阅读说明：本技术 利用微通道反应器合成艾曲波帕的方法 (Method for synthesizing Eltrombopag by using microchannel reactor ) 是由 张之建 陈争一 潘亮 宋帅娟 黄立本 于 2020-12-23 设计创作，主要内容包括：本发明公开了一种利用微通道反应器合成艾曲波帕的方法,方法包括以下步骤：S1、物料合成：将原料3,4-二甲基苯胺加入到酸水溶液中,溶解后为物料一,将亚硝酸钠溶解于水中得到物料二,将亚硫酸氢钠和氢氧化钠溶解于水中得到物料三,将盐酸和水配成的溶液为物料四,将原料3-氨基-2羟基-[1,1-联苯]-3甲酸加到酸水溶液中,溶解得到物料五,将亚硝酸钠溶解于水中得到物料六；S2、物料通入微通道反应器S3、得到第一中间体3,4-二甲基苯肼盐酸盐,与乙酰乙酸乙酯反应得到第二中间体2-(3,4-二甲基苯基)-5-甲基-1H-吡唑-3(2H)-酮；S4、将物料五和物料六通入微通道反应器中进行反应,流出的反应液直接流入装有2-(3,4-二甲基苯基)-5-甲基-1H-吡唑-3(2H)-酮溶液的反应瓶中,得到艾曲波帕。(The invention discloses a method for synthesizing Eltrombopag by using a microchannel reactor, which comprises the following steps: s1, synthesizing materials: adding 3, 4-dimethylaniline serving as a raw material into an acid aqueous solution, dissolving to obtain a first material, dissolving sodium nitrite into water to obtain a second material, dissolving sodium bisulfite and sodium hydroxide into water to obtain a third material, preparing a solution from hydrochloric acid and water to obtain a fourth material, adding 3-amino-2-hydroxy- [1, 1-biphenyl ] -3-formic acid serving as a raw material into the acid aqueous solution, dissolving to obtain a fifth material, and dissolving sodium nitrite into the water to obtain a sixth material; s2, introducing the materials into a microchannel reactor S3 to obtain a first intermediate 3, 4-dimethylphenylhydrazine hydrochloride, and reacting with ethyl acetoacetate to obtain a second intermediate 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -one; s4, feeding the material five and the material six into a microchannel reactor for reaction, and directly feeding the effluent reaction liquid into a reaction bottle filled with a 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -ketone solution to obtain the eltrombopag.)

1. A method for synthesizing eltrombopag using a microchannel reactor, the method comprising the steps of:

s1, synthesizing materials: adding 3, 4-dimethylaniline serving as a raw material into an acid aqueous solution, dissolving to obtain a first material, dissolving sodium nitrite into water to obtain a second material, dissolving sodium bisulfite and sodium hydroxide into water to obtain a third material, preparing a solution from hydrochloric acid and water to obtain a fourth material, adding 3-amino-2-hydroxy- [1, 1-biphenyl ] -3-formic acid serving as a raw material into the acid aqueous solution, dissolving to obtain a fifth material, and dissolving sodium nitrite into the water to obtain a sixth material;

s2, introducing materials into a microchannel reactor: the microchannel reactor comprises: a first temperature zone, a second temperature zone and a third temperature zone; controlling the temperature of each temperature zone of the reactor, controlling the flow rate of the metering pump, and sequentially introducing the material I, the material II, the material III and the material IV into the microchannel reactor for reaction to obtain a reaction solution, wherein the material I, the material II and the material III are positioned in a first temperature zone, and the material IV is positioned in a second temperature zone;

s3, decoloring, filtering, concentrating, cooling and crystallizing the obtained reaction liquid to obtain a first intermediate 3, 4-dimethylphenylhydrazine hydrochloride, and reacting the 3, 4-dimethylphenylhydrazine hydrochloride with ethyl acetoacetate to obtain a second intermediate 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -one;

s4, controlling the temperature of each temperature zone of the microchannel reactor, introducing the material five and the material six into the microchannel reactor for reaction, directly flowing the effluent reaction solution into a reaction bottle filled with a 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -ketone solution, adjusting the pH value to 7.5-8.5 by alkali under stirring, reacting at room temperature, and performing suction filtration to obtain the eltrombopag.

