阅读说明：本技术 一种二酸的制备方法 (Preparation method of diacid ) 是由 王仲清 雷鑫 张蒙 刘越亮 尚威 罗忠华 黄芳芳 于 2019-11-04 设计创作，主要内容包括：本发明涉及一种二酸的制备方法,属于药物化学领域。本发明所述的制备方法,其包括原料在酸作用下进行羧化反应,其中,反应使用连续流反应条件进行。本发明的方法原料廉价易得,工艺简便,成本低,产物纯度高收率高,工艺绿色环保,有利于工业化。(The invention relates to a preparation method of diacid, belonging to the field of medicinal chemistry. The preparation method comprises the step of carrying out carboxylation reaction on raw materials under the action of acid, wherein the reaction is carried out by using continuous flow reaction conditions. The method has the advantages of cheap and easily-obtained raw materials, simple and convenient process, low cost, high product purity and high yield, and the process is green and environment-friendly and is beneficial to industrialization.)

1. A method of making compound 02 comprising: carboxylating the compound 01 under the action of acid to prepare a compound 02

Characterized in that the reaction is carried out using continuous flow reaction conditions.

2. The method of claim 1, further comprising: the compound 00 and trimethyl orthobutyrate are subjected to cyclization reaction to generate a compound 01

Characterized in that the reaction is carried out using continuous flow reaction conditions.

3. The process according to claim 1 or 2, wherein no solvent is added in the carboxylation reaction and/or the cyclization reaction.

4. The process according to claim 1 or 2, wherein the reaction temperature of the carboxylation reaction and/or the cyclization reaction is 40 ℃ to 100 ℃.

5. The method of claim 1, wherein the acid in the carboxylation reaction is at least one of hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid.

6. The method according to claim 1, wherein the acid concentration in the carboxylation reaction is 6 to 12 mol/L.

7. The process of claim 1, wherein the continuous reaction flow rate of the reaction mass during the carboxylation reaction is 3 to 40 ml/min.

8. The process of claim 2, wherein the continuous reaction flow rate of the reaction mass in the cyclization reaction is 1-50 ml/min.

9. The method of claim 1, wherein after the carboxylation reaction is completed, post-treating is performed, the post-treating comprising: adding water into the reaction solution, stirring for 0.1-4 hours at the temperature of-5-25 ℃, filtering, and drying the obtained solid to obtain the compound 02.

10. The method according to claim 2, wherein in the cyclization reaction, a solvent is added, and the solvent is at least one of methanol, ethanol, toluene and acetonitrile; or adding a solvent in the carboxylation reaction, wherein the reaction solvent is at least one of toluene, n-butanol, ethanol, isopropanol and acetonitrile.

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a preparation method of diacid.

Background

The compound shown as the following formula 02 is an important intermediate for preparing various medicines such as olmesartan medoxomil or chemical raw materials and the like, and the preparation method of the compound has important significance for preparing other pharmaceutical chemicals.

In the prior art, diaminomaleonitrile is used as a starting material and reacts with trimethyl orthobutyrate in acetonitrile, toluene or xylene for 7-8 hours under reflux to prepare 2-propylimidazole-4, 5-dinitrile, and then the 2-propylimidazole-4, 5-dinitrile is added into hydrochloric acid to prepare 2-propylimidazole-4, 5-dicarboxylic acid under reflux, so that the method has the problems of difficult recovery and reuse of the solvent and complicated post-treatment; in other documents, diethyl oxalate is used as a raw material and reacts with ethyl chloroacetate to generate alpha-diethyl chlorooxaloacetate, or in the presence of sodium ethoxide, ethyl acetate reacts with diethyl oxalate to obtain a sodium diethyl oxaloacetate salt, the sodium diethyl oxaloacetate salt reacts with thionyl chloride to obtain alpha-diethyl chlorooxaloacetate, and the alpha-diethyl chlorooxaloacetate salt reacts with butylamidine or a salt of butylamidine to obtain 2-propylimidazole-4, 5-dicarboxylic acid diethyl ester, so that the method has low yield and high cost; the method in the prior art has more or less problems and places which are not satisfactory, so that the method which has the advantages of cheap and easily obtained raw materials, simple and convenient process, low cost, high product purity and high yield, green and environment-friendly process and is beneficial to industrialization needs to be researched.

