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Synthesis method of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid

A synthesis method, benzyloxy technology, applied in the field of organic chemical synthesis, can solve the problems of harsh reaction conditions, difficulty in production scale-up, low process safety, etc., and achieve the effect of controllable conditions, strong repeatability and stable process

Pending Publication Date: 2019-03-08
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In view of the deficiencies in the prior art, in order to improve the shortcomings of the 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid synthesis process route, the reaction conditions are harsh, the process safety is low, and it is difficult to produce and scale up. The invention provides a synthetic method of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid

Method used

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  • Synthesis method of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid
  • Synthesis method of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid
  • Synthesis method of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 1. Synthesis of 3-hydroxy-4H-pyran-4-one (compound II)

[0045]

[0046] Add methanol (60L), water (40L) and sodium acetate (20Kg) into the reaction kettle, and cool down to -5°C. Dissolve furfuryl alcohol (compound I) (40kg) in methanol (40L) and water (20L), and add it dropwise into the reaction kettle at a temperature controlled -5°C, and feed chlorine gas (57.8kg) into the reaction kettle while adding dropwise. Keep warm for 1h, the reaction is over, keep warm overnight, and filter. The mother liquor was heated to 50°C, stirred for 2h, and cooled to room temperature. filter. Concentrate under reduced pressure to remove methanol and crystallize to obtain 26.7 kg of 3-hydroxy-4H-pyran-4-one (compound II) with a purity of 95% and a yield of 59%. LC-MS: [M+H] + =113.02.

[0047] 2. Synthesis of 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (compound III)

[0048]

[0049] 3-Hydroxy-4H-pyran-4-one (compound II) (26.7kg) and methanol (134L) were added to the reac...

Embodiment 2

[0057] 1. Synthesis of 3-hydroxy-4H-pyran-4-one (compound II)

[0058]

[0059] Add ethanol (30L), water (20L) and sodium acetate (10Kg) into the reaction kettle, and cool down to 5°C. Dissolve furfuryl alcohol (Compound I) (20kg) in ethanol (20L) and water (10L), and add it dropwise into the reaction kettle at a temperature of 5°C. Chlorine gas (25.5kg) is introduced into the reaction kettle while adding dropwise. Keep warm for 1h, the reaction is over, keep warm overnight, and filter. The temperature of the mother liquor was raised to 70°C, stirred for 2h, and cooled to room temperature. filter. Concentrate under reduced pressure to remove ethanol and crystallize to obtain 14.2 kg of 3-hydroxy-4H-pyran-4-one (compound II) with a purity of 94% and a yield of 62%. LC-MS: [M+H] + =113.02.

[0060] 2. Synthesis of 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (compound III)

[0061]

[0062] 3-Hydroxy-4H-pyran-4-one (compound II) (14.2 kg) and methanol (70 L) were added...

Embodiment 3

[0070] 1. Synthesis of 3-hydroxy-4H-pyran-4-one (compound II)

[0071]

[0072] Add tetrahydrofuran (30L), water (20L) and potassium acetate (10kg) into the reaction kettle and cool down to 5°C. Dissolve furfuryl alcohol (compound I) (20kg) in tetrahydrofuran (20L) and water (10L), and add it dropwise into the reaction kettle at a temperature controlled 5°C, and feed chlorine gas (30kg) into the reaction kettle while adding dropwise. Keep warm for 1h, the reaction is over, keep warm overnight, and filter. The mother liquor was heated to 60°C, stirred for 2h, and cooled to room temperature. filter. Concentrate under reduced pressure to remove tetrahydrofuran and crystallize to obtain 12.4 kg of 3-hydroxy-4H-pyran-4-one (compound II) with a purity of 95% and a yield of 54%. LC-MS: [M+H] + =113.02.

[0073] 2. Synthesis of 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (compound III)

[0074]

[0075] 3-Hydroxy-4H-pyran-4-one (compound II) (12.4 kg) and methanol (76 L) we...

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Abstract

The invention discloses a synthesis method of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. The synthesis method takes furfuryl alcohol as a starting raw material and four-step reaction including rearrangement, addition, hydroxyl protection and oxidization is carried out; the total mol yield of a synthesis route is greater than 32 percent; the synthesis method has the characteristics of relatively moderate reaction conditions and the like, and the yield and purity of the 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid are remarkably improved; meanwhile, the synthesis method has the advantagesof detailed technological operation steps, specific parameters, controllable conditions and stable technology, and can realize industrial large-batch production.

Description

technical field [0001] The present invention relates to the field of organic chemical synthesis, more specifically, to a method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. Background technique [0002] There are a variety of preclinical, clinical and marketed new drugs containing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid fragments. Several types of drug molecules as shown below, as well as marketed drugs such as dolutegravir (GSK1349572) and baloxavir (Baloxavir), contain this important structural fragment. [0003] [0004] At present, there are two main synthetic routes for this structural sheet, and the synthetic routes are as follows. The main disadvantage of this route is that the materials are expensive, the steps are long, and it is difficult to scale up safely: [0005] [0006] Another synthetic method is the following synthetic route. This synthetic route is relatively better, but selenium dioxide is highly toxic and used in large...

Claims

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Application Information

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IPC IPC(8): C07D309/40
CPCC07D309/40Y02P20/55
Inventor 叶伟平周章涛费安杰谢阳银习林刚
Owner RAFFLES PHAMRMATECH CO LTD
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