2. The method for synthesizing eltrombopag using a microchannel reactor according to claim 1, wherein the molar ratio of the 3, 4-dimethylaniline to the hydrochloric acid in step S1 is 1:2.5-3.5, the concentration of the prepared 3, 4-dimethylaniline solution is 0.6-1.0 mol/kg.

3. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 2, wherein the concentration of the aqueous solution of sodium nitrite is 1.5 to 2mol/kg in step S1.

4. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 3, wherein the molar ratio of sodium hydrogen sulfite to sodium hydroxide is 1:0.8-1 and the concentration of the aqueous solution of sodium hydrogen sulfite is 0.9-1.5mol/kg in step S1.

5. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 4, wherein the concentration of the aqueous hydrochloric acid solution in step S1 is 8 to 10 mol/kg.

6. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 5, wherein the temperature of the first temperature zone is controlled to 0 to 25 ℃, the temperature of the second temperature zone is controlled to 80 to 95 ℃, and the temperature of the third temperature zone is controlled to 20 to 30 ℃ in step S2.

7. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 6, wherein in step S2, the flow rate of the first material is 20 to 30g/min, the flow rate of the second material is 8 to 10g/min, the flow rate of the third material is 13 to 18g/min, and the flow rate of the fourth material is 10 to 15 g/min.

8. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 1, wherein the molar ratio of the 3-amino-2 hydroxy- [1, 1-biphenyl ] -3-carboxylic acid to hydrochloric acid is 1:2.5 to 3.5, and the concentration of the 3-amino-2 hydroxy- [1, 1-biphenyl ] -3-carboxylic acid solution is 0.25 to 0.3mol/kg in step S1.

9. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 8, wherein the concentration of the aqueous solution of sodium nitrite is 1.5 to 2mol/kg in step S1.

10. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 9, wherein the temperature of the first temperature zone is controlled to 0 to 10 ℃, the temperature of the second temperature zone is controlled to 0 to 10 ℃, and the temperature of the third temperature zone is controlled to 20 to 30 ℃ in step S4.

11. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 10, wherein the flow rate of the material five is 20 to 30g/min and the flow rate of the material six is 8 to 10g/min in step S4.

12. The method for synthesizing eltrombopag using a microchannel reactor according to claim 1, wherein the base for adjusting the pH is any one of sodium bicarbonate, sodium carbonate and triethylamine in step S4.

13. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 1, wherein the microchannel reactor comprises ten reaction modules, the ten reaction modules are connected, the flow direction of the material is from the first reaction module to the tenth reaction module, the first, second, third, fourth and fifth reaction modules are the first temperature zone, the sixth, seventh, eighth and ninth reaction modules are the second temperature zone, and the tenth reaction module is the third temperature zone.

14. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 13, wherein the first material is pumped into the first reaction module, the second material is pumped into the second reaction module, and the first material and the second material are subjected to diazotization in the third, fourth, and fifth reaction modules.

15. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 14, wherein the third material is pumped into the fifth reaction module and reduction reaction is performed in the sixth, seventh and eighth reaction modules.

16. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 15, wherein the material four is pumped into the eighth reaction module, and is acid-precipitated into salts in the eighth and ninth reaction modules.

17. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 16, wherein the first material, the second material, the third material and the fourth material are all reacted and then flow out of the tenth reaction module.

18. The method for synthesizing eltrombopag using a microchannel reactor as claimed in claim 17, wherein the fifth material is pumped into the first reaction module, the sixth material is pumped into the second reaction module, and the fifth material and the sixth material are diazotized in the third, fourth, fifth, sixth, seventh, eighth, and ninth reaction modules.

Technical Field

The invention belongs to the field of drug synthesis in organic synthesis, and particularly relates to a method for synthesizing eltrombopag by using a microchannel reactor.