Disclosure of Invention

The invention provides a preparation method of a compound 02. A method for preparing compound 02 comprises: performing cyclization reaction on the compound 00 and trimethyl orthobutyrate at a certain temperature to generate a compound 01, and performing carboxylation reaction under the action of acid to prepare a compound 02

Wherein the reaction is carried out using continuous flow reaction conditions.

In the above method, a solvent may be added in the cyclization reaction, and the solvent is at least one of methanol, ethanol, toluene and acetonitrile.

In the method, no solvent can be added in the cyclization reaction, preferably no solvent is added, so that the method is low in cost, does not involve solvent recovery, treatment and the like, and is favorable for industrialization.

In the above process, the cyclization reaction may be carried out at 40 ℃ to 100 ℃. In some embodiments, the cyclization reaction is carried out at 60 ℃ to 100 ℃.

The continuous reaction flow rate of the reaction materials plays an important role in the generation of products, and the reaction is too slow, too long and too fast in reaction time and insufficient in reaction. In the above method, the continuous reaction flow rate of the reaction material in the cyclization reaction may be 1 to 50 ml/min. In some embodiments, the continuous reaction flow rate of the reaction mass may be 1 to 10ml/min in the cyclization reaction. In some embodiments, the continuous reaction flow rate of the reaction mass may be 3 to 10ml/min in the cyclization reaction. In some embodiments, the continuous reaction flow rate of the reaction mass may be 3 to 8ml/min in the cyclization reaction. In some embodiments, the continuous reaction flow rate of the reaction mass may be 3 to 15ml/min in the cyclization reaction. In some embodiments, the continuous reaction flow rate of the reaction mass may be 3 to 25ml/min in the cyclization reaction. In some embodiments, the continuous reaction flow rate of the reaction mass in the cyclization reaction can be 3ml/min, 5ml/min, 8ml/min, 10ml/min, 15ml/min, 20ml/min, 25ml/min, 30ml/min, or 35 ml/min.

In the above process, after the cyclization reaction is completed, a post-treatment may be performed to obtain compound 01, the post-treatment comprising: and removing the solvent from the reaction system, optionally adding toluene for water separation, adding cyclohexane, separating out solids, filtering, and drying the obtained solids to obtain the compound 01.

In the above method, in the cyclization reaction, after the reaction is completed, the product may be used in the next reaction without any post-treatment, and preferably used in the next reaction without any treatment.

In some embodiments, compound 00 is cyclized with trimethyl orthobutyrate at 60 ℃ to 100 ℃ to form compound 01 using continuous flow reaction conditions, wherein no solvent is added.

In the above method, a solvent may be added during the carboxylation reaction, wherein the solvent is at least one of toluene, n-butanol, ethanol, isopropanol and acetonitrile. In the method, no solvent can be added in the carboxylation reaction, and preferably no solvent is added, so that the method has lower cost, does not involve solvent recovery, treatment and the like, and is beneficial to industrialization.

In the above method, the acid in the carboxylation reaction may be at least one of hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid. In some embodiments, the acid is hydrochloric acid.

In the above method, the acid concentration in the carboxylation reaction may be 6 to 12 mol/L. In some embodiments, the concentration of the acid is 8 to 12 mol/L. In some embodiments, the acid is hydrochloric acid at a concentration of 8 to 12mol/L, which facilitates handling and reaction.

