Preparation method of 2-acetyl-5-bromo-4-methylthiophene

Abstract

The invention discloses a preparation method of 2-acetyl-5-bromo-4-methylthiophene, and belongs to the field of medical intermediates. Comprising the following steps: premixing a catalyst and acetyl chloride in a diluent to serve as a raw material A; 2-bromo-3-methylthiophene and a diluent are mixed to serve as a raw material B; diluted hydrochloric acid is used as a raw material C; starting a plunger pump to transport the raw materials to the micro-channel reactor, adjusting the pressure through a back pressure valve, controlling the reaction temperature through a refrigerant, and discharging after the raw materials react in the equipment to obtain quenching reaction liquid; and standing, separating, washing, concentrating and recrystallizing the reaction liquid to obtain a final product. The invention provides the improved preparation method of the lotinia intermediate 2-acetyl-5-bromo-4-methylthiophene, which can be continuously operated and has high purity and high yield, the industrial production is easy, and a high-quality raw material can be provided for the synthesis of downstream lotinia.

Description

Technical Field

[0001] The invention relates to a preparation method of a lotirana intermediate 2-acetyl-5-bromo-4-methylthiophene, and belongs to the field of pharmaceutical intermediate synthesis. Technical Background

[0002] 2-Acetyl-5-bromo-4-methylthiophene, CAS: 859199-06-7, molecular weight: 219.099, melting point 63-67°C, chemical structure: This product is easily soluble in halogenated hydrocarbons such as dichloromethane and is used to prepare an important intermediate of the parasiticide, lotirana. This intermediate is subjected to a series of steps such as condensation and ring closure with 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone to obtain lotirana.

[0003] At present, it is known that the preparation method of 2-acetyl-5-bromo-4-methylthiophene is reported, using 2-bromo-3-methylthiophene as the raw material, and the product is obtained by Friedel-Crafts acylation. WO 2018160878 describes adding aluminum chloride directly to 2-bromo-3-methylthiophene, and then adding acetyl chloride dropwise, with a yield of 97%; but it is well known that thiophene substrates and aluminum chloride will directly react to form resinous substances, and aluminum chloride must be reacted with acylating agents to form active electrophilic reagents, and then react with thiophene substrates. In this method, when aluminum chloride is added, all the raw materials are converted into black colloidal substances, and no product is generated. CN 117447459 describes that after 2-bromo-3-methylthiophene and acetyl chloride are mixed in dichloromethane, aluminum chloride is added in batches for reaction. According to the example calculation, the yield is 49%, and the product is a brown solid. WO 2010070068 describes that after acetyl chloride and aluminum chloride are mixed in dichloromethane, 2-bromo-3-methylthiophene is added dropwise. According to the example calculation, the yield is 57%, and the product is a brown solid. It is difficult to avoid the contact between the thiophene substrate and the aluminum chloride in the above two methods, and part of the raw materials are converted into black colloidal substances, resulting in yield loss of the product and tar coloration, which affects the preparation of downstream lotirana. Summary of the invention

[0004] In order to overcome the above technical defects, the technical problem to be solved by the present invention is to provide an improved preparation method of 2-acetyl-5-bromo-4-methylthiophene, an intermediate of lotirana. 2-Bromo-3-methylthiophene and acetyl chloride are used as raw materials, and the product is obtained by Lewis acid-catalyzed Friedel-Crafts acylation reaction; it is found through experiments that the reaction adopts the traditional kettle reaction operation, although the substrate thiophene is avoided from directly contacting with the Lewis acid catalyst, black colloid is still produced, which ultimately affects the yield and purity of the product. The present invention adopts a microchannel reactor to develop a continuous reaction process, and avoids the production of black colloid by preventing local overheating and timely quenching the product and discharging it from the reaction system, thereby improving the purity and yield of the product.