Background

Eltrombopag was developed by glatiramer, uk and received us FDA approval in the united states at 11 months 2008. Eltrombopag is a thrombopoietin receptor agonist, and is suitable for treating thrombocytopenia in patients with chronic immune thrombocytopenic purpura, and also for patients who do not respond well to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag is the first oral non-peptide thrombopoietin receptor agonist approved for treatment of adult chronic ITP patients, and preclinical and clinical studies show that it can increase proliferation and differentiation of platelet-derived bone marrow megakaryocytes. The chemical name of the compound is 3 '- { (2Z) -2- [1- (3, 4-xylyl) -3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4-ylidene ] hydrazino } -2' -hydroxy-3-biphenylcarboxylic acid, and the structural formula is as follows:

from the structure of the compound, the synthesis of the compound comprises two important intermediates: 3-amino-2-hydroxy- [1, 1-biphenyl ] -3-carboxylic acid and 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -one, the argument of which is confirmed in the patent.

The patent US7160870/WO2001089457 uses 2-bromophenol as a raw material, and 3-amino-2-hydroxy- [1, 1-biphenyl ] -3-formic acid is obtained through nitration, hydroxyl protection, Suzuki coupling, hydroxyl deprotection and reduction. The patent US7414040 uses 4-chloro-2-bromophenol as raw material to improve the yield of nitration reaction, thereby improving the total reaction yield. The patents CN110407702A, CN109704982A and the like are all used for synthesizing the intermediate 3-amino-2-hydroxy- [1, 1-biphenyl ] -3-formic acid. No patents are found for the synthesis of the intermediates 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -one and eltrombopag on microchannel reactors.

Therefore, the synthesis of eltrombopag and its intermediates in the prior art is carried out by the conventional kettle-type diazotization process, but the conventional kettle-type diazotization process has certain dangerousness, and the diazonium salt is extremely easy to decompose especially under the action of light or at a high temperature, and some diazonium salts containing nitro groups can be decomposed even at room temperature. In the dry state, some diazonium salts are unstable and active, and can be decomposed or even exploded by heating, friction or impact.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art.

Therefore, the invention provides a method for synthesizing Eltrombopag by utilizing a microchannel reactor, and the method can greatly improve the process safety by carrying out diazotization reaction in the microchannel reactor; because the microchannel reactor has the characteristic of high-efficiency mass and heat transfer, the reaction time can be effectively shortened, the use amount of raw materials is reduced, and the discharge of three wastes is reduced.

The method for synthesizing Eltrombopag by using the microchannel reactor comprises the following steps: s1, synthesizing materials: adding 3, 4-dimethylaniline serving as a raw material into an acid aqueous solution, dissolving to obtain a first material, dissolving sodium nitrite into water to obtain a second material, dissolving sodium bisulfite and sodium hydroxide into water to obtain a third material, preparing a solution from hydrochloric acid and water to obtain a fourth material, adding 3-amino-2-hydroxy- [1, 1-biphenyl ] -3-formic acid serving as a raw material into the acid aqueous solution, dissolving to obtain a fifth material, and dissolving sodium nitrite into the water to obtain a sixth material; s2, introducing materials into a microchannel reactor: the microchannel reactor comprises: a first temperature zone, a second temperature zone and a third temperature zone; controlling the temperature of each temperature zone of the reactor, controlling the flow rate of the metering pump, and sequentially introducing the material I, the material II, the material III and the material IV into the microchannel reactor for reaction to obtain a reaction solution, wherein the material I, the material II and the material III are positioned in a first temperature zone, and the material IV is positioned in a second temperature zone; s3, decoloring, filtering, concentrating, cooling and crystallizing the obtained reaction solution to obtain 3, 4-dimethylphenylhydrazine hydrochloride, wherein the 3, 4-dimethylphenylhydrazine hydrochloride reacts with ethyl acetoacetate to obtain 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -ketone; s4, controlling the temperature of each temperature zone of the microchannel reactor, introducing the material five and the material six into the microchannel reactor for reaction, directly flowing the effluent reaction solution into a reaction bottle filled with a 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -ketone solution, adjusting the pH value to 7.5-8.5 by alkali under stirring, reacting at room temperature, and performing suction filtration to obtain the eltrombopag.

