CN113105332A

CN113105332A - Method for preparing eltrombopag nitration intermediate in micro-channel continuous flow reactor

Info

Publication number: CN113105332A
Application number: CN202110464161.6A
Authority: CN
Inventors: 费安杰; 叶伟平; 周章涛; 吴桂宝; 曾仰桐
Original assignee: Shenzhen Hwagen Pharmaceutical Co ltd
Current assignee: Shenzhen Hwagen Pharmaceutical Co ltd
Priority date: 2021-04-27
Filing date: 2021-04-27
Publication date: 2021-07-13

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 production process of eltrombopag bulk drugs, and avoid nitration reaction. The invention has the beneficial effects that: the method for preparing the eltrombopag nitration intermediate in the micro-channel continuous flow reactor adopts a novel process technology, and has the characteristics of safety, high efficiency, environmental protection and the like.

Description

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

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for preparing an eltrombopag nitration intermediate in a micro-channel continuous flow reactor.

Background

As shown below, compound EB12 is a key intermediate of the anti-purpura drug eltrombopag.

Synthesis route of EB12 intermediate and eltrombopag

The current method for synthesizing the compound EB12 mainly has two schemes, wherein a synthetic route 1 is shown in the following figure, and a nitration starting material is adopted to carry out bromination reaction to obtain an EB12 intermediate with a nitro group. Although this step does not involve nitration, the starting material is still prepared by nitration, and the high risk nitration process (Tetrahedron Letters,56(44), 6104-.

EB12 scheme 1

In the synthetic route 2, a direct nitration process is adopted, and a large amount of mixed acid is required for completing nitration reaction. The process is a traditional batch production, such as the yield of EB12 in tonnage, a 5000L reaction kettle is needed to complete the production of more than 10 batches, the explosion equivalent of each batch of nitride is equivalent to 600kg equivalent of TNT, and the safety risk is high (Faming Zhuanli Shenqing,110407702,05Nov 2019).

EB12 scheme 2

In summary, the synthetic route to the intermediate EB12, whether nitrated first and then coupled, or coupled first and then nitrated, must be subjected to a nitration reaction. When the nitration process cannot be avoided, the reaction process must be started to reduce the risk of the reaction and improve the operability of the industrial process.

At present, the synthesis process of the eltrombopag bulk drug on the market can not avoid adopting a nitration process, and as shown in the following figure, when the bromination reaction is carried out by adopting o-nitrophenol to obtain the EB12 intermediate with nitro, dibromo impurities are introduced, and the impurities can be converted along with the reaction process and are difficult to remove. The nitration process is also faced with the situation where the ortho-nitration product continues to be nitrated in the reaction system to form dinitrated impurities, which are also difficult to remove.

Disclosure of Invention

According to the invention, by using the micro-channel continuous flow reactor, a small amount of o-bromophenol and one equivalent of nitric acid enter the reaction channel at the same time, the reaction is finished only by staying in the reaction channel for a very short time, the reaction product flows out of the reaction channel along with the reaction liquid, and even if the reaction product is quenched, the reaction product stays for a short time and reacts quickly, and no redundant nitric acid is used for generating dinitrated impurities in the reaction liquid, so that the reaction selectivity is greatly improved and is increased from 60.3% to 95%, and simultaneously, along with the increase of the reaction scale, the reaction selectivity is not reduced due to the increase of the reaction time like the conventional reaction.

In addition, the adoption of the direct nitration process also has greater safety risk, so in order to improve the reaction selectivity in the production process of the Eltrombopag bulk drug and the high risk of the nitration process, the invention adopts the micro-channel continuous flow technology to carry out technical upgrade on the nitration process, realizes the intrinsic safety and reliability, and carries out innovation upgrade on the preparation process of the Eltrombopag bulk drug: injecting the two reaction materials into the micro-channel at a certain flow rate, injecting the mixed and reacted materials into a quenching kettle, after quenching, centrifuging, washing and drying to obtain a target product.

A process for preparing eltrombopag nitrated intermediate in a microchannel continuous flow reactor, said process comprising the steps of:

(1) preparing a reaction material A: mixing the components in a weight ratio of 0.5: 2.0-2.5: 2.1-2.5 of a starting material, namely o-bromophenol, acetic acid and methanol, stirring for dissolving, standing, filtering out insoluble substances, and filling filtrate into a glass container A for later use;

(2) preparing a reaction material B: adding acetic acid into a reaction bottle, cooling to 0-5 ℃, starting stirring, adding concentrated nitric acid, slowly dropwise adding concentrated sulfuric acid under the condition of controlling the temperature, and filling the prepared mixed acid into a glass container B for later use, wherein the weight ratio of the concentrated sulfuric acid to the concentrated nitric acid to the acetic acid is 0.5: 1.5-3.0: 3.0 to 5.0;

(3) respectively conveying the reaction material A and the reaction material B into a microchannel reactor by using constant flow pumps, controlling the flow rate ratio to be 4: 1-10: 1, controlling the temperature to be 20-50 ℃, reacting for 7-20 s, feeding the reacted materials into a reaction kettle filled with water, stirring and quenching, and after the reaction is finished, centrifuging, leaching and drying to obtain a compound EB 12.