In the above method, the continuous reaction flow rate of the reaction material in the carboxylation reaction may be 3 to 40 ml/min. The continuous reaction flow rate of the reaction materials is too slow, the reaction time is too long and too fast, and the reaction cannot be fully carried out. In some embodiments, the continuous reaction flow rate of the reaction mass during the carboxylation reaction may be 3 to 20 ml/min. In some embodiments, the continuous reaction flow rate of the reaction mass during the carboxylation reaction may be 3 to 10 ml/min. In some embodiments, the continuous reaction flow rate of the reaction mass during the carboxylation reaction may be 5 to 20 ml/min. In some embodiments, the continuous reaction flow rate of the reaction mass during the carboxylation reaction may be 5 to 10 ml/min. In some embodiments, the continuous reaction flow rate of the reaction mass during the carboxylation reaction may be between 5 and 8 ml/min. In some embodiments, the continuous reaction flow rate of the reaction mass during the carboxylation reaction is 3ml/min, 5ml/min, 8ml/min, or 10 ml/min.

In the method, the reaction temperature is controlled to be 40-110 ℃ in the carboxylation reaction. In some embodiments, the reaction temperature is controlled to be 70 ℃ to 100 ℃ during the carboxylation reaction.

In the above method, in the carboxylation reaction, after the reaction is completed, a post-treatment may be performed to obtain the compound 02, the post-treatment including: adding water into the reaction solution, optionally filtering, adjusting the pH to 9-11 by using alkali, optionally filtering, then adjusting the pH to 1-3 by using acid, stirring for 0.1-4 hours at the temperature of-5-25 ℃, filtering, and drying the obtained solid to obtain the compound 02.

In some embodiments, in the carboxylation reaction, after the reaction is completed, the post-treatment comprises: adding water into the reaction solution, stirring for 0.1-4 hours at the temperature of-5-25 ℃, filtering, and drying the obtained solid to obtain the compound 02.

In some embodiments, compound 01 is reacted with hydrochloric acid under continuous flow reaction conditions to produce compound 02, wherein no solvent is added.

In the present invention, the continuous flow reaction conditions may be implemented by various pumps or other means that are feasible to carry out the reaction mass in an apparatus or vessel such as a microchannel reactor.

In the present invention, the absence of a solvent means that a solvent other than the reaction material is not present.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., 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 are not necessarily intended to 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. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

In the present invention, the expression "compound a" and "compound represented by formula a" means the same compound.

Drawings

FIG. 1 shows a schematic of the continuous flow reaction scheme of the present invention, using hydrochloric acid as the acid for the carboxylation reaction.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

In the present invention, mol means mol, h means hour, min means minute, g means g, ml means ml, CDCl₃Represents deuterated chloroform.

In the invention, the constant flow pump 316L is 316L (022Cr17Ni12Mo2) according to the national standard GB/T20878-2007, and the constant flow pump HC is C-276(00Cr16Mo16W4) according to the national standard GB/T20878-2007.

Example 1

Adding 10.00g of diaminomaleonitrile and 30.00mL of acetonitrile into a 250mL single-mouth bottle, adding 17.5g of trimethyl orthobutyrate while stirring, refluxing for 5 hours, controlling the temperature to be 85 ℃ and continuing to react for 10 hours, and then carrying out vacuum distillation on the reaction liquid at 40 ℃ to remove the acetonitrile; adding 30mL of toluene, refluxing, dividing water for 16 hours (external temperature 145 ℃), sampling, detecting, reducing the purity to 91.72%, then cooling to 60 ℃, adding 20mL of cyclohexane, reducing the temperature to 30 ℃, stirring for 1 hour, filtering, and drying a wet product at 50 ℃ to constant weight to obtain a compound 01: 12.4g, yield: 83.68 percent.

12.00g of Compound 01 and 100mL of 6mol/L hydrochloric acid were put into a 250mL single-necked flask, and heated to reflux (95 ℃ C.) to react for 5 to 6 hours; then, the temperature is reduced to room temperature, 100mL of water is added, a solid is precipitated, the solid is filtered, 100mL of water is added into the filtrate, the pH of the filtrate is adjusted to 9-10 by 10% sodium hydroxide solution, the filtrate is filtered, the pH of the filtrate is adjusted to 1-2 by hydrochloric acid, the filtrate is stirred for 1 hour at 20 ℃, the filtrate is filtered, and the obtained wet product is dried to constant weight at 55 ℃, so that the compound 02 is obtained: 13.96g, purity 98.76%, yield: 94.04%, detecting:

melting point: 262-264 ℃;