The method for synthesizing Eltrombopag by using the microchannel reactor has the following characteristics: 1) by utilizing the characteristic of high-efficiency mass transfer and heat transfer of the microchannel reactor, 3, 4-dimethyl phenylhydrazine hydrochloride is continuously synthesized by carrying out diazo reduction reaction on the reactor, and the diazonium salt is reduced into hydrazine in a short time after being generated in the microchannel reactor, so that the accumulation of unstable intermediates such as diazonium salt, diazonium sulfonate and the like is avoided, and the occurrence of side reactions such as decomposition, coupling and the like of the diazonium salt is effectively inhibited. Is beneficial to improving the total yield and the product quality and simultaneously improving the process safety. 2) The intermediate 3-amino-2 hydroxy- [1, 1-biphenyl ] -3 formic acid is subjected to diazotization reaction in a microchannel reactor, the material ratio and the reaction temperature can be accurately controlled, the reaction efficiency is improved, and after the diazotization reaction is finished, the intermediate directly performs coupling reaction with another intermediate 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -ketone, so that the side reaction is reduced, and the product quality is improved.

According to an embodiment of the present invention, in step S1, the molar ratio of 3, 4-dimethylaniline to hydrochloric acid is 1:2.5-3.5, the concentration of the prepared 3, 4-dimethylaniline solution is 0.6-1.0 mol/kg.

According to one embodiment of the present invention, in step S1, the concentration of the aqueous solution of sodium nitrite is 1.5-2 mol/kg.

According to one embodiment of the present invention, in step S1, the molar ratio of sodium bisulfite to sodium hydroxide is 1:0.8-1, and the concentration of the aqueous solution of sodium bisulfite is 0.9-1.5 mol/kg.

According to one embodiment of the present invention, in step S1, the concentration of the hydrochloric acid aqueous solution is 8-10 mol/kg.

According to an embodiment of the present invention, in step S2, the temperature of the first temperature zone is controlled to be 0 to 25 ℃, the temperature of the second temperature zone is controlled to be 80 to 95 ℃, and the temperature of the third temperature zone is controlled to be 20 to 30 ℃.

According to an embodiment of the invention, in step S2, the flow rate of the first material is 20-30g/min, the flow rate of the second material is 8-10g/min, the flow rate of the third material is 13-18g/min, and the flow rate of the fourth material is 10-15 g/min.

According to one embodiment of the present invention, in step S1, the molar ratio of 3-amino-2 hydroxy- [1, 1-biphenyl ] -3-carboxylic acid to hydrochloric acid is 1:2.5-3.5, and the concentration of the 3-amino-2 hydroxy- [1, 1-biphenyl ] -3-carboxylic acid solution is 0.25-0.3 mol/kg.

According to one embodiment of the present invention, in step S1, the concentration of the aqueous solution of sodium nitrite is 1.5-2 mol/kg.

According to an embodiment of the present invention, in step S4, the temperature of the first temperature zone is controlled to be 0 to 10 ℃, the temperature of the second temperature zone is controlled to be 0 to 10 ℃, and the temperature of the third temperature zone is controlled to be 20 to 30 ℃.

According to one embodiment of the invention, in step S4, the flow rate of material five is 20-30g/min, and the flow rate of material six is 8-10 g/min.

According to an embodiment of the present invention, in step S4, the base for adjusting the pH value is any one of sodium bicarbonate, sodium carbonate and triethylamine.

According to one embodiment of the invention, the microchannel reactor comprises ten reaction modules, the ten reaction modules are communicated, the flow direction of the materials is from the first reaction module to the tenth reaction module, the first, second, third, fourth and fifth reaction modules are the first temperature zone, the sixth, seventh, eighth and ninth reaction modules are the second temperature zone, and the tenth reaction module is the third temperature zone.

