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Synthesis method for synthesizing 4-ethynyl-tetrahydropyran from 2, 2-dichloroethyl ether

A synthetic method, tetrahydropyran technology, applied in chemical instruments and methods, silicon organic compounds, compounds of group 4/14 elements of the periodic table, etc., can solve problems such as complicated operation, high cost, unsuitable for industrial production, etc. , to achieve the effect of simple operation, low cost and convenient post-processing

Active Publication Date: 2021-03-30
HANGZHOU ALLSINO CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It has been reported that this type of compound was synthesized by catalytic coupling (Organic Letters, 2014, 16, 2566; Tetrahedron Letters, 1998, 39, 8597); it was also reported that the special reagent Ohira's reagent (Ohira-Bestmannphosphonate) (WO2015051244A1) was used, but the above The method is complicated to operate, the cost is high, and it is not suitable for industrialized production

Method used

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  • Synthesis method for synthesizing 4-ethynyl-tetrahydropyran from 2, 2-dichloroethyl ether
  • Synthesis method for synthesizing 4-ethynyl-tetrahydropyran from 2, 2-dichloroethyl ether

Examples

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Embodiment 1

[0037] see figure 1 , this example provides a synthesis method of 4-ethynyl-tetrahydropyran starting from 2,2'-dichloroethyl ether, the specific steps are:

[0038] Under nitrogen protection, compound I (100g, 699.3mmol) was dissolved in DMF (400mL), potassium carbonate (193g, 1398.5mmol) and potassium iodide (58g, 349.6mmol) were added, the temperature was raised to 75-80°C, and acetoacetic acid was added dropwise Ethyl ester (109.2g, 839.1mmol), control the temperature at 80-85°C, keep the temperature for 15-20h, filter after the reaction is completed, add 400g water and 300g ethyl acetate to the filtrate, take the organic phase, and use 300g ethyl acetate for the water phase Extract twice, combine the organic phases, wash twice with 300mL water, wash once with 100mL saturated brine, and remove the solvent to obtain 146g of the product; 730g of 30% sulfuric acid is added dropwise to the product of the previous step, and react at 100-110°C for 15-18h. 300g of dichloromethane...

Embodiment 2

[0043] see figure 1 , this example provides a synthesis method of 4-ethynyl-tetrahydropyran starting from 2,2'-dichloroethyl ether, the specific steps are:

[0044] Under nitrogen protection, compound I (100g, 699.3mmol) was dissolved in DMF (400mL), potassium carbonate (193g, 1398.5mmol) and potassium iodide (58g, 349.6mmol) were added, the temperature was raised to 75-80°C, and acetoacetic acid was added dropwise Ethyl ester (109.2g, 839.1mmol), control the temperature at 80-85°C, keep the temperature for 15-20h, filter after the reaction is completed, add 400g water and 300g ethyl acetate to the filtrate, take the organic phase, and use 300g ethyl acetate for the water phase Extract twice, combine the organic phases, wash twice with 300mL water, wash once with 100mL saturated brine, and remove the solvent to obtain 146g of the product; 730g of 30% sulfuric acid is added dropwise to the product of the previous step, and react at 100-110°C for 15-18h. 300g of dichloromethane...

Embodiment 3

[0048] see figure 1 , this example provides a synthesis method of 4-ethynyl-tetrahydropyran starting from 2,2'-dichloroethyl ether, the specific steps are:

[0049] Under nitrogen protection, compound I (100g, 699.3mmol) was dissolved in DMF (400mL), potassium carbonate (193g, 1398.5mmol) and potassium iodide (58g, 349.6mmol) were added, the temperature was raised to 75-80°C, and acetoacetic acid was added dropwise Ethyl ester (109.2g, 839.1mmol), control the temperature at 80-85°C, keep the temperature for 15-20h, filter after the reaction is completed, add 400g water and 300g ethyl acetate to the filtrate, take the organic phase, and use 300g ethyl acetate for the water phase Extract twice, combine the organic phases, wash twice with 300mL water, wash once with 100mL saturated brine, and remove the solvent to obtain 146g of the product; 730g of 30% sulfuric acid is added dropwise to the product of the previous step, and react at 100-110°C for 15-18h. 300g of dichloromethane...

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Abstract

The invention provides a synthetic method for synthesizing 4-ethynyl-tetrahydropyran from 2, 2 '-dichloroethyl ether, which comprises the following steps: (a) reacting a compound shown in a formula (I) with ethyl acetoacetate under the action of potassium carbonate and potassium iodide, carrying out aftertreatment, and carrying out sulfuric acid decarboxylation to obtain a compound shown in a formula (II); (b) removing hydrogen from the compound shown in the formula (II) by using an organic lithium reagent, and reacting with a diester chlorophosphate reagent to obtain a compound shown in a formula (III); and (c) removing the compound shown in the formula (III) by using an alkaline reagent, and reacting with alkyl chlorosilane to obtain a compound shown in a formula (IV). According to the preparation method, starting raw materials, process routes and post-treatment processes are different, the raw materials are simple and easy to obtain, the cost is low, and the preparation method is suitable for laboratory small-scale preparation and industrial production.

Description

technical field [0001] The invention relates to the technical field of organic compound synthesis, in particular to a method for synthesizing 4-ethynyl-tetrahydropyran from 2,2'-dichloroethyl ether. Background technique [0002] 4-ethynyl-tetrahydropyran is an important pharmaceutical intermediate, which can be used to synthesize bradykinin receptor antagonists, JAK enzyme inhibitors and Trk A enzyme inhibitors (WO2006123113, WO2009013545A2, US20120165338, etc.), and can also be used Combined with anti-tumor drugs (CN1576275A), it is an intermediate in the synthesis of erbB2 receptor selective inhibitors (rather than erbB1 receptor inhibitors), and erbB2 receptor selective inhibitors are candidate compounds for a class of important anti-tumor drugs ( WO2003049740A1); these pharmaceutical intermediates are also used in the synthesis of PI3 kinase agonists and antagonists. PI3 kinase agonists and antagonists are also candidates for an important class of antitumor drugs (WO201...

Claims

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Application Information

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IPC IPC(8): C07F7/08
CPCC07F7/0827
Inventor 何鹏飞刘克允孙飞强郑军微边小科徐滨滨
Owner HANGZHOU ALLSINO CHEM
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