MS(EI)m/z：[M]^-＝197；

¹НNMR(CDCl₃)，δppm:0.91(t，3H，CH₃，J＝7.6Hz)，1.75(m，2H，CH₂),2.84(t，2H，CH₂-imidazole，J＝7.6Hz)，10.12(s，1H，NH)；

¹³C NMR(CDCl₃)δ:169.56，160.1，136.73，35.56，25.67，14.16。

example 2

Adding the compound 01(73.88g, 461mmol) into a 1000ml reaction vessel, adding 369ml of 8mol/L hydrochloric acid, heating to 100 ℃, reacting for 4 hours, then adding 148ml of water, stirring at 0 ℃, crystallizing for 1 hour, filtering, and drying the solid at 55 ℃ in vacuum to obtain the product, namely the compound 02: 84.048g, 98.2% purity, 91.69% yield.

Example 3

And (2) sequentially adding diaminomaleonitrile (100g, 925mmol and 1.00eq) and trimethyl orthobutyrate (137.09g, 925mmol and 1.00eq) into a 500ml reaction vessel A, B, introducing into a microchannel reactor through an advection pump, controlling the flow rate to be 3ml/min, controlling the temperature of a microchannel to be 80 ℃ for reaction, keeping the residence time to be 3.3min, directly using the reaction product in the next step without treatment, and detecting the product with the purity of 98.8%.

Example 4

And (2) sequentially adding diaminomaleonitrile (100g, 925mmol and 1.00eq) and trimethyl orthobutyrate (137.09g, 925mmol and 1.00eq) into a 500ml reaction vessel A, B, respectively introducing the diaminomaleonitrile and the trimethyl orthobutyrate into a microchannel reactor through an advection pump (316L), controlling the flow rate to be 8ml/min, controlling the temperature of a microchannel to be 80 ℃ for reaction, keeping the reaction time to be 1.25min, directly using the reaction product in the next step without treatment, and detecting the reaction product with the purity of 99.1%.

Example 5

Adding compound 01(73.88g, 461mmol) into a 500ml reaction vessel, adding 369ml of 10mol/L hydrochloric acid into another reaction vessel, respectively introducing the hydrochloric acid into a microchannel reactor through an advection pump (316L) and an advection pump (HC), controlling the flow rate to be 5ml/min, controlling the temperature of a microchannel to be 100 ℃ for reaction, keeping the reaction time to be 2min, flowing out of a pipeline into a receiving device, then adding 148ml of water, stirring and crystallizing for 1h at 0 ℃, filtering, and drying the solid in vacuum at 55 ℃ to obtain a gray product compound 02: 88.46g, yield 96.5% and purity 99.23%.

Example 6

Adding compound 01(73.88g, 461mmol) into a 500ml reaction vessel, adding 369ml of 8mol/L hydrochloric acid into another reaction vessel, respectively introducing the hydrochloric acid into a microchannel reactor through an advection pump (316L) and an advection pump (HC), controlling the flow rate to be 5ml/min, controlling the temperature of a microchannel to be 100 ℃ for reaction, keeping the reaction time to be 2min, flowing out of a pipeline into a receiving device, then adding 148ml of water, stirring and crystallizing at 0 ℃ for 1h, filtering, and drying the solid at 55 ℃ in vacuum to obtain a gray product compound 02: 87.17g, yield 95.1% and purity 98.53%.

Example 7

Adding compound 01(73.88g, 461mmol) into a 500ml reaction vessel, adding 369ml of 10mol/L hydrochloric acid into another reaction vessel, respectively introducing the hydrochloric acid into a microchannel reactor through an advection pump (316L) and an advection pump (HC), controlling the flow rate to be 8ml/min, controlling the temperature of a microchannel to be 100 ℃ for reaction, keeping the reaction time to be 1.25min, enabling an outflow pipeline to flow into a receiving device, then adding 148ml of water, stirring and crystallizing for 1h at 0 ℃, filtering, and drying the solid at 55 ℃ in vacuum to obtain a gray product compound 02: 87.82g, yield 95.8% and purity 99.11%.

While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.