According to one embodiment of the invention, the first material is pumped into the first reaction module, the second material is pumped into the second reaction module, and the first material and the second material are subjected to diazotization reaction in the third reaction module, the fourth reaction module and the fifth reaction module.

According to one embodiment of the present invention, the third material is pumped into the fifth reaction module by a pump, and reduction reaction is performed in the sixth, seventh and eighth reaction modules.

According to one embodiment of the invention, the material four is pumped into the eighth reaction module by a pump, and is acid-precipitated into salts in the eighth reaction module and the ninth reaction module.

According to an embodiment of the present invention, after all of the first material, the second material, the third material and the fourth material are reacted, the reaction product flows out of the tenth reaction module.

According to one embodiment of the invention, the fifth material is pumped into the first reaction module, the sixth material is pumped into the second reaction module, and the fifth material and the sixth material are subjected to diazotization in the third, fourth, fifth, sixth, seventh, eighth and ninth reaction modules.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:

fig. 1 is a flow chart of the steps of a method for synthesizing eltrombopag using a microchannel reactor according to an embodiment of the present invention.

Detailed Description

The present invention will be further described with reference to the following examples. The following examples are set forth merely to aid in the understanding of the invention. It should be noted that, for those skilled in the art, it is possible to make several modifications to the present invention without departing from the principle of the present invention, and all changes and modifications that are equivalent to those made in the present invention are also within the scope of the appended claims.

The method for synthesizing eltrombopag using a microchannel reactor according to an embodiment of the present invention is specifically described below.

According to the method for synthesizing eltrombopag by using the microchannel reactor, 3, 4-dimethylaniline is used as a raw material, diazotization reaction is carried out in the microchannel reactor, and reduction and salt formation reaction are directly carried out without separation to obtain an intermediate 3, 4-dimethyl phenylhydrazine hydrochloride. The obtained intermediate 3, 4-dimethyl phenylhydrazine hydrochloride reacts with ethyl acetoacetate to obtain a first intermediate 2- (3, 4-dimethyl phenyl) -5-methyl-1H-pyrazole-3 (2H) -ketone, then, 3-amino-2 hydroxy- [1, 1-biphenyl ] -3 formic acid is subjected to diazotization reaction in a microchannel reactor, and the obtained diazonium salt solution directly reacts with a second intermediate 2- (3, 4-dimethyl phenyl) -5-methyl-1H-pyrazole-3 (2H) -ketone through coupling reaction to obtain the eltrombopag.

Specifically, the method for synthesizing Eltrombopag by using a microchannel reactor comprises the steps of synthesizing a first intermediate M1 of Eltrombopag on the microchannel reactor by using 3, 4-dimethylaniline as a raw material, and reacting the first intermediate M1 of Eltrombopag with a synthesized second intermediate M2 on the microchannel reactor by using 3-amino-2-hydroxy- [1, 1-biphenyl ] -3-formic acid as a raw material. The chemical reaction formula is shown as formula (1), and the route is as follows:

the reaction route involves two-step diazotization reaction, and the traditional kettle type diazotization process has the dangerous characteristics that: diazonium salts are extremely easily decomposed at slightly elevated temperatures or under the action of light, in particular diazonium salts containing nitro groups, some of which are capable of decomposing even at room temperature. In the dry state, some diazonium salts are unstable and active, and can be decomposed or even exploded by heating, friction or impact.

Compared with the prior art, the invention has the advantages that: the diazotization reaction in the microchannel reactor can greatly improve the process safety; because the microchannel reactor has the characteristic of high-efficiency mass and heat transfer, the reaction time can be effectively shortened, the use amount of raw materials is reduced, and the discharge of three wastes is reduced.

It should be noted that the microchannel reactor is a microchannel continuous flow reactor, i.e. the material can continuously flow in the microchannel reactor.