Further, the constant flow pump comprises a pump A for driving the reaction material A to enter the microchannel reactor and a pump B for driving the reaction material B to enter the microchannel reactor.

An eltrombopag nitration intermediate prepared in a micro-channel continuous flow reactor, wherein the eltrombopag nitration intermediate is prepared by the method.

The invention has the beneficial effects that: by adopting the method for preparing the eltrombopag nitration intermediate in the micro-channel continuous flow reactor, the effects of adopting a novel process, being safer, more efficient, being environment-friendly and the like can be realized.

Drawings

FIG. 1 is a simplified schematic diagram of the process for preparing a nitrated intermediate of Eltrombopag according to the present invention;

FIG. 2 is a simplified schematic of the present invention for the preparation of Eltrombopag nitration intermediates using a microchannel continuous flow reactor.

Detailed Description

Example 1

(1) Preparing a reaction material A: the starting materials o-bromophenol (0.5kg), acetic acid (2.2kg) and methanol (2.25kg) were mixed, dissolved by stirring, allowed to stand, the insoluble matter was filtered off, and the filtrate was charged into a glass container A, in which the mass fraction of EB03 was 10.2%.

(2) Preparing a reaction material B: adding acetic acid (142g) into a reaction bottle, cooling to 0-5 ℃, starting stirring, adding nitric acid (138g) with the mass fraction of 69%, then slowly dropwise adding concentrated sulfuric acid (52g) under the temperature control condition, filling the prepared mixed acid into a glass container B, wherein the mass fraction of the nitric acid in the mixed solution is 28.6%.

(3) And starting an external heat exchanger to control the temperature of the microchannel reactor to be 20 ℃ (adopting a Corning heart type structure continuous flow microchannel reactor).

(4) Starting a constant flow pump A, and conveying the material A into the microchannel at a flow rate of 60 mL/min; and simultaneously, opening a constant flow pump B, and conveying the material B into the microchannel at the flow rate of 12.7 mL/min.

(5) The mixed liquid material after passing through the microchannel reactor is injected into a reaction vessel containing water (4L) and stirred for quenching.

(6) And (4) centrifugal filtration.

(7) The filter cake is washed by water (1L), and the yield of the target product after the filter cake is dried is 90 percent, and the liquid phase purity is 99.3 percent.

Example 2

(1) Preparing a reaction material A: the starting materials o-bromophenol (0.60kg), acetic acid (2.61kg) and methanol (2.64kg) were mixed, dissolved by stirring, allowed to stand, insoluble matter was filtered off, and the filtrate was charged into a glass container A, the EB03 mass fraction being 16%.

(2) Preparing a reaction material B: adding acetic acid (142g) into a reaction bottle, cooling to 0-5 ℃, starting stirring, adding 65% nitric acid (138g), then slowly dropwise adding concentrated sulfuric acid (52g) under the temperature control condition, and filling the prepared mixed acid into a glass container B, wherein the mass fraction of the nitric acid is 28.6%.

(3) And starting an external heat exchanger to control the temperature of the microchannel reactor to be 30 ℃.

(4) Opening a constant flow pump A, and conveying the material A into the microchannel at the flow rate of 70 mL/min; meanwhile, the constant flow B of the pump is started, and the material B is conveyed into the microchannel at the flow rate of 16.4 mL/min.

(5) The contents of the mixed reaction were poured into a reaction vessel containing water (4.5L) and quenched with stirring.

(6) And (4) centrifugal filtration.

(7) The filter cake was washed with water (1.0L) and the target product was obtained after drying the filter cake in 91% yield and 99.1% liquid phase purity.

Claims

1. A process for preparing eltrombopag nitrated intermediates in a microchannel continuous flow reactor, the process comprising the steps of:

(2) preparing a reaction material B: adding acetic acid into a reaction bottle, cooling to 0-5 ℃, starting stirring, adding concentrated nitric acid, then slowly dropwise adding concentrated sulfuric acid under the temperature control condition, and filling the prepared mixed acid into a glass container B for later use, wherein the weight ratio of the concentrated sulfuric acid to the concentrated nitric acid to the acetic acid is 0.5: 1.5-3.0: 3.0 to 5.0;

2. The process for preparing an eltrombopag nitration intermediate in a microchannel continuous flow reactor as claimed in claim 1, wherein said constant flow pump comprises a pump a for driving reactant material a into the microchannel reactor and a pump B for driving reactant material B into the microchannel reactor.

3. An eltrombopag nitration intermediate prepared in a microchannel continuous flow reactor, wherein the eltrombopag nitration intermediate is prepared by the method of claim 1.