阅读说明：本技术 一种采用连续流反应装置制备2-氟-6-三氟甲基苯甲醛的方法 (Method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde by adopting continuous flow reaction device ) 是由 张旭 黄小根 刘波静 刘艳玲 于 2019-10-12 设计创作，主要内容包括：本发明实施例公开了一种采用连续流反应装置制备2-氟-6-三氟甲基苯甲醛的方法,属于医药化工合成技术领域。该方法包括：将预冷后的溶液A和溶液B在连续流反应装置中发生反应,得到的反应液D连续接收至溶液C中,淬灭反应,常规后处理,得到的粗产品经减压蒸馏得到2-氟-6-三氟甲基苯甲醛。本发明采用连续流反应装置合成2-氟-6-三氟甲基苯甲醛,反应温度为-20～0℃,反应时间为20～180秒,收率达到84％以上,该方法避免了超低温,具有反应条件温和,反应时间短,副产物少,收率高,成本低的优点,同时该方法操作相对简单,具有潜在的工业应用价值。(The embodiment of the invention discloses a method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde by adopting a continuous flow reaction device, belonging to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: and (3) reacting the pre-cooled solution A and the solution B in a continuous flow reaction device, continuously receiving the obtained reaction liquid D into the solution C, quenching the reaction, carrying out conventional post-treatment, and carrying out reduced pressure distillation on the obtained crude product to obtain the 2-fluoro-6-trifluoromethylbenzaldehyde. The method adopts a continuous flow reaction device to synthesize the 2-fluoro-6-trifluoromethylbenzaldehyde, the reaction temperature is-20-0 ℃, the reaction time is 20-180 seconds, and the yield reaches over 84 percent.)

1. A method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde using a continuous flow reaction apparatus, comprising the steps of:

1) dissolving 3-fluorotrifluorotoluene and tetramethylethylenediamine in tetrahydrofuran to obtain a solution A, dissolving n-butyllithium n-hexane solution in tetrahydrofuran to obtain a solution B, dissolving DMF in tetrahydrofuran to obtain a solution C, and precooling the solution A, the solution B and the solution C respectively;

2) simultaneously and continuously pumping the solution A and the solution B into a continuous flow reaction device for reaction, wherein the reaction temperature is-20-0 ℃, and the reaction time is 20-180 seconds, so as to obtain a reaction solution D;

3) and continuously receiving the reaction liquid D into the solution C, quenching the reaction, carrying out conventional post-treatment, and carrying out reduced pressure distillation on the obtained crude product to obtain the 2-fluoro-6-trifluoromethylbenzaldehyde.

2. The method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde according to claim 1, wherein the ratio of 3-fluorotrifluorotoluene: tetramethylethylenediamine: n-butyl lithium: the molar ratio of DMF is 1: 1.4: 1.2-1.6: 1 to 10.

3. The method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde according to claim 1, wherein the weight ratio of the 3-fluorotrifluorotoluene to the tetrahydrofuran in the solution A is 1: 1 to 15.

4. The method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde according to claim 1, wherein the concentration of n-butyllithium in the solution B is 0.5 to 2.0M.

5. The method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde according to claim 1, wherein the weight ratio of DMF to tetrahydrofuran in the solution C is 1: 1 to 20.

6. The method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde according to claim 1, wherein the pre-cooling temperature in step 1 is-20 to 0 ℃.

7. The method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde according to claim 1, wherein in step 3, the reaction solution D is continuously received into the solution C, the temperature is maintained at-20 to 0 ℃ for 10 to 60min, the pH is adjusted by dilute hydrochloric acid, the stirring is stopped, the solution is allowed to stand, the layers are separated, the organic phases are combined, the organic solvent is dried and evaporated under reduced pressure, and the crude product is distilled under reduced pressure to obtain 2-fluoro-6-trifluoromethylbenzaldehyde.

Technical Field

The embodiment of the invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde by adopting a continuous flow reaction device.

Background

Both uterine fibroids and endometriosis are ovarian sex hormone-mediated diseases. Uterine fibroids are non-cancerous, hormone-responsive tumors of the uterine musculature that can cause severe menstrual bleeding, dysmenorrhea, and even difficulty in pregnancy. At present, the disease has no targeted medicine, and the treatment method is oral contraceptive, progestational hormone, selective progesterone receptor regulator and the like.

Endometriosis refers to a common gynecological disease of women formed by implanting intimal cells at abnormal positions, and symptoms of dysmenorrheal, infertility, dyspareunia and the like seriously affect physical and mental health, work and fertility of women. At present, no medicine can cure endometriosis. Clinically, the disease is mainly treated by oral contraceptives, non-steroidal anti-inflammatory drugs, opioids and the like.