Therefore, the method for synthesizing Eltrombopag by using the microchannel reactor has the following characteristics:

1) by utilizing the characteristic of high-efficiency mass transfer and heat transfer of the microchannel reactor, 3, 4-dimethyl phenylhydrazine hydrochloride is continuously synthesized by carrying out diazo reduction reaction on the reactor, and the diazonium salt is reduced into hydrazine in a short time after being generated in the microchannel reactor, so that the accumulation of unstable intermediates such as diazonium salt, diazonium sulfonate and the like is avoided, and the occurrence of side reactions such as decomposition, coupling and the like of the diazonium salt is effectively inhibited. Is beneficial to improving the total yield and the product quality and simultaneously improving the process safety.

2) The intermediate 3-amino-2 hydroxy- [1, 1-biphenyl ] -3 formic acid is subjected to diazotization reaction in a microchannel reactor, the material ratio and the reaction temperature can be accurately controlled, the reaction efficiency is improved, and after the diazotization reaction is finished, the intermediate directly performs coupling reaction with another intermediate 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -ketone, so that the side reaction is reduced, and the product quality is improved.

According to one embodiment of the invention, the microchannel reactor comprises ten reaction modules, the ten reaction modules are communicated, the flow direction of materials is from the first reaction module to the tenth reaction module, the first, second, third, fourth and fifth reaction modules are first temperature zones, the sixth, seventh, eighth and ninth reaction modules are second temperature zones, and the tenth reaction module is a third temperature zone.

Further, the first material is pumped into the first reaction module by a pump, the second material is pumped into the second reaction module by a pump, the first material and the second material are subjected to diazotization reaction in the third reaction module, the fourth reaction module and the fifth reaction module and stay for a certain time, and the stay time can be 0.9 minute.

According to one embodiment of the invention, the third material is pumped into the fifth reaction module by a pump, and is subjected to reduction reaction in the sixth reaction module, the seventh reaction module and the eighth reaction module, and is kept for a certain time, and the staying time can be 0.6 minutes.

And further pumping the material IV into an eighth reaction module by a pump, carrying out acid precipitation to form salt in the eighth reaction module and the ninth reaction module, and staying for a certain time, wherein the staying time can be 0.3 minute.

In some embodiments of the invention, the first material, the second material, the third material and the fourth material are all reacted and then flow out of the tenth reaction module.

According to one embodiment of the invention, material five is pumped into the first reaction module, material six is pumped into the second reaction module, and material five and material six are diazotized in the third, fourth, fifth, sixth, seventh, eighth and ninth reaction modules. And the mixture is kept for a certain time, and the staying time can be 2.1 minutes.

In summary, the diazotization reaction in the micro-channel continuous flow reactor can greatly improve the process safety, and the micro-channel continuous flow reactor has the characteristic of high-efficiency mass and heat transfer, so that the reaction time can be effectively shortened, the raw material consumption can be reduced, the three-waste discharge can be reduced, and the production efficiency and the product quality can be improved.

The method for synthesizing eltrombopag by using a microchannel reactor according to an embodiment of the present invention will be described in detail with reference to the following embodiments.

The following examples use a microchannel continuous flow reactor, model G1 from corning incorporated, which includes 10 glass reaction modules connected in parallel and in series, a heating and cooling circulating temperature control system, a feed pump, and the like.

Examples 1 to 6 are methods for synthesizing the first intermediate 3, 4-dimethylphenylhydrazine hydrochloride, and examples 7 to 11 are methods for synthesizing eltrombopag.

Example 1

36.7g of 3, 4-dimethylaniline is put into 90g of concentrated hydrochloric acid and 220g of water, and stirred and dissolved to obtain a material I.

② 21.9g of sodium nitrite is put into 178g of water, and the mixture is stirred and dissolved to obtain a material II.

③ putting 38g of sodium bisulfite and 13g of sodium hydroxide into 200g of water, and stirring and dissolving to obtain a material III.

And fourthly, adding 100g of concentrated hydrochloric acid into 50g of water and stirring to obtain a material IV.

