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Synthesis method of (2,2-difluorobenzo[d][1,3]dioxy-5-yl)methanol

A dioxo, difluorobenzene technology, applied in the field of methanol preparation, can solve the problems of high price of reducing agent, dangerous process, high requirements for experimental conditions, and achieve the effect of stable process and product quality

Inactive Publication Date: 2019-03-22
阜新达得利化工股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] One of the technical problems to be solved in the present invention is to overcome the requirements for experimental conditions in the (2,2-difluorobenzo[d][1,3]dioxo-5-yl) methanol synthesis process existing in the prior art high, process risk, expensive reductant and other defects, to provide a simple, lower cost, suitable for industrial production of the preparation (2,2-difluorobenzo [d] [1,3] dioxo 1 -5-yl)methanol method

Method used

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  • Synthesis method of (2,2-difluorobenzo[d][1,3]dioxy-5-yl)methanol
  • Synthesis method of (2,2-difluorobenzo[d][1,3]dioxy-5-yl)methanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Preparation of 5-Bromo-2,2-difluoropiperone

[0044] Add 250.0kg (1.581kmol) of 2,2-difluoropipercycline into a 500L PTFE-lined enamel kettle, add 25.0kg of iron filings under stirring, and replace the air in the kettle with nitrogen. Control the reaction temperature at 20-30°C, add 250.0kg (1.564kmol) bromine dropwise within 8-10 hours, and absorb the tail gas with liquid caustic soda. After the reaction, the reaction system was pumped into another 2000L reactor with 1000kg of cold water, and the temperature was controlled below 30°C. 100kg of 25% sodium bisulfite solution was added dropwise to quench the reaction, and 32% liquid caustic soda was added dropwise to adjust the pH value of the system to 8-9, and the temperature was raised to 100° C. to steam distill all the products. About 310kg of crude 5-bromo-2,2-difluoropipercycline was obtained, and 250kg (1.181kmol) of 5-bromo-2,2-difluoropipercycline was obtained after further separation, with a purity of 99% and ...

Embodiment 2

[0046] Preparation of 2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (Grignard exchange method, sodium borohydride reduction)

[0047] Put 40g (0.169mol) of 5-bromo-2,2-difluoropiperone prepared in Example 1 into a 1L reaction flask, 108g (121.5ml) tetrahydrofuran, under nitrogen protection, start stirring, and cool the system to -10 ℃, control system temperature -10~0 ℃, add dropwise 104g (0.202mol) 20% tetrahydrofuran solution of isopropylmagnesium chloride to the system, control the rate of addition, and drop it in about 3 hours. After dropping, keep the reaction for 2 hours.

[0048] Continue to cool down to -25°C, add 18.5g (0.253mol) N,N-dimethylformamide dropwise, and keep warm for 2h after dropping. Add 200ml of saturated ammonium chloride solution to quench, add 15% hydrochloric acid dropwise to adjust the pH value to 5-6, add 250g of dichloromethane for extraction, separate layers, transfer the lower organic phase to a 500ml reaction flask and concentrate under reduc...

Embodiment 3

[0051] Preparation of 2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (Grignard reaction method-magnesium chips method, sodium borohydride reduction)

[0052] Put 40 g (0.169 mol) of 5-bromo-2,2-difluoropiperonyl prepared in Example 1 and 150 g of tetrahydrofuran into a 500 ml three-necked flask to prepare a tetrahydrofuran solution of 5-bromo-2,2-difluoropiperonyl.

[0053] Add 25ml tetrahydrofuran, 6.0g (0.247mol) magnesium chips, and 1.0g iodine to another 500ml reaction flask. Heat up to reflux at 60°C, under the protection of nitrogen, drop 10ml of the prepared 5-bromo-2,2-difluoropiperonyl tetrahydrofuran solution to initiate the reaction.

[0054] Cool down to -5~0°C, add 18.5g (0.253mol) N,N-dimethylformamide dropwise, and keep warm for 2h after dropping. Post-treatment was carried out in a method similar to that of Example 2 to obtain 24.5 g (0.132 mol) of the intermediate product 2,2-difluoro-1,3-benzodioxol-5-carbaldehyde.

[0055] Cool the system down to 20-30°C, a...

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Abstract

The invention discloses a preparation method of (2,2-difluorobenzo[d][1,3]dioxo-5-yl)methanol as a fine chemical intermediate. The method is simple and feasible, lower in cost, and suitable for preparing (2,2-difluorobenzo[d][1,3]dioxo-5-yl)methanol through industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol. Background technique [0002] (2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methanol (CAS No.: 72768-97-9), also known as (2,2-difluoro-benzene And[1,3]dioxol-5-yl)-methanol is a very important fine chemical intermediate, which can be used in the synthesis of pharmaceutical compounds; The synthesis of the key active ingredient Lumacaftor of the fibrosis drug Orkambi and the active ingredient Tezacaftor of the new drug Symdeko launched in 2018 requires (2,2-difluorobenzo[d][1,3]dioxo-5-yl) Methanol is used as a raw material, and its chemical structural formula is as follows: [0003] [0004] At present, for the synthesis method of (2,2-difluorobenzo[d][1,3]dioxo-5-yl)methanol, it is known that there are mainly the following two types: the report on page 62 of the patent application CN 102743385A specification I...

Claims

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Application Information

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IPC IPC(8): C07D317/46
CPCC07D317/46
Inventor 聂强张金生姜山贾轶桐
Owner 阜新达得利化工股份有限公司
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