[0005] To achieve the above technical solution, a method for preparing 2-acetyl-5-bromo-4-methylthiophene comprises the following steps:

[0006]

[0007] 1) Equipment layout: Make reasonable reaction process arrangement for microchannel reaction equipment;

[0008] 2) Material preparation: premix the catalyst and acetyl chloride in a diluent as raw material A; mix 2-bromo-3-methylthiophene with a diluent as raw material B; and dilute hydrochloric acid as raw material C;

[0009] 3) Reaction process: the plunger pump is pre-set to a flow rate, the plunger pump is turned on to add the material into the microchannel reactor, the back pressure valve adjusts the pressure, the refrigerant controls the temperature of the detection point, the reaction is completed, and a quenched reaction liquid is obtained;

[0010] 4) Post-treatment: The reaction solution was allowed to stand for separation, and the oil phase was washed and concentrated to obtain an oily substance, which was recrystallized to obtain 2-acetyl-5-bromo-4-methylthiophene.

[0011] Further, in the above technical solution, the reaction process of step 1 is arranged as shown in the attached Figure 1 Raw materials A and B are pre-cooled, transported to module 1 by a plunger pump for mixing, and then transported to module 2. After passing through a back pressure valve, they are mixed with pre-cooled raw material C in module 3 and finally discharged. The refrigerants of the three microchannel reactor modules are independent of each other.

[0012] Furthermore, in the above technical solution, the catalyst in step 2 is selected from anhydrous aluminum chloride or anhydrous ferric chloride.

[0013] Furthermore, in the above technical solution, the diluent in step 2 is selected from dichloromethane or dichloroethane.

[0014] Furthermore, in the above technical scheme, in the premixing process of raw material A in step 2, the molar ratio of catalyst to acetyl chloride is 1:0.98-1.15, preferably 1:1.01-1.02; the mass ratio of catalyst to diluent is 1:2-4, preferably 1:2.4-3, and the temperature control range during premixing is -10°C to 20°C, preferably 0-10°C.

[0015] Furthermore, in the above technical solution, in the premixing process of raw material B in step 2, the mass ratio of 2-bromo-3-methylthiophene to diluent is 1:1.65-1.88, preferably 1:1.79-1.81.

[0016] Furthermore, in the above technical solution, the mass concentration of the dilute hydrochloric acid used in the raw material C in step 2 is 5-20%, preferably 5-10%.

[0017] Furthermore, in the above technical scheme, the sum of the plunger pump flow rate for transporting raw material A in step 3 (referred to as A flow rate, the same below) and the B flow rate should be in the range of 10-30 mL / min, the ratio of A flow rate to B flow rate is 1:0.376-0.381, and the ratio of A flow rate to C flow rate should be 1:1-2.

[0018] Furthermore, in the above technical solution, the back pressure valve regulating pressure in step 3 should be controlled at 1-2MPa, the temperature of the refrigerant control temperature detection points 1-5 is 0-5°C, and the raw material residence time in the equipment is 85-110 seconds.

[0019] Furthermore, in the above technical solution, the oil phase in step 4 is washed with a saturated sodium bicarbonate solution until the pH of the aqueous phase is ≥7, the oil phase is concentrated to dryness, and then recrystallized using methylcyclohexane to obtain 2-acetyl-5-bromo-4-methylthiophene.

[0020] Advantageous Effects of the Invention

[0021] 1. The present invention provides a continuous preparation method. During the reaction process, no black colloidal substance is generated in the traditional kettle reaction. The product is a white solid with a yield of up to 97%. The content of the final product is stably higher than 99.5%, which can provide high-quality raw materials for the downstream.

[0022] 2. The reaction and quenching processes of the present invention are continuously integrated into one through microchannels, with high production efficiency and easy industrial promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the process layout diagram of the microchannel reaction equipment;

[0024] Figure 2 This is the mass spectrum of the product 2-acetyl-5-bromo-4-methylthiophene obtained in Example 1;

[0025] Figure 3 This is the H NMR spectrum of the product 2-acetyl-5-bromo-4-methylthiophene obtained in Example 1. DETAILED DESCRIPTION

[0026] The microchannel reactor selected in the following embodiments is a silicon carbide microchannel reactor manufactured by Zhongshan Zhian Chemical Technology Co., Ltd., and the specific models are: ZSMR-0005-2.5 (hereinafter referred to as 5mL module) and ZSMR-0010-2.5 (hereinafter referred to as 10mL module).

