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Synthesis method of 2-(trifluoromethyl) pyrimidine-5-ol

A technology of trifluoromethyl and synthetic methods, applied in the field of drug synthesis, can solve problems such as low yield, inability to prepare large quantities of dangerous oxidants, harsh reaction conditions, etc., and achieve high yield, readily available and cheap raw materials, and controllable reaction conditions Effect

Pending Publication Date: 2020-08-14
LONGXINING SHANGHAI PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The yield of the above-mentioned synthetic route is low, the reaction conditions are harsh (low temperature), and in the synthetic process, the use of dangerous oxidants cannot be prepared in large quantities

Method used

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  • Synthesis method of 2-(trifluoromethyl) pyrimidine-5-ol
  • Synthesis method of 2-(trifluoromethyl) pyrimidine-5-ol
  • Synthesis method of 2-(trifluoromethyl) pyrimidine-5-ol

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preparation example Construction

[0037] The present invention provides a kind of synthetic method of 2-(trifluoromethyl)pyrimidin-5-ol, and its synthetic route and synthetic steps are as follows:

[0038]

[0039] Step 1, Synthesis of Intermediate 1:

[0040] Add 1,3-diamino-2-hydroxypropane and ethyl trifluoroacetate into a reaction bottle equipped with a water separator, heat up to 140-180°C for 3-6 hours, cool down to room temperature, add beating solvent for beating Precipitated solids were filtered to obtain the crystals of Intermediate 1;

[0041] Step 2, synthesis of intermediate 2:

[0042] S1, dissolving intermediate 1 in an organic solvent, adding triethylamine in an ice bath and cooling down to -5-0°C, adding p-toluenesulfonyl chloride in batches to react;

[0043] S2, after the reaction is completed, add the water layer, extract the water phase with a corresponding organic solvent, then combine the organic phases, wash, dry, filter and spin dry to obtain a crude product;

[0044] S3, the cru...

Embodiment 1

[0058] With reference to the following collective route, the present embodiment provides a preferred synthetic method of 2-(trifluoromethyl)pyrimidin-5-ol, comprising the following steps:

[0059]

[0060] Step 1, 2-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-5 alcohol:

[0061] Add 1,3-diamino-2-hydroxypropane (9.0g, 0.1mol) and ethyl trifluoroacetate (14.2g, 0.1mol) into a reaction flask equipped with a water separator, and raise the temperature to 160°C for 6 hours , cooled to room temperature, adding petroleum ether (20ml) to make a slurry to separate out solids, filtered and dried to obtain 10g crystals to obtain 2-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-5 alcohol, yield 60%.

[0062] Step 2, synthesis of 1-p-toluenesulfonyl-2-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidine-5-oxo-p-toluenesulfonyl:

[0063]Dissolve 2-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-5 alcohol (10g, 0.059mol) in dichloromethane (100ml), add triethylamine (18g, 0.178mol) The ice ba...

Embodiment 2

[0070] With reference to the following collective route, the present embodiment provides a preferred synthetic method of 2-(trifluoromethyl)pyrimidin-5-ol, comprising the following steps:

[0071]

[0072] Step 1, 2-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-5 alcohol:

[0073] 1,3-diamino-2-hydroxypropane (9.0g, 0.1mol) and ethyl trifluoroacetate (14.2g, 0.1mol) were dissolved in xylene and added to a reaction flask equipped with a water separator, and the temperature was raised to React at 160°C for 6 hours, cool down to room temperature, spin off the xylene under vacuum, and add n-hexane (20ml) to the crude product to make a slurry to precipitate a solid, filter and dry to obtain 8.3g of crystals to obtain 2-(trifluoromethyl)-1. 4,5,6-tetrahydropyrimidin-5 alcohol, yield 50%.

[0074] Step 2, synthesis of 1-p-toluenesulfonyl-2-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidine-5-oxo-p-toluenesulfonyl:

[0075] 2-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-5 alcohol (8...

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Abstract

The invention provides a synthesis method of 2-(trifluoromethyl) pyrimidine-5-ol. The preparation method comprises the following steps: S1, adding 1, 3-diamino-2-hydroxypropane and ethyl trifluoroacetate into a reaction bottle provided with a water segregator, heating to 160-180 DEG C, reacting for 4-6 hours, cooling to room temperature, adding a pulping solvent, pulping to separate out a solid, filtering, and drying to obtain an intermediate 1; S2, reacting the intermediate 1 with p-toluenesulfonyl chloride at 0 DEG C, and adding water for stratified extraction and desolvation to obtain an intermediate 2; and S3, dissolving the intermediate 2, adding alkali, and reacting at room temperature to obtain the synthesized 2-(trifluoromethyl) pyrimidine-5-ol. According to the invention, the ethyl trifluoroacetate and the 1, 3-diamino-2-hydroxypropane are used as raw materials, the raw materials are easy to obtain and cheap, a dangerous oxidant is not used in the whole synthesis process, reaction conditions are controllable, steps of harsh extremely-low-temperature reaction conditions are avoided, the yield is high, and in conclusion, the synthesis method provided by the invention is lowin cost, high in efficiency, controllable in reaction condition and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of 2-(trifluoromethyl)pyrimidin-5-ol. Background technique [0002] The so-called pharmaceutical intermediates are actually some chemical raw materials or chemical products used in the process of pharmaceutical synthesis. This kind of chemical product does not need a 00000 drug production license, and can be produced in ordinary chemical factories. As long as it reaches a certain level, it can be used for the synthesis of drugs. my country needs more than 2,000 kinds of raw materials and intermediates for chemical industry every year, with a demand of more than 2.5 million tons. Therefore, improving the synthesis yield of important pharmaceutical intermediates, simplifying synthesis operations, and reducing costs will play a good role in promoting the development of drug synthesis. [0003] 2-(trifluoromethyl)pyrimidin-5-ol is an advanced intermediate ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/36C07D239/06
CPCC07D239/36C07D239/06
Inventor 彭如清李春成赵沈江朱宁
Owner LONGXINING SHANGHAI PHARMA TECH CO LTD
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