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

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 a high-risk nitration process involved in an eltrombopag bulk drug production process and avoid the nitration reaction. The method comprises the following steps: injecting two reaction materials into a micro-channel at a certain flow rate respectively; injecting the mixed and reacted materials 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, environmental 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 EB04 is a key intermediate of the anti-purpura drug Eltrombopag.

[0003]

[0004] At present, there are mainly two methods for synthesizing compound EB04. The synthetic route 1 is shown below, using nitration initiators and aryl boronic acid to complete Suzuki coupling to obtain EB04 intermediates with nitro groups. Although this step does not involve nitration reaction, the starting material is still prepared through nitration reaction, and the high-risk nitration process has not been avoided from the source (PCT 2013049605).

[0005]

[0006] Synthetic route 2 adopts the process of direct nitration, which requires a large amount of mixed acid to complete the nitration reaction. This process ...

Examples

Embodiment 1

[0020] (1) Prepare reaction material A: mix starting material EB03 (0.5kg), acetic acid (2.2kg) and tetrahydrofuran (2.25kg), stir and dissolve, let stand, filter out insoluble matter, and filtrate is packed into glass container A, here The mass fraction of EB03 in the mixed liquor was 10.2%.

[0021] (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.

[0022] (3) Turn on the external heat exchanger to control the temperature of the microchannel reactor to 30° C. (a continuous flow microchannel reactor with a Corning heart-shaped structure is used).

[0023] (4) Turn on the constant flow pump A, and deliver material A to the mi...

Embodiment 2

[0028] (1) Preparation of reaction material A: Mix the starting material EB03 (0.60kg), acetic acid (2.61kg) and tetrahydrofuran (2.64kg), stir to dissolve, let stand, filter out insoluble matter, and put the filtrate into glass container A, EB03 The mass fraction is 16%.

[0029] (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) dropwise under temperature control. ), the mixed acid prepared is packed into glass container B, and the mass fraction of nitric acid is 28.6%.

[0030] (3) Turn on the external heat exchanger to control the temperature of the microchannel reactor to 50°C.

[0031] (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.

[0032] (5) ...

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 EB04 is a key intermediate of the anti-purpura drug Eltrombopag.

[0003]

[0004] At present, there are mainly two methods for synthesizing compound EB04. The synthetic route 1 is shown below, using nitration initiators and aryl boronic acid to complete Suzuki coupling to obtain EB04 intermediates with nitro groups. Although this step does not involve nitration reaction, the starting material is still prepared through nitration reaction, and the high-risk nitration process has not been avoided from the source (PCT 2013049605).

[0005]

[0006] Synthetic route 2 adopts the process of direct nitration, which requires a large amount of mixed acid to complete the nitration reaction. This process ...

Examples

Embodiment 1

[0020] (1) Prepare reaction material A: mix starting material EB03 (0.5kg), acetic acid (2.2kg) and tetrahydrofuran (2.25kg), stir and dissolve, let stand, filter out insoluble matter, and filtrate is packed into glass container A, here The mass fraction of EB03 in the mixed liquor was 10.2%.

[0021] (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.

[0022] (3) Turn on the external heat exchanger to control the temperature of the microchannel reactor to 30° C. (a continuous flow microchannel reactor with a Corning heart-shaped structure is used).

[0023] (4) Turn on the constant flow pump A, and deliver material A to the mi...

Embodiment 2

[0028] (1) Preparation of reaction material A: Mix the starting material EB03 (0.60kg), acetic acid (2.61kg) and tetrahydrofuran (2.64kg), stir to dissolve, let stand, filter out insoluble matter, and put the filtrate into glass container A, EB03 The mass fraction is 16%.

[0029] (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) dropwise under temperature control. ), the mixed acid prepared is packed into glass container B, and the mass fraction of nitric acid is 28.6%.

[0030] (3) Turn on the external heat exchanger to control the temperature of the microchannel reactor to 50°C.

[0031] (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.

[0032] (5) ...

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