[0027] Example 1

[0028] Equipment layout: Figure 1 , raw materials A and B are pre-cooled, transported to the 5mL module by a plunger pump for mixing, and then transported to the first 10mL module, and mixed with the pre-cooled raw material C in the second 10mL module through a back pressure valve, and finally discharged. The refrigerants of the three microchannel reactor modules are independent of each other.

[0029] Material preparation: at 0-10℃, put 1.34kg 99% anhydrous aluminum chloride into 4kg dichloromethane, add 0.8kg 99% acetyl chloride dropwise at this temperature, prepare the solution and place it in a low temperature environment of 0-5℃ as raw material A; mix 1.79kg 99% 2-bromo-3-methylthiophene with 1kg dichloromethane at room temperature, prepare the solution and place it in a low temperature environment of 0-5℃ as raw material B; use concentrated hydrochloric acid and water to prepare 10kg 10% hydrochloric acid solution and place it in a low temperature environment of 0-5℃ as raw material C.

[0030] Reaction process: A flow rate was set to 10.5±0.05mL / min, B flow rate was set to 4.0±0.05mL / min, and C flow rate was set to 20.4±0.1mL / min; the plunger pump was turned on to transport the raw materials to the microchannel reactor at the set flow rate, the pressure was adjusted to 1.2MPa by the back pressure valve, and the temperature detection points 1-5 were controlled by the refrigerant to be maintained within 0-5°C. The reaction time was about 93 seconds, and the quenched water-oil two-phase emulsion was obtained by discharging the material.

[0031] Post-treatment: After all the liquid in the microchannel reactor was received, all the materials were discharged by flushing the system with dichloromethane, and the mixture was allowed to stand for separation; the oil phase was washed with saturated sodium bicarbonate until the pH of the aqueous phase was ≥7, and the oil phase was concentrated to near dryness to obtain a light yellow oily substance, which was dissolved at 50°C with 2kg of methylcyclohexane and then cooled to 10-20°C to precipitate white crystals, which were filtered and dried to obtain 2.13kg of 2-acetyl-5-bromo-4-methylthiophene, GC 99.9%, yield 97%, melting range 63.1-63.8°C, and the mass spectrum of the product was Figure 2 , the H NMR spectrum is Figure 3 .

[0032] Example 2

[0033] Equipment layout: Same as Example 1.

[0034] Material preparation: at 0-10℃, put 1.63kg 99% anhydrous ferric chloride into 4kg dichloromethane, add 0.81kg 99% acetyl chloride dropwise at this temperature, prepare the solution and place it in a low temperature environment of 0-5℃ as raw material A; mix 1.8kg 99% 2-bromo-3-methylthiophene with 1kg dichloromethane at room temperature, prepare the solution and place it in a low temperature environment of 0-5℃ as raw material B; use concentrated hydrochloric acid and water to prepare 8kg 5% concentration hydrochloric acid solution and place it in a low temperature environment of 0-5℃ as raw material C.

[0035] Reaction process: A flow rate was set to 9.3±0.05mL / min, B flow rate was set to 3.5±0.05mL / min, and C flow rate was set to 16.2±0.1mL / min; the plunger pump was turned on to transport the raw materials to the microchannel reactor at the set flow rate, the pressure was adjusted to 1.5MPa by the back pressure valve, the temperature detection points 1-5 were controlled by the refrigerant to be maintained within 0-5°C, the reaction time was about 108 seconds, and the quenched water-oil two-phase emulsion was obtained by discharging.

[0036] Post-treatment: Same as Example 1, to obtain 2.02 kg of 2-acetyl-5-bromo-4-methylthiophene, GC 99.5%, yield 91%.

[0037] Example 3

[0038] Equipment layout: Same as Example 1.

