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Method for preparing eltrombopag nitration intermediate in micro-channel continuous flow reactor

A technology of microchannel reactors and intermediates, applied in chemical instruments and methods, chemistry/physics/physicochemical reactors, preparation of nitro compounds, etc., can solve problems such as difficult removal, removal, and transformation of impurities, and achieve novel The effect of craft

Pending Publication Date: 2021-07-13
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The nitration process cannot be avoided in the synthesis process of Eltrombopag raw materials currently on the market. As shown in the figure below, dibrominated impurities will be introduced when o-nitrophenol is used for bromination reaction to obtain the EB12 intermediate with nitro group. This impurity will transform with the progress of the reaction and is difficult to remove
The nitrification process will also face the situation that the ortho-nitration products continue to nitrify in the reaction system to form di-nitration impurities, which are also difficult to remove

Method used

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  • Method for preparing eltrombopag nitration intermediate in micro-channel continuous flow reactor
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  • Method for preparing eltrombopag nitration intermediate in micro-channel continuous flow reactor

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Experimental program
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Effect test

Embodiment 1

[0026] (1) Preparation of reaction material A: Mix the starting materials o-bromophenol (0.5kg), acetic acid (2.2kg) and methanol (2.25kg), stir to dissolve, let stand, filter out insoluble matter, and put the filtrate into glass container A , the mass fraction of EB03 in this mixed solution is 10.2%.

[0027] (2) Preparation of reaction material B: Add acetic acid (142g) into the reaction flask, cool down to 0-5°C, start stirring, add nitric acid (138g) with a mass fraction of 69%, and then slowly add it dropwise under temperature control conditions Concentrated sulfuric acid (52g), the mixed acid prepared is packed into glass container B, and the massfraction of nitric acid is 28.6% in this mixed solution.

[0028] (3) Turn on the external heat exchanger to control the temperature of the microchannel reactor to 20°C (a continuous flow microchannel reactor with a Corning heart-shaped structure is used).

[0029] (4) Turn on the constant flow pump A, and deliver material A to...

Embodiment 2

[0034] (1) Preparation of reaction material A: Mix the starting materials o-bromophenol (0.60kg), acetic acid (2.61kg) and methanol (2.64kg), stir to dissolve, let stand, filter out insoluble matter, and put the filtrate into glass container A , the mass fraction of EB03 was 16%.

[0035] (2) Preparation of reaction material B: Add acetic acid (142g) into the reaction flask, cool down to 0-5°C, start stirring, add 65% nitric acid (138g), and then slowly add concentrated sulfuric acid (52g ), the mixed acid prepared is packed into glass container B, and the mass fraction of nitric acid is 28.6%.

[0036] (3) Turn on the external heat exchanger to control the temperature of the microchannel reactor to 30°C.

[0037] (4) Turn on the constant flow pump A to deliver material A to the microchannel at a flow rate of 70mL / min; simultaneously turn on pump constant flow B to deliver material B to the microchannel at a flow rate of 16.4mL / min.

[0038] (5) The mixed reaction materials ...

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Abstract

The invention discloses a method for preparing an eltrombopag nitration intermediate in a micro-channel continuous flow reactor, belongs to the field of organic chemical synthesis, and aims to improve the high-risk nitration process involved in the eltrombopag raw material medicine production process and inevitable nitration reaction. Two reaction materials are respectively injected into a micro-channel at a certain flow rate; and the mixed and reacted material is injected into a quenching kettle, and after quenching is completed, centrifuging, washing and drying to obtain a target product. The method for preparing the eltrombopag nitration intermediate in the micro-channel continuous flow reactor has the beneficial effects that a novel process technology is adopted, and the method has the characteristics of safety, high efficiency, environment friendliness and the like.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a method for preparing a nitrated intermediate of Eltrombopag in a microchannel continuous flow reactor. Background technique [0002] As shown below, compound EB12 is a key intermediate of the anti-purpura drug Eltrombopag. [0003] [0004] EB12 intermediate and Eltrombopag synthetic route [0005] At present, there are mainly two methods for synthesizing compound EB12. Among them, the synthetic route 1 is shown in the figure below, and the nitrated starting material is used for bromination reaction to obtain the EB12 intermediate with a nitro group. Although this step does not involve nitration reaction, the starting material is still prepared by nitration reaction, and the high-risk nitration process is not avoided from the source (Tetrahedron Letters, 56(44), 6104-6107; 2015). [0006] [0007] EB12 Synthetic Route 1 [0008] Synthetic route 2 a...

Claims

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Application Information

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IPC IPC(8): C07C201/08C07C205/26B01J19/00
CPCC07C201/08C07C205/26B01J19/0093
Inventor 费安杰叶伟平周章涛吴桂宝曾仰桐
Owner SHENZHEN HUAXIAN PHARMA TECH CO LTD
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