtain 1-tert-butoxycarbonyl-4-(3-amino-2-pyridinyl) piperazine (12); performing diazotization iodination reaction on the compound (12) to obtain 1-tert-butoxycarbonyl-4-(3-iodo-2-pyridinyl) piperazine (8); and under an acidic condition, de-protecting the compound (8) to obtain the 4-(3-iodo-2-pyridinyl) piperazine (7). The method is mainly used for the large-scale preparation of 4-(2-pyridinyl) piperazine compounds.

Description

Technical field: [0001] The invention relates to a new synthesis method of 4-(3-iodo-2-pyridyl)piperazine compounds. Background technique: [0002] 4-(2-pyridyl)piperazine compounds are key intermediates for research and / or synthesis of a new class of antagonists for capsaicin receptors (Vanilloid receptor1, TRPV1 or VR1). Vanilloid receptor 1 (according to the literature (Neuropharmacology 2002, 42, 873)) is a member of the transient receptor potential (TRP) ion channel family, and is an important receptor for research on the development of new painkillers. Using 4-(2-pyridyl)piperazine as the backbone to study or synthesize effective antagonists of Vanilloid receptor1 has received widespread attention. So far, there have been a variety of 4-(2-pyridyl)piperazine compounds as The active structure of the backbone. Literature (Bioorg.Med.Chem.Lett.2003,13,3611-3616) has reported antagonist compound 1 and BCTC and corresponding activity test experiment against Vanilloid rece...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/72
Inventor 林道广王小平彭作中廖文胜陈曙辉
Owner SHANGHAI SYNTHEALL PHARM CO LTD
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