[0039] Material preparation: 1.34 kg 99% anhydrous aluminum chloride is added to 4 kg dichloroethane at 0-10°C, 0.8 kg 99% acetyl chloride is added dropwise at this temperature, and the prepared solution is placed in a low temperature environment of 0-5°C as raw material A; 1.79 kg 99% 2-bromo-3-methylthiophene is mixed with 1 kg dichloroethane at room temperature, and the prepared solution is placed in a low temperature environment of 0-5°C as raw material B; 10 kg 10% hydrochloric acid solution is prepared with concentrated hydrochloric acid and water and placed in a low temperature environment of 0-5°C as raw material C.

[0040] Reaction process: A flow rate was set to 18.4±0.05mL / min, B flow rate was set to 7.0±0.05mL / min, and C flow rate was set to 20.4±0.1mL / min; the plunger pump was turned on to transport the liquid to the microchannel reactor at the set flow rate, the pressure was adjusted to 2.0MPa by the back pressure valve, the temperature detection points 1-5 were controlled by the refrigerant to be maintained within 0-5°C, the reaction time was about 86 seconds, and the quenched water-oil two-phase emulsion was obtained by discharging.

[0041] Post-treatment: After all the liquid in the microchannel reactor was received, all the materials were discharged by using a dichloroethane flushing system, and the liquid was allowed to stand for separation. The subsequent operations were the same as in Example 1 to obtain 2.07 kg of 2-acetyl-5-bromo-4-methylthiophene, GC 99.7%, yield 94%,

[0042] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing 2-acetyl-5-bromo-4-methylthiophene, characterized in that: The steps include: (1) Equipment layout: Make reasonable reaction process arrangement for microchannel reaction equipment; (2) Material preparation: premix the catalyst and acetyl chloride in a diluent as material A; mix 2-bromo-3-methylthiophene with a diluent as material B; and dilute hydrochloric acid as material C; (3) Reaction process: the plunger pump is pre-set with a flow rate, the plunger pump is turned on to add the material into the microchannel reactor, the back pressure valve adjusts the pressure, the refrigerant controls the temperature of the detection point, the reaction is completed, and a quenched reaction liquid is obtained; (4) Post-treatment: The reaction solution was allowed to stand for separation, and the oil phase was washed and concentrated to obtain an oily substance, which was recrystallized to obtain 2-acetyl-5-bromo-4-methylthiophene.

2. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: The reaction process arrangement of step (1) is as shown in Figure 1; raw materials A and raw material B are pre-cooled, transported to module 1 by a plunger pump for mixing, and then transported to module 2, passed through a back pressure valve, and mixed with pre-cooled raw material C in module 3, and finally discharged; wherein: the refrigerants of the three microchannel reactor modules are independent of each other.

3. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: The catalyst in step (2) is selected from anhydrous aluminum chloride or anhydrous ferric chloride.

4. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: The diluent in step (2) is selected from dichloromethane or dichloroethane.

5. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: In the premixing process of the raw material A in step (2), the molar ratio of the catalyst to the acetyl chloride is 1:0.98-1.15; the mass ratio of the catalyst to the diluent is 1:2-4; and the temperature control range during premixing is -10°C to 20°C.

6. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: In the premixing process of the raw material B in step (2), the mass ratio of 2-bromo-3-methylthiophene to the diluent is 1:1.65-1.

88.

7. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: The mass concentration of the dilute hydrochloric acid in the raw material C in step (2) is 5-20%.

8. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: In step (3), the sum of the flow rates of plunger pump A and plunger pump B for transporting raw materials is 10-30 mL / min, the ratio of plunger pump A flow rate to plunger pump B flow rate is 1:0.376-0.381, and the ratio of plunger pump A flow rate to plunger pump C flow rate is 1:1-2.

9. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: The back pressure valve adjustment pressure in step (3) should be controlled at 1-2 MPa, the refrigerant control temperature detection point temperature should be 0-5°C, and the material residence time should be 85-110 seconds.

10. The method for preparing 2-acetyl-5-bromo-4-methylthiophene according to claim 1, characterized in that: The oil phase in step (4) is washed with a saturated sodium bicarbonate solution until the pH of the aqueous phase is ≥7, and the oil phase obtained after concentration is recrystallized with methylcyclohexane to obtain 2-acetyl-5-bromo-4-methylthiophene.

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