Synthetic method of thiophene-3-ethanol

A synthesis method and ethanol technology are applied in the synthesis field of thiophene-3-ethanol, can solve the problems of high price of thiophene-3-acetic acid, difficult to remove isomer impurities, unsuitable for large-scale production, etc. The effect of avoiding the generation of isomers and being easy to operate

Inactive Publication Date: 2011-11-16
ASYMCHEM LAB TIANJIN +4
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Problems solved by technology

[0004] (1) Both the Grignard reagent method and the sodium reagent method use thiophene as a raw material to obtain the metal compound of thiophene through different steps, then react with ethylene oxide, and then hydrolyze to obtain thiophene-3-ethanol. These two methods The material used contains ethylene oxide, which is an explosive and dangerous product, and it is more dangerous in the production process;
[0005] (2) The ester reduction method is to use thiophene acetate as a raw material, and under the action of a catalyst, the ester is reduced to a primary alcohol; the yield of this method is relatively low;
[0006] (3) Using methanol and thiophene-3-acetic acid as starting materials, react in a hydrogen chloride system to first obtain thiophene-3-ethanol methyl ester, then thiophene-3-ethanol methyl ester is then used in tetrahydrofuran system with lithium aluminum hydride Carry out reduction to obtain thiophene-3-ethanol; but the raw material thiophene-3-acetic acid price of this method is higher, is not suitable for large-scale production;
[0007] (4) Using tribromothiophene as the starting material, after adding butyllithium dropwise, add 1,3,2-dioxazolethiophene-2,2-dioxide At present, the methods reported in the literature are to add butyllithium dropwise to the tribromothiophene system. The final product obtained by this method contains isomer impurities that are difficult to remove, and the yield is low

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0033] (1) prepare ethylene sulfite,

[0034] Into the 1000L reactor, add 130.0kg ethylene glycol (1.0eq), 689.0kg dichloromethane (1kg / 4L), cool the system down to 30-40°C, slowly add 249.5kg thionyl chloride (1.0eq), Insulation reaction. After the reaction is complete, add sodium carbonate solution to adjust the pH of the system to 8-9, separate liquids, and extract to obtain the organic phase. Contains 223.2kg of product. Yield 98.5%, gas chromatography purity (GC): 98.42%.

[0035] (2) preparation of 1,3,2-dioxazolethiophene-2,2-dioxide,

[0036] Into the 3000L titanium steel reactor, add 113.1kg (1.0eq) system and 450.0kg dichloromethane (1kg / 3L), in the system, add dropwise 789.1kg 4.3% sodium bicarbonate aqueous solution (1kg / 0.3kg) and 1.6% 20.7kg ruthenium trichloride aqueous solution ( 0.0012eq), temperature control 0~10°C, add 119.9kg sodium hypochlorite (1.2eq) aqueous solution dropwise, keep warm for reaction, after the system is detected to be non-oxi...

Embodiment 2

[0043] (1) prepare ethylene sulfite,

[0044] Add 100.0kg of ethylene glycol (1.0eq) and 770kg of chlorobenzene (1kg / 7L) to a 1000L reactor, cool the system down to 30-40°C, slowly add 383.0kg of thionyl chloride (2.0eq), and keep warm for the reaction . After the reaction is complete, add sodium hydroxide solution to adjust the pH of the system to 8-9, separate liquids, and extract to obtain the organic phase. Contains 168.1kg of product. Yield 96.5%, gas chromatography purity (GC): 98.1%.

[0045] (2) preparation of 1,3,2-dioxazolethiophene-2,2-dioxide,

[0046] Into the 3000L titanium steel reactor, add 84kg (1.0eq) system and 447kg dichloromethane (1kg / 3L), in the system, drop 5% 840kg sodium bicarbonate aqueous solution (1kg / 0.5kg) and 2% 17.4kg ruthenium trichloride aqueous solution (0.0018eq ), control the temperature at 0-10°C, add 74.2kg of sodium hypochlorite (1.0eq) aqueous solution dropwise, and keep warm for reaction. After the system is tested to be n...

Embodiment 3

[0053] (1) prepare ethylene sulfite,

[0054] Add 65.0kg of ethylene glycol (1.0eq) and 215.3kg of dichloromethane (1kg / 2.5L) into a 1000L reactor, cool the system down to 30-40°C, and slowly add 62.3kg of thionyl chloride (0.5eq) , insulation reaction. After the reaction is complete, add potassium carbonate solution to adjust the pH of the system to 8-9, separate liquids, and extract to obtain the organic phase. Contains 106.9kg of product. Yield 94.3%, gas chromatography purity (GC): 98.1%.

[0055] (2) preparation of 1,3,2-dioxazolethiophene-2,2-dioxide,

[0056] To the 3000L titanium steel reactor, add 53.4kg (1.0eq) system and 411.2kg chlorobenzene (1kg / 7L), add dropwise 120kg sodium bicarbonate aqueous solution (1kg / 0.1kg) of 4.5% and 1.5% 14.6kg ruthenium trichloride aqueous solution (0.0018eq ), control the temperature at 0-10°C, add 129.3kg of sodium hypochlorite (3eq) aqueous solution dropwise, and keep the temperature for reaction. After the system is de...

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Abstract

The invention discloses a synthetic method of thiophene-3-ethanol. The method comprises the following steps of: adding a halogenated hydrocarbon solvent and ethylene glycol into a reaction kettle, dropwise adding thionyl chloride and preserving heat for reacting; separating liquid and extracting to obtain an organic phase containing a substance shown in the specifications; adding a ruthenium trichloride aqueous solution and a sodium bicarbonate aqueous solution in the presence of the halogenated hydrocarbon solvent and dropwise adding a sodium hypochlorite aqueous solution; after detecting that a system does not have oxidizing property, performing liquid separation, concentration, devitrification and drying to obtain a substance shown in the specifications, adding an ester solvent and butyl lithium into a reaction kettle, adding a prepared ester solution of tribromothiofuran and a prepared ester solution of the substance, separating the liquid and extracting to obtain a system containing a substance shown in the specifications; and adding a dilute sulfuric acid into the system containing the substance shown in the specifications, concentrating, neutralizing, extracting and concentrating to obtain an end product. The method has the advantages of high reaction purity and yield, stable process condition, easiness for operation and mass production capability; and the thiophene-3-ethanol is prepared from tribromothiofuran by performing low-temperature lithiation, so that the use of epoxy ethane serving as an explosive hazard is avoided, and mass production becomes possible.

Description

(1) Technical field: [0001] The invention relates to a method for synthesizing thiophene-3-ethanol. (two) background technology: [0002] Thiophene-3-ethanol is used as an intermediate of antithrombotic drug ticlopidine. It has a good effect and prospect in thienopyridine drugs, especially ticlopidine hydrochloride and clopidogrel. Therefore, a high-efficiency, low-cost thiophene-3-ethanol synthesis process is of great significance. [0003] At present, the methods for preparing thiophene-3-ethanol mainly contain the following: [0004] (1) Both the Grignard reagent method and the sodium reagent method use thiophene as a raw material to obtain the metal compound of thiophene through different steps, then react with ethylene oxide, and then hydrolyze to obtain thiophene-3-ethanol. These two methods The material used contains ethylene oxide, which is an explosive and dangerous product, and it is more dangerous in the production process; [0005] (2) The ester reduction met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/16
Inventor 洪浩韦建杨建波
Owner ASYMCHEM LAB TIANJIN
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