A kind of microchannel reactor, device and preparation method of 5-fluorocytosine

A micro-channel reactor and micro-channel reaction technology, applied in chemical instruments and methods, chemical/physical/physical chemical reactors, organic chemistry, etc. The problems such as low total yield of the synthetic route can achieve the effects of reducing the generation of by-products, making it convenient and simple in structure.

Active Publication Date: 2020-01-17
FUJIAN YONGJING TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The shortcoming that this method mainly exists: at first, take 5-fluorouracil as the route cost height of raw material, the total yield of synthetic route is low (57-65%), be the route of raw material with 5-fluorocytosine precursor need to pressurize Carrying out the ammoniation reaction and using a large amount of anhydrous methanol as a solvent is not conducive to industrial production. In addition, the last step of hydrolysis is easy to convert the amino group on the pyrimidine ring into a hydroxyl group, and then back to 5-fluorouracil, resulting in unstable product quality
However, at the point of convergence, the reagents will form turbulent flow, which is easy to produce side reactants, and is not conducive to mass transfer and diffusion.
The cytosine fluorination reaction is a strong exothermic reaction. Due to the poor heat transfer of the traditional reactor, the heat cannot be taken out of the system quickly, and the local temperature in the reaction system rises instantaneously, resulting in the formation of difluorocytosine as a by-product.
Currently there is no special equipment suitable for the fluorination of cytosine to 5-fluorocytosine

Method used

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  • A kind of microchannel reactor, device and preparation method of 5-fluorocytosine
  • A kind of microchannel reactor, device and preparation method of 5-fluorocytosine
  • A kind of microchannel reactor, device and preparation method of 5-fluorocytosine

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Experimental program
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Effect test

Embodiment 1

[0076] After dissolving 44.4g of cytosine with 200ml of anhydrous hydrofluoric acid, a cytosine solution with a concentration of 2mol / L was obtained. After filtering with a special acid-resistant filter membrane, it entered the microchannel reaction device through a mass flow valve at a flow rate of 5ml / L. h, feed fluorine gas content through the gas flowmeter and be that the fluorine gas of 15%, nitrogen mixed gas enters the microchannel reaction device, flow rate is 50ml / min, reaction constant temperature is at-15 ℃, and total residence time is 15min, gets crude product, The content of 5-fluorocytosine is 95%, using CaCO 3 Neutralize excess acid, adjust Ph value at 7-8, remove CaF by hot filtration at 70°C 2 , after decolorization and drying by activated carbon, white blocky 5-fluorocytosine was obtained, the purity was 99.1% and the yield was 85% as determined by liquid chromatography mass spectrometry.

Embodiment 2

[0081] Dissolve 22.2g of cytosine with 200ml of formic acid to obtain a 1mol / L cytosine solution, which is filtered by a special filter membrane for liquid phase to prevent insoluble impurities from clogging the microchannel during sample injection, and enters the microchannel reaction device through a mass flow valve In the process, the flow rate is 5ml / h, the microchannel reaction device is passed into the mixed gas of fluorine gas and nitrogen gas with a fluorine content of 20%, the flow rate is 50ml / min, the reaction temperature is controlled at -20°C, and the residence time is 10min to obtain the crude product , wherein the content of 5-fluorocytosine is 90%, with weakly alkaline NaHCO 3 After neutralizing excess acid, NaF was removed by recrystallization, and after drying at 105° C., blocky 5-fluorocytosine was obtained with a purity of 99.5% and a yield of 85% as determined by liquid chromatography mass spectrometry.

Embodiment 3

[0083] After dissolving 22.2g of cytosine with 200ml of formic acid, a 1mol / L cytosine solution was obtained. After filtering with a special filter membrane for liquid phase, it entered the microchannel reaction device through a mass flow valve with a flow rate of 5ml / h. Microchannel reaction The device was fed with a mixed gas of fluorine and nitrogen with a fluorine content of 10%, the flow rate was 50ml / min, the reaction constant temperature was at -20°C, and the residence time was 10min to obtain a crude product, wherein the 5-fluorocytosine content was 81%. Weakly alkaline NaHCO 3 After neutralizing excess acid, NaF was removed by recrystallization, and after drying at 105° C., blocky 5-fluorocytosine was obtained with a purity of 99% and a yield of 75% as determined by liquid chromatography mass spectrometry.

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Abstract

The invention relates to a microchannel reactor, a device and a method for preparing 5-fluorocytosine. The microchannel reactor performs sample injection in a front and rear feeding mode, reaction reagents can form wave propulsion in a micro reaction channel, turbulence formed when the reaction reagents are mixed with each other or reaction gas and the reaction reagents are mixed is reduced, the reaction reagents undergo better mass transfer diffusion in the channel, and byproducts generated in the reaction are reduced. According to the method for preparing 5-fluorocytosine provided by the technical scheme, formic acid, trifluoroacetic acid or a mixed solution of formic acid and trifluoroacetic acid serving as a solvent can form a hypo-fluoric acid compound together with fluorine, to be favorable of dissolution of fluorine in the solvent and improve conversion efficiency of 5-fluorocytosine. The use of a micro reaction device, the generation of the byproduct difluorocytosine, to obtainhigh-purity 5-fluorocytosine, while the yield is very high; and the reaction process is safe, to avoid an explosion.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a microchannel reactor, a device and a preparation method of 5-fluorocytosine. Background technique [0002] 5-fluorocytosine is widely used as a pharmaceutical intermediate, and its downstream product, capecitabine, is a new generation of oral fluorouracil drugs. It not only has specific targeting, but also is effective against tumors resistant to other chemotherapy drugs. It is used to treat breast cancer and colorectal cancer; Emtricitabine, a downstream product of flucytosine, is a new type of nucleoside reverse transcriptase inhibitor, which has a significant virus inhibitory effect on HIV-infected patients and is used for hepatitis B Treatment can reduce the level of hepatitis B virus in patients with chronic infection. Emtricitabine has less toxicity and its safety is significantly better than lamivudine, especially for children. It has better efficacy and safety; the down...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): B01J19/00C07D239/47
CPCB01J19/0013B01J19/0093B01J2219/00087C07D239/47
Inventor 杜宏军方建辉
Owner FUJIAN YONGJING TECH CO LTD
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