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Method for synthetizing medical intermediate heterocyclic group pyridine N-oxide

A technology of pyridine nitrogen oxide and synthesis method, which is applied in the synthesis of heterocyclic compounds and the synthesis field of heterocyclic substituted pyridine nitrogen oxides, and can solve the problems of low reaction yield and narrow application range.

Active Publication Date: 2015-10-07
福建未来药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] As mentioned above, although there are multiple synthetic methods of pyridine nitrogen oxides in the prior art, there are still some defects, such as narrow application range, low reaction yield and many other disadvantages

Method used

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  • Method for synthetizing medical intermediate heterocyclic group pyridine N-oxide

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Experimental program
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Effect test

Embodiment 1

[0033]

[0034] Under a nitrogen atmosphere, add 100mmol formula (I) compound and 300mmol tetrahydrofuran to the reactor, then add 6mmol catalyst, 100mmol base triisopropanolamine, 200mmol oxidant cumene hydroperoxide and 5mmol auxiliary agent p-toluenesulfonic acid Sodium, stirred and heated to 80°C for 10 hours, cooled to room temperature after the reaction, added saturated brine, extracted three times with ether, combined organic phases, dried with anhydrous magnesium sulfate, concentrated in vacuo, passed through a 300-400 mesh silica gel column Chromatography, using a mixture of acetone and ethyl acetate at a volume ratio of 1:2 as the eluent, thereby obtaining the compound of formula (II) with a yield of 97.2%.

[0035] Among them, the catalyst is Fe(acac) 3 And the mixture of N-methyl-N-n-butylpyrrole bis(trifluoromethanesulfonyl)imide salt, where Fe(acac) 3 The molar ratio of N-methyl-N-n-butylpyrrole bis(trifluoromethanesulfonyl)imide salt is 1:0.1.

[0036] 1 H...

Embodiment 2

[0039]

[0040] Under a nitrogen atmosphere, add 100mmol formula (I) compound and 320mmol tetrahydrofuran to the reactor, then add 8mmol catalyst, 130mmol base triisopropanolamine, 250mmol oxidant cumene hydroperoxide and 7mmol auxiliary agent p-toluenesulfonic acid Sodium, stirred and heated to 90°C for 9 hours, cooled to room temperature after the reaction, added saturated brine, extracted three times with ether, combined organic phases, dried with anhydrous magnesium sulfate, concentrated in vacuo, passed through a 300-400 mesh silica gel column Chromatography, using a mixture of acetone and ethyl acetate at a volume ratio of 1:3 as the eluent, thereby obtaining the compound of formula (II) with a yield of 97.5%.

[0041] Among them, the catalyst is Fe(acac) 3 And the mixture of N-methyl-N-n-butylpyrrole bis(trifluoromethanesulfonyl)imide salt, where Fe(acac) 3 The molar ratio of N-methyl-N-n-butylpyrrole bis(trifluoromethanesulfonyl)imide salt is 1:0.15.

[0042] 1 H...

Embodiment 3

[0045]

[0046] Under a nitrogen atmosphere, add 100mmol formula (I) compound and 350mmol tetrahydrofuran to the reactor, then add 10mmol catalyst, 150mmol base triisopropanolamine, 300mmol oxidant cumene hydroperoxide and 8mmol auxiliary agent p-toluenesulfonic acid Sodium, stirred and heated to 100°C for 8 hours, cooled to room temperature after the reaction, added saturated brine, extracted three times with ether, combined organic phases, dried with anhydrous magnesium sulfate, concentrated in vacuo, passed through a 300-400 mesh silica gel column Chromatography, using a mixture of acetone and ethyl acetate at a volume ratio of 1:2 as the eluent, thereby obtaining the compound of formula (II) with a yield of 97.7%.

[0047] Among them, the catalyst is Fe(acac) 3 And the mixture of N-methyl-N-n-butylpyrrole bis(trifluoromethanesulfonyl)imide salt, where Fe(acac) 3 The molar ratio of N-methyl-N-n-butylpyrrole bis(trifluoromethanesulfonyl)imide salt is 1:0.2.

[0048] 1 ...

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Abstract

The invention relates to a method for synthetizing medical intermediate heterocyclic group pyridine N-oxide of the following chemical formula (II). The method comprises the steps that in an inert gas atmosphere, compound of the formula (I) and tetrahydrofuran are added to a reaction still, then catalyst, alkali, oxidizing agents and addition agents are sequentially added into the reaction still, stirring is carried out to warming up to 80-100 DEG C to carry out reaction for 8-10 hours, the chemicals are cooled down to room temperature after reaction, a saturated salt solution is added to the chemicals, extraction is carried out for three times through diethyl ether, organic phases are combined, anhydrous magnesium sulfate is adopted for drying, vacuum concentration is carried out, and column purification is carried out to obtain the compound of the chemical formula (II) (please see the specification), wherein R is selected from H, halogen, C1-C6 alkyl groups and phenyl groups with or without substituent groups. According to the method, target products can be obtained in high yield through appropriate selection and combination of the catalyst, the alkali, the addition agents and the oxidizing agents, and the method has wide application prospects and industrialized potential productivity in the technical field of medical intermediate synthetic technology and the field of organic chemical synthesis.

Description

technical field [0001] The invention relates to a synthesis method of a heterocyclic compound, more specifically to a synthesis method of a heterocyclic substituted pyridine nitrogen oxide, and belongs to the field of synthesis of chemical intermediates and the technical field of pharmaceutical intermediates. Background technique [0002] Pyridine compounds are building blocks for natural products, drugs and synthetic materials, but due to the weak reactivity and poor regioselectivity of pyridine itself, pre-functionalization is often required in the synthesis. A variety of N-activated pyridine compounds have been reported, especially pyridine nitrogen oxides, which have attracted much attention. [0003] In recent years, there have been many reports on the modification or transformation of pyridine nitrogen oxides, such as: [0004] A benzo The coupling reaction method of pyridine nitrogen oxide and alkenyl, the reaction formula is as follows: [0005] [0006] Tan Yi...

Claims

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Application Information

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IPC IPC(8): C07D405/04
CPCC07D405/04
Inventor 王伍顺
Owner 福建未来药业有限公司
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