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Preparation method of sulfydryl alkenyl ester compound

A technology of ester compounds and mercaptoalkenes, which is applied in the field of preparation of synthetic mercaptoalkene esters, can solve problems such as enlarged production risks and difficult safety control, so as to improve overall safety and environmental protection, solve industrialization problems, The effect of novel technology

Inactive Publication Date: 2021-07-20
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In summary, the above-mentioned various defects make the safety control of this route difficult, and the risk of enlarged production is high
Therefore, there is no relatively mature process in the industry to prepare mercaptoenol esters (J.Phys.Org.Chem.2009,22,1188-1192; J.Med.Chem.2005,48,7457-7467)

Method used

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  • Preparation method of sulfydryl alkenyl ester compound
  • Preparation method of sulfydryl alkenyl ester compound
  • Preparation method of sulfydryl alkenyl ester compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]

[0023] (1) Synthesis of ethyl 2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate (intermediate 1a, 122135-83-5)

[0024] In a 500mL three-neck flask, add 60% sodium hydrogen (3.5g, 1.5eq.), add 200mL dichloromethane, and replace with nitrogen three times. React at 0-5°C, add ethyl 2-cyclohexanone carboxylate (10.0 g, 1.0eq.) dropwise, keep stirring for 10 min, then continue to lower the temperature to -70°C, add Tf dropwise 2 O (24.3g, 1.5eq.) in the reaction solution (control the addition rate), keep stirring for 15 minutes, then naturally warm up to 25°C and stir overnight; then add saturated NaHCO 3 The pH of the solution was adjusted to 8-9, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain intermediate 1a (15.6 g, 90.0% yield).

[0025]

[0026] (2) Synthesis of ethyl 2-(4-methoxythiophenol)cyclohex-1-enecarboxylate (intermediate 2a)

[0027] In a 500 mL three-neck flask, add 60% sodium hydrogen (1.90 g, 1.2 eq....

Embodiment 2

[0032]

[0033] (1) Synthesis of ethyl 2-(trifluoromethylsulfonyloxy)cyclopent-1-enecarboxylate (intermediate 1b, 122539-74-6)

[0034] In a 500mL three-neck flask, add 60% sodium hydrogen (3.5g, 1.5eq.), add 200mL dichloromethane, and replace with nitrogen three times. React at 0-5°C, add ethyl 2-cyclopentanone carboxylate (9.2g, 1.0eq.) dropwise, keep stirring for 10min, then continue to drop the temperature to -70°C, and continue to add Tf 2 O (24.9g, 1.5eq.) in the reaction solution (control the addition rate), keep stirring for 15 minutes, then naturally warm up to 25°C and stir overnight; then add saturated NaHCO 3 The pH of the solution was adjusted to 8-9, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain intermediate 1b (14.9 g, 88.0% yield).

[0035]

[0036] (2) Synthesis of ethyl 2-(4-methoxythiophenol)cyclopent-1-enecarboxylate (intermediate 2b)

[0037] In a 500mL three-neck flask, add 60% sodium hydrogen (1.67g, 1.2...

Embodiment 3

[0042]

[0043] (1) Synthesis of ethyl 2-(trifluoromethylsulfonyloxy)cyclohep-1-enecarboxylate (intermediate 1c, 122539-74-6)

[0044] In a 500mL three-neck flask, add 60% sodium hydrogen (3.3g, 1.5eq.), add 200mL dichloromethane, and replace with nitrogen three times. React at 0-5°C, add ethyl 2-cycloheptanonecarboxylate (10.1g, 1.0eq.) dropwise, keep stirring for 10min, then continue to drop the temperature to -70°C, and continue to add Tf 2 O (23.2g, 1.5eq.) in the reaction solution (control the addition rate), keep stirring for 15 minutes, then naturally warm up to 25°C and stir overnight; then add saturated NaHCO 3 The pH of the solution was adjusted, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 1c (14.7 g, 85.0% yield).

[0045]

[0046](2) Synthesis of ethyl 2-(4-methoxythiophenol) cyclohept-1-enecarboxylate (intermediate 2c)

[0047] In a 500mL three-neck flask, add 60% sodium hydrogen (1.5g, 1.2eq.), add 12...

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Abstract

The invention relates to a preparation method of a sulfydryl alkenyl ester compound, belongs to the field of organic chemical synthesis, and aims to solve the problems of high risk of large-scale production and the like, and the synthesis route provided by the invention comprises the following three steps: (1) carrying out a reaction on a starting material ethyl 2-oxo carboxylate compound and Tf2O (trifluoromethanesulfonic anhydride) under the action of alkali and a solvent A, so as to generate an enol intermediate 1 protected by trifluoromethanesulfonyl; (2) carrying out substitution reaction with a sulfo reagent to obtain an intermediate 2; and (3) performing deprotection on the intermediate 2 under the action of a deprotection reagent to obtain a target product 3. The method for preparing the sulfydryl alkenyl ester compound has the beneficial effects that the process is novel, toxic gases such as hydrogen sulfide are prevented from being used, the overall safety and environmental protection property of the process are improved, and the method is more suitable for large-scale production and solves the industrialization problem.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, in particular to a preparation method for synthesizing mercaptoalkenyl esters. Background technique [0002] Mercaptoenol esters are key intermediates used in the preparation of innovative drugs such as sepsis. At present, the main route for the synthesis of this type of substance is shown in the following formula. In the reaction process, it is necessary to prepare a relatively high concentration of hydrogen sulfide methanol solution, and then introduce hydrogen chloride into the reaction solution. Although the synthesis scheme is simple, hydrogen sulfide has toxicity and foul smell, and there is a big safety hazard when used in large quantities. In addition, hydrogen chloride gas is also strongly irritating. [0003] [0004] In summary, the above-mentioned various defects make the safety control of this route difficult, and the risk of enlarged production is high. Therefore, ther...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C319/06C07C323/61
CPCC07C319/06C07C319/14C07C303/26C07C2601/16C07C2601/10C07C2601/18
Inventor 叶伟平费安杰周章涛王杨谢辛欣
Owner SHENZHEN HUAXIAN PHARMA TECH CO LTD
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