Elagolix is a novel non-peptide gonadotropin releasing hormone receptor (GnRH receptor) antagonist, primarily for the treatment of several sex hormone mediated diseases, such as e.g. uterine fibroids and endometriosis. Among them, 2-fluoro-6-trifluoromethylbenzaldehyde is an important intermediate for synthesizing Elagolix.

At present, 3-fluorotrifluorotoluene and an organic lithium reagent are mainly adopted to carry out a hydrogen-lithium exchange reaction to synthesize 2-fluoro-6-trifluoromethylbenzaldehyde, Chinese patent application CN 107935863A discloses a synthesis method of 2-fluoro-6-trifluoromethylbenzaldehyde, 3-fluorotrifluorotoluene, tetramethylethylenediamine and diisopropanolamine are dissolved in an anhydrous organic solvent, the organic lithium reagent is added under the condition of-20 to-80 ℃, DMF is added after the reaction is carried out for 1 to 8 hours under the temperature, the reaction is continuously carried out for 0.5 to 8 hours under the temperature, then the reaction is slowly raised to the ortho-position, the reaction is quenched, and the 2-fluoro-6-trifluoromethylbenzaldehyde is obtained by separation and purification.

Because the existing synthesis method is complicated in operation and harsh in reaction conditions (ultralow temperature is required), the preparation method of the 2-fluoro-6-trifluoromethylbenzaldehyde needs to be improved.

Disclosure of Invention

Therefore, the embodiment of the invention provides a method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde by adopting a continuous flow reaction device, which aims to solve the problems of complex operation and harsh reaction conditions in the existing synthesis method.

In order to achieve the above object, the embodiments of the present invention provide the following technical solutions:

a method for preparing 2-fluoro-6-trifluoromethylbenzaldehyde using a continuous flow reaction apparatus, comprising the steps of:

1) dissolving 3-fluorotrifluorotoluene and tetramethylethylenediamine in tetrahydrofuran to obtain a solution A, dissolving n-butyllithium n-hexane solution in tetrahydrofuran to obtain a solution B, dissolving DMF in tetrahydrofuran to obtain a solution C, and precooling the solution A, the solution B and the solution C respectively;

2) simultaneously and continuously pumping the solution A and the solution B into a continuous flow reaction device for reaction, wherein the reaction temperature is-20-0 ℃, and the reaction time is 20-180 seconds, so as to obtain a reaction solution D;

3) and continuously receiving the reaction liquid D into the solution C, quenching the reaction, carrying out conventional post-treatment, and carrying out reduced pressure distillation on the obtained crude product to obtain the 2-fluoro-6-trifluoromethylbenzaldehyde.

Further, 3-fluorotrifluorotoluene: tetramethylethylenediamine: n-butyl lithium: the molar ratio of DMF is 1: 1.4: 1.2-1.6: 1 to 10.

Further, in the solution a, the weight ratio of 3-fluorotrifluorotoluene to tetrahydrofuran is 1: 1 to 15.

Further, the concentration of n-butyllithium is 0.5 to 2.0M.

Further, in solution C, the weight ratio of DMF to tetrahydrofuran was 1: 1 to 20.

Further, in the step 1, the precooling temperature is-20-0 ℃.

Further, in the step 3, continuously receiving the reaction liquid D into the solution C, preserving the heat for 10-60 min at the temperature of-20-0 ℃, adjusting the pH value by using dilute hydrochloric acid, stopping stirring, standing, layering, extracting, combining organic phases, drying, removing the organic solvent by reduced pressure evaporation, and distilling the obtained crude product under reduced pressure to obtain the 2-fluoro-6-trifluoromethylbenzaldehyde.

The embodiment of the invention has the following advantages:

the method adopts a continuous flow reaction device to synthesize the 2-fluoro-6-trifluoromethylbenzaldehyde, the reaction temperature is-20-0 ℃, the reaction time is 20-180 seconds, and the yield reaches over 84 percent.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It should be apparent that the drawings in the following description are merely exemplary, and that other embodiments can be derived from the drawings provided by those of ordinary skill in the art without inventive effort.

FIG. 1 is a schematic view of a process for preparing 2-fluoro-6-trifluoromethylbenzaldehyde using a continuous flow reaction apparatus according to an embodiment of the present invention.

Detailed Description

The present invention is described in terms of particular embodiments, other advantages and features of the invention will become apparent to those skilled in the art from the following disclosure, and it is to be understood that the described embodiments are merely exemplary of the invention and that it is not intended to limit the invention to the particular embodiments disclosed. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The continuous flow reactor used in the following examples was CS1005, with a liquid hold up of 10.4mL, from Shandong Haemai chemical technology Co., Ltd. The reagents or instruments are not indicated by the manufacturer, and are all conventional products available by commercial purchase.