Controlling the temperature of the first temperature zone (the first, second, third, fourth and fifth reaction modules) to be 5 ℃, the temperature of the second temperature zone (the sixth, seventh, eighth and ninth reaction modules) to be 85 ℃, and the temperature of the third temperature zone (the tenth reaction module) to be 25 ℃.

Pumping the first material into the first reaction module at a first flow rate of 20g/min, pumping the second material into the second reaction module at a second flow rate of 7.9g/min, and performing diazotization reaction in the third, fourth and fifth reaction modules for 0.9 min. And pumping the material with the third flow rate of 11g/min into the fifth reaction module by a pump, carrying out reduction reaction in the sixth reaction module, the seventh reaction module and the eighth reaction module, wherein the retention time is 0.6 min, pumping the material with the fourth flow rate of 18g/min into the eighth reaction module by a pump, carrying out acid precipitation to form salt in the eighth reaction module and the ninth reaction module, wherein the retention time is 0.3 min, and finally cooling all the materials, flowing out of the tenth reaction module, collecting and carrying out post-treatment. The total reaction time was 2 minutes.

Seventhly, adding activated carbon into the effluent material, filtering, decompressing and concentrating the obtained filtrate to remove about half volume, cooling to 5-10 ℃, carrying out suction filtration, and carrying out forced air drying on a filter cake at 60 ℃ to obtain 44.8g of 3, 4-dimethyl phenylhydrazine hydrochloride, wherein the yield is 85.7%, and the HPLC purity is 99.2%.

Example 2

Different from example 1, in this example, the diazotization reaction temperature of the first temperature zone is 10 ℃, and 46.2g of 3, 4-dimethyl phenylhydrazine hydrochloride is obtained, the yield is 88.3%, and the HPLC purity is 99.3%.

Example 3

Different from example 1, in this example, the diazotization reaction temperature of the first temperature zone is 20 ℃, and 43.7g of 3, 4-dimethyl phenylhydrazine hydrochloride is obtained, the yield is 83.6%, and the HPLC purity is 99.0%.

Example 4

The difference between this embodiment and embodiment 1 is that the temperature of the reduction reaction in the second temperature zone is 80 deg.C. 41.0g of 3, 4-dimethylphenylhydrazine hydrochloride is obtained, the yield is 78.5 percent, and the HPLC purity is 98.8 percent.

Example 5

The difference between this embodiment and embodiment 1 is that the temperature of the reduction reaction in the second temperature zone is 90 deg.C in the step of this embodiment. 44.7g of 3, 4-dimethylphenylhydrazine hydrochloride is obtained, the yield is 85.5 percent, and the HPLC purity is 99.3 percent.

Example 6

The difference between the present embodiment and embodiment 1 is that in the step of the present embodiment, the first material flow rate is 25ml/min, the second material flow rate is 9.9ml/min, the third material flow rate is 13.7ml/min, and the fourth material flow rate is 22.5 ml/min.

41.9g of 3, 4-dimethylphenylhydrazine hydrochloride is obtained, the yield is 80.3 percent, and the HPLC purity is 98.9 percent.

Example 7

50g of 3-amino-2-hydroxy- [1, 1-biphenyl ] -3-carboxylic acid was dissolved in 60g of hydrochloric acid and 700g of water to give material five.

Sodium nitrite 16g was dissolved in water 200g to give feed six.

The temperature of the first temperature zone (first, second, third, fourth and fifth reaction modules) was controlled to be 5 ℃, the temperature of the second temperature zone (sixth, seventh, eighth and ninth reaction modules) was controlled to be 5 ℃, and the temperature of the third temperature zone (tenth reaction module) was controlled to be 25 ℃.

And fourthly, controlling the flow rate of the fifth material to be 20g/min, pumping the fifth material into the first reaction module by a pump, controlling the flow rate of the sixth material to be 8g/min, pumping the sixth material into the second reaction module by a pump, and carrying out diazotization reaction in the third, fourth, fifth, sixth, seventh, eighth and ninth reaction modules, wherein the retention time is 2.1 minutes. The reaction solution was poured into a reaction flask containing a solution of 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -one (M2), the pH was adjusted to 7.5 to 8.5 with triethylamine while stirring, and after 12 hours of reaction at room temperature, 86.1g of eltrombopag was obtained by suction filtration and oven-drying, the yield was 89.2%, and the HPLC purity was 98.9%.

Example 8

The difference between this embodiment and embodiment 7 is that in step (c) of this embodiment, the temperature of the first temperature zone (the first, second, third, fourth, and fifth reaction modules) is 10 ℃, and the temperature of the second temperature zone (the sixth, seventh, eighth, and ninth reaction modules) is 10 ℃. 80.5g of eltrombopag was obtained in 83.4% yield and 98.0% HPLC purity.

Example 9

The difference between the present embodiment and embodiment 7 is that in the step (r) of the present embodiment, the flow rate of five materials is 30g/min, and the flow rate of six materials is 12 g/min. 79.6g of eltrombopag was obtained in 82.5% yield and 98.5% HPLC purity.

Example 10

This example differs from example 7 in that the base used to adjust the pH in step (iv) of this example is sodium bicarbonate.

80.0g of eltrombopag was obtained in 83.0% yield and 98.0% HPLC purity.

Example 11

This example differs from example 7 in that the base used in the pH adjustment in step (iv) of this example is sodium carbonate.

77.7g of eltrombopag was obtained in 80.5% yield and 97.5% HPLC purity.

Comparative example 1

The kettle type reaction process comprises the following steps: 50g of water, 20g (0.2mol) of concentrated hydrochloric acid and 8.1g (0.067mol) of 3, 4-dimethylaniline are put into a 250ml three-necked bottle, stirred and cooled to 0-5 ℃, a prepared sodium nitrite solution (5g of sodium nitrite and 10g of water) is dripped, and the reaction is finished for 15 minutes at the temperature of 5 ℃ to obtain the transparent diazonium solution. Adding 17.4g (0.16mol) of sodium bisulfite, 5.7g (0.14mol) of sodium hydroxide and 50g of water into a 500ml three-necked bottle, stirring, slowly adding the diazo liquid, controlling the temperature to be 20-30 ℃, stirring for 1 hour after the addition, heating to 80-85 ℃, preserving the temperature for 1 hour, continuously dropwise adding 21g of concentrated hydrochloric acid, heating to 90-95 ℃ after the dropwise addition, preserving the temperature for 1 hour, adding activated carbon, filtering, cooling the filtrate after concentration to precipitate a solid, and performing suction filtration and drying to obtain 8.8g of 3, 4-dimethyl phenylhydrazine hydrochloride, wherein the yield is 76.4%, and the purity is 98.0%.

Comparative example 2

The kettle type reaction process comprises the following steps: adding 300ml of 1M hydrochloric acid solution into a 500ml reaction bottle, adding 20g of 3-amino-2 hydroxy- [1, 1-biphenyl ] -3-formic acid, stirring and cooling to 0-5 ℃, slowly dropwise adding a solution prepared from 6.4g of sodium nitrite and 100g of water, reacting for 1 hour at 0-5 ℃, then adding 18g of 2- (3, 4-dimethylphenyl) -5-methyl-1H-pyrazol-3 (2H) -ketone and 300ml of methanol, stirring, adding sodium bicarbonate solid in batches to adjust the pH value to be 7.5-8.5, reacting for 24 hours at room temperature, performing suction filtration and drying to obtain 29.1g of eltrombopag, wherein the yield is 75.3%, and the HPLC purity is 97.5%.

Therefore, compared with the traditional kettle type reaction process for producing the Eltrombopag, the invention utilizes the characteristic of high-efficiency mass and heat transfer of the microchannel reactor to quickly complete the reaction, reduces side reactions, improves the product quality, ensures the intrinsic safety of the continuous flow reaction on the microchannel reactor and avoids the danger of the high-risk process.

In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an illustrative embodiment," "an example," "a specific example," or "some examples" or the like mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.